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Empagliflozin

Class: Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors
VA Class: 0000
Chemical Name: (1S) - 1,5 - Anhydro - 1 - C - [4 - chloro - 3 - [[4 - [[(3S) - tetrahydro - 3 - furanyl]oxy]phenyl]methyl]phenyl] - d - glucitol
Molecular Formula: C23H27ClO7
CAS Number: 864070-44-0
Brands: Jardiance

Introduction

Antidiabetic agent; sodium-glucose cotransporter 2 (SGLT2) inhibitor.1

Uses for Empagliflozin

Diabetes Mellitus

Used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1 2

Used in combination with other antidiabetic agents (e.g., metformin, a sulfonylurea, a peroxisome proliferator-activated receptorγ [PPARγ] agonist [thiazolidinedione], a dipeptidylpeptidase-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.1 3 4 5 6 7 8 9

Not indicated for type 1 diabetes mellitus or treatment of diabetic ketoacidosis.1

Empagliflozin Dosage and Administration

General

  • Correct volume depletion prior to initiating empagliflozin; assess renal function prior to treatment and periodically thereafter.1

Administration

Oral Administration

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

If a dose is missed, take missed dose as soon as it is remembered followed by resumption of the regular schedule.1 14 If the missed dose is not remembered until it is almost time for the next dose, skip the missed dose and resume the regular schedule; do not double the dose to replace a missed dose.1 14

Dosage

Adults

Diabetes Mellitus
Oral

Initially, 10 mg once daily in the morning.1

If well tolerated, increase dosage to 25 mg once daily in patients who require additional glycemic control.1

Special Populations

Hepatic Impairment

Mild, moderate, or severe: No dosage adjustment necessary.13

Renal Impairment

Estimated GFR (eGFR) ≥45 mL/minute per 1.73 m2: No dosage adjustment necessary.1

eGFR <45 mL/minute per 1.73 m2: Do not initiate drug.1 Discontinue drug if eGFR is persistently <45 mL/minute per 1.73 m2.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No dosage adjustment necessary based solely on age.1

Cautions for Empagliflozin

Contraindications

  • History of serious hypersensitivity reaction to empagliflozin.1

  • Severe renal impairment (eGFR <30 mL/minute per 1.73 m2), end-stage renal disease, or 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., <200 mg/dL).39 40 41 42

Evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing signs or symptoms of acidosis; discontinue SGLT2 inhibitor and initiate appropriate treatment to correct acidosis if confirmed.39 40 (See Advice to Patients.)

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

Hypotension

May cause intravascular volume contraction.1 Symptomatic hypotension can occur, particularly in patients with impaired renal function, geriatric patients, patients receiving diuretics, or patients with low systolic BP.1 (See Specific Drugs and Laboratory Tests under Interactions.) Assess and correct intravascular volume status prior to initiating empagliflozin in patients.1

Monitor patients for signs and symptoms of hypotension after initiating therapy; increase monitoring in clinical situations in which volume contraction is expected.1

Renal Effects

May increase Scr concentration and decrease eGFR.1 Risk of impaired renal function is increased in geriatric patients and patients with moderate renal impairment; more frequent monitoring is recommended in these patients.1

Evaluate renal function prior to initiation of empagliflozin and periodically thereafter.1

Concomitant Therapy with Hypoglycemic Agents

When adding empagliflozin 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

Genital Mycotic Infections

Possible increased risk of genital mycotic infections in males (e.g., balanitis, balanoposthitis) and females (e.g., vulvovaginitis).1 Patients with a history of chronic or recurrent genital mycotic infections more likely to develop such infections.1 Genital mycotic infections also occurred more frequently in female than in male patients.1

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

Urinary Tract Infections

May increase the risk of urinary tract infections (e.g., urinary tract infection, asymptomatic bacteriuria, cystitis).1 Patients with a history of chronic or recurrent urinary tract infections more likely to develop such infections.1 Urinary tract infections also occurred more frequently in female than in male patients, and risk of urinary tract infections increased in patients ≥75 years of age.1

