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    Sodium Glucose Co-transporter 2 (SGLT2) Inhibitors and Biguanide Antidiabetic Combinations

    DEA CLASS

    Rx

    DESCRIPTION

    Oral biguanide antidiabetic agent and a sodium-glucose co-transporter 2 (SGLT2) inhibitor combined in 1 tablet.
    Used for the treatment of type 2 diabetes mellitus in adults.
    Carries a black box warning for lactic acidosis due to metformin.

    COMMON BRAND NAMES

    Xigduo XR

    HOW SUPPLIED

    Xigduo XR Oral Tab ER: 10-1000mg, 10-500mg, 5-1000mg, 5-500mg

    DOSAGE & INDICATIONS

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

    Individualize the dose based on efficacy and tolerability. In patients currently treated with dapagliflozin, initiate at the dose that contains metformin 500 mg with a similar total daily dose of dapagliflozin; increase the dose gradually to reduce the GI side effects due to metformin. In patients currently treated with metformin, initiate at the dose containing dapagliflozin 5 mg with a similar total daily dose of metformin. Patients taking an evening dose of metformin XR should skip their last dose before starting dapagliflozin; metformin. Patients already treated with dapagliflozin and metformin may switch to combination product using the same total daily doses of each component. Give dose PO once daily in the morning with food. In older patients, the initial and maintenance dose of metformin should be conservative due to the potential for decreased renal function; carefully assess renal function before dose selection. The maximum dose is metformin 2,000 mg/day and dapagliflozin 10 mg/day PO. Patients with volume depletion must have this corrected prior to initiation of dapagliflozin.

    MAXIMUM DOSAGE

    Adults

    Dapagliflozin 10 mg/day PO and metformin 2000 mg/day PO.

    Geriatric

    Dapagliflozin 10 mg/day PO and metformin 2000 mg/day PO.

    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

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

    Renal Impairment

    eGFR 60 mL/min/1.73 m2 or greater: No dosage adjustment needed.
    eGFR less than 60 mL/min/1.73 m2 or CrCl less than 60 mL/min: Do not use dapagliflozin; metformin in these patients. If during treatment in a patient with a previous eGFR 60 mL/min/1.73 m2 or above, the renal function is persistently reduced to an eGFR less than 60 mL/min/1.73 m2, discontinue dapagliflozin; metformin.
     
    Intermittent hemodialysis:
    Dapagliflozin; 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.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Do not cut, crush or chew the extended-release tablet; swallow whole.
    Administer once daily in the morning with food.
    Occasionally, the inactive ingredients will be eliminated in the feces as a soft, hydrated mass that may resemble the original tablet.

    STORAGE

    Xigduo XR:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Dapagliflozin; metformin is contraindicated in patients with a known history of a serious hypersensitivity to dapagliflozin or metformin. Hypersensitivity reactions, including urticaria, serious anaphylactic reactions, severe cutaneous reactions, and angioedema were reported in patients treated with dapagliflozin. Discontinue use of dapagliflozin; metformin if hypersensitivity reactions occur, and treat per standard of care; monitor until signs and symptoms resolve.
     
    Monitoring of glycemic control with urine glucose tests and the 1,5 Anhydroglucitol assay (1,5-AG assay) is not recommended in patients receiving dapagliflozin; metformin. Use of urine glucose tests will result in positive urine glucose tests and measurements of 1,5-AG are unreliable in patients taking dapagliflozin. Use alternative methods to monitor glycemic control.

