XIGDUO XR 10 MG-1,000 MG TAB

Uses Dosage and Administration Cautions Drug Interactions

Uses

Diabetes Mellitus

Dapagliflozin propanediol is used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Dapagliflozin is also used in combination with other antidiabetic agents (e.g., metformin, a sulfonylurea, a peroxisome proliferator-activated receptor_γ [PPAR_γ] agonist [thiazolidinedione], a dipeptidyl peptidase-4 [DPP-4] inhibitor), or insulin as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control.

Dapagliflozin should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Dapagliflozin Monotherapy

When given as monotherapy for the management of type 2 diabetes mellitus, dapagliflozin improves glycemic control compared with placebo as evidenced by reductions in glycosylated hemoglobin (hemoglobin A_1c; HbA_1c) and in fasting and 2-hour postprandial plasma glucose concentrations. Efficacy of dapagliflozin as monotherapy has been established in 2 double-blind, placebo-controlled studies of 24-weeks' duration in 840 treatment-naive patients with type 2 diabetes mellitus and baseline HbA_1c concentrations of 7-10%. In the first study, HbA_1c was reduced by 0.8 or 0.9% in patients receiving dapagliflozin 5 or 10 mg once daily, respectively, compared with a decrease of 0.2% in those receiving placebo. In patients who received dapagliflozin 5 or 10 mg, approximately 44 or 51%, respectively, had HbA_1c reductions to less than 7%, compared with approximately 32% of patients receiving placebo. In the second study, mean HbA_1c reduction at week 24 was 0.68, 0.72, or 0.82% in patients receiving 1, 2.5, or 5 mg of dapagliflozin, respectively, compared with an increase of 0.02% in those receiving placebo.

Combination Therapy

When given in combination with one or more oral antidiabetic agents (e.g., metformin, a sulfonylurea, a thiazolidinedione, a DPP-4 inhibitor) or insulin, dapagliflozin improves glycemic control compared with monotherapy with these drugs and generally is associated with reductions in body weight and systolic blood pressure. Dapagliflozin generally is well tolerated, although genital mycotic infections appear to be more common with dapagliflozin than with other antidiabetic therapy.

Efficacy of dapagliflozin in combination with other antidiabetic agents for the management of type 2 diabetes mellitus is supported by results from several randomized, active- or placebo-controlled studies in patients receiving dapagliflozin with metformin, a sulfonylurea, metformin and a sulfonylurea, a thiazolidinedione, a DPP-4 inhibitor, or insulin. In these studies, initial combined therapy with dapagliflozin (5 or 10 mg once daily) and one or more antidiabetic drugs or addition of dapagliflozin to existing therapy improved glycemic control as evidenced by reductions in HbA_1c, fasting plasma glucose, and 2-hour postprandial plasma glucose concentrations; combined therapy also had beneficial effects on weight reduction and blood pressure compared with placebo and/or monotherapy.

In two 24-week studies in treatment-naive patients with baseline mean HbA_1c concentrations of 9-9.2%, the combination of extended-release metformin hydrochloride (up to 2 g daily) and dapagliflozin 5 or 10 mg once daily resulted in a reduction of 2.1 or 2%, respectively, in HbA_1c compared with a reduction of 1.5, 1.2 or 1.4% in HbA_1c with dapagliflozin 10 mg, dapagliflozin 5 mg, or extended-release metformin hydrochloride alone, respectively. Dapagliflozin 10 mg once daily was noninferior to metformin in reducing HbA_1c, and superior in reducing fasting plasma glucose; dapagliflozin in this dosage also was associated with substantially greater weight loss than metformin monotherapy.

In a 24-week study in patients with HbA_1c concentrations of 7-10% while receiving metformin hydrochloride (dosage of at least 1.5 g daily), the addition of dapagliflozin 5 or 10 mg resulted in a reduction of 0.7 or 0.8%, respectively, in HbA_1c compared with a 0.3% HbA_1c reduction with placebo. In these patients, add-on therapy with dapagliflozin 5 or 10 mg resulted in HbA_1c reductions to less than 7% in 37.5 or 40.6% of patients, respectively, compared with 25.9% of patients receiving add-on placebo. In a 78-week extension of this study, add-on dapagliflozin was associated with sustained reductions in HbA_1c, fasting plasma glucose, and body weight.

