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    Dipeptidyl Peptidase-4/DPP-4 Inhibitors and Biguanide Antidiabetic Combinations

    DEA CLASS

    Rx

    DESCRIPTION

    Combination oral biguanide (metformin) and dipeptidyl peptidase-IV inhibitor (sitagliptin)
    Used for type 2 diabetes mellitus; available for twice daily or once-daily administration.
    Boxed warning for lactic acidosis risk.

    COMMON BRAND NAMES

    Janumet, Janumet XR

    HOW SUPPLIED

    Janumet Oral Tab: 50-1000mg, 50-500mg
    Janumet XR Oral Tab ER: 100-1000mg, 50-1000mg, 50-500mg

    DOSAGE & INDICATIONS

    For the treatment of type 2 diabetes mellitus uncontrolled by diet and exercise and when treatment with one antidiabetic agent alone does not result in adequate control.
    NOTE: During concurrent use of metformin; sitagliptin and insulin or sulfonylureas, it may be necessary to lower the dose of insulin or the sulfonylurea to minimize the risk of hypoglycemia.
    For use when switching from metformin plus sitagliptin as separate tablets to the single, combination tablet.
    Oral dosage (immediate-release tablets, Janumet)
    Adults

    The usual starting dose is the dose of metformin and sitagliptin already being taken. Administer the total daily dose in 2 divided doses as Janumet tablets (500 mg metformin; 50 mg sitagliptin or 1,000 mg metformin; 50 mg sitagliptin), with meals. Gradually titrate after assessing adequacy of therapeutic response. The maximum recommended dose of sitagliptin 100 mg and metformin 2,000 mg.

    Oral dosage (extended-release tablets, Janumet XR)
    Adults

    The usual starting dose is the total daily dose of sitagliptin and metformin already being taken. Administer the dose required PO once daily with a meal, preferably in the evening. In patients with inadequate glycemic control on this dose of metformin, titrate gradually in order to reduce gastrointestinal side effects associated with metformin. Do not exceed the maximum daily recommended dose of sitagliptin 100 mg and metformin 2,000 mg.

    For use when initial treatment with metformin alone does not result in adequate glycemic control.
    Oral dosage (immediate-release tablets, Janumet)
    Adults

    For patients taking metformin 500 mg twice daily, the usual starting dose is sitagliptin 50 mg; metformin 500 mg PO twice daily with meals. For patients taking metformin 850 mg twice daily, the usual starting dose is sitagliptin 50 mg; metformin 1,000 mg PO twice daily with meals. Do not exceed the maximum daily recommended dose of sitagliptin 100 mg and metformin 2,000 mg.

    Oral dosage (extended-release tablets, Janumet XR)
    Adults

    For patients taking metformin, the usual starting dose for combination treatment is the previously prescribed dose of metformin with the addition of sitagliptin 100 mg/day. Administer the dose PO once daily with a meal, preferably in the evening. For patients taking metformin immediate-release 850 mg twice daily or 1,000 mg twice daily, the starting dose is two 50 mg sitagliptin/1,000 mg metformin extended-release tablets PO once daily with a meal, preferably in the evening. Do not exceed the maximum recommended daily dose of sitagliptin 100 mg/day with metformin 2,000 mg/day.

    For use when initial treatment with sitagliptin alone does not result in adequate glycemic control.
    Oral dosage (immediate-release tablets, Janumet)
    Adults

    The usual starting dose is 500 mg metformin; 50 mg sitagliptin PO twice daily with meals. Titrate to 1,000 mg metformin; 50 mg sitagliptin PO twice daily if needed. A gradual increase in dose is recommended to minimize gastrointestinal side effects associated with metformin. Do not exceed the maximum daily recommended dose of sitagliptin 100 mg and metformin 2,000 mg.

    Oral dosage (extended-release tablets, Janumet XR)
    Adults

    The usual starting dose is sitagliptin 100 mg; metformin 1,000 mg PO once daily with a meal preferably in the evening. Patients with inadequate glycemic control on this dose of metformin can be titrated gradually, to reduce gastrointestinal side effects associated with metformin. Do not exceed the maximum daily recommended dose of sitagliptin 100 mg and metformin 2,000 mg.

    MAXIMUM DOSAGE

    Adults

    2000 mg/day PO metformin; 100 mg/day PO sitagliptin.

    Geriatric

    2000 mg/day PO metformin; 100 mg/day PO sitagliptin.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Not indicated.

    Neonates

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Generally avoid use in hepatic impairment; hepatic disease increases the risk of metformin-associated lactic acidosis.

    Renal Impairment

    eGFR more than 45 mL/minute/1.73 m2: No metformin dosage adjustment needed. Obtain an eGFR at least annually in all patients taking metformin. Sitagliptin dosing is recommended to be decreased in patients with a CrCl less than 50 mL/min. Sitagliptin 50 mg PO once daily is recommended for patients with CrCl 30 mL/min to 49 mL/min.
    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). Sitagliptin dosing is recommended to be decreased in patients with a CrCl less than 50 mL/min. A dose of sitagliptin 50 mg once daily is recommended for patients with CrCl 30 mL/min to 49 mL/min.
    eGFR less than 30 mL/minute/1.73 m2: Use of sitagliptin; metformin is contraindicated. Sitagliptin 25 mg PO once daily (NOT in combination with metformin) may be used.
     
    Intermittent hemodialysis or peritoneal dialysis
    Sitagliptin; metformin use is contraindicated. Metformin is dialyzable; hemodialysis will efficiently remove accumulated metformin in the case of drug-induced lactic acidosis, provided metformin is halted. Sitagliptin 25 mg PO once daily (NOT in combination with metformin) may be used in patients requiring hemodialysis or peritoneal dialysis. It may be given without regard to the timing of dialysis.

    ADMINISTRATION

    Oral Administration

    Immediate-release tablets: Administer orally with meals to reduce gastrointestinal side effects.
     
    Extended-release tablets: Administer orally once a day with a meal, preferably in the evening. Do not split, break, crush, or chew; swallow whole. There have been reports of incompletely dissolved tablets being eliminated in the feces. It is not known whether this material seen in feces contains active, unabsorbed drug. If a patient reports repeatedly seeing tablets in feces, make sure to assess the adequacy of glycemic control.

    STORAGE

    Janumet:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Janumet XR:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in a dry place

    CONTRAINDICATIONS / PRECAUTIONS

    Angioedema, risk of serious hypersensitivity reactions or anaphylaxis, serious rash

    Metformin; sitagliptin is contraindicated in patients with a known metformin hypersensitivity or sitagliptin hypersensitivity such as anaphylaxis, angioedema, or exfoliative skin conditions or other serious rash, including Stevens-Johnson syndrome. Use caution in patients with a history of angioedema to another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with metformin; sitagliptin. A risk of serious hypersensitivity reactions or anaphylaxis has been reported in patients during the first 3 months of therapy with sitagliptin; some reports occurred after the first dose. Postmarketing cases of serious rash, specifically bullous pemphigoid, requiring hospitalization have been reported with DPP-4 inhibitor use. Treatment with topical or systemic immunosuppressives and discontinuation of the DPP-4 inhibitor has typically resulted in resolution of the rash. Inform patients of the risk of serious rash and tell them to report development of blisters or erosions while receiving sitagliptin. If a serious reaction is suspected, discontinue metformin; sitagliptin and refer the patient to a dermatologist for diagnosis and appropriate treatment.

    Diabetic ketoacidosis, type 1 diabetes mellitus

    Metformin; sitagliptin use is contraindicated in patients with diabetic ketoacidosis (DKA), with or without coma; DKA is treated with insulin. This combination is not intended for the treatment of type 1 diabetes mellitus.