    Diabetic ketoacidosis, type 1 diabetes mellitus

    The use of dapagliflozin; metformin is contraindicated in patients with diabetic ketoacidosis (DKA). This combination is also not intended for the treatment of type 1 diabetes mellitus. Both conditions require the use of insulin. Fatal cases of ketoacidosis have been reported in patients receiving dapagliflozin. In addition, the FDA has identified 73 cases of ketoacidosis in patients with type 1 or type 2 diabetes treated with SGLT2 inhibitors. All patients required emergency room visits or hospitalization to treat the ketoacidosis. Signs and symptoms at presentation were consistent with severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. However, the presence of ketoacidosis was not immediately recognized, and treatment was delayed because the presenting blood glucose levels were below those typically expected for DKA (often less than 250 mg/dL). Factors identified in some reports as having potentially triggered the ketoacidosis included infection, low carbohydrate diet or an overall reduction of caloric intake, reduction in dose of exogenous insulin or discontinuation of exogenous insulin, discontinuation of an oral insulin secretagogue, and alcohol use. The FDA is continuing to investigate this issue and is requiring manufacturers of SGLT2 inhibitors to conduct a required postmarketing study, including specialized follow-up to collect additional information for a period of 5 years. Before initiating an SGLT2 inhibitor, consider factors in the patients’ histories that may predispose them to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. In patients treated with an SGLT2 inhibitor, consider monitoring for ketoacidosis and temporarily discontinuing the drug in clinical situations known to predispose to ketoacidosis, such as prolonged fasting due to acute illness or surgery. Patients should report any signs of ketoacidosis and immediately seek medical attention if they experience symptoms such as difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue or sleepiness. Health care professionals should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing these signs or symptoms. If ketoacidosis is suspected, discontinue dapagliflozin; metformin and institute treatment, which may include insulin, fluids, and carbohydrate replacement.

    Acidemia, hypoxemia, lactic acidosis, metabolic acidosis

    Dapagliflozin; metformin is contraindicated in patients with acute or chronic metabolic acidosis. It should not be used in patients with 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 with increasing renal dysfunction. Certain medications used concomitantly with metformin may also increase the risk of lactic acidosis. Lactic acidosis is characterized by elevated blood lactate levels, acidemia, electrolyte disturbances, an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels more than 5 mcg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin is very low; in more than 20,000 patient-years exposure to metformin in clinical trials, there have been no reports of lactic acidosis and approximately 0.03 cases/1,000 patient-years have been estimated with post-marketing surveillance. A nested case-control study of 50,048 patients with type 2 diabetes mellitus demonstrated that during concurrent use of oral diabetes drugs, there were 6 identified cases of lactic acidosis. The crude incidence rate was 3.3 cases per 100,000 person-years in patients treated with metformin; it should be noted that all of the subjects had relevant comorbidities known to be risk factors for lactic acidosis. The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradycardia with more marked acidemia. The patient and the prescriber must be aware of such symptoms and the patient should be instructed to notify the physician immediately if they occur. If ketoacidosis or lactic acidosis is suspected, evaluation of the following parameters is necessary: serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate, pyruvate, and metformin levels. In addition, dapagliflozin; metformin must be stopped immediately and appropriate corrective measures initiated.

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

    According to the manufacturer, metformin should be used with caution in patients with congestive heart failure requiring pharmacologic treatment. However, a systematic review evaluating antidiabetic agents and outcomes in patients with heart failure and diabetes concluded that metformin is not associated with any measurable harm in patients with heart failure; in this analysis, metformin was associated with reduced mortality. It should be noted that in acute congestive heart failure characterized by acute hypoxia, lactic acidosis has occurred in patients taking metformin. To reduce the risk of lactic acidosis, metformin 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. If such events occur, discontinue dapagliflozin; metformin.

