Dapagliflozin (Monograph)

Brand name: Farxiga
Drug class: Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors
Chemical name: (1S)-1,5-Anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-d-glucitol,
Molecular formula: C₂₁H₂₅ClO₆
CAS number: 461432-26-8

Medically reviewed by Drugs.com on May 30, 2023. Written by ASHP.

Introduction

Antidiabetic agent; sodium-glucose cotransporter 2 (SGLT2) inhibitor.^{1 53 55}

Uses for Dapagliflozin

Type 2 Diabetes Mellitus

Glycemic Control

Used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.^{1 2 3 15 32 34}

Used in combination with other antidiabetic agents (e.g., metformin and/or a sulfonylurea, a peroxisome proliferator-activated receptor_γ [PPAR_γ] agonist [thiazolidinedione], a dipeptidyl peptidase-4 [DPP-4] inhibitor), a glucagon-like peptide 1 [GLP-1] receptor agonist, and/or insulin) as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control with dapagliflozin monotherapy.^{1 4 5 6 7 8 9 10 12 13 16 52}

Used in fixed combination with extended-release metformin hydrochloride (Xigduo XR) as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus when treatment with both drugs is appropriate.⁵³

Used in fixed combination with saxagliptin (Qtern) or with saxagliptin and extended-release metformin hydrochloride (Qternmet XR) as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.^{55 101} Manufacturer states that the fixed combination of dapagliflozin, saxagliptin, and extended-release metformin (Qternmet XR) is intended for use only in patients currently receiving metformin.¹⁰¹

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality).^{698 704 705}

In patients with metformin contraindications or intolerance (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a GLP-1 receptor agonist, SGLT2 inhibitor, DPP-4 inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.⁶⁹⁸

May need to initiate therapy with 2 agents (e.g., metformin plus another drug) in patients with high initial HbA_1c (>7.5% or ≥1.5% above target).^{698 704} In such patients with metformin intolerance, some experts suggest initiation of therapy with 2 drugs from other drug classes with complementary mechanisms of action. ⁶⁹⁸

Consider early initiation of combination therapy for the treatment of type 2 diabetes mellitus to extend the time to treatment failure and more rapidly attain glycemic goals.⁷⁰⁴

For patients with inadequate glycemic control on metformin monotherapy, consider patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preferences when selecting additional antidiabetic agents for combination therapy.^{698 704 705 706}

Consider early introduction of insulin for severe hyperglycemia (e.g., blood glucose of ≥300 mg/dL or HbA_1c >9–10%), especially if accompanied by catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.^{698 704}

Experts recommend that patients with type 2 diabetes mellitus who have established (or are at a high risk for) ASCVD, established kidney disease, or heart failure receive a GLP-1 receptor agonist or SGLT2 inhibitor with demonstrated cardiovascular disease benefit.^{704 705} In patients with these comorbidities, consider GLP-1 receptor agonist or SGLT2 inhibitor therapy independently of patient's HbA_1c.⁷⁰⁴

In patients with type 2 diabetes mellitus and CKD, consider a GLP-1 receptor agonist or SGLT2 inhibitor shown to reduce the risk of CKD progression, cardiovascular events, or both, in addition to metformin therapy or in those in whom metformin cannot be used.^{704 705 706}

In patients on metformin monotherapy without established ASCVD or indicators of high ASCVD risk, heart failure, or CKD, base decision regarding addition of other antidiabetic agents on avoidance of adverse effects, cost, and individual patient factors.⁷⁰⁴

Not indicated for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.^{1 53 55}

Reduction in Heart Failure-Related Hospitalization

Used to reduce the risk of hospitalization for heart failure in patients with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors.^{1 70 698 699 704 705}

Beneficial Effects on Renal Function

Some experts suggest that SGLT2 inhibitor therapy be considered to reduce risk of CKD progression, cardiovascular events, or both in patients with type 2 diabetes mellitus and diabetic kidney disease with albuminuria^{† [off-label]} (eGFR ≥30 mL/minute per 1.73 m² and urinary albumin >30 mg/g [particularly >300 mg/g] creatinine).⁷⁰⁶

Reduction in Cardiovascular Death and Heart Failure-Related Hospitalization

Used to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure and reduced ejection fraction (NYHA class II–IV).^{1 90}