In a study in patients with HbA_1c concentrations of approximately 6.5-10% while receiving metformin hydrochloride (dosage of at least 1.5 g daily), add-on therapy with dapagliflozin (titrated to 10 mg once daily) was noninferior to add-on glipizide (titrated to 20 mg once daily) in reducing HbA_1c after 52 weeks of therapy. In addition, weight loss with add-on dapagliflozin therapy (3.2 kg) was superior to that with add-on glipizide therapy (1.4 kg).

In a 24-week study in patients who had inadequate glycemic control (HbA_1c concentration of 7-10%) while receiving a sulfonylurea antidiabetic agent (glimepiride), add-on therapy with dapagliflozin 2.5, 5, or 10 mg once daily resulted in a reduction of approximately 0.6, 0.6, or 0.8%, respectively, in HbA_1c compared with a reduction of approximately 0.1% with add-on placebo. In a 24-week study in patients who had inadequate glycemic control (HbA_1c concentration of 7-10.5%) on pioglitazone (30 or 45 mg daily), the addition of dapagliflozin 5 or 10 mg resulted in a reduction of 0.8 or 1%, respectively, in HbA_1c compared with a reduction of 0.4% with add-on placebo. Dapagliflozin also improved postprandial and fasting plasma glucose concentrations as well as reducing body weight and systolic blood pressure. In a 24-week study in patients who were treatment naive or who had inadequate glycemic control (HbA_1c concentration of 7-10%) while receiving sitagliptin (100 mg once daily) with or without metformin hydrochloride (dosage of at least 1.5 g daily), addition of dapagliflozin 10 mg once daily reduced HbA_1c by 0.45%, while patients receiving add-on placebo experienced no appreciable change. Patients receiving dapagliflozin add-on therapy also showed improved fasting plasma glucose and reduced body weight.

In a 24-week study in patients who had inadequate glycemic control (HbA_1c concentration 7-10.5%) while receiving immediate- or extended-release metformin hydrochloride (at least 1.5 g daily) plus a sulfonylurea antidiabetic agent at the maximum tolerated dosage (and at least 50% of the maximum dosage), add-on therapy with dapagliflozin 10 mg once daily was associated with a 0.7% reduction in HbA_1c compared with add-on placebo at 24 weeks. Add-on dapagliflozin therapy also was associated with reductions in fasting plasma glucose and body weight at week 24, and systolic blood pressure at week 8 compared with placebo.

In a 24-week study examining the effects of dapagliflozin on total body weight in patients with inadequate glycemic control on metformin hydrochloride, addition of dapagliflozin 10 mg once daily reduced total body weight by 2.96 kg compared with a reduction of 0.88 kg in those receiving add-on placebo.

Efficacy of dapagliflozin as add-on therapy to insulin in the management of type 2 diabetes mellitus in patients who have inadequate glycemic control (HbA_1c concentration of 7.5-10.5%) with insulin is supported by results of a 24-week, randomized, placebo-controlled study. In this study, addition of dapagliflozin (5 or 10 mg daily) to existing stable therapy with insulin (mean daily dosage of at least 30 units) with or without up to 2 additional oral antidiabetic agents resulted in improvements in HbA_1c, fasting plasma glucose, 2-hour postprandial plasma glucose concentrations, and body weight. In patients who received dapagliflozin 5 or 10 mg as add-on to insulin therapy with or without 1 or 2 additional antidiabetic agents, addition of dapagliflozin 5 or 10 mg reduced HbA_1c by 0.8 or 0.9%, respectively, compared with a 0.3% reduction in those receiving add-on placebo. During extended treatment and follow-up in this study, reductions in HbA_1c, body weight, and insulin dosage were maintained for 104 weeks with dapagliflozin therapy.