    Dialysis, hypovolemia, renal disease, renal failure, renal impairment

    Dapagliflozin; metformin is contraindicated in patients with renal failure or those with moderate to severe renal impairment, as defined by an estimated glomerular filtration rate (eGFR) below 60 mL/minute/1.73 m2 or CrCl below 60 mL/min, including patients with end stage renal failure on dialysis. Metformin is substantially eliminated by the kidney and the risk of lactic acidosis increases with the degree of intrinsic renal disease or impairment. The pharmacodynamic response to dapagliflozin declines with increasing severity of renal impairment. Before initiation of treatment and at least annually thereafter, obtain an estimated glomerular filtration rate (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 dapagliflozin; metformin whose eGFR persistently falls below 60 mL/minute/1.73 m2, discontinue treatment. Dapagliflozin increases serum creatinine and decreases eGFR; patients with hypovolemia or the elderly may be more susceptible to these changes. Renal function abnormalities can occur after initiating dapagliflozin. Renal impairment may also occur as a result of certain medical conditions such as cardiovascular collapse, acute heart attack, and septicemia. Acute kidney injury, some requiring hospitalization and dialysis, has been reported postmarketing; some reports involved patients younger than 65 years of age. The FDA has identified 101 confirmable cases of acute kidney injury, some requiring hospitalization and dialysis, with canagliflozin (73 patients) or dapagliflozin (28 patients) use during the time period from March 2013 to October 2015. There are likely additional cases. In approximately half of the cases, acute kidney injury occurred within 1 month of starting the drug, and most patients improved after drug discontinuation. Hospitalization for evaluation and management of acute kidney injury was necessary in 96 of the 101 cases, and 22 cases involved admission to an intensive care unit. Four deaths occurred during hospitalization, 2 of which were cardiac-related. Fifteen patients received dialysis. Of the 101 cases, 51 reported concomitant angiotensin converting enzyme (ACE) inhibitor use, 26 reported concomitant diuretic use, and 6 reported concomitant nonsteroidal anti-inflammatory drug (NSAID) use. A prior history of chronic kidney disease was reported in 10 of the 101 cases. Forty-five of the 101 cases reported a change in serum creatinine or eGFR at the time of diagnosis. Eleven patients did not recover, which included the 4 deaths noted previously. Three patients recovered with sequelae upon discontinuation. If acute kidney injury occurs, promptly discontinue the drug and treat the renal impairment. Consider factors that may predispose patients to acute kidney injury prior to starting them on dapagliflozin; metformin, including hypovolemia; chronic renal insufficiency; congestive heart failure; and concomitant medications such as diuretics, ACE inhibitors, angiotensin II receptor blockers (ARBs),and NSAIDs. Consider temporarily discontinuing dapagliflozin; metformin in any setting of reduced oral intake such as acute illness or fasting, or with fluid losses such as gastrointestinal illness or excessive heat exposure. 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.

    Dehydration, hypotension

    Dapagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating dapagliflozin; metformin. Patients at risk include those with dehydration or hypovolemia, particularly in patients with impaired renal function (eGFR < 60 ml/min/1.73 m2), the elderly, patients receiving diuretics or other medications that interfere with the renin-angiotensin-aldosterone (RAA) system (e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Volume status should be assessed and corrected before initiating dapagliflozin; metformin in patients with one or more of these characteristics. Monitor for signs and symptoms after initiating therapy. To reduce the risk of lactic acidosis from metformin, dapagliflozin; metformin should be promptly withheld in the presence of any condition associated with significant dehydration.

    Bladder cancer

    Dapagliflozin; metformin should not be used in patients with active bladder cancer. In patients with prior history of bladder cancer, consider the benefits of glycemic control versus unknown risks for cancer recurrence, as data is insufficient to determine whether dapagliflozin has an effect on pre-existing bladder tumors. Across 22 clinical studies, newly diagnosed cases of bladder cancer were reported in 10/6045 patients (0.17%) treated with dapagliflozin and 1/3512 patients (0.03%) treated with placebo or comparator. After excluding patients in whom exposure to study drug was < 1 year at the time of diagnosis of bladder cancer, there were 4 cases with dapagliflozin and no cases with placebo or comparator. Bladder cancer risk factors and hematuria (a potential indicator of preexisting tumors) were balanced between treatment arms at baseline. There were too few cases to determine whether the emergence of these events is related to dapagliflozin.

    Alcoholism, ethanol ingestion, ethanol intoxication, hepatic disease

    Metformin administration increases the risk for lactic acidosis. Since the liver is important for clearing accumulated lactic acid, metformin is not recommended in patients with clinical or laboratory evidence of 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. Patients should be warned against excessive ethanol ingestion (ethanol intoxication) while taking dapagliflozin; metformin due to the increased risk for lactic acidosis. Those with ethanol intoxication are also particularly susceptible to hypoglycemic effects of oral antidiabetic agents. Dapagliflozin; metformin use should be avoided by those patients with alcoholism.