Beneficial effects of dapagliflozin demonstrated in patients with chronic heart failure with or without coexisting type 2 diabetes mellitus.^{1 90}

Related/similar drugs

lisinopril, metoprolol, furosemide, metformin, carvedilol, spironolactone, triamcinolone

Dapagliflozin Dosage and Administration

General

• Correct volume depletion prior to initiating dapagliflozin; assess renal function prior to treatment and periodically thereafter.^{1 50 53 101}

Administration

Oral Administration

Dapagliflozin: Administer once daily in the morning, with or without food.¹

Fixed combination of dapagliflozin and extended-release metformin or dapagliflozin, saxagliptin, and extended-release metformin: Administer once daily in the morning with food to reduce the adverse GI effects of the metformin component.^{53 101}

Fixed combination of dapagliflozin and saxagliptin: Administer once daily in the morning, with or without food.⁵⁵

Fixed-combination tablets of dapagliflozin and extended-release metformin; dapagliflozin and saxagliptin; or dapagliflozin, extended-release metformin, and saxagliptin: Swallow whole; do not crush, cut, or chew.^{53 55 101}

If a dose of dapagliflozin, the fixed combination of dapagliflozin and extended-release metformin, or the fixed combination of dapagliflozin and saxagliptin is missed, take missed dose as soon as it is remembered followed by resumption of regular schedule.^{1 53 56} If missed dose is not remembered until the time of the next dose, skip missed dose and resume regular schedule.^{1 53 56} Do not double dose to replace a missed dose.^{1 53 56}

If a dose of the fixed combination containing dapagliflozin, extended-release metformin, and saxagliptin is missed and it is ≥12 hours until the next dose, take the missed dose as soon as remembered.¹⁰¹ If a dose is missed and it is <12 hours until the next dose, skip the missed dose and take the next dose at the usual time.¹⁰¹

Dosage

Dosage of dapagliflozin propanediol is expressed in terms of dapagliflozin.¹

Adults

Type 2 Diabetes Mellitus - Glycemic Control

Dapagliflozin

Oral

Initially, 5 mg once daily.¹

If well tolerated, increase dosage to 10 mg once daily in patients who require additional glycemic control.¹

Dapagliflozin/Extended-release Metformin Hydrochloride Fixed-combination Therapy

Oral

Initial dosage based on patient's current regimen with dapagliflozin and/or metformin hydrochloride.⁵³ May gradually increase dosage based on effectiveness and tolerability.⁵³

In patients currently not receiving dapagliflozin, initial recommended dosage of the dapagliflozin component is 5 mg once daily.⁵³ Titrate gradually based on effectiveness and tolerability, up to a maximum dosage of 10 mg of dapagliflozin and 2 g of extended-release metformin hydrochloride daily.⁵³

Patients who are already receiving extended-release metformin hydrochloride in the evening and are switching to the fixed combination of dapagliflozin and extended-release metformin hydrochloride should skip their last dose of metformin hydrochloride before initiating therapy with the fixed combination the following morning.⁵³

Dapagliflozin/Saxagliptin Fixed-combination Therapy

Oral

Recommended initial dosage in patients not already receiving dapagliflozin therapy is 5 mg of dapagliflozin and 5 mg of saxagliptin once daily in the morning.⁵⁵

In patients requiring additional glycemic control and tolerating initial dosage, may increase dosage of fixed combination to 10 mg of dapagliflozin and 5 mg of saxagliptin once daily.⁵⁵

Do not use fixed combination in patients receiving concomitant therapy with a potent CYP3A4/5 inhibitor (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin).⁵⁵

Dapagliflozin/Extended-release Metformin Hydrochloride/Saxagliptin Fixed-combination Therapy

Oral

Manufacturer states that the fixed-combination preparation containing dapagliflozin, saxagliptin, and extended-release metformin is intended only for patients currently taking metformin.¹⁰¹ Recommended initial dosage based on patient's current antidiabetic drug regimen.¹⁰¹

In patients not already receiving dapagliflozin, recommended initial total daily dosage is dapagliflozin 5 mg, saxagliptin 5 mg, and extended-release metformin hydrochloride 1 or 2 g once daily in the morning.¹⁰¹

Do not use fixed combination in patients receiving concomitant therapy with a potent CYP3A4/5 inhibitor (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin).¹⁰¹