    Acidemia, hypoxemia, lactic acidosis, metabolic acidosis

    Metformin; sitagliptin is contraindicated in patients with metabolic acidosis. Metformin is associated with a risk for 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. Metformin; sitagliptin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful.

    Pancreatitis

    Use metformin; sitagliptin with caution in patients with a history of pancreatitis. During postmarketing surveillance between October 2006 and February 2009, acute pancreatitis was reported in 88 patients taking sitagliptin or metformin; sitagliptin. In 19 of the 88 reported cases (21%), pancreatitis occurred within 30 days of starting sitagliptin or metformin; sitagliptin. Upon discontinuation of sitagliptin, 47 of the 88 cases (53%) resolved. At least one other risk factor for developing pancreatitis was evident in 45 cases (51%). In March 2013, the FDA announced that it is evaluating unpublished findings that suggest an increased risk of pancreatitis and pre-cancerous cellular changes called pancreatic duct metaplasia in patients treated with incretin mimetics. These findings were based on examination of a small number of pancreatic tissue specimens taken from patients after they died from unspecified causes. In February 2014, the FDA and EMA stated that after reviewing a number of clinical trials and animal studies, the current data does not support an increased risk of pancreatitis and pancreatic cancer in patients receiving incretin mimetics, including the dipeptidyl peptidase 4 (DPP-4) inhibitors. The agencies have not reached any new conclusions about safety risks of the incretin mimetics, although the totality of the reviewed data provides reassurance. Recommendations will be communicated once the review is complete; continue to consider precautions related to pancreatic risk until more data are available. Monitor patients carefully after initiation or dose increases; if pancreatitis is suspected, sitagliptin should be discontinued. Sitagliptin has not been studied in patients with a history of pancreatitis; therefore, it is not known whether these patients are at an increased risk for developing pancreatitis. Sitagliptin should be used with caution and with appropriate monitoring in these patients.

    Adrenal insufficiency, diarrhea, fever, gastroparesis, GI obstruction, hypercortisolism, hyperglycemia, hyperthyroidism, hypoglycemia, hypothyroidism, ileus, malnutrition, pituitary insufficiency, vomiting

    Conditions that predispose patients to developing hypoglycemia or hyperglycemia may alter antidiabetic agent efficacy. Conditions associated with hypoglycemia include debilitated physical condition, drug interactions, malnutrition, uncontrolled adrenal insufficiency, pituitary insufficiency, or hypothyroidism. The risk of hypoglycemia is also increased when metformin; sitagliptin is used in combination with insulin or sulfonylureas. The risk of hypoglycemia when metformin; sitagliptin is used in combination with other drugs known to cause hypoglycemia (e.g., exenatide, nateglinide, repaglinide) is not known. Hyperglycemia related conditions include drug interactions, female hormonal changes, high fever, severe psychological stress, and uncontrolled hypercortisolism or hyperthyroidism. More frequent blood glucose monitoring may be necessary in patients with these conditions. Gastrointestinal (GI) side effects may occur during metformin; sitagliptin initiation; however, later occurrence of GI symptoms may be due to a change in clinical status and may increase the risk of lactic acidosis. Patients stable on metformin; sitagliptin who complain of an increase in GI symptoms should undergo laboratory investigation to determine the etiology of the GI symptoms and rule out serious GI conditions. Furthermore, withholding metformin; sitagliptin therapy until the cause of the GI symptoms is known may be necessary. Finally, diarrhea and nausea/vomiting may alter gastric emptying and caloric intake, which could all affect blood glucose control, especially increasing the risk of low blood glucose. Patients should be advised to contact their prescriber if an increase in GI symptoms occurs while taking metformin; sitagliptin. Patients should also be advised to monitor their blood glucose concentrations more frequently. Changes in gastric emptying may alter blood glucose control; monitor patients with diarrhea, gastroparesis, GI obstruction, ileus, or vomiting carefully.

    Renal disease, renal failure, renal impairment

    Due to the metformin component, sitagliptin; metformin is contraindicated for use in patients with renal failure or severe renal impairment, defined as an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2. Initiating metformin in patients with an eGFR between 30 to 45 mL/minute/1.73 m2 is not recommended. Metformin is substantially eliminated by the kidney and the risk of lactic acidosis increases with the degree of intrinsic renal disease or impairment. Certain medications that are eliminated via the kidney when used concomitantly with metformin may also increase the risk of lactic acidosis. Sitagliptin requires dosage adjustment in renal impairment when patients have a CrCl less than 50 mL/min. Before initiation of metformin; sitagliptin and at least annually thereafter, renal function should be assessed in all patients receiving sitagliptin; metformin, using an eGFR to assess renal function. In those patients at increased risk for the development of renal impairment such as the elderly, renal function should be assessed more frequently. In patients taking sitagliptin; metformin whose eGFR later falls below 45 mL/minute/1.73 m2, assess the benefits and risks of continuing treatment. Discontinue sitagliptin; metformin if the patient’s eGFR later falls below 30 mL/minute/1.73 m2. Based on the results of a comprehensive FDA safety review, the FDA concluded that metformin can be used safely in patients with mild renal impairment, and in some patients with moderate renal impairment. The measure of kidney function used to determine whether a patient can receive metformin has been changed from serum creatinine to the eGFR; this is because in addition to serum creatinine concentration, the eGFR takes into account additional parameters that are important, such as the patient’s age, gender, race and/or weight.

    Acute heart failure, acute myocardial infarction, cardiac disease, cardiogenic shock, heart failure

    Use metformin; sitagliptin with caution in patients who have a history of or who have increased risk factors for heart failure, including patients with existing cardiac disease or kidney disease. Observe patients receiving metformin; sitagliptin for signs and symptoms of heart failure, and if heart failure develops, consider discontinuing the drug and monitoring for diabetic control. In patients receiving other DPP-4 inhibitors, including linagliptin and saxagliptin, an increased risk of hospitalization for heart failure has been reported. In the EXAMINE trial, 5,380 patients with type 2 diabetes and established cardiovascular disease who had a recent acute coronary syndrome event were randomized to receive either alogliptin therapy or placebo. More patients randomized to the alogliptin group (3.9%) experienced at least 1 hospitalization for heart failure compared to patients randomized to placebo (3.3%). In the SAVOR trial, 16,492 patients with type 2 diabetes who had either a history of cardiovascular events or a risk for cardiovascular events were randomized to receive either saxagliptin therapy or placebo. Although the SAVOR trial was not specifically designed to assess heart failure risk, results showed that 3.5% of patients in the saxagliptin group were hospitalized for heart failure compared to 2.8% of patients in the placebo group (HR 1.27, 95% CI 1.07 to 1.51; p = 0.007). Metformin; sitagliptin should also be used with caution in patients with congestive heart failure requiring pharmacologic treatment. Acute congestive heart failure characterized by acute hypoxia has been associated with the development of lactic acidosis in patients taking metformin. To reduce the risk of lactic acidosis, metformin; sitagliptin should be promptly withheld in the presence of any condition associated with hypoxemia. Acute hypoxia and acute cardiac disease (e.g., acute heart failure, cardiogenic shock, or acute myocardial infarction) and other conditions characterized by acute hypoxia have been associated with the development of lactic acidosis and may cause prerenal azotemia.