    Balanitis, pyelonephritis, vaginitis

    In December 2015 the FDA required manufacturers of sodium-glucose co-transporter 2 (SGLT2) inhibitors to update the prescribing information to include warnings of serious urinary tract infections, including urosepsis and pyelonephritis. The FDA has identified 19 cases of urosepsis reported with the SGLT2 inhibitors (10 patients were receiving canagliflozin and 9 patients were receiving dapagliflozin). All cases resulted in hospitalization. No deaths were reported. Patients should be told to report any signs of urinary tract infection and seek medical attention if they experience symptoms such as a feeling of burning when urinating or the need to urinate often or right away, pain in the lower part of the stomach area or pelvis, fever, or blood in the urine. If urinary tract infection is suspected, treat promptly if indicated. Use dapagliflozin; metformin cautiously in patients with a history of genital fungal infection, including vaginitis or balanitis, and in uncircumcised males since these patients were more likely to develop genital mycotic infections during treatment with dapagliflozin. Monitor and treat appropriately.

    Diarrhea, vomiting

    Gastrointestinal side effects are common during metformin initiation. However, once a patient is stabilized on any dose of metformin, GI symptoms are unlikely to be drug related. Later occurrence of GI symptoms may be due to a change in clinical status and may increase the risk of lactic acidosis or other serious disease. Patients stable on metformin therapy who complain of an increase in GI symptoms should undergo laboratory investigation to determine the etiology of the GI symptoms. These include, but are not limited to, diarrhea and nausea/vomiting. Furthermore, withholding metformin 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 gastrointestinal symptoms occurs while taking dapagliflozin; metformin; patients should also be advised to monitor their blood glucose concentrations more frequently.

    Burns, fever, infection, sepsis, surgery, trauma

    To reduce the risk of lactic acidosis, dapagliflozin; metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Metformin 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 dapagliflozin; metformin and may require the drug be withheld.

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

    Delayed stomach emptying may alter blood glucose control; monitor patients with diarrhea, gastroparesis, GI obstruction, ileus, or vomiting carefully. 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. 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 while receiving dapagliflozin; metformin. Insulin and insulin secretagogues are also known to cause hypoglycemia. Dapagliflozin can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with dapagliflozin; metformin.

    Pernicious anemia

    Metformin may result in suboptimal vitamin B12 absorption, possibly due to interference with the B12-intrinsic factor complex. 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—3.87) as did taking metformin for >= 3 years (OR 2.39, 95% CI 1.46—3.91). Regular measurement of hematologic parameters is recommended in all patients on chronic dapagliflozin; metformin treatment. For those patients with inadequate vitamin B12 or calcium intake or absorption who appear to be predisposed to subnormal vitamin B12 concentrations, monitoring of serum vitamin B12 concentrations are recommended every 2—3 years.

    Radiographic contrast administration

    Administration of intravascular iodinated radiographic contrast in patients taking metformin has led to an acute decrease in renal function and an increased risk for lactic acidosis. Discontinue dapagliflozin; metformin at the time of or before iodinated radiographic contrast administration 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 estimated glomerular filtration rate (eGFR) 48 hours after the imaging procedure; restart dapagliflozin; metformin if renal function is stable.

    Hypercholesterolemia

    Dose-related increases in LDL-C occur with dapagliflozin, and these changes may require treatment or adjustment of previous therapy in patients with pre-existing hypercholesterolemia. Monitor LDL-C and treat per standard of care after initiating dapagliflozin; metformin therapy.

    Geriatric

    Use dapagliflozin; metformin with caution in geriatric patients. In particular, treatment of the geriatric patient should be accompanied by careful monitoring of renal function and volume status. An estimated glomerular filtration rate (eGFR) should be obtained before initiation of dapagliflozin; metformin. Metformin treatment should not be initiated in a geriatric patient unless assessment of renal function determines that renal function is normal or only mild impairment is present. Before initiating dapagliflozin; metformin, also assess serum potassium, and volume status, and correct hypovolemia. The risk of lactic acidosis from metformin increases with the degree of renal dysfunction and the patient's age. Metformin is substantially excreted by the kidney and the risk of adverse reactions is greater in geriatric patients with reduced renal function. Geriatric patients receiving dapagliflozin also experienced a higher incidence of adverse reactions related to reduced intravascular volume (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration) compared to younger adults. Geriatric patients may also have an increased risk for hyperkalemia. Extra care should be taken with dose selection and titration. Assess renal function at least annually once therapy is initiated; geriatric patients should have renal function assessed more frequently. Dapagliflozin; metformin should be discontinued if evidence of moderate to severe renal impairment is present. 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).