Type 2 Diabetes Mellitus - Reduction in Heart Failure-Related Hospitalization

Dapagliflozin

Oral

10 mg once daily.¹

Dapagliflozin/Extended-release Metformin Hydrochloride Fixed-combination Therapy

Oral

10 mg of dapagliflozin once daily.⁵³

Reduction in Cardiovascular Death and Heart Failure-Related Hospitalization

Dapagliflozin

Oral

10 mg once daily.¹

Prescribing Limits

Adults

Type 2 Diabetes Mellitus - Glycemic Control

Oral

Dapagliflozin: Maximum of 10 mg daily.¹

Fixed combination with extended-release metformin hydrochloride: Maximum of 10 mg of dapagliflozin and 2 g of extended-release metformin hydrochloride daily.⁵³

Fixed combination with saxagliptin: Maximum of 10 mg of dapagliflozin and 5 mg of saxagliptin daily.⁵⁵

Fixed combination with saxagliptin and extended-release metformin hydrochloride: Maximum of 10 mg of dapagliflozin, 5 mg of saxagliptin, and 2 g of extended-release metformin hydrochloride daily.¹⁰¹

Type 2 Diabetes Mellitus - Reduction in Heart Failure-Related Hospitalization

Oral

Dapagliflozin: Maximum of 10 mg daily.¹

Fixed combination with extended-release metformin hydrochloride: Maximum of 10 mg of dapagliflozin and 2 g of extended-release metformin hydrochloride daily.⁵³

Reduction in Cardiovascular Death and Heart Failure-Related Hospitalization

Oral

Dapagliflozin: Maximum of 10 mg daily.¹

Special Populations

Hepatic Impairment

Dapagliflozin

Oral

Mild, moderate, or severe hepatic impairment: No dosage adjustment necessary.¹

Dapagliflozin/Extended-release Metformin Hydrochloride Fixed-combination Therapy

Oral

Avoid use in patients with hepatic impairment.⁵³

Dapagliflozin/Saxagliptin Fixed-combination Therapy

Oral

Mild, moderate, or severe hepatic impairment: No dosage adjustment necessary.⁵⁵

Dapagliflozin/Extended-release Metformin Hydrochloride/Saxagliptin Fixed-combination Therapy

Oral

Avoid use in patients with hepatic impairment.¹⁰¹

Renal Impairment

Dapagliflozin

Oral

Glycemic control: No dosage adjustment necessary for eGFR ≥45 mL/minute per 1.73 m².¹ Use not recommended if eGFR 30 to <45 mL/minute per 1.73 m².¹ Contraindicated if eGFR <30 mL/minute per 1.73 m² and in patients with ESRD or undergoing dialysis.¹

Reduction in risk of heart failure-related hospitalization in patients with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors: No dosage adjustment necessary for eGFR ≥45 mL/minute per 1.73 m².¹ Insufficient data to support dapagliflozin dosage recommendation in patients with eGFR <45 mL/minute per 1.73 m².¹ Contraindicated in patients with ESRD or undergoing dialysis.¹

Reduction in risk of cardiovascular death or heart failure-related hospitalization in patients with heart failure and reduced ejection fraction with or without type 2 diabetes mellitus: No dosage adjustment necessary for eGFR ≥30 mL/minute per 1.73 m².¹ Insufficient data to support dapagliflozin dosage recommendation in patients with eGFR <30 mL/minute per 1.73 m².¹ Contraindicated in patients with ESRD or undergoing dialysis.¹

Dapagliflozin/Extended-release Metformin Hydrochloride Fixed-combination Therapy

Oral

Mild renal impairment (eGFR ≥45 mL/minute per 1.73 m²): No dosage adjustment necessary.⁵³

Moderate renal impairment: Not recommended if eGFR <45 mL/minute per 1.73 m².⁵³

Severe renal impairment (eGFR <30 mL/minute per 1.73 m²): Contraindicated.⁵³

Dapagliflozin/Saxagliptin Fixed-combination Therapy

Oral

Mild renal impairment (eGFR ≥45 mL/minute per 1.73 m²): No dosage adjustment necessary.⁵⁵

Moderate or severe renal impairment: Contraindicated in patients with an eGFR <45 mL/minute per 1.73 m².⁵⁵