In a 12-week randomized, double-blind study in patients receiving insulin with or without up to 2 oral antidiabetic agents, HbA_1c was reduced by 0.7 or 0.78% with addition of dapagliflozin 10 or 20 mg once daily, respectively, to existing therapy compared with addition of placebo. The mean change from baseline in body weight at the end of the study was 4.5, 4.3, or 1.9 kg with dapagliflozin 10 mg, 20 mg, or placebo, respectively. Patients receiving add-on dapagliflozin 10 or 20 mg had mean reductions in insulin dosage from baseline of 1.4 and 0.8 units, respectively, at the end of the study compared with a mean increase from baseline of 1.7 units in those receiving add-on placebo.

Dosage and Administration

Administration

Dapagliflozin propanediol is administered orally once daily in the morning, with or without food.

If a dose is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule. If the missed dose is not remembered until it is almost time for the next dose, the missed dose should be skipped and the regular schedule resumed; the dose should not be doubled to replace a missed dose.

Dosage

Dosage of dapagliflozin propanediol is expressed in terms of dapagliflozin.

The recommended initial dosage of dapagliflozin for the management of type 2 diabetes mellitus in adults is 5 mg once daily. If well tolerated, the dosage may be increased to 10 mg once daily in patients who require additional glycemic control.

Special Populations

No dosage adjustment is necessary in patients with mild, moderate, or severe hepatic impairment.

No dosage adjustment is necessary in patients with mild renal impairment (estimated glomerular filtration rate [eGFR] of at least 60 mL/minute per 1.73 m).

Dapagliflozin should not be initiated in patients with an eGFR of less than 60 mL/minute per 1.73 m.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.) Continued use of dapagliflozin is not recommended in patients with an eGFR persistently between 30 and less than 60 mL/minute per 1.73 m. The drug is contraindicated in patients with an eGFR of less than 30 mL/minute per 1.73 m.

No dosage adjustment is necessary based solely on age. In addition, dosage adjustment is not recommended based on gender, race, or body weight.

Cautions

Contraindications

History of serious hypersensitivity reaction to dapagliflozin propanediol.

Severe renal impairment (estimated glomerular filtration rate [eGFR] less than 30 mL/minute per 1.73 m), end-stage renal disease, or on dialysis.

Warnings/Precautions

Ketoacidosis

Use of sodium glucose cotransporter 2 (SGLT2) inhibitors (canagliflozin, dapagliflozin, empagliflozin) in patients with type 2 diabetes mellitus may lead to ketoacidosis requiring hospitalization. Ketoacidosis associated with use of SGLT2 inhibitors may be present without markedly elevated blood glucose concentrations (e.g., less than 250 mg/dL).

FDA identified 73 cases of acidosis (reported as diabetic ketoacidosis [DKA], ketoacidosis, or ketosis) associated with SGLT2 inhibitor use in the FDA Adverse Event Reporting System (FAERS) between March 2013 and May 2015. DKA had an atypical presentation in most of the reported cases in that type 2 diabetes mellitus was noted as the indication for the drug, and glucose concentrations were only slightly elevated (median: 211 mg/dL); type 1 diabetes mellitus was named as the indication in a few cases, and in some reports the indication was not specified. The median time to onset of symptoms of acidosis following initiation or increase in dosage of the SGLT2 inhibitor was 43 days (range: 1-365 days). No trend demonstrating a relationship between the dosage of an SGLT2 inhibitor and the risk of ketoacidosis was identified. In all reported episodes, a diagnosis of DKA or ketoacidosis was made by the clinician and hospitalization or treatment in an emergency department was warranted. In most cases, at least 1 diagnostic laboratory criterion suggestive of ketoacidosis (e.g., high anion gap metabolic acidosis, ketonemia, reduced serum bicarbonate) was reported. Potential factors for the development of ketoacidosis with SGLT2 inhibitor therapy identified in the 73 cases included infection, low carbohydrate diet or reduced caloric intake (due to illness or surgery), pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes mellitus, history of pancreatitis, pancreatic surgery), reduced dosage or discontinuance of insulin, discontinuance of an oral insulin secretagogue, and alcohol use.