    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. There are no adequate and well-controlled studies of dapagliflozin; metformin use during human pregnancy. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. The potential risks of dapagliflozin to human kidney development are of concern. When dapagliflozin was administered to juvenile rats during periods of animal development that correspond to the late second and third trimester of human development, increased incidence and/or severity of renal pelvic and tubular dilatation were evident at the lowest tested dose which was approximately 15 times human clinical exposure from a 10 mg dose. When dapagliflozin was studied in rabbits during intervals coinciding with the first trimester period of organogenesis in humans, no developmental toxicities were observed at any dose tested.

    58334]58334
    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 births in 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 those exposed in utero 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. 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 1or 2 diabetes mellitus, and, if diet therapy alone is not successful, for those patients with gestational diabetes.

    Breast-feeding

    There is no information regarding the presence of dapagliflozin; metformin in human milk, the effects on breast-feeding infants, or the effects on milk production. Since dapagliflozin is present in the milk of lactating rats and human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Due to the potential for serious adverse reactions in a breast-feeing infant, breast-feeding during use of the combination of dapagliflozin; metformin is not recommended. Some publications have suggested that metformin monotherapy may be an option. 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 for 6 months does not affect growth, motor, or social development in the infant; 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. While the manufacturers of metformin recommend that a decision should be made to discontinue breast-feeding or discontinue the drug, the results of these studies indicate that maternal ingestion of metformin during breast-feeding is probably safe to the infant. If patients elect to continue metformin monotherapy while breast-feeding, the mother should be aware of the potential risks to the infant. If metformin is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Other oral hypoglycemics may be considered. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected.. 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. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
     

    Children, infants, neonates

    The safety and efficacy of dapagliflozin; metformin have not been established in adolescents and children < 18 years of age. There is no known indication for the use of this drug combination in infants or neonates.

    ADVERSE REACTIONS

    Severe

    renal failure (unspecified) / Delayed / 0-1.0
    megaloblastic anemia / Delayed / 0-1.0
    angioedema / Rapid / 0.3-0.3
    anaphylactoid reactions / Rapid / 0.3-0.3
    lactic acidosis / Delayed / Incidence not known
    bone fractures / Delayed / Incidence not known
    diabetic ketoacidosis / Delayed / Incidence not known

    Moderate

    vaginitis / Delayed / 9.3-9.4
    candidiasis / Delayed / 3.6-9.4
    vitamin B12 deficiency / Delayed / 7.0-7.0
    cystitis / Delayed / 5.5-6.1
    prostatitis / Delayed / 5.5-6.1
    palpitations / Early / 1.0-5.0
    chest pain (unspecified) / Early / 1.0-5.0
    balanitis / Delayed / 3.6-4.3
    constipation / Delayed / 1.9-2.9
    hyperlipidemia / Delayed / 0-2.7
    hypercholesterolemia / Delayed / 1.5-2.7
    hyperphosphatemia / Delayed / 1.7-1.7
    hypoglycemia / Early / 0.7-1.5
    hypovolemia / Early / 0.6-1.1
    secondary malignancy / Delayed / 0-0.2
    metabolic acidosis / Delayed / Incidence not known
    orthostatic hypotension / Delayed / Incidence not known
    dehydration / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    hepatitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known