    Geriatric

    Use the combination of metformin; sitagliptin with caution in geriatric patients. Metformin is substantially excreted by the kidney and the risk of adverse reactions (including lactic acidosis) is greater in patients with reduced renal function. Because aging is associated with renal function decline, care should be taken with dose selection and titration. Sitagliptin dosing is recommended to be decreased in patients with a CrCl less than 50 mL/min. Obtain an estimated glomerular filtration rate (eGFR) at least annually in all patients taking metformin; sitagliptin. In patients at increased risk for the development of renal impairment such as geriatric patients, renal function should be assessed more frequently. Unless estimated renal function via the eGFR is determined to not be reduced, do not use metformin in geriatric patients 80 years of age and older. Generally, geriatric or debilitated patients should not be titrated up to maximum metformin dosages. Older, debilitated, or malnourished patients are also particularly susceptible to hypoglycemic effects of antidiabetic agents; monitor blood glucose frequently. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, the use of antidiabetic medications should include monitoring (e.g., periodic blood glucose) for effectiveness based on desired goals for that individual and to identify complications of treatment such as hypoglycemia or impaired renal function. Metformin has been associated with lactic acidosis, which is more likely to occur under the following conditions: serum creatinine of 1.5 mg/dL or higher in males or 1.4 mg/dL or higher in females, abnormal creatinine clearance from any cause, age of 80 years or older unless measurement of creatinine clearance verifies normal renal function, radiologic studies in which intravascular iodinated contrast materials are given, congestive heart failure requiring pharmacologic management, or acute/chronic metabolic acidosis with or without coma (including diabetic ketoacidosis).

    Alcoholism, ethanol intoxication, hepatic disease

    The use of metformin has been associated with lactic acidosis in rare instances. Since the liver is important for clearing accumulated lactic acid, metformin; sitagliptin should generally be avoided in patients with hepatic disease as the risk of lactic acidosis may be increased. Hepatic disease also causes altered gluconeogenesis, which may affect glycemic control. Alcohol is known to potentiate the effect of metformin on lactate metabolism and patients should be warned against ethanol intoxication (acute or chronic) while on metformin; sitagliptin. This drug is not recommended for those with alcoholism.

    Radiographic contrast administration

    Discontinue sitagliptin; metformin at the time of or before radiographic contrast administration in patients with an estimated glomerular filtration rate (eGFR) between 30 and 60 mL/minute/1.73 m2; in patients with a history of hepatic disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate the eGFR 48 hours after the imaging procedure; restart sitagliptin; metformin if renal function is stable.

    Burns, dehydration, infection, sepsis, surgery, trauma

    The use of metformin has been associated with lactic acidosis in rare instances. To reduce the risk of lactic acidosis, metformin; sitagliptin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Metformin; sitagliptin therapy should be temporarily suspended for any surgery, except for minor procedures where intake of fluids and food is not restricted. Do not restart this drug until oral intake is resumed and renal function has been evaluated as normal. Temporary use of insulin in place of oral antidiabetic agents may be necessary during periods of physiologic stress (e.g., burns, systemic infection, trauma, surgery, or fever). Any change in clinical status, including diarrhea or vomiting, may also increase the risk of lactic acidosis and may require laboratory evaluation in patients on metformin; sitagliptin and may require the drug be withheld.

    Anemia, pernicious anemia, vitamin B12 deficiency

    As the metformin component of metformin; sitagliptin has been associated with suboptimal vitamin B12 absorption, possibly due to interference with the B12-intrinsic factor complex, use this medication with caution, if at all, in patients with vitamin B12 deficiency or vitamin B12-dependent anemia. The interaction very rarely results in a pernicious anemia that appears reversible with discontinuation of metformin or with cyanocobalamin supplementation. Certain individuals may be predisposed to this type of anemia; a nested case-control study of 465 patients taking metformin (155 with vitamin B12 deficiency and 310 without) demonstrated that dose and duration of metformin use may be associated with an increased odds of vitamin B12 deficiency. Each 1 gram/day increment in dose significantly increased the odds of vitamin B12 deficiency (OR 2.88, 95% CI 2.15 to 3.87) as did taking metformin for 3 or more years (OR 2.39, 95% CI 1.46 to 3.91). Annual measurement of hematologic parameters is recommended in all patients on chronic metformin; sitagliptin treatment.

    Arthralgia

    Cases of severe, sometimes disabling, arthralgia (joint pain) have been reported with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors, including sitagliptin. Advise patients not to discontinue therapy but to contact their health care professional immediately if they experience severe and persistent joint pain while taking metformin; sitagliptin. Consider metformin; sitagliptin as a possible cause of joint pain and discontinue if appropriate. The FDA has identified 33 cases of severe arthralgia with the use of DPP-4 inhibitors, all of which resulted in substantial reduction of the patient’s prior level of activity and, in 10 cases, required hospitalization. In the reported cases, the onset of symptoms occurred from 1 day to several years after the start of therapy with a DPP-4 inhibitor. Symptoms resolved with discontinuation of therapy, usually in less than a month; however, some patients experienced a recurrence of joint pain when restarting the same drug or switching to another DPP-4 inhibitor.

    Polycystic ovary syndrome, pregnancy

    Premenopausal anovulatory females with insulin resistance (i.e., 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 in those not desiring to become pregnant. Metformin; sitagliptin is classified as FDA pregnancy risk category B; however, combination therapy should be used during pregnancy only if clearly needed as no adequate and well-controlled studies have been conducted in pregnant women. Sitagliptin doses of up to 30 times the human exposure at the maximum recommended human dose (MRHD) were not teratogenic when administered to rats and rabbits on gestation days 6 to 20; a dose of 1,000 mg/kg (100 times the human exposure at the MRHD) caused rib malformations in offspring and the dose resulted in a decrease in offspring weight; neither functional nor behavioral toxicity was observed. Based on the results of a small study, it appears that metformin does pass through the placenta and the fetus is exposed to therapeutic concentrations of metformin. A study of 109 women with PCOS who were treated with metformin 1.5 to 2.55 grams/day at the time of conception and continued treatment throughout pregnancy found no difference in the development of preeclampsia and a lower rate of gestational diabetes when compared to a control group of pregnant women without PCOS. Among the 126 infants born to the women with PCOS, 2 birth defects occurred: 1 sacrococcygeal teratoma and 1 tethered spinal cord. Follow up to 18 months of age found no differences in height or weight in infants exposed to metformin compared to controls and no abnormalities in motor or social development. Other epidemiologic data suggest no increase in the rates of expected birth defects in women taking metformin who become pregnant. Metformin has been studied during the second and third trimesters of pregnancy; the neonatal mortality rate appeared lower in patients receiving metformin than in mildly diabetic controls, but slightly higher incidences of polycythemia and necrotizing enterocolitis were noted in the metformin group and the most frequently encountered infant problems were jaundice, polycythemia, and hypoglycemia. The American College of Obstetrician and Gynecologists recommends insulin as the therapy of choice to maintain blood glucose as close to normal as possible during pregnancy in patients with type 1 or 2 diabetes mellitus, and, if diet therapy alone is not successful, for those patients with gestational diabetes. More recent studies comparing metformin to insulin in the treatment of gestational diabetes found no significant differences in glycemic control or pregnancy outcomes. One study comparing metformin (n = 100) to insulin (n = 100) for the treatment of gestational diabetes found significantly lower weight gain during pregnancy and improved neonatal morbidity with respect to prematurity, neonatal jaundice, and admission to the neonatal unit in the metformin group. Placental transfer of sitagliptin has been demonstrated in animal studies. Merck maintains a registry to monitor the pregnancy outcomes of women exposed to metformin; sitagliptin during pregnancy. Health care providers are encouraged to report any prenatal exposure to metformin; sitagliptin by calling the pregnancy registry at 800-986-8999.