Prior to initiating therapy with an SGLT2 inhibitor, clinicians should consider patient factors that may predispose the patient to ketoacidosis such as pancreatic insulin deficiency from any cause, reduced caloric intake, and alcohol abuse. Clinicians should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing signs or symptoms of acidosis while receiving SGLT2 inhibitors, regardless of the patient's blood glucose concentration. Additionally, clinicians should consider monitoring for ketoacidosis and temporarily discontinuing therapy with an SGLT2 inhibitor in clinical situations known to predispose individuals to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery). If acidosis is confirmed, the SGLT2 inhibitor should be discontinued and appropriate treatment initiated to correct the acidosis; glucose concentrations should be monitored appropriately. In addition, supportive medical treatment should be instituted to treat and correct factors that may have precipitated or contributed to the metabolic acidosis. Euglycemic DKA associated with SGLT2 inhibitors may be detected and potentially prevented by having patients monitor urine and/or plasma ketone levels if they feel unwell, regardless of ambient glucose concentrations. Clinicians should inform patients and caregivers of the signs and symptoms of ketoacidosis (e.g., tachypnea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy, mental status changes) and instruct patients to discontinue the SGLT2 inhibitor and immediately seek medical attention should they experience such signs or symptoms.

Hypotension

Dapagliflozin may cause intravascular volume contraction. Following initiation of dapagliflozin, symptomatic hypotension can occur, particularly in patients with impaired renal function (eGFR less than 60 mL/minute per 1.73 m), geriatric patients, or patients receiving loop diuretics.(See Drug Interactions: Diuretics.) Prior to initiating dapagliflozin in such patients, intravascular volume status should be assessed and corrected. Patients should be monitored for signs and symptoms of hypotension after initiating dapagliflozin therapy.

Renal Effects

Dapagliflozin causes intravascular volume contraction and can cause renal impairment. Dapagliflozin may increase serum creatinine concentration and decrease eGFR; geriatric patients and patients with impaired renal function may be more susceptible to these changes. Adverse reactions related to renal function can occur following initiation of the drug. Renal function should be evaluated prior to initiation of dapagliflozin and periodically thereafter.

FDA identified 101 cases of acute kidney injury associated with canagliflozin or dapagliflozin therapy in FAERS between March 2013 and October 2015. Hospitalization for evaluation and management of kidney injury was warranted in most cases, and some cases required admission to an intensive care unit and dialysis. In approximately half of the cases, onset of acute kidney injury occurred within 1 month or less of initiating canagliflozin or dapagliflozin therapy, and most patients' kidney function improved after stopping the drug. However, kidney injury may not be fully reversible in some situations and has led to death in some patients.

Prior to initiating dapagliflozin therapy, clinicians should consider patient factors that may predispose the patient to acute kidney injury, including hypovolemia, chronic renal insufficiency, heart failure, and concomitant medications (e.g., diuretics, angiotensin converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory agents [NSAIAs]). Clinicians should consider temporarily discontinuing dapagliflozin in any setting of reduced oral intake (e.g., acute illness, fasting) or fluid losses (e.g., GI illness, excessive heat exposure). Patients should be monitored for acute kidney injury and the drug should be discontinued and appropriate treatment should be initiated if such injury occurs.

Concomitant Therapy with Hypoglycemic Agents

When dapagliflozin is added to therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin, the incidence of hypoglycemia is increased compared with sulfonylurea or insulin monotherapy. Therefore, patients receiving dapagliflozin may require a reduced dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.(See Drug Interactions: Antidiabetic Agents.)

Genital Mycotic Infections

Dapagliflozin may increase the risk of genital mycotic infections in males (e.g., balanitis) and females (e.g., vulvovaginal mycotic infection). In clinical trials, patients with a history of genital mycotic infections were more likely to develop such infections. Patients should be monitored for genital mycotic infections and appropriate treatment should be instituted if these infections occur.