Monitor patients for urinary tract infections and initiate appropriate treatment if these infections occur.1

Effects on Lipoproteins

Dose-related increases in LDL-cholesterol concentration can occur.1 Monitor serum LDL-cholesterol concentrations and treat such lipid elevations according to standard of care.1

Potential 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 FDA continuing to evaluate bone fracture risk with SGLT2 inhibitors.43

Macrovascular Outcomes

Evidence of macrovascular risk reduction with empagliflozin or any other antidiabetic agent has not been conclusively demonstrated in clinical trials.1

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

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

Geriatric Use

Geriatric patients with renal impairment expected to experience reduced efficacy.1

Risk of volume depletion-related adverse effects and urinary tract infections increased in patients ≥75 years of age.1

Hepatic Impairment

No dosage adjustment necessary for patients with mild, moderate, or severe hepatic impairment.13

Renal Impairment

Glucose-lowering effect of empagliflozin 25 mg was reduced in patients with worsening renal function in a clinical study.1 9 In addition, risk of renal impairment and of volume depletion-related and urinary tract infection-related adverse effects increased with worsening renal function.1

Efficacy and safety not established in patients with severe renal impairment, end-stage renal disease, or in those receiving dialysis; empagliflozin is not expected to be effective in these patients and is contraindicated in such patients.1

Do not initiate drug in patients with eGFR <45 mL/minute per 1.73 m2.1 Discontinue drug if eGFR is persistently <45 mL/minute per 1.73 m2.1

Assess renal function before initiating empagliflozin and during therapy.1 More frequent monitoring recommended in patients with eGFR <60 mL/minute per 1.73 m2.1

Common Adverse Effects

Urinary tract infection,1 2 4 5 7 8 9 female genital mycotic infections,1 upper respiratory tract infection,1 4 5 increased urination,1 dyslipidemia,1 arthralgia,1 male genital mycotic infections,1 and nausea.1

Interactions for Empagliflozin

Metabolized principally by glucuronidation via uridine diphosphate-glucuronosyltransferase (UGT) isoenzymes 2B7, 1A3, 1A8, and 1A9.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Did not inhibit, inactivate, or induce CYP isoforms in vitro;1 no effect of empagliflozin expected on concomitantly administered drugs that are substrates of the major CYP isoforms.1

Drugs Affecting or Affected by Organic Anion Transporters

Substrate of organic anion transporter (OAT) 3 and organic anion transport proteins (OATP) 1B1 and 1B3.1 Not a substrate of OAT1.1 Does not inhibit any of these transporters at clinically relevant plasma concentrations; no effect of empagliflozin expected on concomitantly administered drugs that are substrates of these transporters.1

Drugs Affecting or Affected by Organic Cation Transporters

Not a substrate of organic cation transporter (OCT)2; does not inhibit OCT2 at clinically relevant plasma concentrations.1 No effect of empagliflozin expected on concomitantly administered drugs that are substrates of this transporter.1

Drugs Affecting or Metabolized by Uridine Diphosphate-glucuronosyltransferase

Did not inhibit UGT1A1 in vitro; no effect of empagliflozin expected on concomitantly administered drugs that are substrates of UGT1A1.1 Manufacturer states effect of UGT induction on empagliflozin exposure has not been studied.1

Drugs Affecting or Affected by P-glycoprotein Transport

Substrate of P-glycoprotein (P-gp); does not inhibit P-gp at therapeutic doses.1 Considered unlikely to cause interactions with drugs that are P-gp substrates based on in vitro studies.1

Drugs Affecting or Affected by Breast Cancer Resistance Protein

Substrate of breast cancer resistance protein (BCRP); does not inhibit BCRP at therapeutic doses.1

