Kombiglyze XR

Biguanide and Dipeptidyl Peptidase-4 (DPP-4) Inhibitors Antidiabetic Combinations

Oral Administration

Administer once daily with the evening meal.
Do not crush, cut, or chew; swallow whole.
The inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

Severe

megaloblastic anemia / Delayed / 0-1.0
pancreatitis / Delayed / 0.2-0.2
lactic acidosis / Delayed / 0-0.1
pemphigus / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
bone fractures / Delayed / Incidence not known
heart failure / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
rhabdomyolysis / Delayed / Incidence not known

Moderate

peripheral edema / Delayed / 2.1-8.1
hypoglycemia / Early / 3.4-7.8
vitamin B12 deficiency / Delayed / 7.0-7.0
chest pain (unspecified) / Early / 1.0-5.0
palpitations / Early / 1.0-5.0
lymphopenia / Delayed / 0.5-1.5
metabolic acidosis / Delayed / 0-0.1
folate deficiency / Delayed / Incidence not known
bullous rash / Early / Incidence not known
thrombocytopenia / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
cholestasis / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known

Mild

flatulence / Early / 1.0-12.1
diarrhea / Early / 5.8-9.9
infection / Delayed / 0.1-7.7
headache / Early / 6.5-7.5
dyspepsia / Early / 1.0-7.1
pharyngitis / Delayed / 6.9-6.9
nausea / Early / 6.5-6.5
vomiting / Early / 2.2-6.5
malaise / Early / 1.0-5.0
myalgia / Early / 1.0-5.0
dysgeusia / Early / 1.0-5.0
anorexia / Delayed / 1.0-5.0
metallic taste / Early / 1.0-5.0
chills / Rapid / 1.0-5.0
flushing / Rapid / 1.0-5.0
hyperhidrosis / Delayed / 1.0-5.0
dizziness / Early / 1.0-5.0
sinusitis / Delayed / 2.6-2.9
abdominal pain / Early / 1.7-2.4
rash / Early / 0.2-1.5
urticaria / Rapid / 1.5-1.5
purpura / Delayed / Incidence not known
arthralgia / Delayed / Incidence not known

Acidemia, hypoxemia, lactic acidosis, metabolic acidosis

Metformin; saxagliptin is contraindicated in patients with acute or chronic metabolic acidosis. Metformin is associated with a risk of lactic acidosis. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a rare but serious complication that can occur due to metformin accumulation; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia or significant renal dysfunction. Certain medications used concomitantly with metformin may also increase the risk of lactic acidosis. Lactic acidosis is characterized by elevated blood lactate levels, acidemia, electrolyte disturbances, an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels more than 5 mcg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin is very low; in more than 20,000 patient-years exposure to metformin in clinical trials, there have been no reports of lactic acidosis and approximately 0.03 cases/1,000 patient-years have been estimated with post-marketing surveillance. A nested case-control study of 50,048 patients with type 2 diabetes mellitus demonstrated that during concurrent use of oral diabetes drugs, there were 6 identified cases of lactic acidosis. The crude incidence rate was 3.3 cases per 100,000 person-years in patients treated with metformin; it should be noted that all of the subjects had relevant comorbidities known to be risk factors for lactic acidosis. The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradycardia with more marked acidemia. The patient and the prescriber must be aware of such symptoms and the patient should be instructed to notify the physician immediately if they occur. If ketoacidosis or lactic acidosis is suspected, evaluation of the following parameters is necessary: serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate, pyruvate, and metformin levels. In addition, metformin; saxagliptin must be stopped immediately and appropriate corrective measures initiated.

Kombiglyze XR

Rx

Oral combination of a biguanide (metformin) and a dipeptidy-peptidase-4 (DPP-4) inhibitor (saxagliptin)
Used in adults for the treatment of type 2 diabetes mellitus
Per boxed warning the risk of lactic acidosis due to metformin requires care in prescribing and monitoring

For the treatment of type 2 diabetes mellitus in combination with diet and exercise. Oral dosage Adults

Give prescribed dose PO once daily with the evening meal. In patients who need 5 mg of saxagliptin and who are not currently treated with metformin, the recommended starting dose is 500 mg metformin; 5 mg saxagliptin PO once daily; increase the dose gradually to reduce the GI side effects due to metformin. In patients currently treated with metformin, initiate at the current daily dose of metformin or the nearest therapeutically appropriate dose. Patients who need 2.5 mg of saxagliptin in combination with metformin extended-release may be treated with 1,000 mg metformin; 2.5 mg saxagliptin PO once daily. Patients who need 2.5 mg saxagliptin who are metformin-naive or who require a dose of metformin greater than 1,000 mg should use the individual components. Use a conservative initial and maintenance dose in older patients due to the potential for decreased renal function; adjust based on a careful assessment of renal function. Max: metformin 2,000 mg/day and saxagliptin 5 mg/day. In patients taking a strong CYP3A4/5 inhibitor, max dose of saxagliptin is 2.5 mg/day PO.

Hepatic Impairment

Avoid use in patients with clinical or laboratory evidence of hepatic disease as there is an increased risk of lactic acidosis secondary to the use of metformin.

Renal Impairment

eGFR more than 45 mL/minute/1.73 m2: No metformin or saxagliptin dosage adjustments are needed. Obtain an eGFR at least annually in all patients taking metformin.
eGFR 30 to 45 mL/minute/1.73 m2: Initiation of metformin is not recommended. Obtain an eGFR at least annually in all patients taking metformin. In patients whose eGFR is initially greater than 45 mL/minute/1.73 m2, and then later falls below 45 mL/minute/1.73 m2, assess the benefits and risks of continuing treatment. Discontinue metformin if the patient’s eGFR later falls below 30 mL/minute/1.73 m2. The ADA and others suggest it is reasonable to decrease the dose by 50% (or use one-half the maximum recommended dose) and monitor renal function every 3 months in those with an eGFR less than 45 mL/minute/1.73 m2. Do not initiate metformin in patients at this stage. Additional caution is required in patients with anticipated significant fluctuations in renal status or those at risk for abrupt deterioration in kidney function, based on previous history, other comorbidities, albuminuria, and medication regimen (e.g., potent diuretics or nephrotoxic agents). Decrease the saxagliptin dose in patients with a eGFR less than 45 mL/minute/1.73 m2; the recommended saxagliptin dose is 2.5 mg PO once daily in these patients.
eGFR less than 30 mL/minute/1.73 m2: Use of saxagliptin; metformin is contraindicated. Saxagliptin 2.5 mg PO once daily (NOT in combination with metformin) may be used in patients with moderate or severe renal impairment or with end-stage renal disease (ESRD) requiring hemodialysis.
 
Intermittent hemodialysis
Metformin; saxagliptin use is contraindicated. Metformin is dialyzable; hemodialysis will efficiently remove accumulated metformin in the case of drug-induced lactic acidosis, provided metformin is halted. Saxagliptin 2.5 mg PO once daily (NOT in combination with metformin) may be used in patients with end-stage renal disease (ESRD), with the dose administered following hemodialysis.

Abacavir; Dolutegravir; Lamivudine: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Abacavir; Lamivudine, 3TC: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Acalabrutinib: (Moderate) Consider the benefits and risks of concomitant therapy of acalabrutinib with metformin. Concomitant use o fmedications that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., MATE inhibitors) could increase systemic exposure to metformin and increase the risk for lactic acidosis. The active metabolite of acalabrutinib (ACP-5862) inhibits MATE1 in vitro and may have the potential to increase concentrations of coadministered substrates of these transporters.
Acebutolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Acetaminophen; Aspirin: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Acetaminophen; Phenylephrine: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Acetaminophen; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Acetazolamide: (Moderate) Carbonic anhydrase inhibitors such as acetazolamide frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of acetazolamide with metformin may increase the risk for lactic acidosis; consider more frequent monitoring. Carbonic anhydrase inhibitors may also alter blood sugar; both hyperglycemia and hypoglycemia have been described. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction. (Minor) Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus who are receiving antidiabetic agents. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
Acrivastine; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Adagrasib: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with adagrasib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the saxagliptin AUC up to 3.7-fold.
Adefovir: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion (e.g., adefovir) may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
Albuterol; Budesonide: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Amiodarone: (Minor) Monitor patients for hypoglycemia if saxagliptin and amiodarone are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as amiodarone.
Amlodipine; Benazepril: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Amlodipine; Olmesartan: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Amlodipine; Valsartan: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Amoxicillin; Clarithromycin; Omeprazole: (Major) The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as clarithromycin. The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia, especially with antidiabetic drugs metabolized via CYP3A4/5. Careful monitoring of blood glucose is recommended. (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Amphetamine: (Moderate) Monitor for loss of glycemic control when amphetamines are administered to patients taking antidiabetic agents. Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Sympathomimetic agents, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Amphetamine; Dextroamphetamine: (Moderate) Monitor for loss of glycemic control when amphetamines are administered to patients taking antidiabetic agents. Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Sympathomimetic agents, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Amphetamines: (Moderate) Monitor for loss of glycemic control when amphetamines are administered to patients taking antidiabetic agents. Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Sympathomimetic agents, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells.
Androgens: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together.
Angiotensin II receptor antagonists: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Angiotensin-converting enzyme inhibitors: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Apalutamide: (Moderate) Monitor for increased blood sugars if coadministration of saxagliptin with apalutamide is necessary. Saxagliptin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased saxagliptin exposure by 76%.
Aprepitant, Fosaprepitant: (Moderate) Use caution if saxagliptin and aprepitant, fosaprepitant are used concurrently and monitor for an increase in saxagliptin-related adverse effects, for several days after administration of a multi-day aprepitant regimen. Saxagliptin is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of saxagliptin. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Articaine; Epinephrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Aspirin, ASA: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Aspirin, ASA; Caffeine: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Aspirin, ASA; Carisoprodol: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Aspirin, ASA; Dipyridamole: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Aspirin, ASA; Omeprazole: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Aspirin, ASA; Oxycodone: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Atazanavir: (Major) The metabolism of saxagliptin is primarily mediated by CYP3A4/5. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as atazanavir. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have also been reported with use of anti-retroviral protease inhibitors. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Atazanavir; Cobicistat: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with cobicistat due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively. (Major) The metabolism of saxagliptin is primarily mediated by CYP3A4/5. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as atazanavir. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have also been reported with use of anti-retroviral protease inhibitors. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed.
Atenolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
Atenolol; Chlorthalidone: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
atypical antipsychotic: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Azelastine; Fluticasone: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Azilsartan: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Azilsartan; Chlorthalidone: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Beclomethasone: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Benazepril: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Benzphetamine: (Moderate) Monitor for loss of glycemic control when amphetamines are administered to patients taking antidiabetic agents. Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Sympathomimetic agents, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Beta-blockers: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
Betamethasone: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Betaxolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is advised when administering bictegravir with metformin, as coadministration may increase exposure to metformin and increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Close monitoring of blood glucose and patient clinical status is recommended. In drug interaction studies, bictegravir increased both the Cmax and AUC of metformin at a metformin dose of 500 mg PO twice daily. Bictegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1]).
Bismuth Subsalicylate: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Bisoprolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Bortezomib: (Moderate) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients taking antidiabetic agents and receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.
Brigatinib: (Moderate) Consider the benefits and risks of concomitant therapy of brigatinib with metformin. Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., MATE inhibitors) could increase systemic exposure to metformin and increase the risk for lactic acidosis. Brigatinib inhibits MATE1 and MATE2K in vitro and may have the potential to increase concentrations of coadministered substrates of these transporters.
Brimonidine; Timolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathom

imetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Brompheniramine; Phenylephrine: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Brompheniramine; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Budesonide: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Budesonide; Formoterol: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Coadministration of glycopyrrolate with metformin my increase metformin plasma concentrations, which may lead to increased metformin effects and possible adverse events. If coadministration is necessary, monitor clinical response to metformin and adjust metformin dose accordingly. (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Bumetanide: (Minor) Bumetanide has been associated with hyperglycemia, possibly due to potassium depletion, and, glycosuria has been reported. Because of this, a potential pharmacodynamic interaction exists between bumetanide and all antidiabetic agents. This interference can lead to a loss of diabetic control, so diabetic patients should be monitored closely.
Bupivacaine; Epinephrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Minor) Famotidine may decrease the renal clearance of metformin secondary to competition for renal tubular transport systems. Such an interaction has been observed when cimetidine was administered with metformin. The decrease in renal excretion led to a 40% increase in metformin AUC. Although interactions with cationic drugs remain theoretical (except for cimetidine), caution is warranted when famotidine and metformin are prescribed concurrently. Famotidine may be less likely to interact with metformin versus cimetidine or ranitidine because of less tubular excretion.
Candesartan: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Capmatinib: (Moderate) Monitor for an increased risk of metformin-related adverse reactions including lactic acidosis if coadministration with capmatinib is necessary; consider the benefits and risks of concomitant use. Metformin is a substrate of multidrug and toxin extrusion (MATE) and capmatinib is a MATE1 and MATE2K inhibitor. Coadministration may interfere with the renal elimination of metformin and increase metformin exposure.
Captopril: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Carbonic anhydrase inhibitors: (Minor) Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus who are receiving antidiabetic agents. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
Carteolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
Carvedilol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
Cephalexin: (Moderate) Monitor for metformin-related adverse reactions during concomitant cephalexin use; a metformin dosage adjustment may be necessary. Concomitant use results in increased serum metformin concentrations and decreased renal clearance of metformin. In healthy subjects given single cephalexin 500 mg doses and metformin, serum metformin mean Cmax and AUC increased by an average of 34% and 24%, respectively, and metformin mean renal clearance decreased by 14%.
Ceritinib: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with ceritinib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively.
Cetirizine; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Chloramphenicol: (Minor) Monitor patients for hypoglycemia if saxagliptin and chloramphenicol are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as chloramphenicol.
Chloroquine: (Major) Careful monitoring of blood glucose is recommended when chloroquine and antidiabetic agents, including metformin, are coadministered. A decreased dose of the antidiabetic agent may be necessary as severe hypoglycemia has been reported in patients treated concomitantly with chloroquine and an antidiabetic agent. (Major) Careful monitoring of blood glucose is recommended when chloroquine and antidiabetic agents, including the dipeptidyl peptidase-4 inhibitors, are coadministered. A decreased dose of the antidiabetic agent may be necessary as severe hypoglycemia has been reported in patients treated concomitantly with chloroquine and an antidiabetic agent.
Chlorothiazide: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Chlorpheniramine; Phenylephrine: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Chlorpheniramine; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Chlorpropamide: (Moderate) A lower sulfonylurea dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with a sulfonylurea, the incidence of hypoglycemia was increased compared to a placebo used in combination with a sulfonylurea. (Moderate) Monitor blood glucose during concomitant sulfonylurea and metformin use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Chlorthalidone: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Chlorthalidone; Clonidine: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Minor) Increased frequency of blood glucose monitoring may be required when clonidine is given with antidiabetic agents. Since clonidine inhibits the release of catecholamines, clonidine may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Clonidine does not appear to impair recovery from hypoglycemia, and has not been found to impair glucose tolerance in diabetic patients.
Choline Salicylate; Magnesium Salicylate: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Chromium: (Moderate) Chromium dietary supplements may lower blood glucose. As part of the glucose tolerance factor molecule, chromium appears to facilitate the binding of insulin to insulin receptors in tissues and to aid in glucose metabolism. Because blood glucose may be lowered by the use of chromium, patients who are on antidiabetic agents may need dose adjustments. Close monitoring of blood glucose is recommended.
Ciclesonide: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Cimetidine: (Moderate) Concomitant administration of metformin and cimetidine may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. After administration of single doses of cimetidine 400 mg and metformin 850 mg, mean metformin exposure increased by 40%. Metformin is an OCT2 substrate; cimetidine is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion.
Cisapride: (Moderate) Because cisapride can enhance gastric emptying in diabetic patients, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. Monitor blood glucose and adjust if cliniically indicated.
Clarithromycin: (Major) The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as clarithromycin. The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia, especially with antidiabetic drugs metabolized via CYP3A4/5. Careful monitoring of blood glucose is recommended. (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Clofarabine: (Moderate) Concomitant use of clofarabine and metformin may result in altered clofarabine levels because both agents are a substrate of OCT1. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g., hand and foot syndrome, rash, pruritus) in patients also receiving OCT1 substrates.
Clonidine: (Minor) Increased frequency of blood glucose monitoring may be required when clonidine is given with antidiabetic agents. Since clonidine inhibits the release of catecholamines, clonidine may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Clonidine does not appear to impair recovery from hypoglycemia, and has not been found to impair glucose tolerance in diabetic patients.
Cobicistat: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with cobicistat due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively. (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Codeine; Phenylephrine; Promethazine: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Colesevelam: (Moderate) The clinical response to metformin extended-release (metformin ER) should be monitored in patients receiving concomitant therapy with colesevelam. Be alert for changes in glycemic control, increased metformin side effects, such as gastrointestinal disturbances and a risk for lactic acidosis. Colesevelam increases the Cmax and AUC of metformin ER by approximately 8% and 44%, respectively. The mechanism of the interaction is not known. Colesevelam has no significant effect on the bioavailability of immediate-release metformin.
Conjugated Estrogens: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis.
Conjugated Estrogens; Bazedoxifene: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis.
Conjugated Estrogens; Medroxyprogesterone: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Corticosteroids: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells. (Moderate) Monitor blood glucose during concomitant corticosteroid and metformin use; a metformin dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Cortisone: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Cyanocobalamin, Vitamin B12: (Minor) Metformin may result in suboptimal oral vitamin B12 absorption by competitively blocking the calcium-dependent binding of the intrinsic factor-vitamin B12 complex to its receptor. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.
Cyclosporine: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
Daclatasvir: (Moderate) Closely monitor blood glucose levels if daclatasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as daclatasvir.
Dalfopristin; Quinupristin: (Major) The manufacturer recommends limiting the saxagliptin dose to 2.5 mg/day if used with strong CYP3A4/5 inhibitors such as dalfopristin; quinupristin. The metabolism of saxagliptin is primarily mediated by CYP3A4/5, and maximum serum concentrations and exposure of saxagliptin are increased when administered with strong inhibitors. Monitor patients for hypoglycemia if these drugs are used together.
Danazol: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together.
Darunavir: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with darunavir due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A substrate; darunavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the saxagliptin AUC up to 3.7-fold.
Darunavir; Cobicistat: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with cobicistat due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively. (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with darunavir due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A substrate; darunavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the saxagliptin AUC up to 3.7-fold. (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with cobicistat due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively. (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with darunavir due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A substrate; darunavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the saxagliptin AUC up to 3.7-fold. (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed.
Deflazacort: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Delavirdine: (Major) The manufacturer recommends limiting the saxagliptin dose to 2.5 mg/day if used with strong CYP3A4/5 inhibitors such as delavirdine. The metabolism of saxagliptin is primarily mediated by CYP3A4/5, and maximum serum concentrations and exposure of saxagliptin are increased when administered with strong inhibitors. Monitor patients for hypoglycemia if these drugs are used together.
Desloratadine; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Desogestrel; Ethinyl Estradiol: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Dexamethasone: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Dexbrompheniramine; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Dexmethylphenidate: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes .
Dextroamphetamine: (Moderate) Monitor for loss of glycemic control when amphetamines are administered to patients taking antidiabetic agents. Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Sympathomimetic agents, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Diazoxide: (Minor) Diazoxide, when administered intravenously or orally, produces a prompt dose-related increase in blood glucose level, due primarily to an inhibition of insulin release from the pancreas, and also to an extrapancreatic effect. The hyperglycemic effect begins within an hour and generally lasts no more than 8 hours in the presence of normal renal function. The hyperglycemic effect of diazoxide is expected to be antagonized by certain antidiabetic agents (e.g., insulin or a sulfonylurea). Blood glucose should be closely monitored.
Dichlorphenamide: (Moderate) Carbonic anhydrase inhibitors such as dichlorphenamide frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of dichlorphenamide with metformin may increase the risk for lactic acidosis; consider more frequent monitoring. Carbonic anhydrase inhibitors may also alter blood sugar; both hyperglycemia and hypoglycemia have been described. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
Dienogest; Estradiol valerate: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Diethylpropion: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Diethylstilbestrol, DES: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis.
Digoxin: (Moderate) Metformin may increase digoxin concentrations, but the magnitude is unclear. Measure serum digoxin concentrations before initiating metformin, and periodically after that. Monitor heart rate and other clinical parameters. Adjust digoxin dose as necessary. (Moderate) The AUC and Cmax of digoxin may be increased in the presence of saxagliptin. Dosage adjustment of digoxin is not recommended, but patients receiving these 2 drugs at the same time should be monitored closely.