    Breast-feeding

    Caution should be used when administering metformin; sitagliptin to women who are breast-feeding. No studies have been conducted with the combined ingredients of metformin; sitagliptin. Sitagliptin is secreted in the milk of lactating rats at a plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Animal data show that metformin is excreted into breast milk and reaches levels similar to those in plasma. Small studies indicate that metformin is excreted in human breast milk. Infant hypoglycemia or other side effects are a possibility; however, adverse effects on infant plasma glucose have not been reported in human studies. Furthermore, the use of metformin 2,550 mg/day by mothers breast-feeding their infants for 6 months does not affect growth, motor, or social development; the effects beyond 6 months are not known. In all of these studies, the estimated weight-adjusted infant exposure to metformin ranged from 0.11% to 1.08% of the mother's dose. The results of these studies indicate that maternal ingestion of metformin during breast-feeding is probably safe to the infant. However, a risk and benefit analysis should be made for each mother and her infant. If patients elect to continue metformin; sitagliptin while breast-feeding, the mother should be aware of the potential risks to the infant. If metformin; sitagliptin is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Metformin monotherapy may be a consideration. Other oral hypoglycemics may also be considered. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected ; therefore, this agent may represent a reasonable alternative for some patients. Tolbutamide is usually considered compatible with breast-feeding. Glyburide may be a suitable alternative since it was not detected in the breast milk of lactating women who received single and multiple doses of glyburide. If any oral hypoglycemics are used during breast-feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence.

    Children

    The safety and effectiveness of metformin; sitagliptin in children and adolescents less than 18 years of age has not been established.

    ADVERSE REACTIONS

    Severe

    megaloblastic anemia / Delayed / 0-1.0
    lactic acidosis / Delayed / 0-0.1
    pancreatitis / Delayed / Incidence not known
    pemphigus / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    vasculitis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known

    Moderate

    peripheral edema / Delayed / 8.3-8.3
    hypoglycemia / Early / 1.2-1.2
    metabolic acidosis / Delayed / 0-0.1
    constipation / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    vitamin B12 deficiency / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known