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Antidiabetic agents

Increased risk of hypoglycemia when used concomitantly with insulin or insulin secretagogues (e.g., sulfonylurea)1

Reduced dosage of insulin or insulin secretagogue may be required to reduce risk of hypoglycemia1

Digoxin

No clinically relevant effect on digoxin pharmacokinetics1

No adjustment of digoxin dosage necessary10

Diuretics

Concomitant use may increase urine volume and frequency of voids, which may increase risk of volume depletion1

Assess for volume contraction and correct prior to initiating empagliflozin;1 monitor for manifestations of hypotension after initiating therapy; increase monitoring in situations in which volume contraction expected1

Gemfibrozil

Increased empagliflozin AUC; however, effect not clinically relevant1

No adjustment of empagliflozin dosage necessary1

Glimepiride

No clinically relevant effect on pharmacokinetics of glimepiride or empagliflozin1 10

No adjustment of either drug dosage necessary10

Hormonal contraceptives

No clinically relevant effect on pharmacokinetics of ethinyl estradiol or levonorgestrel1

No adjustment of ethinyl estradiol or levonorgestrel dosage necessary10

Hydrochlorothiazide

No clinically relevant effect on pharmacokinetics of hydrochlorothiazide or empagliflozin1 10

No adjustment of either drug dosage necessary10

Linagliptin

No clinically relevant effect on pharmacokinetics of linagliptin or empagliflozin1 10

No adjustment of either drug dosage necessary10

Metformin

No clinically relevant effect on pharmacokinetics of metformin or empagliflozin1 10

No adjustment of either drug dosage necessary10

Pioglitazone

No clinically relevant effect on pharmacokinetics of empagliflozin or pioglitazone1

No adjustment of empagliflozin dosage necessary1

Probenecid

Increased empagliflozin AUC; however, effect not clinically relevant1

Concomitant use decreased fraction of empagliflozin excreted in urine by 30% without affecting 24-hour urinary glucose excretion in patients with normal renal function1

No adjustment of empagliflozin dosage necessary1

Ramipril

No clinically relevant effect on pharmacokinetics of ramipril, ramiprilat (metabolite), or empagliflozin1 10

No adjustment of ramipril or empagliflozin dosage necessary10

Rifampin

Increased empagliflozin AUC; however, effect not clinically relevant1

No adjustment of empagliflozin dosage necessary1

Simvastatin

No clinically relevant effect on pharmacokinetics of simvastatin, simvastatin acid (metabolite), or empagliflozin1 10

No adjustment of either drug dosage necessary10

Sitagliptin

No clinically relevant effect on pharmacokinetics of sitagliptin or empagliflozin1 10

No adjustment of either drug dosage necessary10

Torsemide

No clinically relevant effect on pharmacokinetics of torsemide or empagliflozin1 10

No adjustment of either drug dosage necessary10

Urine glucose tests (e.g., 1,5-anhydroglucitol assay)

SGLT2 inhibitors increase urinary glucose excretion and will result in false-positive urine glucose tests1

Use alternative methods to monitor glycemic control1

Verapamil

No clinically relevant effect on pharmacokinetics of empagliflozin1 10

No adjustment of verapamil dosage necessary10

Warfarin

No clinically relevant effect on pharmacokinetics of warfarin or empagliflozin1 10

No adjustment of either drug dosage necessary10

Empagliflozin Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentration usually attained within 1 hour after oral dosing in fasted state.13 Empagliflozin exposure increases in proportion to the dose.1 13

Food

Administration with a high-fat and high-calorie meal decreased peak concentration and AUC by approximately 37 and 16%, respectively, compared with fasting condition.1 These changes not considered clinically relevant; administer empagliflozin with or without food.1

Special Populations

Mild hepatic impairment (Child-Pugh class A): AUC and peak plasma concentration increased by 23 and 4%, respectively, compared with that in individuals with normal hepatic function.1 13