Diltiazem: (Minor) Saxagliptin did not meaningfully alter the pharmacokinetics of diltiazem. However, coadministration increased the maximum serum saxagliptin concentration by 63% and the systemic exposure by 2.1-fold. As expected, the maximum serum concentration of the saxagliptin active metabolite was decreased by 44% and the systemic exposure was decreased by 36%. Saxagliptin dose adjustment is not advised when coadministered with diltiazem.
Diphenhydramine; Phenylephrine: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Disopyramide: (Moderate) Disopyramide may enhance the hypoglycemic effects of antidiabetic agents. Patients receiving disopyramide concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
Dobutamine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Dofetilide: (Major) Dofetilide should be co-administered with metformin with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Reduced clearance of metformin may increase the risk for lactic acidosis; increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of metformin and dofetilide is recommended.
Dolutegravir: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
Dolutegravir; Lamivudine: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Dolutegravir; Rilpivirine: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
Donepezil; Memantine: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
Dopamine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Dorzolamide; Timolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
Doxapram: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Dronedarone: (Minor) Monitor patients for hypoglycemia if saxagliptin and dronedarone are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as dronedarone.
Drospirenone: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Drospirenone; Estetrol: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Drospirenone; Estradiol: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Drospirenone; Ethinyl Estradiol: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together. (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Elagolix; Estradiol; Norethindrone acetate: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Elbasvir; Grazoprevir: (Moderate) Administering metformin; saxagliptin with elbasvir; grazoprevir may result in elevated saxagliptin plasma concentrations. Saxagliptin is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events. (Moderate) Closely monitor blood glucose levels if elbasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as elbasvir.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with cobicistat due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively. (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with cobicistat due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively. (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed.
Enalapril, Enalaprilat: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Entecavir: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion (e.g., entecavir) may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
Ephedrine: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Ephedrine; Guaifenesin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Epinephrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Eprosartan: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Erdafitinib: (Moderate) Consider the benefits and risks of concomitant treatment with metformin and erdafitinib. Metformin is a substrate of organic cationic transporter-2 (OCT2). Erdafitinib is an OCT2 inhibitor. Coadministration with OCT2 inhibitors could increase systemic exposure to metformin and increase the risk for lactic acidosis.
Erythromycin: (Minor) Saxagliptin plasma concentrations are expected to increase in the presence of moderate CYP 3A4/5 inhibitors such as erythromycin, but saxagliptin dose adjustment is not advised.
Esmolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
Esterified Estrogens: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis.
Esterified Estrogens; Methyltestosterone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together. (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis.
Estradiol: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis.
Estradiol; Levonorgestrel: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Estradiol; Norethindrone: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Estradiol; Norgestimate: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Estradiol; Progesterone: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Estramustine: (Minor) Estramustine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Estramustine may decrease glucose tolerance leading to hyperglycemia.
Estrogens: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis.
Estropipate: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis.
Ethacrynic Acid: (Moderate) Loop diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. Patients receiving antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary.
Ethanol: (Major) Patients taking metformin should be advised to avoid alcohol use. Blood lactate concentrations and the lactate to pyruvate ratio are increased during excessive (acute or chronic) intake of alcohol with metformin.
Ethinyl Estradiol; Norelgestromin: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Ethinyl Estradiol; Norethindrone Acetate: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, pat ches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Ethinyl Estradiol; Norgestrel: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Ethotoin: (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Ethynodiol Diacetate; Ethinyl Estradiol: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Etonogestrel: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Etonogestrel; Ethinyl Estradiol: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Famotidine: (Minor) Famotidine may decrease the renal clearance of metformin secondary to competition for renal tubular transport systems. Such an interaction has been observed when cimetidine was administered with metformin. The decrease in renal excretion led to a 40% increase in metformin AUC. Although interactions with cationic drugs remain theoretical (except for cimetidine), caution is warranted when famotidine and metformin are prescribed concurrently. Famotidine may be less likely to interact with metformin versus cimetidine or ranitidine because of less tubular excretion.
Fedratinib: (Moderate) Concurrent use of metformin and fedratinib may produce unpredictable effects. Concomitant administration may increase the risk for metformin adverse events (e.g., lactic acidosis) or reduce metformin's efficacy. If these drugs are given together, monitor for metformin toxicity and efficacy; metformin dose adjustments may be needed. Fedratinib inhibits the common renal tubular transport systems involved in the renal elimination of metformin (e.g., OCT2/MATE1 and MATE2). In a drug interaction study, fedratinib was observed to have no clinically meaningful effect on metformin overall exposure; however, the renal clearance of metformin was decreased by 36% and the glucose lowering effect of metformin appeared to be reduced. The baseline adjusted glucose exposure was about 50% higher in response to an oral glucose challenge when these drugs were administered together.
Fenofibrate: (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 inhibitor (DPP-4) and fibric acid derivative use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Fenofibric Acid: (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 inhibitor (DPP-4) and fibric acid derivative use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Fexofenadine; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Fibric acid derivatives: (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 inhibitor (DPP-4) and fibric acid derivative use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Fludrocortisone: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Flunisolide: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Fluoxetine: (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 (DPP-4) inhibitor and fluoxetine use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and fluoxetine use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Fluticasone: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Fluticasone; Salmeterol: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Fluticasone; Umeclidinium; Vilanterol: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Fluticasone; Vilanterol: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Fluvoxamine: (Minor) Monitor patients for hypoglycemia if saxagliptin and fluvoxamine are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as fluvoxamine.
Formoterol; Mometasone: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Fosamprenavir: (Moderate) Closely monitor for changes in glycemic control and hyperglycemia if saxagliptin is coadministered with fosamprenavir. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
Fosinopril: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Fosphenytoin: (Minor) Fosphenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Furosemide: (Minor) Furosemide may cause hyperglycemia and glycosuria in patients with diabetes mellitus, probably due to diuretic-induced hypokalemia. (Minor) Furosemide may cause hyperglycemia and glycosuria in patients with diabetes mellitus, probably due to diuretic-induced hypokalemia. Because of this, a potential pharmacodynamic interaction exists between these drugs and all antidiabetic agents. This interference can lead to a loss of diabetic control, so diabetic patients should be monitored closely if these drugs are initiated.
Garlic, Allium sativum: (Moderate) Patients receiving antidiabetic agents should use dietary supplements of Garlic, Allium sativum with caution. Constituents in garlic might have some antidiabetic activity, and may increase serum insulin levels and increase glycogen storage in the liver. Monitor blood glucose and glycemic control. Patients with diabetes should inform their health care professionals of their intent to ingest garlic dietary supplements. Some patients may require adjustment to their hypoglycemic medications over time. One study stated that additional garlic supplementation (0.05 to 1.5 grams PO per day) contributed to improved blood glucose control in patients with type 2 diabetes mellitus within 1 to 2 weeks, and had positive effects on total cholesterol and high/low density lipoprotein regulation over time. It is unclear if hemoglobin A1C is improved or if improvements are sustained with continued treatment beyond 24 weeks. Other reviews suggest that garlic may provide modest improvements in blood lipids, but few studies demonstrate decreases in blood glucose in diabetic and non-diabetic patients. More controlled trials are needed to discern if garlic has an effect on blood glucose in patients with diabetes. When garlic is used in foods or as a seasoning, or at doses of 50 mg/day or less, it is unlikely that blood glucose levels are affected to any clinically significant degree.
Gemfibrozil: (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 inhibitor (DPP-4) and fibric acid derivative use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Glecaprevir; Pibrentasvir: (Moderate) Closely monitor blood glucose levels if glecaprevir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as glecaprevir. (Moderate) Closely monitor blood glucose levels if pibrentasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as pibrentasvir.
Glimepiride: (Moderate) A lower sulfonylurea dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with a sulfonylurea, the incidence of hypoglycemia was increased compared to a placebo used in combination with a sulfonylurea. (Moderate) Monitor blood glucose during concomitant sulfonylurea and metformin use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Glipizide: (Moderate) A lower sulfonylurea dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with a sulfonylurea, the incidence of hypoglycemia was increased compared to a placebo used in combination with a sulfonylurea. (Moderate) Monitor blood glucose during concomitant sulfonylurea and metformin use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Glipizide; Metformin: (Moderate) A lower sulfonylurea dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with a sulfonylurea, the incidence of hypoglycemia was increased compared to a placebo used in combination with a sulfonylurea. (Moderate) Monitor blood glucose during concomitant sulfonylurea and metformin use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Glyburide: (Moderate) A lower sulfonylurea dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with a sulfonylurea, the incidence of hypoglycemia was increased compared to a placebo used in combination with a sulfonylurea. (Moderate) Monitor blood glucose during concomitant sulfonylurea and metformin use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Glyburide; Metformin: (Moderate) A lower sulfonylurea dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with a sulfonylurea, the incidence of hypoglycemia was increased compared to a placebo used in combination with a sulfonylurea. (Moderate) Monitor blood glucose during concomitant sulfonylurea and metformin use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Glycopyrrolate: (Moderate) Coadministration of glycopyrrolate with metformin my increase metformin plasma concentrations, which may lead to increased metformin effects and possible adverse events. If coadministration is necessary, monitor clinical response to metformin and adjust metformin dose accordingly.