Urosepsis and Pyelonephritis

Dapagliflozin may increase the risk of serious urinary tract infections.

FDA identified 19 cases of urosepsis and pyelonephritis, which began as urinary tract infections associated with SGLT2 inhibitor use, in FAERS between March 2013 and October 2014. In all cases reported, hospitalization was warranted and some patients required admission to an intensive care unit or dialysis for treatment. The median time to onset of infection following initiation of the SGLT2 inhibitor was 45 days (range: 2-270 days).

Prior to initiating therapy with an SGLT2 inhibitor, clinicians should consider patient factors that may predispose the patient to serious urinary tract infections such as a history of difficulty urinating or infections of the bladder, kidneys, or urinary tract. Patients should be monitored for urinary tract infections and treatment instituted if indicated.

Risk of Bone Fracture

An increased risk of bone fracture, along with dose-related decreases in bone mineral density in older adults, has been observed in patients receiving another drug in the SGLT2 inhibitor class (canagliflozin). In a clinical trial, bone fractures were reported more frequently than with placebo in patients with moderate renal impairment (eGFR 30 to less than 60 mL/minute per 1.73 m) receiving dapagliflozin for up to 104 weeks; most fractures occurred within 52 weeks of initiating therapy. FDA is continuing to evaluate the risk of bone fracture with SGLT2 inhibitors.

Effects on Lipoproteins

Increases in low-density lipoprotein (LDL)-cholesterol can occur during dapagliflozin therapy. Serum LDL-cholesterol concentrations should be monitored during treatment with dapagliflozin and such lipid elevations treated according to the standard of care.

Bladder Cancer

In clinical studies, newly diagnosed cases of bladder cancer were reported in 0.17% of 6045 patients receiving dapagliflozin and 0.03% of 3512 patients receiving placebo or comparator drugs. In patients receiving the study drug for at least one year, there were 4 cases of bladder cancer with dapagliflozin and none with placebo or comparator drugs. There were too few cases to determine whether the emergence of these events is related to dapagliflozin; there are insufficient data to determine whether dapagliflozin has an effect on pre-existing bladder tumors.

The manufacturer states that dapagliflozin should not be used in patients with active bladder cancer. In patients with a history of bladder cancer, the benefits of glycemic control versus unknown risks for cancer recurrence with dapagliflozin should be considered.

Macrovascular Outcomes

Evidence of macrovascular risk reduction with dapagliflozin or any other antidiabetic agent has not been conclusively demonstrated in clinical trials.

Laboratory Test Interferences

SGLT2 inhibitors such as dapagliflozin increase urinary glucose excretion and will result in false-positive urine glucose tests. In addition, the manufacturer states that the 1,5-anhydroglucitol assay is unreliable for monitoring glycemic control in patients taking SGLT2 inhibitors. Alternative methods of monitoring glycemic control should be used in patients receiving SGLT2 inhibitors.

Sensitivity Reactions

Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity), some serious, have been reported with dapagliflozin treatment. If a hypersensitivity reaction occurs, the drug should be discontinued, appropriate treatment instituted, and the patient monitored until signs and symptoms resolve.

Specific Populations

Pregnancy

Category C.

There are no adequate and well-controlled studies of dapagliflozin in pregnant women. Based on the results of reproductive and developmental toxicity studies in animals, dapagliflozin use during pregnancy may affect renal development and maturation. During pregnancy, appropriate alternative therapies should be considered, especially during the second and third trimesters. Dapagliflozin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation

Dapagliflozin is distributed into milk in rats; it is not known whether the drug is distributed into human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from dapagliflozin, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Pediatric Use

Safety and efficacy of dapagliflozin have not been established in pediatric patients younger than 18 years of age.

Geriatric Use

Among patients in 21 clinical trials, 1424 (24%) were 65 years of age or older and 207 (3.5%) were 75 years of age or older. Efficacy of dapagliflozin was similar for patients younger than 65 years of age and those 65 years of age or older after controlling for renal function (eGFR). Geriatric patients receiving dapagliflozin were more likely to experience certain adverse reactions related to volume depletion and renal impairment or failure compared with patients treated with placebo.