Moderate hepatic impairment (Child-Pugh class B): AUC and peak plasma concentration increased by 47 and 23%, respectively, compared with that in individuals with normal hepatic function.1 13

Severe hepatic impairment (Child-Pugh class C): AUC and peak plasma concentration increased by 75 and 48%, respectively, compared with that in individuals with normal hepatic function.1 13

Mild renal impairment (eGFR 60 to <90 mL/minute per 1.73 m2): AUC and peak plasma concentration increased by approximately 18 and 20%, respectively, compared with that in individuals with normal renal function.1

Moderate renal impairment (eGFR 30 to <60 mL/minute per 1.73 m2): AUC increased by 20% and peak plasma concentrations were similar compared with that in individuals with normal renal function.1

Severe renal impairment (eGFR <30 mL/minute per 1.73 m2): AUC and peak plasma concentration increased by approximately 66 and 20%, respectively, compared with that in individuals with normal renal function.1

Patients with renal failure/end-stage renal disease: AUC increased by approximately 48% and peak plasma concentrations were similar compared with that in individuals with normal renal function.1

Distribution

Plasma Protein Binding

86.2%1

Elimination

Metabolism

Metabolized principally via glucuronidation by UGT isoenzymes 2B7, 1A3, 1A8, and 1A9.1

Elimination Route

Following administration of radiolabeled dose of empagliflozin, eliminated in feces (41.2%) and urine (54.4%).1

Half-life

Approximately 12.4 hours1

Special Populations

Apparent oral clearance of empagliflozin decreases with a reduction in eGFR.1 Fraction of empagliflozin excreted unchanged in urine and urinary glucose excretion decline with decrease in eGFR.1

Gender, race, and body weight have no clinically meaningful effect on pharmacokinetics of empagliflozin.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Inhibits SGLT2, the transporter principally responsible for reabsorption of glucose from the glomerular filtrate back into the circulation.1 11 12

  • Reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion.1 11 12

  • Increases glucose excretion independent of insulin secretion.1 11 12

  • Reduces blood glucose concentrations.1 11 12

Advice to Patients

  • Importance of patient reading patient information before initiating therapy and each time the drug is dispensed.1 14

  • Importance of informing patients of the potential risks and benefits of empagliflozin and of alternative therapies.1 Importance of informing patients that use of empagliflozin with other antidiabetic agents may increase risk of hypoglycemia.1 14 Importance of not using empagliflozin in patients with type 1 diabetes mellitus or diabetic ketoacidosis.1

  • Importance of informing patients and their caregivers of the signs and symptoms of metabolic acidosis (e.g., tachypnea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy, mental status changes) and of instructing patients to seek medical attention immediately should they experience any such signs or symptoms.39 42 Patients should not discontinue empagliflozin without consulting the prescribing clinician.39

  • Importance of informing patients that hypotension may occur with empagliflozin and to report such symptoms to their clinicians.1 14 Inform patients that empagliflozin-induced dehydration may increase the risk of hypotension and that patients should maintain adequate fluid intake.1 14

  • Importance of informing female patients that vaginal yeast infections may occur (e.g., vulvovaginitis).1 14 Importance of informing male patients that yeast infections may occur (e.g., balanitis, balanoposthitis), especially in uncircumcised males.1 14 Importance of informing patients that yeast infections occur more frequently in females and in patients with chronic and recurrent infections.1 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, foul-smelling discharge from the penis, pain in skin around penis).1 14 Advise patients of treatment options and when to seek medical advice.1

  • Importance of informing patients that urinary tract infections may occur.1 14 Advise patients of the signs and symptoms of urinary tract infections (e.g. dysuria, cloudy urine, pelvic or back pain) and the need to report such symptoms to their clinicians.1 14

  • Importance of informing patients that due to the mechanism of action of empagliflozin, patients taking the drug will test positive for glucose in the urine.1 14 Importance of not using urine glucose tests to monitor glycemic status while taking empagliflozin.1