Glycopyrrolate; Formoterol: (Moderate) Coadministration of glycopyrrolate with metformin my increase metformin plasma concentrations, which may lead to increased metformin effects and possible adverse events. If coadministration is necessary, monitor clinical response to metformin and adjust metformin dose accordingly.
Grapefruit juice: (Minor) Saxagliptin plasma concentrations are expected to increase in the presence of moderate CYP 3A4/5 inhibitors such as grapefruit juice, but saxagliptin dose adjustment is not advised.
Green Tea: (Moderate) Green tea catechins have been shown to decrease serum glucose concentrations in vitro. Patients with diabetes mellitus taking antidiabetic agents should be monitored closely for hypoglycemia if consuming green tea products. (Moderate) Green tea catechins have been shown to decrease serum glucose concentrations in vitro. Patients with diabetes mellitus taking antidiabetic agents should be monitored closely for hypoglycemia if consuming green tea products.
Guaifenesin; Phenylephrine: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Guaifenesin; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Hydantoins: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Hydrocodone; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Hydrocortisone: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Hydroxychloroquine: (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 inhibitor (DPP-4) and hydroxychloroquine use; a DPP-4 dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and hydroxychloroquine use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Hydroxyprogesterone: (Minor) Progestins, like hydroxyprogesterone, can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Ibuprofen; Famotidine: (Minor) Famotidine may decrease the renal clearance of metformin secondary to competition for renal tubular transport systems. Such an interaction has been observed when cimetidine was administered with metformin. The decrease in renal excretion led to a 40% increase in metformin AUC. Although interactions with cationic drugs remain theoretical (except for cimetidine), caution is warranted when famotidine and metformin are prescribed concurrently. Famotidine may be less likely to interact with metformin versus cimetidine or ranitidine because of less tubular excretion.
Ibuprofen; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Imatinib: (Minor) Monitor patients for hypoglycemia if saxagliptin and imatinib, STI-571 are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as imatinib, STI-571.
Indacaterol; Glycopyrrolate: (Moderate) Coadministration of glycopyrrolate with metformin my increase metformin plasma concentrations, which may lead to increased metformin effects and possible adverse events. If coadministration is necessary, monitor clinical response to metformin and adjust metformin dose accordingly.
Indapamide: (Moderate) A potential pharmacodynamic interaction exists between indapamide and antidiabetic agents, like metformin. Indapamide can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. (Moderate) A potential pharmacodynamic interaction exists between indapamide and antidiabetic agents, like saxagliptin. Indapamide can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia.
Indinavir: (Major) The metabolism of saxagliptin is primarily mediated by CYP3A4/5. Limit the saxagliptin dose to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as indinavir. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have also been reported with use of anti-retroviral protease inhibitors. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Insulin Aspart: (Moderate) A lower insulin dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with insulin, the incidence of hypoglycemia was increased compared to a placebo used in combination with insulin. (Moderate) Monitor blood glucose during concomitant metformin and insulin use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Insulin Aspart; Insulin Aspart Protamine: (Moderate) A lower insulin dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with insulin, the incidence of hypoglycemia was increased compared to a placebo used in combination with insulin. (Moderate) Monitor blood glucose during concomitant metformin and insulin use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Insulin Degludec: (Moderate) A lower insulin dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with insulin, the incidence of hypoglycemia was increased compared to a placebo used in combination with insulin. (Moderate) Monitor blood glucose during concomitant metformin and insulin use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Insulin Degludec; Liraglutide: (Moderate) A lower insulin dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with insulin, the incidence of hypoglycemia was increased compared to a placebo used in combination with insulin. (Moderate) Monitor blood glucose during concomitant metformin and insulin use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Insulin Detemir: (Moderate) A lower insulin dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with insulin, the incidence of hypoglycemia was increased compared to a placebo used in combination with insulin. (Moderate) Monitor blood glucose during concomitant metformin and insulin use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Insulin Glargine: (Moderate) A lower insulin dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with insulin, the incidence of hypoglycemia was increased compared to a placebo used in combination with insulin. (Moderate) Monitor blood glucose during concomitant metformin and insulin use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Insulin Glargine; Lixisenatide: (Moderate) A lower insulin dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with insulin, the incidence of hypoglycemia was increased compared to a placebo used in combination with insulin. (Moderate) Monitor blood glucose during concomitant metformin and insulin use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Insulin Glulisine: (Moderate) A lower insulin dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with insulin, the incidence of hypoglycemia was increased compared to a placebo used in combination with insulin. (Moderate) Monitor blood glucose during concomitant metformin and insulin use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Insulin Lispro: (Moderate) A lower insulin dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with insulin, the incidence of hypoglycemia was increased compared to a placebo used in combination with insulin. (Moderate) Monitor blood glucose during concomitant metformin and insulin use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Insulin Lispro; Insulin Lispro Protamine: (Moderate) A lower insulin dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with insulin, the incidence of hypoglycemia was increased compared to a placebo used in combination with insulin. (Moderate) Monitor blood glucose during concomitant metformin and insulin use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Insulin, Inhaled: (Moderate) A lower insulin dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with insulin, the incidence of hypoglycemia was increased compared to a placebo used in combination with insulin. (Moderate) Monitor blood glucose during concomitant metformin and insulin use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Insulins: (Moderate) A lower insulin dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with insulin, the incidence of hypoglycemia was increased compared to a placebo used in combination with insulin. (Moderate) Monitor blood glucose during concomitant metformin and insulin use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Iodipamide Meglumine: (Contraindicated) Metformin and combination products containing metformin should be temporarily discontinued prior to the administration of iodinated contrast media. Metformin should be held for at least 48 hours after contrast administration and not restarted until renal function returns to normal post-procedure. Lactic acidosis has been reported in patients taking metformin that experience nephrotoxicity after use of iodinated contrast media.
Ionic Contrast Media: (Contraindicated) Metformin and combination products containing metformin should be temporarily discontinued prior to the administration of iodinated contrast media. Metformin should be held for at least 48 hours after contrast administration and not restarted until renal function returns to normal post-procedure. Lactic acidosis has been reported in patients taking metformin that experience nephrotoxicity after use of iodinated contrast media.
Ioxaglate Meglumine; Ioxaglate Sodium: (Contraindicated) Metformin and combination products containing metformin should be temporarily discontinued prior to the administration of iodinated contrast media. Metformin should be held for at least 48 hours after contrast administration and not restarted until renal function returns to normal post-procedure. Lactic acidosis has been reported in patients taking metformin that experience nephrotoxicity after use of iodinated contrast media.
Irbesartan: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with saxagliptin may result in increased serum concentrations of saxagliptin. Saxagliptin is a substrate of the hepatic isoenzyme CYP3A4); isavuconazole, the active moiety of isavuconazonium, is an inhibitor of CYP3A4. Caution and close monitoring for adverse effects, such as hypoglycemia, are advised if these drugs are used together.
Isocarboxazid: (Moderate) Monitor blood glucose during concomitant saxagliptin and monoamine oxidase inhibitor (MAOI) use; a saxagliptin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Minor) Coadministration of saxagliptin and rifampin decreased the maximum serum saxagliptin concentration by 53% and the systemic exposure by 76%. As expected, the maximum serum concentration of the saxagliptin active metabolite was increased by 39%; no significant change in the systemic exposure was noted. Saxagliptin dose adjustment is not advised when coadministered with rifampin, as the plasma dipeptidyl peptidase-4 activity over a 24-hour period was unaffected.
Isoniazid, INH; Rifampin: (Minor) Coadministration of saxagliptin and rifampin decreased the maximum serum saxagliptin concentration by 53% and the systemic exposure by 76%. As expected, the maximum serum concentration of the saxagliptin active metabolite was increased by 39%; no significant change in the systemic exposure was noted. Saxagliptin dose adjustment is not advised when coadministered with rifampin, as the plasma dipeptidyl peptidase-4 activity over a 24-hour period was unaffected.
Isophane Insulin (NPH): (Moderate) A lower insulin dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with insulin, the incidence of hypoglycemia was increased compared to a placebo used in combination with insulin. (Moderate) Monitor blood glucose during concomitant metformin and insulin use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Isoproterenol: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Itraconazole: (Major) Do not exceed 2.5 mg PO daily of saxagliptin when combined with itraconazole; monitor for evidence of hypoglycemia. Itraconazole is a strong CYP3A4 inhibitor; saxagliptin is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the saxagliptin AUC up to 3.7-fold.
Ketoconazole: (Major) Saxagliptin is a p-glycoprotein substrate, and the metabolism of saxagliptin is primarily mediated by CYP3A4/5. Ketoconazole is a strong inhibitor of both p-glycoprotein and CYP3A4/5. Saxagliptin did not meaningfully alter the pharmacokinetics of ketoconazole, but coadministration increased the maximum serum saxagliptin concentration by 62% and the systemic exposure by 2.5-fold. As expected, the maximum serum concentration of the saxagliptin active metabolite was decreased by 95% and the systemic exposure was decreased by 91%. In another study, the maximum serum saxagliptin concentration increased by 2.4-fold and the systemic exposure increased by 3.4-fold. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP 3A4/5 inhibitor such as ketoconazole. (Moderate) Concomitant administration of metformin and ketoconazole may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion (MATE) and OCT2 substrate and ketoconazole is a MATE and OCT2 inhibitor. MATE and OCT2 inhibitors may decrease metformin elimination by blocking renal tubular secretion.
Labetalol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
Lamivudine, 3TC: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Lamotrigine: (Moderate) Concomitant administration of metformin and lamotrigine may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; lamotrigine is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion.