Hepatic Impairment

No dosage adjustment is recommended for patients with mild, moderate, or severe hepatic impairment. However, the benefits versus risks of using dapagliflozin in patients with severe hepatic impairment should be individually assessed since the safety and efficacy of dapagliflozin have not been established in this population.

Compared with values in healthy individuals, values for peak plasma dapagliflozin concentration were increased by 40% in patients with severe hepatic impairment (Child-Pugh Class C) following a single 10-mg dose of the drug. The area under the concentration-time curve (AUC) of dapagliflozin was increased by 67% in patients with severe hepatic impairment compared with that in healthy individuals. Differences in peak plasma concentration and AUC in patients with mild or moderate hepatic impairment were not considered clinically important.

Renal Impairment

Safety and efficacy of dapagliflozin were evaluated in a randomized, placebo-controlled study that included patients with moderate renal impairment (eGFR of 30 to less than 60 mL/minute per 1.73 m). Patients with moderate renal impairment receiving dapagliflozin had no overall improvement in glycemic control and had higher rates of renal-related adverse reactions and more bone fractures compared with those receiving placebo; therefore, dapagliflozin should not be initiated in patients with eGFR less than 60 mL/minute per 1.73 m. Based on its mechanism of action, dapagliflozin is not expected to be effective in patients with severe renal impairment (eGFR less than 30 mL/minute per 1.73 m) or end-stage renal disease.(See Cautions: Contraindications.)

In patients with type 2 diabetes mellitus with mild, moderate, or severe renal impairment, geometric mean systemic exposures of dapagliflozin at steady state (20 mg once daily for 7 days) were 45%, 2.04-fold, or 3.03-fold higher, respectively, compared with patients with type 2 diabetes mellitus and normal renal function. Higher systemic exposure of dapagliflozin did not result in a correspondingly higher 24-hour urinary glucose excretion.

The impact of hemodialysis on dapagliflozin exposure is not known.(See Cautions: Contraindications.)

Renal function should be assessed prior to initiation of therapy and periodically thereafter.

Common Adverse Effects

Adverse effects reported in at least 2% of patients receiving dapagliflozin in clinical trials and more commonly than with placebo include female genital mycotic infection, nasopharyngitis, urinary tract infection, back pain, increased urination, male genital mycotic infection, nausea, dyslipidemia, constipation, discomfort with urination, and pain in extremity.

Drug Interactions

The metabolism of dapagliflozin is primarily mediated by uridine diphosphate-glucuronosyltransferase (UGT) isoenzyme 1A9.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Dapagliflozin and dapagliflozin 3-O-glucuronide, an inactive metabolite of dapagliflozin, did not inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4 in in vitro studies. Dapagliflozin also does not induce CYP isoenzymes 1A2, 2B6, or 3A4 in vitro.

Drugs Affected by Organic Anion Transporter

Dapagliflozin 3-O-glucuronide is a substrate of organic anion transport (OAT) 3. Dapagliflozin and dapagliflozin 3-O-glucuronide did not meaningfully inhibit OAT1 or OAT3 active transporters; pharmacokinetic interactions are unlikely with substrates of OAT1 or OAT3.

Drugs Affected by Organic Cation Transporter

Dapagliflozin and dapagliflozin 3-O-glucuronide did not meaningfully inhibit organic cation transporter (OCT) 2; pharmacokinetic interactions are unlikely with substrates of OCT2.

Drugs Affected by P-glycoprotein Transport

Dapagliflozin is a weak P-glycoprotein substrate, but does not meaningfully inhibit P-glycoprotein. The manufacturer states that dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered P-glycoprotein substrates.

Antidiabetic Agents

When dapagliflozin is added to therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin, the incidence of hypoglycemia is increased compared with sulfonylurea or insulin monotherapy. Patients receiving dapagliflozin may require a reduced dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.