    Mild

    flatulence / Early / 1.0-12.1
    dyspepsia / Early / 1.0-7.1
    anorexia / Delayed / 1.0-5.0
    dysgeusia / Early / 1.0-5.0
    metallic taste / Early / 1.0-5.0
    myalgia / Early / 1.0-5.0
    malaise / Early / 1.0-5.0
    diarrhea / Early / 2.4-2.4
    abdominal pain / Early / 2.2-2.2
    nausea / Early / 1.3-1.3
    vomiting / Early / 1.1-1.1
    pharyngitis / Delayed / 5.0
    asthenia / Delayed / 5.0
    headache / Early / 5.0
    infection / Delayed / 5.0
    rash (unspecified) / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    weight loss / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    back pain / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Major) Caution is advised when administering dolutegravir with metformin, as coadministration 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. If these drugs are used in combination, the total daily dose of metformin must not exceed 1000 mg/day. Close monitoring of blood glucose and patient clinical status 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 was administered at a dose of 500 mg PO twice daily. 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.
    Acebutolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Acetaminophen; Propoxyphene: (Moderate) Propoxyphene may enhance the hypoglycemic action of antidiabetic agents. Patients should be closely monitored for changes in glycemic control while receiving propoxyphene in combination with antidiabetic agents.
    Acetaminophen; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Acetazolamide: (Moderate) 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. Carbonic anhydrase inhibitors frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use these drugs with caution in patients treated with metformin, as the risk of lactic acidosis may increase. Monitor electrolytes and renal function.
    Acrivastine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    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.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Aliskiren; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Amlodipine; Benazepril: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Amlodipine; Olmesartan: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Amlodipine; Telmisartan: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Amlodipine; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    Amphetamine; Dextroamphetamine Salts: (Moderate) Amphetamines may potentiate the actions of some antidiabetic agents. As long as blood glucose is carefully monitored to avoid hypoglycemia, it appears that amphetamines can be used concurrently.
    Amprenavir: (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 agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Androgens: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Angiotensin II receptor antagonists: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Angiotensin-converting enzyme inhibitors: (Moderate) ACE inhibitors may enhance the hypoglycemic effects antidiabetic agents by improving insulin sensitivity. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, coadministration may increase the risk for angioedema. (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Articaine; Epinephrine: (Moderate) Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Atazanavir: (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 agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Atazanavir; Cobicistat: (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. (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 agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Atenolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Atenolol; Chlorthalidone: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    atypical antipsychotic: (Moderate) Patients taking metformin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The 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. Temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported. (Moderate) Patients taking sitagliptin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The 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. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (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 (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. When used at daily doses of 750 to 2000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy. Monitor patients on antidiabetic therapy for blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary. (Moderate) Niacinamide interferes with glucose metabolism and can result in hyperglycemia. Monitor patients taking antidiabetic agents for changes in glycemic control if niacinamide is added or deleted to the medication regimen. Dosage adjustments may be necessary. (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.
    Azilsartan: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Azilsartan; Chlorthalidone: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Baclofen: (Minor) Because baclofen can increase blood glucose, doses of antidiabetic agents may need adjustment in patients receiving these drugs concomitantly. (Minor) Coadministration of metformin and baclofen may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of metformin. Baclofen can increase blood glucose. Patients receiving metformin should be closely monitored for signs indicating loss of diabetic control when therapy with baclofen is instituted. Doses of metformin may need adjustment in patients receiving these drugs concomitantly.
    Benazepril: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Bendroflumethiazide; Nadolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Benzphetamine: (Moderate) Benzphetamine may potentiate the actions of some antidiabetic agents. As long as blood glucose is carefully monitored to avoid hypoglycemia, it appears that benzphetamine can be used concurrently.
    Beta-blockers: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent. (Moderate) Beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
    Betaxolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Bexarotene: (Moderate) Patients receiving bexarotene with antidiabetic agents that enhance insulin secretion like sitagliptin or saxagliptin should be monitored for hypoglycemia.
    Bisoprolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Bortezomib: (Moderate) Coadministration of metformin and bortezomib may require close blood glucose monitoring and dosage adjustment. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents, including metformin. (Minor) During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medications.
    Brimonidine; Timolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Brompheniramine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    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.
    Candesartan: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Captopril: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbetapentane; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbetapentane; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Carbinoxamine; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbinoxamine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    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) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Carvedilol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Cephalexin: (Moderate) In healthy subjects given single 500 mg doses of cephalexin and metformin, plasma metformin Cmax and AUC increased by an average of 34% and 24%, respectively; metformin renal clearance decreased by an average of 14%. No information is available about the interaction of cephalexin and metformin following multiple dose administration.
    Cetirizine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    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) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Chlorpheniramine; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Chlorpromazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Chlorthalidone: (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Chlorthalidone; Clonidine: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    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.
    Cimetidine: (Moderate) Caution is advised when administering cimetidine with metformin. Cimetidine inhibits renal elimination of metformin. Increased metformin exposure may lead to hypoglycemia, gastrointestinal complaints, and an increased risk for lactic acidosis. Consider alternatives to cimetidine. If medically necessary to use cimetidine, carefully monitor. Metformin dose reduction may be needed. An interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Cimetidine 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]).
    Ciprofloxacin: (Moderate) Careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents, including metformin, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. (Moderate) Careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents, including sitagliptin, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    Cisapride: (Moderate) Because cisapride 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.
    Clarithromycin: (Moderate) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    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: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Cobicistat: (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.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, 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. (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.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, 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. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir, PMPA 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. (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; Phenylephrine; Promethazine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated. (Minor) Promethazine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Phenothiazines have been reported to increase blood glucose concentrations.
    Codeine; Promethazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated. (Minor) Promethazine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Phenothiazines have been reported to increase blood glucose concentrations.
    Colesevelam: (Moderate) Colesevelam increases the Cmax and AUC of extended-release metformin (metformin ER) by approximately 8% and 44%, respectively. According to the manufacturer of colesevelam, the clinical response to metformin ER should be monitored in patients receiving concomitant therapy. Colesevelam has no significant effect on the bioavailability of immediate-release metformin.
    Conjugated Estrogens: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Corticosteroids: (Moderate) Endogenous counter-regulatory hormones such as glucocorticoids are released in response to hypoglycemia. When released, blood glucose concentrations rise. When corticosteroids are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. In addition, blood lactate concentrations and the lactate to pyruvate ratio increase when metformin is coadministered with corticosteroids (e.g., hydrocortisone). Elevated lactic acid concentrations are associated with increased morbidity rates. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted. (Moderate) Systemic corticosteroids increase blood glucose levels. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent.
    Crizotinib: (Moderate) Monitor for an increase in metformin-related adverse reactions and toxicities (e.g., lactic acidosis) if coadministration with crizotinib is necessary; consider the risks and benefits of coadministration. Metformin is a substrate of the renal uptake transporter, OCT2. Crizotinib inhibits OCT2 at clinically relevant concentrations, and has the potential to increase plasma concentrations of drugs that are substrates of OCT2. Coadministration with another OCT2 inhibitor increased the Cmax and AUC of metformin by 60% and 40%, respectively; there was no change in the elimination half-life of metformin.
    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) Cyclosporine has been reported to cause hyperglycemia. Patients should be monitored for changes in glycemic control if therapy with cyclosporine is initiated in patients receiving sitagliptin. (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
    Danazol: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Darunavir: (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 agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Darunavir; Cobicistat: (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. (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 agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (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 agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Desiccated Thyroid: (Minor) Addition of thyroid hormones to metformin may result in increased dosage requirements of metformin. Monitor blood sugars carefully when thyroid therapy is added, discontinued or doses changed.
    Desloratadine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Dexmethylphenidate: (Moderate) Sympathomimetics may increase blood sugar via stimulation of beta-2 receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with a sympathomimetic agent, such as dexmethylphenidate, is instituted.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Dextromethorphan; Promethazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated. (Minor) Promethazine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Phenothiazines have been reported to increase blood glucose concentrations.
    Diazoxide: (Minor) Because diazoxide increases blood glucose, a pharmacodynamic interaction exists between this drug and all other antidiabetic agents, including metformin. (Minor) Diazoxide increases blood glucose by inhibiting insulin release from the pancreas and/or by stimulating the release of catecholamines, which in turn stimulate glycogenolysis. The dosage of antidiabetic agents may need to be adjusted when diazoxide is added to the regimen.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and metformin together with caution. Lactic acidosis, a rare and serious form of metabolic acidosis, has been reported with the use of metformin, and metabolic acidosis has been reported with the use of dichlorphenamide. Concurrent use may increase the severity of metabolic acidosis. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Dienogest; Estradiol valerate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Diethylpropion: (Moderate) Diethylpropion exhibits intrinsic hypoglycemic activity and can lower postprandial blood glucose concentrations. Diethylpropion should be used cautiously in diabetic patients who are stabilized on antidiabetic agents.
    Diethylstilbestrol, DES: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Digoxin: (Moderate) There was an 11% increase in the AUC and an 18% increase in the plasma Cmax of digoxin when digoxin 0.25 mg/day PO is administered with sitagliptin 100 mg PO once daily for 10 days. Dosage adjustment of digoxin is not recommended, but patients receiving these 2 drugs at the same time should be monitored closely.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Diphenhydramine; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    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) Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    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) Caution is advised when administering dolutegravir with metformin, as coadministration 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. If these drugs are used in combination, the total daily dose of metformin must not exceed 1000 mg/day. Close monitoring of blood glucose and patient clinical status 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 was administered at a dose of 500 mg PO twice daily. 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) Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dorzolamide; Timolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Drospirenone; Estradiol: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Drospirenone; Ethinyl Estradiol: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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) 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.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, 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. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir, PMPA 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.
    Emtricitabine: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, 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.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, 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.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, 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. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir, PMPA 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.
