Invokana

Generic Name: Canagliflozin
Class: Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors
Chemical Name: (1S)-Hydrate (2:1), 1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-d-glucitol
Molecular Formula: C24H25FO5S·½H2O
CAS Number: 928672-86-0

Introduction

Antidiabetic agents; sodium–glucose co-transporter 2 (SGLT2) inhibitor.1 15

Uses for Invokana

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 11

Slideshow: Flashback: FDA Drug Approvals 2013

Used in combination with other antidiabetic agents (e.g., metformin, a sulfonylurea, a peroxisome proliferator-activated receptorγ [PPARγ] agonist [thiazolidinedione]) 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 10

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

Invokana Dosage and Administration

Administration

Oral Administration

Administer once daily, before the first meal of the day.1

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

Dosage

Dosage expressed in terms of anhydrous canagliflozin.1

Adults

Diabetes Mellitus
Oral

Initially, 100 mg once daily.1

If well tolerated, increase dosage to 300 mg once daily in patients with an estimated GFR ≥ 60 mL/minute per 1.73 m2 who require additional glycemic control.1

Special Populations

Hepatic Impairment

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

Severe hepatic impairment: Data lacking; use not recommended.1

Renal Impairment

Mild renal impairment (estimated GFR ≥60 mL/minute per 1.73 m2): No dosage adjustment necessary.1

Moderate renal impairment (estimated GFR 45 to <60 mL/minute per 1.73 m2): 100 mg once daily.1 Do not initiate if GFR <45 mL/minute per 1.73 m2.1 If GFR is persistently <45 mL/minute per 1.73 m2, discontinue canagliflozin.1

Severe renal impairment (estimated GFR <30 mL/minute per 1.73 m2): Contraindicated.1

Geriatric Patients

No specific dosage recommendations.1

Cautions for Invokana

Contraindications

  • History of serious hypersensitivity reaction to canagliflozin.1

  • Severe renal impairment (estimated GFR <30 mL/minute per 1.73 m2), end-stage renal disease, or on hemodialysis.1

Warnings/Precautions

Hypotension

May cause intravascular volume contraction.1 Symptomatic hypotension can occur, particularly in patients with impaired renal function (estimated GFR <60 mL/minute per 1.73 m2), geriatric patients, patients receiving diuretics or medications that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists), or patients with low systolic BP.1 Assess and correct intravascular volume prior to initiating canagliflozin in such patients.1

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

Renal Effects

May increase Scr concentration and decrease estimated GFR; hypovolemic patients may be more susceptible.1 Renal function abnormalities can occur following initiation.1

Monitor patients with an estimated GFR <60 mL/minute per 1.73 m2 more frequently.1

Hyperkalemia

May cause hyperkalemia, particularly in patients with moderate renal impairment who are taking drugs that interfere with potassium excretion (e.g., potassium-sparing diuretics) or drugs that interfere with the renin-angiotensin-aldosterone system.1

Monitor serum potassium concentrations periodically following initiation in patients with impaired renal function and those predisposed to hyperkalemia due to drug therapy or other medical conditions.1

Concomitant Therapy with Hypoglycemic Agents

When adding canagliflozin 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 under Interactions.)

Genital Mycotic Infections

Possible increased risk of genital mycotic infections (e.g., balanoposthitis, candidal balanitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis).1 Patients with a history of genital mycotic infections and uncircumcised males more likely to develop genital mycotic infections.1

Monitor patients for such infections and institute appropriate treatment if infections occur.1

Sensitivity Reactions

Hypersensitivity reactions (e.g., generalized urticaria), some serious, reported.1 Discontinue the drug if hypersensitivity reaction occurs, institute appropriate treatment, and monitor patients until signs and symptoms resolve.1

Effects on Lipoproteins

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

Macrovascular Outcomes

Evidence of macrovascular risk reduction with canagliflozin 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

Reduced efficacy compared with younger patients, which may be related to decreased renal function in geriatric patients.1 8 Such patients more likely to experience certain adverse effects related to reduced intravascular volume (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, dehydration), particularly with canagliflozin 300 mg daily.1 8

Hepatic Impairment

No dosage adjustment necessary in patients with mild or moderate hepatic impairment.1

Not studied in severe hepatic impairment (Child-Pugh class C); use not recommended.1

Renal Impairment

No dosage adjustment necessary in patients with mild renal impairment.1 Dosage adjustment recommended in patients with moderate renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Contraindicated in patients with severe renal impairment, end-stage renal disease, or on hemodialysis.1