  • Importance of informing patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and glycosylated hemoglobin (hemoglobin A1c; HbA1c) testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications.1 14

  • Importance of seeking medical advice promptly during periods of stress such as fever, trauma, infection, or surgery as dosage requirements may change.1 14

  • Importance of informing patient not to take empagliflozin if allergic to the drug or any ingredients in the formulation.1 14

  • Importance of taking empagliflozin exactly as directed by clinician.14 Importance of informing patients that if a dose is missed, it should be taken as soon as remembered; the dose should not be doubled to make up for the missed dose.1 14 (See Dosage and Administration: Administration.)

  • Importance of informing patients that renal function should be assessed prior to initiation of empagliflozin and monitored periodically thereafter.1

  • Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.1 14

  • 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.1 14

  • Importance of informing patients of other important precautionary information.1 (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.

Empagliflozin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

10 mg

Jardiance

Boehringer Ingelheim

25 mg

Jardiance

Boehringer Ingelheim

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Boehringer Ingelheim Pharmaceuticals, Inc. Jardiance (empagliflozin) tablets prescribing information. Ridgefield, CT; 2015 Jun.

2. Roden M, Weng J, Eilbracht J et al. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2013; 1:208-19. [PubMed 24622369]

3. Häring HU, Merker L, Seewaldt-Becker E et al. Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2014; 37:1650-9. [PubMed 24722494]

4. Häring HU, Merker L, Seewaldt-Becker E et al. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2013; 36:3396-404. [PubMed 23963895]

5. Ridderstråle M, Andersen KR, Zeller C et al. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol. 2014; 2:691-700. [PubMed 24948511]

6. Ridderstråle M, Svaerd R, Zeller C et al. Rationale, design and baseline characteristics of a 4-year (208-week) phase III trial of empagliflozin, an SGLT2 inhibitor, versus glimepiride as add-on to metformin in patients with type 2 diabetes mellitus with insufficient glycemic control. Cardiovasc Diabetol. 2013; 12:129. [PubMed 24007456]

7. Kovacs CS, Seshiah V, Swallow R et al. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab. 2014; 16:147-58. [PubMed 23906415]

8. Rosenstock J, Jelaska A, Frappin G et al. Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care. 2014; 37:1815-23. [PubMed 24929430]

9. Barnett AH, Mithal A, Manassie J et al. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014; 2:369-84. [PubMed 24795251]

10. Scheen AJ. Pharmacokinetic and pharmacodynamic profile of empagliflozin, a sodium glucose co-transporter 2 inhibitor. Clin Pharmacokinet. 2014; 53:213-25. [PubMed 24430725]

11. . Empagliflozin (Jardiance) for diabetes. Med Lett Drugs Ther. 2014; 56:99-100. [PubMed 25296258]

12. Jahagirdar V, Barnett AH. Empagliflozin for the treatment of type 2 diabetes. Expert Opin Pharmacother. 2014; 15:2429-41. [PubMed 25301180]

13. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 204629Orig1s000: Clinical Pharmacology and Biopharmaceutics Review(s). From FDA website.

14. Boehringer Ingelheim Pharmaceuticals, Inc. Jardiance (empagliflozin) tablets patient information.. 2015 Jun

39. US Food and Drug Administration. FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. From FDA website. Accessed 2015 July 6.

40. Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015; 38:1638-42. [PubMed 26294774]

41. Erondu N, Desai M, Ways K et al. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program. Diabetes Care. 2015; 38:1680-6. [PubMed 26203064]

42. Peters AL, Buschur EO, Buse JB et al. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015; 38:1687-93. [PubMed 26078479]

43. US Food and Drug Administration. FDA Drug Safety Communication: FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density. 2015 Sep 10. From FDA website. Accessed 2015 Sep 13.

44. DeFronzo RA, Lewin A, Patel S et al. Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diab Care. 2015 Mar; 38:384-93.

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