    Emtricitabine; Tenofovir alafenamide: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, 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.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, 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. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir, PMPA 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.
    Enalapril, Enalaprilat: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Enalapril; Felodipine: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    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) Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Epinephrine: (Moderate) Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Eprosartan: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Erythromycin; Sulfisoxazole: (Moderate) Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Esmolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Esterified Estrogens: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Esterified Estrogens; Methyltestosterone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Estradiol: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Estradiol; Levonorgestrel: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Estradiol; Norethindrone: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Estradiol; Norgestimate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    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) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued.
    Estropipate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    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: (Moderate) Alcohol (ethanol) may cause variable effects on glycemic control when used in patients receiving antidiabetic therapy. Alcohol ingestion can decrease endogenous glucose production potentiating the risk of hypoglycemia. Alternatively, alcohol can worsen glycemic control as it provides a source of additional calories. Blood glucose concentrations should be closely monitored and dosage adjustments of antidiabetic agents may be necessary if alcohol is consumed. Patients should be encouraged to limit or moderate their intake of alcoholic beverages. Because of its effects on endogenous glucose production, patients should be encouraged to avoid alcohol ingestion during the fasting state. Many non-prescription drug products may be formulated with ethanol; have patients scrutinize product labels prior to consumption. (Moderate) Patients should be advised to limit their use of ethanol during use of metformin. Blood lactate concentrations and the lactate to pyruvate ratio are increased during excessive (acute or chronic) intake of alcohol with metformin. Elevated lactic acid concentrations are associated with increased morbidity rates as the risk for lactic acidosis is increased. Many non-prescription drug products may be formulated with alcohol; have patients scrutinize product labels prior to consumption. In patients with diabetes, alcohol intake can also cause hypoglycemia or worsen glycemic control as it provides a source of additional calories.
    Ethinyl Estradiol: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Ethinyl Estradiol; Desogestrel: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Ethinyl Estradiol; Etonogestrel: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Ethinyl Estradiol; Levonorgestrel: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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) 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.
    Ethinyl Estradiol; Norelgestromin: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Ethinyl Estradiol; Norethindrone: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Ethinyl Estradiol; Norgestimate: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Ethinyl Estradiol; Norgestrel: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    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.
    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.
    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.
    Famotidine; Ibuprofen: (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.
    Fenofibrate: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Fenofibric Acid: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Fexofenadine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Fibric acid derivatives: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Fluoxetine: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Fluoxetine; Olanzapine: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Fluoxymesterone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Fluphenazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Folic Acid, Vitamin B9: (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.
    Fosamprenavir: (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 agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Fosinopril: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    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.
    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.
    Gadoterate meglumine: (Severe) 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.
    Garlic, Allium sativum: (Moderate) Garlic, Allium sativum might have some antidiabetic activity, resulting in increased serum insulin concentrations and increased glycogen storage in the liver. Until more data are available, individuals receiving antidiabetic agents should use caution in consuming dietary supplements containing garlic, and follow their normally recommended strategies for blood glucose monitoring. (Moderate) Limited animal data suggest that selected constituents in Garlic, Allium sativum might have some antidiabetic activity, resulting in increased serum insulin concentrations and increased glycogen storage in the liver. Patients with diabetes frequently purchase alternative remedies that have been purported to improve glycemic control, but there is no scientific or controlled evidence in humans of this action. Limited clinical evidence suggests that garlic does not affect blood glucose in those without diabetes. Until more data are available, individuals receiving antidiabetic agents should use caution in consuming dietary supplements containing garlic, and follow their normally recommended strategies for blood glucose monitoring.
    Gemfibrozil: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Gemifloxacin: (Moderate) Hyperglycemia and hypoglycemia have been reported in patients treated concomitantly with quinolones and antidiabetic agents. Rare cases of severe hypoglycemia have been reported with concomitant use of quinolones and glyburide. Therefore, careful monitoring of blood glucose is recommended when gemifloxacin and antidiabetic agents are coadministered. (Moderate) Hyperglycemia and hypoglycemia have been reported in patients treated concomitantly with quinolones and antidiabetic agents. Rare cases of severe hypoglycemia have been reported with concomitant use of quinolones and glyburide. Therefore, careful monitoring of blood glucose is recommended when gemifloxacin and antidiabetic agents are coadministered.
    Glucagon: (Minor) Exogenously administered glucagon increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents. (Minor) Glucagon administration results in increases in blood glucose concentrations thereby decreasing the hypoglycemic effect of metformin.
    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.
    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.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Guaifenesin; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Guaifenesin; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    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.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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. (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.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Hydrocodone; Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Hydrocodone; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Hydroxychloroquine: (Major) Careful monitoring of blood glucose is recommended when hydroxychloroquine 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 hydroxychloroquine and an antidiabetic agent. (Major) Careful monitoring of blood glucose is recommended when hydroxychloroquine 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 hydroxychloroquine and an antidiabetic agent.
    Hydroxyprogesterone: (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.
    Ibuprofen; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    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 sitagliptin. Indapamide can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia.
    Indinavir: (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 agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Iodipamide Meglumine: (Severe) 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: (Severe) 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: (Severe) 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) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Isoniazid, INH: (Minor) Although a rare side effect, isoniazid, INH may increase blood sugar. Patients receiving antidiabetic agents should closely monitor their blood glucose concentrations if isoniazid is coadministered. (Minor) Isoniazid, INH may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when this drug is initiated.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Minor) Although a rare side effect, isoniazid, INH may increase blood sugar. Patients receiving antidiabetic agents should closely monitor their blood glucose concentrations if isoniazid is coadministered. (Minor) Isoniazid, INH may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when this drug is initiated.
    Isoniazid, INH; Rifampin: (Minor) Although a rare side effect, isoniazid, INH may increase blood sugar. Patients receiving antidiabetic agents should closely monitor their blood glucose concentrations if isoniazid is coadministered. (Minor) Isoniazid, INH may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when this drug is initiated.
    Isoproterenol: (Moderate) Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Labetalol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    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.
    Lamotrigine: (Moderate) Coadministration of metformin and lamotrigine may decrease metformin clearance, resulting in increased plasma concentrations and the potential for adverse events, including hypoglycemia. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and metformin is excreted via this route.
    Lanreotide: (Moderate) Monitor blood glucose levels if administration of lanreotide is necessary with antidiabetic agents; adjust the dosage of the antidiabetic agent as clinically appropriate. Lanreotide inhibits the secretion of insulin and glucagon.
    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.
    Levobetaxolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Levobunolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Levocarnitine: (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.
    Levofloxacin: (Moderate) Careful monitoring of blood glucose is recommended when levofloxacin and antidiabetic agents, including metformin, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. (Moderate) Careful monitoring of blood glucose is recommended when levofloxacin and antidiabetic agents, including the dipeptidyl peptidase-4 inhibitors, are coadministered. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent.
    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.
    Levomefolate; Mecobalamin; Pyridoxal-5-phosphate: (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.
    Levothyroxine: (Minor) Addition of thyroid hormones to metformin may result in increased dosage requirements of metformin. Monitor blood sugars carefully when thyroid therapy is added, discontinued or doses changed.
    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 metformin may result in increased dosage requirements of metformin. Monitor blood sugars carefully when thyroid therapy is added, discontinued or doses changed.
    Liotrix: (Minor) Addition of thyroid hormones to metformin may result in increased dosage requirements of metformin. Monitor blood sugars carefully when thyroid therapy is added, discontinued or doses changed.
    Lisdexamfetamine: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Lisinopril: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Lithium: (Moderate) Lithium may cause variable effects on glycemic control when used in patients receiving antidiabetic agents. Monitor blood glucose concentrations closely if lithium is coadministered with antidiabetic agents. Dosage adjustments of antidiabetic agents may be necessary. (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.
    Lomefloxacin: (Moderate) Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents are co-administered.
    Lomitapide: (Moderate) Concomitant use of lomitapide and sitagliptin may result in increased serum concentrations of sitagliptin. According to the manufacturer of lomitapide, dose reduction of sitagliptin should be considered during concurrent use. Lomitapide is an inhibitor of P-glycoprotein (P-gp) and sitagliptin is a P-gp substrate.
    Lopinavir; Ritonavir: (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 agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Loratadine; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    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) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Lovastatin; Niacin: (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 (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.
    Mecasermin rinfabate: (Moderate) Use caution in coadministering mecasermin products with antidiabetic agents. A hypoglycemic effect may be exacerbated in some patients. Glucose monitoring is important when initializing or adjusting mecasermin therapies, when adjusting concomitant antidiabetic therapy, and in the event of hypoglycemic symptoms. (Moderate) Use caution in combining mecasermin, recombinant, rh-IGF-1 and mecasermin rinfabate (rh-IGF-1/rh-IGFBP-3) with antidiabetic agents. The hypoglycemic effect induced by IGF-1 activity may be exacerbated. Although the rh-IGF-1/rh-IGFBP-3 complex has less propensity to rapidly lower blood glucose compared to unbound mecasermin, hypoglycemia is possible with either agent. 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 (rh-IGF-1) 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. 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.
    Mecasermin, Recombinant, rh-IGF-1: (Moderate) Use caution in coadministering mecasermin products with antidiabetic agents. A hypoglycemic effect may be exacerbated in some patients. Glucose monitoring is important when initializing or adjusting mecasermin therapies, when adjusting concomitant antidiabetic therapy, and in the event of hypoglycemic symptoms. (Moderate) Use caution in combining mecasermin, recombinant, rh-IGF-1 and mecasermin rinfabate (rh-IGF-1/rh-IGFBP-3) with antidiabetic agents. The hypoglycemic effect induced by IGF-1 activity may be exacerbated. Although the rh-IGF-1/rh-IGFBP-3 complex has less propensity to rapidly lower blood glucose compared to unbound mecasermin, hypoglycemia is possible with either agent. 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 (rh-IGF-1) 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. 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.
    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.
    Megestrol: (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.
    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.
    Meperidine; Promethazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated. (Minor) Promethazine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Phenothiazines have been reported to increase blood glucose concentrations.
    Mesoridazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Mestranol; Norethindrone: (Minor) Estrogens can decrease the hypoglycemic effects of metformin by impairing glucose tolerance. Patients receiving metformin should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (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.
    Methamphetamine: (Moderate) Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Methazolamide: (Moderate) Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide, and similar effects may be noted with methazolamide. 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. Carbonic anhydrase inhibitors frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use these drugs with caution in patients treated with metformin, as the risk of lactic acidosis may increase. Monitor electrolytes and renal function.