Geriatric Patients

No dosage adjustment of dapagliflozin necessary based solely on age.¹

Sex

Dosage adjustment of dapagliflozin based on patient's sex not necessary.¹

Race

Dosage adjustment of dapagliflozin based on race not necessary.¹

Body Weight

Dosage adjustment of dapagliflozin based on body weight not necessary.¹

Cautions for Dapagliflozin

Contraindications

• History of serious hypersensitivity reaction to dapagliflozin.¹

• Dapagliflozin is contraindicated in patients with severe renal impairment (eGFR <30 mL/minute per 1.73 m²) when used for glycemic control in patients without established cardiovascular disease or multiple cardiovascular risk factors.¹

• Dapagliflozin is contraindicated in patients with ESRD or undergoing dialysis.¹

Warnings/Precautions

Ketoacidosis

Ketoacidosis (e.g., diabetic ketoacidosis, ketoacidosis, ketosis) requiring hospitalization reported with SGLT2 inhibitors; may occur without markedly elevated blood glucose concentrations (e.g., <250 mg/dL).^{1 39 40 41 42 50}

Evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing signs or symptoms of acidosis regardless of the patient's blood glucose concentration; discontinue SGLT2 inhibitor and initiate appropriate treatment to correct acidosis if confirmed.^{1 39 40 50} (See Advice to Patients.)

Prior to initiating dapagliflozin therapy, consider risk factors that may predispose patients to ketoacidosis (e.g., pancreatic insulin deficiency, reduced caloric intake, alcohol abuse).^{1 50}

Consider discontinuing dapagliflozin for ≥3 days prior to surgery for patients with scheduled surgery.¹

Consider temporarily discontinuing SGLT2 inhibitor in patients with other clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery).^{1 50} Resolve factors for ketoacidosis prior to restarting dapagliflozin.¹

Some clinicians suggest monitoring of urine and/or plasma ketone levels if patients feel unwell, regardless of ambient glucose concentrations.^{40 42}

Volume Depletion

May cause intravascular volume contraction.¹ Symptomatic hypotension can occur, particularly in patients with impaired renal function (eGFR <60 mL/minute per 1.73 m²), geriatric patients, or patients receiving loop diuretics.¹ (See Specific Drugs and Laboratory Tests under Interactions.) Assess and correct intravascular volume status prior to initiating dapagliflozin in such patients.¹

Monitor patients for signs and symptoms of hypotension after initiating therapy.¹

Renal Effects

Causes intravascular volume contraction and can cause acute kidney injury.^{1 51}

May increase S_cr concentration and decrease eGFR; geriatric patients and patients with impaired renal function may be more susceptible to these changes.¹ Adverse reactions related to renal function can occur following initiation of the drug.¹

Prior to initiating dapagliflozin therapy, consider factors that may predispose patients to acute kidney injury, such as hypovolemia, chronic renal insufficiency, heart failure, and concomitant medications (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIAs).^{1 51}

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).^{1 51}

Evaluate renal function prior to initiation of dapagliflozin and monitor periodically thereafter.¹ Discontinue dapagliflozin and initiate appropriate treatment if kidney injury occurs.^{1 51}

Concomitant Therapy with Hypoglycemic Agents

When adding dapagliflozin to therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin, consider reducing dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.¹ (See Specific Drugs and Laboratory Tests under Interactions.)

Fournier Gangrene

Fournier gangrene (necrotizing fasciitis of the perineum), a rare but serious life-threatening bacterial infection requiring urgent surgical intervention, reported during postmarketing surveillance of men and women with type 2 diabetes mellitus receiving an SGLT2 inhibitor.^{1 59 60 61 62}

Assess patient for necrotizing fasciitis if pain or tenderness, erythema, or swelling in the genital or perineal area occurs in addition to fever or malaise.^{1 60}

If Fournier gangrene suspected, discontinue dapagliflozin and initiate treatment immediately with broad-spectrum antibiotics and, if necessary, perform surgical debridement.^{1 60} Closely monitor blood glucose concentrations and initiate alternative antidiabetic agent to maintain glycemic control.^{1 60}

Genital Mycotic Infections

Possible increased risk of genital mycotic infections in males (e.g., balanitis) and females (e.g., vulvovaginal mycotic infection).^{1 11 37} Patients with a history of genital mycotic infections were more likely to develop such infections.^{1 37}