Lanreotide: (Moderate) Monitor blood glucose levels regularly in patients with diabetes, especially when lanreotide treatment is initiated or when the dose is altered. Adjust treatment with antidiabetic agents as clinically indicated. Lanreotide inhibits the secretion of insulin and glucagon. Patients treated with lanreotide may experience either hypoglycemia or hyperglycemia.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as clarithromycin. The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia, especially with antidiabetic drugs metabolized via CYP3A4/5. Careful monitoring of blood glucose is recommended. (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Ledipasvir; Sofosbuvir: (Moderate) Closely monitor blood glucose levels if ledipasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agent(s) may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as ledipasvir. (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Letermovir: (Moderate) An increase in the plasma concentration of saxagliptin may occur if given with letermovir. Limit the saxagliptin dose to 2.5 mg once per day if the patient is also receiving cyclosporine because the magnitude of this interaction may be increased. Saxagliptin is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with another strong CYP3A4 inhibitor increased the maximum plasma concentration and exposure of saxagliptin by 1.62- and 2.45-fold, respectively.
Leuprolide; Norethindrone: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Levobunolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovasc ular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
Levoketoconazole: (Major) Saxagliptin is a p-glycoprotein substrate, and the metabolism of saxagliptin is primarily mediated by CYP3A4/5. Ketoconazole is a strong inhibitor of both p-glycoprotein and CYP3A4/5. Saxagliptin did not meaningfully alter the pharmacokinetics of ketoconazole, but coadministration increased the maximum serum saxagliptin concentration by 62% and the systemic exposure by 2.5-fold. As expected, the maximum serum concentration of the saxagliptin active metabolite was decreased by 95% and the systemic exposure was decreased by 91%. In another study, the maximum serum saxagliptin concentration increased by 2.4-fold and the systemic exposure increased by 3.4-fold. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP 3A4/5 inhibitor such as ketoconazole. (Moderate) Concomitant administration of metformin and ketoconazole may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion (MATE) and OCT2 substrate and ketoconazole is a MATE and OCT2 inhibitor. MATE and OCT2 inhibitors may decrease metformin elimination by blocking renal tubular secretion.
Levomefolate: (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Levonorgestrel: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Levonorgestrel; Ethinyl Estradiol: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Levothyroxine: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed. (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin.
Levothyroxine; Liothyronine (Porcine): (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed. (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin.
Levothyroxine; Liothyronine (Synthetic): (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed. (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin.
Lidocaine; Epinephrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Linezolid: (Moderate) Hypoglycemia, including symptomatic episodes, has been noted in post-marketing reports with linezolid in patients with diabetes mellitus receiving therapy with antidiabetic agents, such as insulin and oral hypoglycemic agents. Diabetic patients should be monitored for potential hypoglycemic reactions while on linezolid. If hypoglycemia occurs, discontinue or decrease the dose of the antidiabetic agent or discontinue the linezolid therapy. Linezolid is a reversible, nonselective MAO inhibitor and other MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or oral hypoglycemic agents.
Liothyronine: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed. (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin.
Lisdexamfetamine: (Moderate) Monitor for loss of glycemic control when amphetamines are administered to patients taking antidiabetic agents. Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Sympathomimetic agents, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Lisinopril: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Lithium: (Moderate) Lithium may cause variable effects on glycemic control when used in patients receiving antidiabetic therapy. Blood glucose concentrations should be closely monitored if lithium is taken by the patient. Dosage adjustments may be necessary.
Lonafarnib: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with lonafarnib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the saxagliptin AUC up to 3.7-fold.
Lonapegsomatropin: (Moderate) Patients with diabetes mellitus should be monitored closely during somatropin (recombinant rhGH) therapy. Antidiabetic drugs (e.g., insulin or oral agents) may require adjustment when somatropin therapy is instituted in these patients. Growth hormones, such as somatropin, may decrease insulin sensitivity, leading to glucose intolerance and loss of blood glucose control. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors for diabetes mellitus.
Lopinavir; Ritonavir: (Major) The metabolism of saxagliptin is primarily mediated by CYP3A4/5. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as ritonavir. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have also been reported with use of anti-retroviral protease inhibitors, such as ritonavir. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients, including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Loratadine; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Lorcaserin: (Moderate) In general, weight reduction may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with antidiabetic agents, such as insulin and/or insulin secretagogues (e.g., sulfonylureas). In clinical trials, lorcaserin use was associated with reports of hypoglycemia. Blood glucose monitoring is warranted in patients with type 2 diabetes prior to starting and during lorcaserin treatment. Dosage adjustments of anti-diabetic medications should be considered. If a patient develops hypoglycemia during treatment, adjust anti-diabetic drug regimen accordingly. Of note, lorcaserin has not been studied in combination with insulin.
Losartan: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may decrease the systemic exposure of saxagliptin; if used together, monitor blood glucose concentrations closely. Saxagliptin is a substrate of CYP3A (primary). Lumacaftor is a strong CYP3A inducer. Induction of saxagliptin metabolism through the CYP3A pathway may lead to decreased drug efficacy.
Mafenide: (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Magnesium Salicylate: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Mecasermin, Recombinant, rh-IGF-1: (Moderate) Use caution in combining mecasermin, recombinant, rh-IGF-1 or mecasermin rinfabate (rh-IGF-1/rh-IGFBP-3) with antidiabetic agents. Patients should be advised to eat within 20 minutes of mecasermin administration. Glucose monitoring is important when initializing or adjusting mecasermin therapies, when adjusting concomitant antidiabetic therapy, and in the event of hypoglycemic symptoms. An increased risk for hypoglycemia is possible. The hypoglycemic effect induced by IGF-1 activity may be exacerbated. The amino acid sequence of mecasermin (rh-IGF-1) is approximately 50 percent homologous to insulin and cross binding with either receptor is possible. Treatment with mecasermin has been shown to improve insulin sensitivity and to improve glycemic control in patients with either Type 1 or Type 2 diabetes mellitus when used alone or in conjunction with insulins.
Medroxyprogesterone: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Meglitinides: (Moderate) Use of metformin with a meglitinide ("glinide") may increase the risk of hypoglycemia. Meglitinides are insulin secretagogues and are known to cause hypoglycemia. To manage hypoglycemic risk, lower doses of the meglitinide may be needed. Monitor blood sugar.
Memantine: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
Metformin; Repaglinide: (Moderate) Use of metformin with a meglitinide ("glinide") may increase the risk of hypoglycemia. Meglitinides are insulin secretagogues and are known to cause hypoglycemia. To manage hypoglycemic risk, lower doses of the meglitinide may be needed. Monitor blood sugar.
Methamphetamine: (Moderate) Monitor for loss of glycemic control when amphetamines are administered to patients taking antidiabetic agents. Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Sympathomimetic agents, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Methazolamide: (Moderate) Carbonic anhydrase inhibitors such as methazolamide frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of methazolamide with metformin may increase the risk for lactic acidosis; consider more frequent monitoring. Carbonic anhydrase inhibitors may also alter blood sugar; both hyperglycemia and hypoglycemia have been described. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction. (Minor) Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus who are receiving antidiabetic agents. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
Methenamine; Sodium Salicylate: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Methyclothiazide: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Methylphenidate: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Methylprednisolone: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Methyltestosterone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together.
Metolazone: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Metoprolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Metyrapone: (Moderate) In patients taking insulin or other antidiabetic agents, the signs and symptoms of acute metyrapone toxicity (e.g., symptoms of acute adrenal insufficiency) may be aggravated or modified.
Midodrine: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, like midodrine, may decrease metformin elimination by competing for common renal tubular transport systems. Careful patient monitoring and dose adjustment of metformin and/or midodrine is recommended. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Mifepristone: (Moderate) Monitor patients for hypoglycemia if saxagliptin and mifepristone are used together; dosage reduction of saxagliptin may be needed in some patients. In patients taking CYP3A substrates, the manufacturer of mifepristone recommends that the lowest dose of the CYP3A substrate that achieves the proper clinical response and tolerability be used. When potent CYP3A inhibitors are used, the initial dose of saxagliptin should be limited to 2.5 mg/day; mifepristone is a CYP3A inhibitor and has been noted to increase concentrations of CYP3A substrates. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
Moexipril: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Mometasone: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Monoamine oxidase inhibitors: (Moderate) Monitor blood glucose during concomitant metformin and monoamine oxidase inhibitor (MAOI) use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant saxagliptin and monoamine oxidase inhibitor (MAOI) use; a saxagliptin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Nadolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
Naproxen; Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Nateglinide: (Moderate) Use of metformin with a meglitinide ("glinide") may increase the risk of hypoglycemia. Meglitinides are insulin secretagogues and are known to cause hypoglycemia. To manage hypoglycemic risk, lower doses of the meglitinide may be needed. Monitor blood sugar.
Nebivolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
Nebivolol; Valsartan: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present. (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Nefazodone: (Major) The metabolism of saxagliptin is primarily mediated by CYP3A4/5. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP 3A4/5 inhibitor such as nefazodone.
Nelfinavir: (Major) The metabolism of saxagliptin is primarily mediated by CYP3A4/5. Limit the saxagliptin dose to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as nelfinavir. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Neostigmine; Glycopyrrolate: (Moderate) Coadministration of glycopyrrolate with metformin my increase metformin plasma concentrations, which may lead to increased metformin effects and possible adverse events. If coadministration is necessary, monitor clinical response to metformin and adjust metformin dose accordingly.
Niacin, Niacinamide: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary. (Moderate) Niacin interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Niacin; Simvastatin: (Moderate) Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary. (Moderate) Niacin interferes with glucose metabolism and can result in hyperglycemia. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients taking antidiabetic agents for changes in glycemic control if niacin is added or deleted to the medication regimen. Dosage adjustments may be necessary.