    Mild

    vomiting / Early / 6.5-25.5
    flatulence / Early / 1.0-12.1
    dyspepsia / Early / 1.0-7.1
    abdominal pain / Early / 1.0-6.4
    pharyngitis / Delayed / 5.2-6.3
    diarrhea / Early / 4.2-5.9
    headache / Early / 3.3-5.4
    myalgia / Early / 1.0-5.0
    malaise / Early / 1.0-5.0
    flushing / Rapid / 1.0-5.0
    hyperhidrosis / Delayed / 1.0-5.0
    anorexia / Delayed / 1.0-5.0
    dysgeusia / Early / 1.0-5.0
    metallic taste / Early / 1.0-5.0
    chills / Rapid / 1.0-5.0
    infection / Delayed / 0-5.0
    influenza / Delayed / 2.6-4.1
    nausea / Early / 2.6-3.9
    back pain / Delayed / 2.5-3.4
    dizziness / Early / 1.8-3.2
    cough / Delayed / 1.4-3.2
    polyuria / Early / 2.4-2.6
    increased urinary frequency / Early / 2.4-2.6
    urticaria / Rapid / 0-1.0
    diuresis / Early / Incidence not known
    rash (unspecified) / Early / 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 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 pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and 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.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and 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.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and 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.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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. (Minor) Carbonic anhydrase inhibitors may alter blood sugar. Both hyperglycemia and hypoglycemia have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus who are receiving antidiabetic agents. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Acrivastine; Pseudoephedrine: (Moderate) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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 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. (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 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. (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 (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) When dapagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating dapagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, dapagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of dapagliflozin by improving insulin sensitivity.ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Amiloride; Hydrochlorothiazide, HCTZ: (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. (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.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and 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.
    Amlodipine; Benazepril: (Moderate) 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 (i.e., captopril or enalapril) are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (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 (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 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. (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. (Moderate) When dapagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating dapagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, dapagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of dapagliflozin by improving insulin sensitivity.ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (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 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. (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. (Moderate) When dapagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating dapagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, dapagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of dapagliflozin by improving insulin sensitivity.ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Amlodipine; Olmesartan: (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) When dapagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating dapagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, dapagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of dapagliflozin by improving insulin sensitivity.ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Amlodipine; Telmisartan: (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) When dapagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating dapagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, dapagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of dapagliflozin by improving insulin sensitivity.ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Amlodipine; Valsartan: (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) When dapagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating dapagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, dapagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of dapagliflozin by improving insulin sensitivity.ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, 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: (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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    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.
    Amphetamine; Dextroamphetamine: (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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    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. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    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 (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) When dapagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating dapagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, dapagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of dapagliflozin by improving insulin sensitivity.ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Angiotensin-converting enzyme inhibitors: (Moderate) 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 (i.e., captopril or enalapril) are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (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.
    Aripiprazole: (Moderate) Patients taking dapagliflozin 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.
    Articaine; Epinephrine: (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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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.
    Asenapine: (Moderate) Patients taking dapagliflozin 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.
    Aspirin, ASA: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and 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.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and 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.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and 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.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and 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.
    Aspirin, ASA; Carisoprodol: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and 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.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and 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.
    Aspirin, ASA; Dipyridamole: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and 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.
    Aspirin, ASA; Omeprazole: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and 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.
    Aspirin, ASA; Oxycodone: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and 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.
    Aspirin, ASA; Pravastatin: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and 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.
    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. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    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. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Atenolol: (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 pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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.
    Atenolol; Chlorthalidone: (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 pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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. (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. (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.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and 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.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) The metabolism of dapagliflozin is primarily mediated by UGT1A9. Coadministration of dapagliflozin with phenobarbital, a UGT enzyme inducer, may theoretically decrease serum concentrations of dapagliflozin leading to decreased efficacy of dapagliflozin. Monitor for changes in blood glucose control.
    atypical antipsychotic: (Moderate) Patients taking dapagliflozin 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. (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.
    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. (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.
    Azelastine; Fluticasone: (Moderate) Systemic corticosteroids increase blood glucose levels; a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent. Blood lactate concentrations and the lactate to pyruvate ratio increased when metformin was coadministered with corticosteroids (e.g., hydrocortisone). Elevated lactic acid concentrations are associated with an increased risk of lactic acidosis, so patients on metformin concurrently with systemic steroids should be monitored closely.