Monitor patients for genital mycotic infections and institute appropriate treatment if these infections occur.¹

Urosepsis and Pyelonephritis

May increase the risk of serious urinary tract infections (e.g., urosepsis, pyelonephritis requiring hospitalization).^{1 50}

Prior to initiating dapagliflozin therapy, consider patient factors that may predispose to serious urinary tract infections (e.g., history of difficulty urinating; infection of the bladder, kidneys, or urinary tract).⁵⁰

Monitor patients for urinary tract infections and initiate treatment if indicated.^{1 50}

Risk of Bone Fracture

Increased risk of bone fracture, along with dose-related decreases in bone mineral density in older adults, observed in patients receiving another SGLT2 inhibitor (canagliflozin).⁴³ Bone fractures observed more frequently than with placebo in patients with moderate renal impairment (eGFR 30 to <60 mL/minute per 1.73 m²) receiving dapagliflozin, usually within 52 weeks of initiating therapy.¹ FDA continuing to evaluate bone fracture risk with SGLT2 inhibitors.⁴³

Use of Fixed Combinations

When dapagliflozin is used in fixed combination with metformin, saxagliptin, or other drugs, consider the cautions, precautions, contraindications, and interactions associated with the concomitant agent(s) in addition to those associated with dapagliflozin.^{1 53 55}

Sensitivity Reactions

Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity), some serious, reported.^{1 53 55} If a hypersensitivity reaction occurs, discontinue dapagliflozin, institute appropriate treatment, and monitor patients until signs and symptoms resolve.¹

Specific Populations

Pregnancy

No adequate and well-controlled studies of dapagliflozin in pregnant women.¹

Studies in animals indicate that dapagliflozin use during pregnancy may affect renal development and maturation.¹

Dapagliflozin therapy not recommended in pregnant women during the second and third trimesters of pregnancy.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Use of dapagliflozin in women who are breast-feeding not recommended.¹

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.¹

Geriatric Use

Efficacy similar in patients <65 years of age and those ≥65 years of age after controlling for renal function (eGFR).¹ Such patients more likely to experience hypotension.¹

Hepatic Impairment

Assess benefits versus risks of dapagliflozin or the fixed combination of dapagliflozin and saxagliptin in patients with severe hepatic impairment; safety and efficacy not established in such patients.^{1 22} Avoid use of the fixed-combination preparations containing dapagliflozin and extended-release metformin or dapagliflozin, saxagliptin, and extended-release metformin in patients with clinical or laboratory evidence of hepatic impairment.^{53 101}

Renal Impairment

Patients with an eGFR of 45 to <60 mL/minute per 1.73 m² receiving dapagliflozin had substantial improvement in glycemic control and experienced adverse effects similar to those without renal impairment.^{1 71} Patients receiving dapagliflozin therapy had a greater reduction in eGFR compared with those receiving placebo; however, renal function generally increased back to baseline values after discontinuing treatment with dapagliflozin.^{1 71} Patients with renal impairment receiving dapagliflozin for glycemic control may be more likely to experience hypotension and may be at an increased risk for acute kidney injury.¹ Patients with an eGFR of 30 to <60 mL/minute per 1.73 m² receiving dapagliflozin had a greater incidence of bone fractures compared with those receiving placebo.^{1 35}

Impact of hemodialysis on dapagliflozin exposure is not known; contraindicated in patients on dialysis.¹

Assess renal function prior to initiation of therapy and periodically thereafter.¹

Common Adverse Effects

Dapagliflozin monotherapy: Female genital mycotic infection,^{1 2 3 4 6 7 8} nasopharyngitis,^{1 2 3 5 6 7 8} urinary tract infection,^{1 2 3 4 5 6 8 33} back pain,^{1 5 8} increased urination,¹ male genital mycotic infection,^{1 2 3 4 7} nausea,^{1 4} dyslipidemia,^{1 4 8} constipation,¹ discomfort with urination,¹ pain in extremity.^{1 8}

Dapagliflozin in combination with extended-release metformin hydrochloride: Female genital mycotic infection,⁵³ nasopharyngitis,⁵³ urinary tract infection,⁵³ diarrhea,⁵³ headache,⁵³ male genital mycotic infection,⁵³ influenza,⁵³ nausea,⁵³ back pain,⁵³ dizziness,⁵³ cough,⁵³ constipation,⁵³ dyslipidemia,⁵³ pharyngitis,⁵³ increased urination,⁵³ discomfort with urination.⁵³