Nicotine: (Minor) Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments of metformin may be needed. Nicotine may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
Nifedipine: (Minor) Nifedipine may increase the plasma metformin Cmax and AUC and increase the amount of metformin excreted in the urine. Metformin half-life is unaffected. Nifedipine appears to enhance the absorption of metformin.
Nirmatrelvir; Ritonavir: (Major) The metabolism of saxagliptin is primarily mediated by CYP3A4/5. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as ritonavir. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have also been reported with use of anti-retroviral protease inhibitors, such as ritonavir. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Non-Ionic Contrast Media: (Major) Discontinue metformin at the time of, or before, administration of non-ionic contrast media to patients with an eGFR of 30 to 60 mL/minute/1.73 m2, history of liver disease, alcoholism, or heart failure, or who will be administered intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after the imaging procedure; restart metformin if renal function is stable. Iodinated contrast agents appear to increase the risk of metformin-induced lactic acidosis, possibly as a result of worsening renal function.
Norepinephrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Norethindrone: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Norethindrone; Ethinyl Estradiol: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Norgestimate; Ethinyl Estradiol: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Norgestrel: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Octreotide: (Moderate) Monitor patients receiving octreotide concomitantly with insulin or other antidiabetic agents for changes in glycemic control and adjust doses of these medications accordingly. Octreotide alters the balance between the counter-regulatory hormones of insulin, glucagon, and growth hormone, which may result in hypoglycemia or hyperglycemia. The hypoglycemia or hyperglycemia which occurs during octreotide acetate therapy is usually mild but may result in overt diabetes mellitus or necessitate dose changes in insulin or other hypoglycemic agents. In patients with concomitant type1 diabetes mellitus, octreotide is likely to affect glucose regulation, and insulin requirements may be reduced. Symptomatic hypoglycemia, which may be severe, has been reported in type 1 diabetic patients. In Type 2 diabetes patients with partially intact insulin reserves, octreotide administration may result in decreases in plasma insulin levels and hyperglycemia.
Olanzapine; Fluoxetine: (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 (DPP-4) inhibitor and fluoxetine use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and fluoxetine use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Olmesartan: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Olopatadine; Mometasone: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Orlistat: (Minor) Weight-loss may affect glycemic control in patients with diabetes mellitus. In many patients, glycemic control may improve. A reduction in dose of oral hypoglycemic medications may be required in some patients taking orlistat. Monitor blood glucose and glycemic control and adjust therapy as clinically indicated.
Oxandrolone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together.
Oxymetholone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together.
Pasireotide: (Moderate) Monitor blood glucose levels regularly in patients with diabetes, especially when pasireotide treatment is initiated or when the dose is altered. Adjust treatment with antidiabetic agents as clinically indicated. Pasireotide inhibits the secretion of insulin and glucagon. Patients treated with pasireotide may experience either hypoglycemia or hyperglycemia.
Patiromer: (Moderate) Separate the administration of patiromer and metformin by at least 3 hours if concomitant use is necessary. Simultaneous coadministration may reduce gastrointestinal absorption of metformin and reduce its efficacy. Patiromer has been observed to bind some oral medications when given at the same time and separating administration by at least 3 hours has effectively mitigated this risk.
Pegvisomant: (Moderate) Monitor blood glucose levels regularly in patients with diabetes, especially when pegvisomant treatment is initiated or when the dose is altered. Adjust treatment with antidiabetic agents as clinically indicated. Pegvisomant increases sensitivity to insulin by lowering the activity of growth hormone, and in some patients glucose tolerance improves with treatment. Patients with diabetes treated with pegvisomant and antidiabetic agents may be more likely to experience hypoglycemia.
Pentamidine: (Moderate) Pentamidine can be harmful to pancreatic cells. This effect may lead to hypoglycemia acutely, followed by hyperglycemia with prolonged pentamidine therapy. Patients on antidiabetic agents should be monitored for the need for dosage adjustments during the use of pentamidine. (Moderate) Pentamidine can be harmful to pancreatic cells. This effect may lead to hypoglycemia acutely, followed by hyperglycemia with prolonged pentamidine therapy. Patients on antidiabetic agents should be monitored for the need for dosage adjustments during the use of pentamidine.
Pentoxifylline: (Moderate) Pentoxiphylline has been used concurrently with antidiabetic agents without observed problems, but it may enhance the hypoglycemic action of antidiabetic agents. Patients should be monitored for changes in glycemic control while receiving pentoxifylline in combination with antidiabetic agents.
Perindopril: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Perindopril; Amlodipine: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Phendimetrazine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Phenelzine: (Moderate) Monitor blood glucose during concomitant saxagliptin and monoamine oxidase inhibitor (MAOI) use; a saxagliptin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Phenothiazines: (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. Patients who are taking antidiabetic agents should monitor for worsening glycemic control when a phenothiazine is instituted. (Minor) Phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Hyperglycemia and glycosuria have been reported. When such drugs are administered to a patient receiving metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, observe the patient closely for hypoglycemia.
Phentermine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Phentermine; Topiramate: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Phenylephrine: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Phenytoin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Pindolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
Pioglitazone; Glimepiride: (Moderate) A lower sulfonylurea dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with a sulfonylurea, the incidence of hypoglycemia was increased compared to a placebo used in combination with a sulfonylurea. (Moderate) Monitor blood glucose during concomitant sulfonylurea and metformin use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Posaconazole: (Minor) Monitor patients for hypoglycemia if saxagliptin and posaconazole are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as posaconazole.
Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together.
Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together.
Prednisolone: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Prednisone: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Prilocaine; Epinephrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Progesterone: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Progestins: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Promethazine; Phenylephrine: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Propantheline: (Moderate) Propantheline slows GI motility, which may increase the absorption of metformin from the small intestine. A 19% increase in metformin AUC has been reported in studies of this interaction in healthy volunteers. However, no serious side effects resulted.
Propranolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Protease inhibitors: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Pseudoephedrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Pseudoephedrine; Triprolidine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine is administered to patients taking metformin. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Quinapril: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Quinine: (Moderate) Monitor patients for hypoglycemia if saxagliptin and quinine are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as quinine.
Quinolones: (Moderate) Monitor blood glucose carefully when systemic quinolones and antidiabetic agents, including metformin, are coadministered. Discontinue the quinolone if a hypoglycemic reaction occurs and initiate appropriate therapy immediately. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Hypoglycemia, sometimes resulting in coma, can occur. (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 inhibitors and quinolone use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Racepinephrine: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Ramipril: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Ranolazine: (Major) Limit the dose of metformin to 1,700 mg/day in adults if coadministered with ranolazine 1,000 mg twice daily. Coadministration of metformin with ranolazine 1,000 mg twice daily results in increased exposure to metformin. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). Consider the benefits and risks of concomitant use of ranolazine with metformin. Monitor blood sugar and for gastrointestinal side effects, and increase monitoring for a risk for lactic acidosis, including renal function and electrolytes/acid-base balance.
Regular Insulin: (Moderate) A lower insulin dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with insulin, the incidence of hypoglycemia was increased compared to a placebo used in combination with insulin. (Moderate) Monitor blood glucose during concomitant metformin and insulin use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Regular Insulin; Isophane Insulin (NPH): (Moderate) A lower insulin dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with insulin, the incidence of hypoglycemia was increased compared to a placebo used in combination with insulin. (Moderate) Monitor blood glucose during concomitant metformin and insulin use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Relugolix; Estradiol; Norethindrone acetate: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Repaglinide: (Moderate) Use of metformin with a meglitinide ("glinide") may increase the risk of hypoglycemia. Meglitinides are insulin secretagogues and are known to cause hypoglycemia. To manage hypoglycemic risk, lower doses of the meglitinide may be needed. Monitor blood sugar.
Ribociclib: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with ribociclib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively.
Ribociclib; Letrozole: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with ribociclib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively.
Rifampin: (Minor) Coadministration of saxagliptin and rifampin decreased the maximum serum saxagliptin concentration by 53% and the systemic exposure by 76%. As expected, the maximum serum concentration of the saxagliptin active metabolite was increased by 39%; no significant change in the systemic exposure was noted. Saxagliptin dose adjustment is not advised when coadministered with rifampin, as the plasma dipeptidyl peptidase-4 activity over a 24-hour period was unaffected.
Risdiplam: (Moderate) Concomitant administration of metformin and risdiplam may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion 1 (MATE1) substrate and risdiplam is a an MATE1/2-K inhibitor. MATE inhibitors may decrease metformin elimination by blocking renal tubular secretion.
Ritonavir: (Major) The metabolism of saxagliptin is primarily mediated by CYP3A4/5. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as ritonavir. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have also been reported with use of anti-retroviral protease inhibitors, such as ritonavir. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Sacubitril; Valsartan: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Salicylates: (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Salsalate: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Saquinavir: (Major) The metabolism of saxagliptin is primarily mediated by CYP3A4/5. Limit the saxagliptin dose to 2.5 mg once daily when coadministered with a strong CYP 3A4/5 inhibitor such as saquinavir. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Segesterone Acetate; Ethinyl Estradiol: (Minor) Monitor blood glucose periodically in patients on metformin for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Patients receiving antidiabetic agents should be periodically monitored for changes in glycemic control when hormone therapy is instituted or discontinued. Estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving 50 mcg or more of ethinyl estradiol (or equivalent) per day in combined oral contraceptives (COCs), which are not commonly used in practice since the marketing of lower dose COCs, patches, injections and rings. The presence or absence of a concomitant progestin may influence the significance of any hormonal effect on glucose homeostasis. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