    Azilsartan: (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) When dapagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating dapagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, dapagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of dapagliflozin by improving insulin sensitivity.ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Azilsartan; Chlorthalidone: (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 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. (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. (Moderate) When dapagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating dapagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, dapagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of dapagliflozin by improving insulin sensitivity.ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    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.
    Beclomethasone: (Moderate) Systemic corticosteroids increase blood glucose levels; a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent. Blood lactate concentrations and the lactate to pyruvate ratio increased when metformin was coadministered with corticosteroids (e.g., hydrocortisone). Elevated lactic acid concentrations are associated with an increased risk of lactic acidosis, so patients on metformin concurrently with systemic steroids should be monitored closely.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) The metabolism of dapagliflozin is primarily mediated by UGT1A9. Coadministration of dapagliflozin with phenobarbital, a UGT enzyme inducer, may theoretically decrease serum concentrations of dapagliflozin leading to decreased efficacy of dapagliflozin. Monitor for changes in blood glucose control.
    Benazepril: (Moderate) 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 (i.e., captopril or enalapril) are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (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) 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 (i.e., captopril or enalapril) are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (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 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. (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 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 pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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. (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. (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.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and 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.
    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. (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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Beta-adrenergic blockers: (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 pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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.
    Beta-blockers: (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.
    Betamethasone: (Moderate) Systemic corticosteroids increase blood glucose levels; a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent. Blood lactate concentrations and the lactate to pyruvate ratio increased when metformin was coadministered with corticosteroids (e.g., hydrocortisone). Elevated lactic acid concentrations are associated with an increased risk of lactic acidosis, so patients on metformin concurrently with systemic steroids should be monitored closely.
    Betaxolol: (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 pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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.
    Bismuth Subsalicylate: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and 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.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and 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.
    Bisoprolol: (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 pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (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 pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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. (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. (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) Patients on antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose concentrations; medication dosage adjustment may be needed. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in patients with diabetes receiving oral hypoglycemics.
    Brexpiprazole: (Moderate) Patients taking dapagliflozin 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.
    Brimonidine; Timolol: (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 pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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.
    Brompheniramine; Carbetapentane; Phenylephrine: (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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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.
    Budesonide: (Moderate) Systemic corticosteroids increase blood glucose levels; a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent. Blood lactate concentrations and the lactate to pyruvate ratio increased when metformin was coadministered with corticosteroids (e.g., hydrocortisone). Elevated lactic acid concentrations are associated with an increased risk of lactic acidosis, so patients on metformin concurrently with systemic steroids should be monitored closely.
    Budesonide; Formoterol: (Moderate) Systemic corticosteroids increase blood glucose levels; a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent. Blood lactate concentrations and the lactate to pyruvate ratio increased when metformin was coadministered with corticosteroids (e.g., hydrocortisone). Elevated lactic acid concentrations are associated with an increased risk of lactic acidosis, so patients on metformin concurrently with systemic steroids should be monitored closely.
    Bumetanide: (Moderate) Loop diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. Patients receiving dapagliflozin should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. (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 (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) When dapagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating dapagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, dapagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of dapagliflozin by improving insulin sensitivity.ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Candesartan; Hydrochlorothiazide, HCTZ: (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 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. (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. (Moderate) When dapagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating dapagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, dapagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of dapagliflozin by improving insulin sensitivity.ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Captopril: (Moderate) 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 (i.e., captopril or enalapril) are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (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) 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 (i.e., captopril or enalapril) are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (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 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. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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.
    Cariprazine: (Moderate) Patients taking dapagliflozin 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.
    Carteolol: (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 pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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.
    Carvedilol: (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 pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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.
    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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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 SGLT2 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 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. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) The phenothiazines, especially chlorpromazine, may increase blood glucose concentrations. Patients should be closely monitored for worsening glycemic control.
    Chlorthalidone: (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. (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. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (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. (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.
    Choline Salicylate; Magnesium Salicylate: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and 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.
    Chromium: (Moderate) Chromium dietary supplements may lower blood glucose. As part of the glucose tolerance factor molecule, chromium appears to facilitate the binding of insulin to insulin receptors in tissues and to aid in glucose metabolism. Because blood glucose may be lowered by the use of chromium, patients who are on antidiabetic agents may need dose adjustments. Close monitoring of blood glucose is recommended.
    Ciclesonide: (Moderate) Systemic corticosteroids increase blood glucose levels; a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent. Blood lactate concentrations and the lactate to pyruvate ratio increased when metformin was coadministered with corticosteroids (e.g., hydrocortisone). Elevated lactic acid concentrations are associated with an increased risk of lactic acidosis, so patients on metformin concurrently with systemic steroids should be monitored closely.