    Methyclothiazide: (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Methylphenidate: (Moderate) Sympathomimetics, such as methylphenidate, may increase blood sugar via stimulation of beta-2 receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Methyltestosterone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Metoclopramide: (Moderate) Because metoclopramide 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 metformin may require adjustment in patients who receive metoclopramide concomitantly. (Moderate) Because metoclopramide can enhance gastric emptying in patients with diabetes, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents, including sitagliptin. The dosing of antidiabetic agents may require adjustment in patients who receive metoclopramide concomitantly.
    Metolazone: (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Metoprolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    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.
    Moexipril: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Monoamine oxidase inhibitors: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents. Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost. (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor selegiline, are added to any regimen containing antidiabetic agents.Although at low doses selegiline is selective for MAO type B, in doses above 30 to 40 mg/day, this selectivity is lost.
    Moxifloxacin: (Moderate) Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Monitor blood glucose when quinolones and antidiabetic agents are coadministered. (Moderate) Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents are coadministered.
    Nadolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Nandrolone Decanoate: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Naproxen; Pseudoephedrine: (Moderate) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Nebivolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Nebivolol; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Nelfinavir: (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 agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    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 (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.
    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 (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.
    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.
    Non-Ionic Contrast Media: (Severe) Metformin and combination products containing metformin should be temporarily discontinued prior to the administration of iodinated radiopaque contrast agents. 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 iodinated contrast media.
    Norepinephrine: (Moderate) Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    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.
    Norfloxacin: (Moderate) Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents are coadministered. (Moderate) Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones like norfloxacin and an antidiabetic agent like metformin. Monitor blood glucose when norfloxacin and metformin are coadministered.
    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.
    Octreotide: (Moderate) Administration of octreotide to patients receiving oral antidiabetic agents can produce hypoglycemia. Patients should be monitored closely and doses of these medications adjusted accordingly if octreotide is added. (Moderate) Administration of octreotide to patients receiving oral antidiabetic agents or insulin can produce hypoglycemia due to slowing of gut motility which leads to decreased postprandial glucose concentrations. Patients should be monitored closely and doses of these medications adjusted accordingly if octreotide is added.
    Ofloxacin: (Moderate) Hyperglycemia and hypoglycemia have been reported in patients treated concomitantly with quinolones and antidiabetic agents. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents are coadministered. (Moderate) Hyperglycemia and hypoglycemia have been reported in patients treated concomitantly with quinolones and antidiabetic agents. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents are coadministered.
    Olmesartan: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) The manufacturer recommends against concurrent administration of ombitasvir; paritaprevir; ritonavir and metformin in patients with hepatic or renal impairment. If these drugs are given together, closely monitor blood glucose concentrations and for signs of lactic acidosis (i.e., abdominal or respiratory distress, worsening renal function, somnolence).
    Ombitasvir; Paritaprevir; Ritonavir: (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 agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Orlistat: (Moderate) Changes in dietary intake and weight loss induced by orlistat may improve metabolic control in obese diabetic patients, which may be additive to the effects of metformin. Lower blood glucose as a result of orlistat-induced changes in body composition may necessitate a dosage reduction of metformin with time. (Minor) Changes in dietary intake and weight loss induced by orlistat may improve metabolic control in diabetic patients. Lower blood glucose may necessitate a dosage reduction of antidiabetic agents.
    Oxandrolone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Oxymetholone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Pasireotide: (Major) Pasireotide may cause hyperglycemia. Closely monitor patients receiving antidiabetic therapy for changes in glycemic control; adjustments in the dosage of antidiabetic agents may be necessary during pasireotide receipt and after its discontinuation.
    Pegvisomant: (Moderate) Patients who have both acromegaly and diabetes mellitus and are being treated with antidiabetic agents may require dose reductions of these medications after the initiation of pegvisomant. Growth hormone decreases insulin sensitivity by opposing the effects of insulin on carbohydrate metabolism; therefore, pegvisomant, which antagonizes growth hormone, is expected to have the opposite effect. Although none of the acromegalic patients with diabetes mellitus who were treated with pegvisomant during the clinical studies developed clinically relevant hypoglycemia, such patients should monitor their blood glucose regularly, with doses of anti-diabetic medications reduced as necessary. (Moderate) Pegvisomant, which antagonizes growth hormone, is expected to increase insulin sensitivity. Monitor blood glucose regularly, and reduce doses of antidiabetic medications as necessary.
    Penbutolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    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) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Perindopril; Amlodipine: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Perphenazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Perphenazine; Amitriptyline: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Phendimetrazine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Phenothiazines: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated. (Minor) The phenothiazines may increase blood sugar. Patients should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.
    Phentermine: (Moderate) Phentermine may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Diabetic patients may have decreased requirements of antidiabetic agents in association with the use of phentermine.
    Phentermine; Topiramate: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown. (Moderate) Phentermine may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Diabetic patients may have decreased requirements of antidiabetic agents in association with the use of phentermine.
    Phenylephrine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Phenylephrine; Promethazine: (Moderate) Sympathomimetics may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated. (Minor) Promethazine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Phenothiazines have been reported to increase blood glucose concentrations.
    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.
    Pindolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Ponatinib: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and sitagliptin, a P-gp substrate, may increase the exposure of sitagliptin.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Prilocaine; Epinephrine: (Moderate) Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Prochlorperazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    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.
    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: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated. (Minor) Promethazine should be used cautiously in patients receiving metformin. Patients should routinely monitor their blood glucose as indicated. Phenothiazines have been reported to increase blood glucose concentrations.
    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.
    Propoxyphene: (Moderate) Propoxyphene may enhance the hypoglycemic action of antidiabetic agents. Patients should be closely monitored for changes in glycemic control while receiving propoxyphene in combination with antidiabetic agents.
    Propranolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    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 agents 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. 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) Pseudoephedrine may increase blood sugar via stimulation of beta2 receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with pseudoephedrine is instituted.
    Pyrimethamine; Sulfadoxine: (Moderate) Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Quinapril: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Racepinephrine: (Moderate) Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Ramipril: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Ranolazine: (Major) Limit the dose of metformin to 1700 mg/day if coadministered with ranolazine 1000 mg twice daily. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Monitor blood glucose concentrations, for common metformin side effects such as gastrointestinal complaints. 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 when coadministered 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]).
    Rasagiline: (Moderate) Animal data indicate that monoamine oxidase inhibitors (MAO inhibitors) may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. Serum glucose should be monitored closely when MAOI-type medications, including the selective MAO-B inhibitor rasagiline, are added to any regimen containing antidiabetic agents.
    Reserpine: (Moderate) Reserpine may mask the signs and symptoms of hypoglycemia because of their sympatholytic activity. Patients receiving reserpine concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Reserpine may mask the signs and symptoms of hypoglycemia. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control.
    Ritodrine: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. Racepinephrine may increase blood glucose concentrations by a similar mechanism. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Ritonavir: (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 agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Sacubitril; Valsartan: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Salicylates: (Moderate) Large doses of salicylates may enhance hypoglycemia in diabetic patients via inhibition of prostaglandin synthesis. If these agents are administered or discontinued in patients receiving oral antidiabetic agents, patients should be monitored for hypoglycemia or loss of blood glucose control. (Moderate) Salicylates can indirectly increase insulin secretion, decreasing blood glucose concentrations. In large doses, salicylates may cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents.
    Saquinavir: (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 agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Somatropin, rh-GH: (Minor) Coadministration of metformin and somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of metformin. Patients receiving metformin should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin is instituted. (Minor) Exogenously administered somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents.
    Sotalol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Sparfloxacin: (Moderate) Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones like sparfloxacin and an antidiabetic agent like metformin. Monitor blood glucose when sparfloxacin and metformin are coadministered. (Moderate) Hyperglycemia and hypoglycemia have been reported in patients treated concomitantly with quinolones and antidiabetic agents. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents are coadministered.
    Sulfadiazine: (Moderate) Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Sulfasalazine: (Moderate) Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Sulfisoxazole: (Moderate) Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Sulfonamides: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. (Moderate) Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Sympathomimetics: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    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.
    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) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Tenofovir Alafenamide: (Moderate) According to the manufacturer, interactions are not expected when metformin is administered with tenofovir alafenamide; however, because tenofovir and metformin can compete for elimination through the kidneys, use of these medications together may increase the risk for side effects, such as lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir alafenamide, 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.
    Tenofovir, PMPA: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir, PMPA 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.
    Testolactone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Testosterone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Thiazide diuretics: (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. (Moderate) Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. 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, 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.
    Thiethylperazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    Thioridazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    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) Addition of thyroid hormones to metformin may result in increased dosage requirements of metformin. Monitor blood sugars carefully when thyroid therapy is added, discontinued or doses changed.
    Timolol: (Moderate) Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis or can promote hyperglycemia. In addition, beta-blockers may mask the signs and symptoms of hypoglycemia and exaggerate the hypertensive response to hypoglycemia. Patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response to the antidiabetic agent.
    Tipranavir: (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 agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Tobacco: (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. (Minor) Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and 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. Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments in antidiabetic agents may be needed.
    Topiramate: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown.
    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) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Trandolapril; Verapamil: (Moderate) Angiotensin-converting enzyme (ACE) inhibitors may enhance the hypoglycemic effects of insulin or other antidiabetic agents by improving insulin sensitivity. Patients receiving antidiabetic agents can become hypoglycemic if ACE inhibitors are administered concomitantly. ACE inhibitors may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    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.
    Trifluoperazine: (Minor) Phenothiazines have been reported to increase blood glucose concentrations. Use cautiously in patients receiving antidiabetic agents; patients should routinely monitor their blood glucose as indicated.
    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.
    Valsartan: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control.
    Vandetanib: (Moderate) Vandetanib inhibits renal elimination of metformin. Increased metformin exposure may lead to hypoglycemia and an increased risk for metformin related side effects, such as hypoglycemia, gastrointestinal complaints, or an increased risk for lactic acidosis. Caution is advised. Carefully monitor the patient. Dosage adjustment of metformin may be necessary. Coadministration with vandetanib increased the Cmax and AUC of metformin by 50% and 74%, respectively. Vandetanib 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]).
    Zonisamide: (Moderate) Zonisamide frequently decreases serum bicarbonate and induces non-anion gap, hyperchloremic metabolic acidosis. Use zonisamide with caution in patients treated with metformin, as the risk of lactic acidosis may increase.