Dapagliflozin in combination with saxagliptin and extended-release metformin hydrochloride: Upper respiratory tract infection,⁵⁵ urinary tract infection,⁵⁵ dyslipidemia,⁵⁵ headache,⁵⁵ diarrhea,⁵⁵ back pain,⁵⁵ genital infection,⁵⁵ arthralgia.⁵⁵

Drug Interactions

Metabolism principally mediated by uridine diphosphate-glucuronosyltransferase (UGT) isoenzyme 1A9.^{1 20}

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Did not inhibit CYP-450 isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro.^{1 19} Did not induce CYP isoenzymes 1A2, 2B6, or 3A4 in vitro.^{1 19}

Drugs Affected by Organic Anion Transporter

Dapagliflozin 3-O-glucuronide, inactive metabolite of dapagliflozin, is a substrate of organic anion transport (OAT) 3.¹ Dapagliflozin and dapagliflozin 3-O-glucuronide did not meaningfully inhibit OAT1 or OAT3 active transporters; pharmacokinetic interactions unlikely with OAT1 or OAT3 substrates.¹

Drugs Affected by Organic Cation Transporter

Did not meaningfully inhibit organic cation transporter (OCT) 2; pharmacokinetic interactions unlikely with substrates of OCT2.¹

Drugs Affected by P-glycoprotein Transport

Weak P-glycoprotein substrate; did not meaningfully inhibit P-glycoprotein.^{1 19 20} Unlikely to affect pharmacokinetics of concurrently administered P-glycoprotein substrates.¹

Specific Drugs and Laboratory Tests

Dapagliflozin Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability: 78%.^{1 27} Peak plasma concentration usually attained within 2 hours after oral dosing in fasted state.^{1 18 19 20 23 30}

Food

Administration with a high-fat meal decreased peak plasma concentration by up to 50% and prolonged time to peak plasma concentration by approximately 1 hour, but did not alter AUC.^{1 20 21} These changes are not considered clinically meaningful; administer dapagliflozin with or without food.^{1 20 21}

Special Populations

Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: No clinically important differences in peak plasma concentration or AUC.¹

Severe hepatic impairment (Child-Pugh class C): AUC and peak plasma concentration increased by 67 and 40%, respectively, compared with individuals with normal hepatic function following a single 10-mg dose of dapagliflozin.^{1 22}

Mild renal impairment: Geometric mean systemic exposure of dapagliflozin at steady state increased by 45% compared with individuals with normal renal function.¹

Moderate renal impairment: Geometric mean systemic exposure of dapagliflozin at steady state increased 2.04-fold compared with individuals with normal renal function.¹

Severe renal impairment: Geometric mean systemic exposure of dapagliflozin at steady state increased 3.03-fold compared with individuals with normal renal function.¹

Distribution

Extent

Extensively distributed.²⁰

Plasma Protein Binding

Approximately 91%.^{1 19}

Special Populations

Renal or hepatic impairment does not meaningfully alter plasma protein binding.¹

Elimination

Metabolism

Metabolized principally by UGT1A9 to inactive metabolites.¹

Elimination Route

75 and 21% of total radioactivity excreted in urine and feces, respectively, with <2^{1 19} and approximately 15% in urine and feces, respectively, as parent drug.^{1 20}

Half-life

Approximately 12.9 hours following a single oral dose of 10 mg.¹

Stability

Storage

Oral

Tablets

Dapagliflozin, the fixed combination of dapagliflozin and extended-release metformin, or the fixed combination of dapagliflozin and saxagliptin: 20–25°C (may be exposed to 15–30°C).^{1 53 55}

Actions

• Inhibits SGLT2, a transporter expressed in proximal renal tubules and responsible for majority of reabsorption of filtered glucose from the tubular lumen.^{1 20}

• Reduces reabsorption of filtered glucose and lowers the renal threshold for glucose in a dose-dependent manner, leading to increased urinary glucose excretion.^{1 17 30 31}

• Increases glucose excretion independent of insulin secretion.³⁶

• Improves muscle insulin sensitivity;^{28 29} however, glucosuria induction appears to increase endogenous glucose production.²⁸