Serdexmethylphenidate; Dexmethylphenidate: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Sofosbuvir: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir.
Sofosbuvir; Velpatasvir: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir. (Moderate) Closely monitor blood glucose levels if velpatasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as velpatasvir.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Closely monitor blood glucose levels if sofosbuvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as sofosbuvir. (Moderate) Closely monitor blood glucose levels if velpatasvir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as velpatasvir. (Moderate) Closely monitor blood glucose levels if voxilaprevir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as voxilaprevir.
Somapacitan: (Moderate) Patients with diabetes mellitus should be monitored closely during somapacitan therapy. Antidiabetic drugs (e.g., insulin or oral agents) may require adjustment when somapacitan therapy is instituted in these patients. Growth hormones, such as somapacitan, may decrease insulin sensitivity, leading to glucose intolerance and loss of blood glucose control. Therefore, glucose levels should be monitored periodically in all patients treated with somapacitan, especially in those with risk factors for diabetes mellitus.
Somatrogon: (Moderate) Monitor for loss of glycemic control if concomitant use of somatrogon and antidiabetic drugs is necessary; a dose adjustment of the antidiabetic drug may be needed. Growth hormones, such as somatrogon, may decrease insulin sensitivity, leading to glucose intolerance and loss of blood glucose control.
Somatropin, rh-GH: (Moderate) Patients with diabetes mellitus should be monitored closely during somatropin (recombinant rhGH) therapy. Antidiabetic drugs (e.g., insulin or oral agents) may require adjustment when somatropin therapy is instituted in these patients. Growth hormones, such as somatropin, may decrease insulin sensitivity, leading to glucose intolerance and loss of blood glucose control. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors for diabetes mellitus.
Sotalol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Streptogramins: (Major) The manufacturer recommends limiting the saxagliptin dose to 2.5 mg/day if used with strong CYP3A4/5 inhibitors such as dalfopristin; quinupristin. The metabolism of saxagliptin is primarily mediated by CYP3A4/5, and maximum serum concentrations and exposure of saxagliptin are increased when administered with strong inhibitors. Monitor patients for hypoglycemia if these drugs are used together.
Sulfadiazine: (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Sulfasalazine: (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Sulfonamides: (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Sulfonylureas: (Moderate) A lower sulfonylurea dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with a sulfonylurea, the incidence of hypoglycemia was increased compared to a placebo used in combination with a sulfonylurea. (Moderate) Monitor blood glucose during concomitant sulfonylurea and metformin use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Sympathomimetics: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
Tacrolimus: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Monitor for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Tafenoquine: (Moderate) Consider the benefits and risks of coadministration of tafenoquine and metformin due to the potential for increased metformin concentrations and lactic acidosis. If coadministration cannot be avoided, monitor for metformin-related toxicities, and consider metformin dosage reduction, if needed. The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates, like metformin, in humans is unknown; however, in vitro observations suggest the potential for increased concentrations of OCT2 and MATE substrates. Tafenoquine may interfere with these common renal tubular transport systems involved in the renal elimination of metformin.
Tegaserod: (Moderate) Because tegaserod can enhance gastric emptying in diabetic patients, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of antidiabetic agents may require adjustment in patients who receive GI prokinetic agents concomitantly. (Moderate) Because tegaserod can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of antidiabetic agents may require adjustment in patients who receive tegaserod concomitantly.
Telmisartan: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Telmisartan; Amlodipine: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Testosterone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Monitor blood glucose and HbA1C when these drugs are used together.
Thiazide diuretics: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Thyroid hormones: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed. (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin.
Timolol: (Moderate) Increased frequency of blood glucose monitoring may be required when a beta blocker is given with antidiabetic agents. Since beta blockers inhibit the release of catecholamines, these medications may hide symptoms of hypoglycemia such as tremor, tachycardia, and blood pressure changes. Other symptoms, like headache, dizziness, nervousness, mood changes, or hunger are not blunted. Beta-blockers also exert complex actions on the body's ability to regulate blood glucose. Some beta-blockers, particularly non-selective beta-blockers such as propranolol, have been noted to potentiate insulin-induced hypoglycemia and a delay in recovery of blood glucose to normal levels. Hyperglycemia has been reported as well and is possibly due to beta-2 receptor blockade in the beta cells of the pancreas. A selective beta-blocker may be preferred in patients with diabetes mellitus, if appropriate for the patient's condition. Selective beta-blockers, such as atenolol or metoprolol, do not appear to potentiate insulin-induced hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes and their use should not be avoided in patients with compelling indications for beta-blocker therapy when no other contraindications are present.
Tipranavir: (Major) The manufacturer recommends limiting the saxagliptin dose to 2.5 mg/day if used with strong CYP3A4/5 inhibitors such as tipranavir boosted with ritonavir. The metabolism of saxagliptin is primarily mediated by CYP3A4/5, and maximum serum concentrations and exposure of saxagliptin are increased when administered with strong inhibitors. Monitor patients for hypoglycemia if these drugs are used together. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have also been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Tolazamide: (Moderate) A lower sulfonylurea dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with a sulfonylurea, the incidence of hypoglycemia was increased compared to a placebo used in combination with a sulfonylurea. (Moderate) Monitor blood glucose during concomitant sulfonylurea and metformin use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Tolbutamide: (Moderate) A lower sulfonylurea dose may be required when used in combination with saxagliptin to minimize the risk of hypoglycemia. When saxagliptin was used in combination with a sulfonylurea, the incidence of hypoglycemia was increased compared to a placebo used in combination with a sulfonylurea. (Moderate) Monitor blood glucose during concomitant sulfonylurea and metformin use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Topiramate: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
Torsemide: (Minor) Hyperglycemia has been detected during torsemide therapy, but the incidence is low. Because of this, a potential pharmacodynamic interaction exists between torsemide and all antidiabetic agents, including metformin. Monitor blood glucose. (Minor) Torsemide may cause hyperglycemia and glycosuria in patients with diabetes mellitus, probably due to diuretic-induced hypokalemia. Because of this, a potential pharmacodynamic interaction exists between these drugs and all antidiabetic agents. This interference can lead to a loss of diabetic control, so diabetic patients should be monitored closely if these drugs are initiated.
Trandolapril: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) inhibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Trandolapril; Verapamil: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin-converting enzyme (ACE) in hibitor use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Minor) Saxagliptin plasma concentrations are expected to increase in the presence of moderate CYP 3A4/5 inhibitors such as verapamil, but saxagliptin dose adjustment is not advised.
Tranylcypromine: (Moderate) Monitor blood glucose during concomitant saxagliptin and monoamine oxidase inhibitor (MAOI) use; a saxagliptin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Triamcinolone: (Moderate) Monitor blood glucose during concomitant corticosteroid and dipeptidyl peptidase-4 (DPP-4) inhibitor use; a DPP-4 dose adjustment may be necessary. Corticosteroids may increase blood glucose concentrations. Risk factors for impaired glucose tolerance due to corticosteroids include the corticosteroid dose and duration of treatment. Corticosteroids stimulate hepatic glucose production and inhibit peripheral glucose uptake into muscle and fatty tissues, producing insulin resistance. Decreased insulin production may occur in the pancreas due to a direct effect on pancreatic beta cells.
Triamterene: (Minor) Triamterene can interfere with the hypoglycemic effects of antidiabetic agents. This can lead to a loss of diabetic control, so diabetic patients should be monitored closely.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity. (Minor) Triamterene can interfere with the hypoglycemic effects of antidiabetic agents. This can lead to a loss of diabetic control, so diabetic patients should be monitored closely.
Trilaciclib: (Moderate) Concomitant administration of metformin and trilaciclib may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 and MATE substrate; trilaciclib is an OCT2 and MATE inhibitor that may decrease metformin elimination by blocking renal tubular secretion.
Trospium: (Moderate) Trospium, if used concomitantly with metformin, may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion like trospium may decrease metformin elimination by competing for common renal tubular transport systems.
Tucatinib: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with tucatinib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively.
Valsartan: (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Certain drugs, such as thiazide diuretics, tend to produce hyperglycemia and may lead to loss of glycemic control. The effects of thiazide diuretics on glycemic control appear to be dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary in some patients. (Moderate) Monitor blood glucose during concomitant metformin and angiotensin receptor blocker use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and antidiabetic agents. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control. In addition, diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes. However, patients taking antidiabetic agents should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. Finally, both thiazides and sulfonylureas have been reported to cause photosensitivity reactions; concomitant use may increase the risk of photosensitivity.
Vandetanib: (Moderate) Vandetanib could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Vandetanib increased the plasma concentrations of metformin, which is transported by the renal organic cation transporter type 2 (OCT2). Use caution and closely monitor for toxicities when administering vendetanib with metformin.
Verapamil: (Minor) Saxagliptin plasma concentrations are expected to increase in the presence of moderate CYP 3A4/5 inhibitors such as verapamil, but saxagliptin dose adjustment is not advised.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as clarithromycin. The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia, especially with antidiabetic drugs metabolized via CYP3A4/5. Careful monitoring of blood glucose is recommended. (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Voriconazole: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with voriconazole due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively.
Zafirlukast: (Minor) Monitor patients for hypoglycemia if saxagliptin and zafirlukast are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as zafirlukast.
Zonisamide: (Moderate) Carbonic anhydrase inhibitors such as zonisamide frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use of zonisamide with metformin may increase the risk for lactic acidosis; consider more frequent monitoring. Carbonic anhydrase inhibitors may also alter blood sugar; both hyperglycemia and hypoglycemia have been described. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.