Diuretics

Concomitant use of dapagliflozin with loop diuretics may increase the incidence of symptomatic hypotension. Prior to initiation of dapagliflozin, volume status should be assessed and corrected in patients receiving diuretics. Patients should be monitored for signs and symptoms of symptomatic hypotension following initiation of dapagliflozin therapy.

Bumetanide

Administration of a single dose of bumetanide (1 mg) to individuals receiving dapagliflozin (10 mg once daily for 7 days) increased bumetanide area under the concentration-time curve (AUC) and peak plasma concentrations by 13%. The manufacturer states that no dosage adjustment of dapagliflozin or bumetanide is necessary.(See also Drug Interactions: Diuretics.)

Digoxin

Administration of a single dose of digoxin (0.25 mg) with dapagliflozin (20 mg loading dose, then 10 mg once daily for 7 days) did not have a clinically meaningful effect on the AUC or peak plasma concentration of digoxin. The manufacturer states that no dosage adjustment of digoxin is necessary.

Glimepiride

Administration of a single dose of glimepiride (4 mg) with a single dose of dapagliflozin (20 mg) increased glimepiride AUC by 13%; no dosage adjustment of either drug is necessary.

Hydrochlorothiazide

Administration of a single dose of hydrochlorothiazide (25 mg) with a single dose of dapagliflozin (50 mg) did not have a clinically important effect on the pharmacokinetics of hydrochlorothiazide or dapagliflozin. The manufacturer states that no dosage adjustment of dapagliflozin or hydrochlorothiazide is necessary.(See also Drug Interactions: Diuretics.)

Mefenamic Acid

Concurrent use of mefenamic acid (loading dose of 500 mg, then 250 mg every 6 hours for 14 doses) and a single dose of dapagliflozin (10 mg) increased dapagliflozin peak plasma concentration and AUC by 13 and 51%, respectively. No dosage adjustment of dapagliflozin is necessary.

Metformin

Administration of a single dose of metformin (1 g) with a single dose of dapagliflozin (20 mg) did not have a clinically meaningful effect on the pharmacokinetics of dapagliflozin or metformin. No dosage adjustment of either drug is necessary.

Pioglitazone

Administration of a single dose of pioglitazone (45 mg) with a single dose of dapagliflozin (50 mg) decreased pioglitazone peak plasma concentration by 7%. No dosage adjustment of either drug is necessary.

Rifampin

Administration of rifampin (600 mg once daily for 6 days) with a single dose of dapagliflozin (10 mg) decreased dapagliflozin peak plasma concentration and AUC by 7 and 22%, respectively. No dosage adjustment of dapagliflozin is necessary.

Simvastatin

Administration of a single dose of simvastatin (40 mg) with a single dose of dapagliflozin (20 mg) increased simvastatin AUC by 19%. The manufacturer states that no dosage adjustment of dapagliflozin or simvastatin is necessary.

Sitagliptin

Administration of a single dose of sitagliptin (100 mg) with a single dose of dapagliflozin (20 mg) did not have a clinically meaningful effect on the pharmacokinetics of dapagliflozin or sitagliptin. No dosage adjustment of either drug is necessary.

Valsartan

Administration of a single dose of valsartan (320 mg) with a single dose of dapagliflozin (20 mg) decreased peak plasma concentrations of valsartan and dapagliflozin by 6 and 12%, respectively, and increased valsartan AUC by 5%. The manufacturer states that no dosage adjustment of dapagliflozin or valsartan is necessary.

Voglibose

Concomitant administration of voglibose (0.2 mg three times daily; not commercially available in the US) with a single dose of dapagliflozin (10 mg) did not have a clinically meaningful effect on the pharmacokinetics of dapagliflozin.

Warfarin

Administration of a single dose of warfarin (25 mg) in individuals receiving dapagliflozin (20 mg loading dose, then 10 mg once daily for 7 days) did not have a clinically meaningful effect on the pharmacokinetics or pharmacodynamics of warfarin. No warfarin dosage adjustment is necessary.

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