    PREGNANCY AND LACTATION

    Pregnancy

    Caution should be used when administering metformin; sitagliptin to women who are breast-feeding. No studies have been conducted with the combined ingredients of metformin; sitagliptin. Sitagliptin is secreted in the milk of lactating rats at a plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Animal data show that metformin is excreted into breast milk and reaches levels similar to those in plasma. Small studies indicate that metformin is excreted in human breast milk. Infant hypoglycemia or other side effects are a possibility; however, adverse effects on infant plasma glucose have not been reported in human studies. Furthermore, the use of metformin 2,550 mg/day by mothers breast-feeding their infants for 6 months does not affect growth, motor, or social development; the effects beyond 6 months are not known. In all of these studies, the estimated weight-adjusted infant exposure to metformin ranged from 0.11% to 1.08% of the mother's dose. The results of these studies indicate that maternal ingestion of metformin during breast-feeding is probably safe to the infant. However, a risk and benefit analysis should be made for each mother and her infant. If patients elect to continue metformin; sitagliptin while breast-feeding, the mother should be aware of the potential risks to the infant. If metformin; sitagliptin is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Metformin monotherapy may be a consideration. Other oral hypoglycemics may also be considered. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected ; therefore, this agent may represent a reasonable alternative for some patients. Tolbutamide is usually considered compatible with breast-feeding. Glyburide may be a suitable alternative since it was not detected in the breast milk of lactating women who received single and multiple doses of glyburide. If any oral hypoglycemics are used during breast-feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence.

    MECHANISM OF ACTION

    Mechanism of Action: Combination products containing metformin and sitagliptin are used to improve glycemic control in type 2 diabetes mellitus. Clinicians may wish to consult the individual monographs for more information about each agent.•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 actually decrease. Metformin improve 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. Metformin causes a 10—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) and/or hypoxia is present. Clinically, metformin lowers fasting and postprandial hyperglycemia. The decrease in fasting plasma glucose is approximately 25—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. 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.•Sitagliptin: Sitagliptin is a dipeptidyl peptidase-IV (DPP-IV) inhibitor, which exerts its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active, intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-IV. 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. Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner; GLP-1 does not increase insulin secretion when the glucose concentration is < 90 mg/dl. The contributions of GIP, which increases insulin secretion and regulates fat metabolism, to the overall effects of sitagliptin are unclear at this time. Sitagliptin is of benefit in patients with type 2 diabetes mellitus as their GLP-1 concentrations are decreased in response to a meal. The long-term safety of DPP-IV inhibitors are currently under investigation as DPP-IV is not an enzyme specific for the breakdown of incretin hormones. In fact, DPP-IV is responsible for the metabolism of many peptides including peptide YY, neuropeptide Y, and growth hormone-releasing hormone. DPP-IV is involved with T-cell activation and is expressed on lymphocytes as CD26. Whether there are long-term neurological or immunological consequences of inhibiting DPP-IV is unclear at this time.

    PHARMACOKINETICS

    Metformin; sitagliptin is administered orally.
    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 in the kidney, liver, and salivary gland tissue. Metformin does not bind to hepatic or plasma proteins. In healthy adult subjects receiving two metformin 1000 mg; sitagliptin 50 mg XR tablets once daily with the evening meal for 7 days, steady-state for metformin is reached by Day 5 and the median Tmax value for metformin is approximately 8 hours postdose. The median Tmax value for metformin after a single tablet of Janumet is 3.5 hours postdose. 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 is distributed to and accumulates in red blood cells, which leads to a much longer elimination half-life in the blood (17.6 hours).
    Sitagliptin: Sitagliptin is not highly bound to plasma proteins (38%). In healthy adult subjects receiving two metformin 1000 mg; sitagliptin 50 mg XR tablets once daily with the evening meal for 7 days, steady-state for sitagliptin is reached by Day 4 and the median Tmax value for sitagliptin is approximately 3 hours postdose. The median Tmax value for sitagliptin after a single tablet of Janumet is 3 hours postdose. Metabolism is a minor pathway of elimination with approximately 16% of a dose excreted as metabolites. Six metabolites have been detected at trace concentrations and are not expected to contribute significantly to sitagliptin activity. The primary enzymes responsible for metabolism are CYP3A4 and CYP2C8. Elimination occurs primarily via renal excretion and involves active tubular secretion; approximately 79% of a dose is excreted unchanged in the urine. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in it's renal elimination; the clinical relevance of this has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating renal elimination. The apparent terminal half-life of sitagliptin 100 mg is 12.4 hours. One-hundred percent of an administered dose is excreted in the urine (87%) or feces (13%) within 1 week of dosing.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: Organic cationic transporter-2 (OCT2), multidrug and toxin extrusion (MATE1 and MATE2k), CYP3A4, CYP2C8, P-glycoprotein (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.
    Sitagliptin: Sitagliptin is not an inhibitor of CYP isozymes 3A4, 2C8, 2C9, 2D6, 1A2, 2C19, or 2B6, and is not an inducer of CYP 3A4. Sitagliptin is a p-glycoprotein (P-gp) substrate, but does not inhibit P-gp mediated transport. Based on these results, sitagliptin is considered unlikely to cause interactions with drugs that utilize these pathways.

    Oral Route

    Bioequivalence between the separate tablets and the combination products metformin; sitagliptin tablets (Janumet) and metformin; sitagliptin extended-release tablets (Janumet XR) has been demonstrated. The Janumet XR formulation consists of an extended-release metformin core tablet coated with an immediate-release layer of sitagliptin.
    Metformin: Metformin 500 mg tablets have a bioavailability of 50% to 60% with peak plasma levels achieved at approximately 2.5 hours. Food decreases the extent and slightly delays the absorption. Studies indicate that dose proportionality is lacking with increasing doses due to a decrease in the oral absorption at higher doses. After administration of sitagliptin; metformin XR (Janumet XR) tablets with a high-fat breakfast, the AUC for metformin increased 62%, the Cmax for metformin decreased by 9%, and the median Tmax for metformin occurred 2 hours later relative to the fasted state.
    Sitagliptin: Sitagliptin is rapidly absorbed with peak plasma concentrations occurring in 1 to 4 hours in healthy subjects; the absolute bioavailability of a 100 mg dose is 87%. The plasma AUC increases in a dose-proportional manner. After administration of sitagliptin; metformin XR (Janumet XR) tablets with a high-fat breakfast, the AUC for sitagliptin was not altered. The mean Cmax was decreased by 17%, although the median Tmax was unchanged relative to the fasted state.