    Cimetidine: (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 in patients who receive cisapride concomitantly. (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 the sodium-glucose co-transporter 2 (SGLT2) inhibitors, 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. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Clozapine: (Moderate) Patients taking dapagliflozin 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.
    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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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) 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. (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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.
    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. (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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.
    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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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; a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent. Blood lactate concentrations and the lactate to pyruvate ratio increased when metformin was coadministered with corticosteroids (e.g., hydrocortisone). Elevated lactic acid concentrations are associated with an increased risk of lactic acidosis, so patients on metformin concurrently with systemic steroids should be monitored closely.
    Corticotropin, ACTH: (Moderate) Systemic corticosteroids increase blood glucose levels; a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent. Blood lactate concentrations and the lactate to pyruvate ratio increased when metformin was coadministered with corticosteroids (e.g., hydrocortisone). Elevated lactic acid concentrations are associated with an increased risk of lactic acidosis, so patients on metformin concurrently with systemic steroids should be monitored closely.
    Cortisone: (Moderate) Systemic corticosteroids increase blood glucose levels; a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent. Blood lactate concentrations and the lactate to pyruvate ratio increased when metformin was coadministered with corticosteroids (e.g., hydrocortisone). Elevated lactic acid concentrations are associated with an increased risk of lactic acidosis, so patients on metformin concurrently with systemic steroids should be monitored closely.
    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) Both cyclosporine and tacrolimus have been reported to cause hyperglycemia. Tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Both of these drugs may have direct beta-cell toxicity; the effects from cyclosporine may be dose-related. Patients should be monitored for changes in glycemic control if therapy with either of these immunosuppressant drugs is initiated in patients receiving dapagliflozin. (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. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    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. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    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. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Deflazacort: (Moderate) Systemic corticosteroids increase blood glucose levels; a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent. Blood lactate concentrations and the lactate to pyruvate ratio increased when metformin was coadministered with corticosteroids (e.g., hydrocortisone). Elevated lactic acid concentrations are associated with an increased risk of lactic acidosis, so patients on metformin concurrently with systemic steroids should be monitored closely.
    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. (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued
    Desloratadine; Pseudoephedrine: (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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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.
    Dexamethasone: (Moderate) Systemic corticosteroids increase blood glucose levels; a potential pharmacodynamic interaction exists between corticosteroids and all antidiabetic agents. Diabetic patients who are administered systemic corticosteroid therapy may require an adjustment in the dosing of the antidiabetic agent. Blood lactate concentrations and the lactate to pyruvate ratio increased when metformin was coadministered with corticosteroids (e.g., hydrocortisone). Elevated lactic acid concentrations are associated with an increased risk of lactic acidosis, so patients on metformin concurrently with systemic steroids should be monitored closely.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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.
    Dextroamphetamine: (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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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. (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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    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. (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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 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 pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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.
    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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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) 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 (i.e., captopril or enalapril) are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (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) 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 (i.e., captopril or enalapril) are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (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) 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 (i.e., captopril or enalapril) are administered concomitantly. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (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 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. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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) 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. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (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 (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) When dapagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating dapagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, dapagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of dapagliflozin by improving insulin sensitivity.ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Eprosartan; Hydrochlorothiazide, HCTZ: (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 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. (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. (Moderate) When dapagliflozin is initiated in patients already receiving angiotensin II receptor antagonists (ARBs), symptomatic hypotension can occur. Patients with impaired renal function, low systolic blood pressure, or who are elderly may be at a greater risk. Before initiating dapagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. In addition, dapagliflozin can lead to hyperkalemia. Patients with renal impairment who are taking medications that interfere with potassium excretion, such as medications that interfere with the renin-angiotensin-aldosterone (RAA) system, are more likely to develop hyperkalemia. Monitor serum potassium levels periodically. ARBs may enhance the hypoglycemic effects of dapagliflozin by improving insulin sensitivity.ARBs have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in volume status, renal function, and glycemic control.
    Erythromycin; Sulfisoxazole: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. 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. (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 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 pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, 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.
    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. (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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.
    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. (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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.
    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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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. (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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.
    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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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.
    Ethacrynic Acid: (Moderate) Loop diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. Patients receiving dapagliflozin should be monitored for changes in blood glucose control if such diuretics are added or deleted. Dosage adjustments may be necessary. (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. (Minor) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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.
    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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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) Estrogens can impair glucose tolerance and may decrease the hypoglycemic effects of antidiabetic agents. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of concomitant progestin use may influence the significance of this effect. 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. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents 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. (Minor) Pheny