• Endogenous glucose production increases, accompanied by an increase in fasting plasma glucagon concentration.²⁸

Advice to Patients

• Importance of patient reading medication guide before initiating therapy and each time the drug is dispensed.^{1 38 53 54 55 56}

• When dapagliflozin is used in fixed combination with other drugs, importance of informing patients of important cautionary information about the concomitant agents.^{1 53 55}

• Importance of informing patients of the potential risks and benefits of dapagliflozin and of alternative therapies.^{1 38} Importance of not using dapagliflozin in patients with type 1 diabetes mellitus or diabetic ketoacidosis.^{1 38}

• Importance of informing patients that ketoacidosis, which can be a life-threatening condition, has been reported with dapagliflozin therapy (sometimes associated with illness or surgery among other risk factors).¹ Importance of informing patients and their caregivers of the signs and symptoms of ketoacidosis (e.g., tachypnea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy, mental status change) and of instructing patients to discontinue dapagliflozin and seek medical advice immediately should they experience any such signs or symptoms.^{1 39 42 50} Advise patients to use a ketone dipstick to check for ketones in their urine (when possible) if symptoms of ketoacidosis occur, even if blood glucose is not elevated (e.g., <250 mg/dL).^{1 38 50}

• Importance of informing patients that symptomatic hypotension may occur with dapagliflozin and to report such symptoms to their clinicians.^{1 38} Inform patients that dapagliflozin-induced dehydration may increase the risk of hypotension and changes in kidney function and that patients should maintain adequate fluid intake.^{1 38}

• Importance of informing patients that acute kidney injury has been reported with dapagliflozin therapy.^{1 38 51} Advise patients to seek medical attention immediately if they experience decreased urine output or swelling of the legs or feet.⁵¹ Advise patients to seek medical advice immediately if they have reduced oral intake (such as due to acute illness or fasting) or increased fluid losses (such as due to vomiting, diarrhea, or excessive heat exposure), as it may be appropriate to temporarily discontinue dapagliflozin in those settings.^{1 51}

• Importance of informing patients that necrotizing infections of the perineum (Fournier gangrene) have occurred with SGLT2 inhibitor therapy.^{1 60} Advise patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, in addition to fever (>38°C) or malaise.^{1 60}

• Importance of informing patients that yeast infection may occur (e.g., vulvovaginitis, balanitis, balanoposthitis).^{1 38} Importance of informing female patients of the signs and symptoms of vaginal yeast infections (e.g., vaginal discharge, odor, itching) and male patients of the signs and symptoms of balanitis or balanoposthitis (e.g., rash or redness of the glans or foreskin of the penis).^{1 38 53 55} Advise patients of treatment options and when to seek medical advice.^{1 38}

• Importance of informing patients of the potential for urinary tract infections, which may be serious.^{1 38} Advise patients of the signs and symptoms of urinary tract infection and the need to contact a clinician promptly if such signs and symptoms occur.^{1 50}

• Importance of informing patients that due to the mechanism of action of dapagliflozin, patients taking the drug will test positive for glucose in their urine.¹ Importance of not using urine glucose tests to monitor glycemic status while taking dapagliflozin.¹

• Risk of serious hypersensitivity reactions, such as urticaria and angioedema.^{1 38} If signs or symptoms of such a reaction occur, importance of discontinuing dapagliflozin and promptly informing clinician.^{1 38}

  Importance of informing patients to promptly report any signs of macroscopic hematuria or other symptoms potentially indicative of bladder cancer.^{1 38}

• Importance of informing patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and glycosylated hemoglobin (hemoglobin A_1c; HbA_1c) testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications.^{1 38}

• Importance of promptly seeking medical advice during periods of stress such as fever, trauma, infection, or surgery as medication requirements may change.^{1 38}

• Importance of taking dapagliflozin exactly as directed by clinician.^{1 38} (See Administration under Dosage and Administration.)

• Importance of women informing their clinicians immediately if they are or plan to become pregnant or plan to breast-feed.^{1 38}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., severe kidney disease).^{1 38 53 55}

• Importance of informing patients of other important precautionary information.^{1 38} (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Frequently asked questions

• What are the ingredient drugs contained in Qternmet XR?

Medical Disclaimer