Kombiglyze XR/Saxagliptin, Metformin/Saxagliptin, Metformin Hydrochloride Oral Tab ER: 2.5-1000mg, 5-1000mg, 5-500mg

Adults

2000 mg/day PO metformin; 5 mg/day PO saxagliptin.

Geriatric

2000 mg/day PO metformin; 5 mg/day PO saxagliptin.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Combination products containing metformin and saxagliptin are used to improve glycemic control in type 2 diabetes mellitus (DM).[42331]
Metformin: Metformin decreases hepatic gluconeogenesis production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization; insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.[28550] Metformin improves glucose utilization in skeletal muscle and adipose tissue by increasing cell membrane glucose transport. This effect may be due to improved binding of insulin to insulin receptors since metformin is not effective in diabetics without some residual functioning pancreatic islet cells.[24568] Metformin causes a 10% to 20% decrease in fatty acid oxidation and a slight increase in glucose oxidation. Unlike phenformin, metformin does not inhibit the mitochondrial oxidation of lactate unless its plasma concentrations become excessive (i.e., in patients with renal failure) or hypoxia is present.[24438] Clinically, metformin lowers fasting and postprandial hyperglycemia. The decrease in fasting plasma glucose is approximately 25% to 30%. Unlike oral sulfonylureas, it rarely causes hypoglycemia. Thus, metformin demonstrates more of an antihyperglycemic action than a hypoglycemic action. Metformin does not cause weight gain and in fact, may cause a modest weight loss due to drug-induced anorexia.[28550] Metformin also decreases plasma VLDL triglycerides resulting in modest decreases in plasma triglycerides and total cholesterol. Patients receiving metformin show a significant improvement in hemoglobin A1C, and a tendency toward improvement in the lipid profile, especially when baseline values are abnormally elevated.[42549]
Saxagliptin: Saxagliptin is a competitive dipeptidyl peptidase-4 (DPP-4) inhibitor, which exerts its actions in patients with type 2 DM by slowing the inactivation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both GLP-1 and GIP are released by the intestine throughout the day, and their concentrations are increased in response to a meal. Normally, both GLP-1 and GIP are inactivated by DPP-4 within minutes. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells leading to reduced hepatic glucose production, and GLP-1 slows gastric emptying time, which decreases postprandial glucose excursions.[32810] [32811] Saxagliptin increases insulin release and decreases glucagon concentrations in the circulation in a glucose-dependent manner; GLP-1 does not increase insulin secretion when the glucose concentration is less than 90 mg/dL.[32810] Saxagliptin is of benefit in patients with type 2 DM as their GLP-1 concentrations are decreased in response to a meal.[32810] [32811] Although GLP-1 concentrations are reduced, the insulin response to GLP-1 is preserved. Among patients with type 2 DM who receive saxagliptin, both fasting and postprandial serum glucose concentrations are reduced in a glucose-dependent manner.[42331]

Metformin; saxagliptin is administered orally as an extended-release tablet.
Metformin: Metformin is distributed rapidly into peripheral body tissues and fluids and appears to distribute slowly into erythrocytes and to a deep tissue compartment (most likely GI tissues). The highest concentrations of metformin are found in the GI tract (10 times the concentrations in the plasma) and lower concentrations are found in the kidney, liver, and salivary gland tissue. Metformin is negligibly bound to plasma proteins. It is not metabolized by the liver, which may explain why the risk of lactic acidosis is much less for metformin than for phenformin (i.e., approximately 10% of patients have an inherited defect in the ability to metabolize phenformin). About 90% of a dose is excreted by the kidneys, largely unchanged, through an active tubular process. Tubular secretion may be altered by many cationic drugs. Approximately 10% of an oral dose is excreted in the feces, presumably as unabsorbed metformin. Although the average elimination half-life in the plasma is 6.2 hours in patients with normal renal function, metformin accumulates in red blood cells, which leads to a much longer elimination half-life in the blood (17.6 hours).
Saxagliptin: In vitro, protein binding of saxagliptin and its active metabolite was negligible. Saxagliptin is a p-glycoprotein substrate and a cytochrome P450 3A4/5 enzyme system substrate. Metabolism of saxagliptin is primarily mediated by CYP3A4/5 to produce 5-hydroxy saxagliptin, which is one-half as potent as saxagliptin as a DPP-4 inhibitor. Thus, strong CYP 3A4/5 inhibitors or inducers will alter the pharmacokinetic parameters of saxagliptin and its active metabolite. Saxagliptin is both hepatic and renally eliminated; some active renal excretion of saxagliptin appears to occur. After a 50 mg oral, radiolabeled dose, 24% of the dose was excreted renally as saxagliptin, and 36% was excreted renally as 5-hydroxy saxagliptin. In addition to renal excretion, some fecal elimination also occurs. Of the administered radioactivity, 22% was recovered in the feces; some was excreted in the bile, and some was unabsorbed drug from the gastrointestinal tract. Among healthy patients who took a single 5 mg oral dose, the mean plasma terminal half-life was 2.5 hours for saxagliptin and 3.1 hours for 5-hydroxy saxagliptin. Inhibition of dipeptidyl peptidase-4 (DPP-4) enzyme by saxagliptin lasts for 24 hours. After an oral glucose load or meal, the circulating concentrations of active glucagon-like peptide-1 and glucose-dependent insulinotrophic polypeptide increased 2- to 3-fold. Also, glucagon concentrations decreased and glucose-dependent insulin secretion from pancreatic beta cells increased.
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: Organic cationic transporter-2 (OCT2), multidrug and toxin extrusion (MATE1 and MATE2k), CYP3A4/5, P-glycoproteine (P-gp)
Metformin: Drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin. An interaction between metformin and oral cimetidine has been observed, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC, but no change in metformin elimination half-life. Careful patient monitoring and dose adjustment of metformin and/or the potentially interfering drug is recommended with concurrent use.
Saxagliptin: Saxagliptin is a CYP3A4/5 substrate. Neither saxagliptin nor its active metabolite are inhibitors of CYP isozymes 3A4, 2C9, 2D6, 1A2, 2C19, 2A6, 2E1, or 2B6 or inducers of CYP 3A4, 2B6, 2C9, or 1A2. It is also is a P-glycoprotein (P-gp) substrate but is not a significant inhibitor or inducer of P-gp. It is not an inhibitor of hOCT-2-mediated transport.

Oral Route

Bioequivalence studies indicate that metformin; saxagliptin is bioequivalent to coadministration of saxagliptin and metformin extended release tablets as single agents under fed conditions.
Metformin: Peak plasma concentrations are achieved at approximately 7 hours (range, 4 to 8 hours) following a single oral dose of metformin extended-release tablet. Food increases the extent of absorption of extended-release tablets (as per AUC) by approximately 50%, although Cmax and Tmax are unaltered. Food has no significant effect on the pharmacokinetics of metformin when administered as metformin; saxagliptin combination tablets.
Saxagliptin: After a 5 mg oral dose, the mean time to maximum saxagliptin concentration was 2 hours, and the mean time to the maximum concentration of the active metabolite, 5-hydroxy saxagliptin, was 4 hours. Compared to fasting, administration of saxagliptin with a high-fat meal increased the time to the maximum saxagliptin concentration by about 20 minutes, and the systemic exposure increased by 27%. Food has no significant effect on the pharmacokinetics of saxagliptin when administered as metformin; saxagliptin combination tablets.

Pregnancy

There are no adequate and well-controlled studies with the combination of metformin; saxagliptin in pregnant women; use the combination products of saxagliptin; metformin during pregnancy only if clearly needed. Saxagliptin was not teratogenic at any dose tested when administered to pregnant rats and rabbits during periods of organogenesis. Incomplete ossification of the pelvis, a form of developmental delay, occurred in rats at a dose of 240 mg/kg, or approximately 1,503 and 66 times human exposure to saxagliptin and the active metabolite, respectively, at the maximum recommended human dose (MRHD) of 5 mg. Minor skeletal variations in rabbits occurred at a maternally toxic dose of 200 mg/kg, or approximately 1,432 times the MRHD for saxagliptin. Metformin has been studied as monotherapy during human pregnancy. The American College of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA) continue to recommend human insulin as the standard of care in women with gestational diabetes mellitus (GDM) requiring medical therapy; insulin does not cross the placenta. Per ACOG, in women who decline insulin therapy or are unable to safely administer insulin, metformin is the preferred second-line choice. Per the ADA, metformin monotherapy may be used to treat GDM as a treatment option; however, no long term safety data are available for any oral agent. Metformin may cause a lower risk of neonatal hypoglycemia and less maternal weight gain than insulin; however, some data suggest that metformin may slightly increase the risk of prematurity. The ADA notes that in some clinical studies, nearly 50% of GDM patients initially treated with metformin have needed the addition of insulin in order to achieve acceptable glucose control. Premenopausal anovulatory females with insulin resistance, such as those with polycystic ovary syndrome (PCOS), may resume ovulation as a result of metformin therapy; patients may be at risk of conception if adequate contraception is not used.