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

Common Adverse Effects

Female genital mycotic infections,1 urinary tract infection,1 increased urination.1

Interactions for Invokana

Major metabolic elimination pathway is O-glucuronidation; mainly glucuronidated by uridine disphosphoglucuronosyltransferase (UGT) isoenzymes UGT1A9 and UGT2B4.1

P-glycoprotein substrate and weak P-glycoprotein inhibitor.1 Also a substrate of MRP2.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Did not induce CYP-450 isoenzymes 3A4, 2C9, 2C19, 2B6, or 1A2 in cultured human hepatocytes; did not inhibit CYP1A2, 2A6, 2C19, 2D6, or 2E1 but weakly inhibits CYP2B6, 2C8, 2C9, and 3A4 in human hepatic microsomes.1

UGT Enzyme Inducers

Concomitant use of canagliflozin with an inducer of UGT enzymes may decrease the efficacy of canagliflozin.1 If concomitant use with an inducer of these UGT isoenzymes cannot be avoided, consider increasing the daily dosage of canagliflozin to 300 mg once daily in patients currently tolerating 100 mg once daily with an estimated GFR >60 mL/minute per 1.73 m2 who require additional glycemic control.1 Consider alternative antidiabetic agent in patients with an estimated GFR of 45 to <60 mL/minute per 1.73 m2 receiving concomitant therapy with a UGT inducer who require additional glycemic control.1

Specific Drugs

Drug

Interaction

Comments

ACE inhibitors

May increase the incidence of symptomatic hypotension1

May cause hyperkalemia in patients with moderate renal impairment1

Assess and correct intravascular volume prior to canagliflozin initiation; monitor for signs and symptoms of hypotension after initiating therapy1

Monitor serum potassium concentrations periodically in patients predisposed to hyperkalemia due to drug therapy1

Acetaminophen

Increased acetaminophen AUC1

No adjustment of acetaminophen dosage necessary1

Angiotensin II receptor antagonists

May increase the incidence of symptomatic hypotension1

May cause hyperkalemia in patients with moderate renal impairment1

Assess and correct intravascular volume prior to canagliflozin initiation; monitor for signs and symptoms of hypotension after initiating therapy1

Monitor serum potassium concentrations periodically in patients predisposed to hyperkalemia due to drug therapy1

Antidiabetic agents

Risk of hypoglycemia increased when canagliflozin is used concomitantly with a sulfonylurea or insulin1

Glyburide (single dose) with concomitant canagliflozin increased glyburide AUC and decreased peak plasma glyburide concentration1

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

No adjustment of glyburide dosage necessary1

Cyclosporine

Increased cyclosporine AUC and peak plasma concentration1

No adjustment of canagliflozin dosage necessary1

Digoxin

Increased AUC and peak plasma concentration of digoxin1

Monitor appropriately when canagliflozin and digoxin used concomitantly1

Diuretics

Risk of hypotension may be increased when canagliflozin is used concomitantly with diuretics1

Potassium-sparing diuretics: Patients with moderate renal impairment receiving concomitant canagliflozin and potassium-sparing diuretics more likely to develop hyperkalemia1

Assess and correct intravascular volume prior to canagliflozin initiation; monitor for signs and symptoms of hypotension after initiating therapy1

Monitor serum potassium concentrations periodically in patients predisposed to hyperkalemia due to drug therapy1

Hormonal contraceptives

Increased AUCs and peak plasma concentrations of ethinyl estradiol and levonorgestrel; decreased canagliflozin AUC and peak plasma concentration1

No dosage adjustment necessary1

Hydrochlorothiazide

Increased canagliflozin AUC and peak plasma concentration; decreased hydrochlorothiazide AUC and peak plasma concentration1

No dosage adjustment necessary1

Metformin

Increased canagliflozin and metformin AUCs and peak plasma concentrations1

No dosage adjustment necessary1

Phenobarbital

Possible decreased efficacy of canagliflozin1

Estimated GFR >60 mL/minute per 1.73 m2: if concomitant use cannot be avoided, increase canagliflozin to 300 mg once daily1

Estimated GFR 45 to <60 mL/minute per 1.73 m2: consider alternative antidiabetic agent1

Phenytoin

Possible decreased efficacy of canagliflozin1

Estimated GFR >60 mL/minute per 1.73 m2: if concomitant use cannot be avoided, increase canagliflozin to 300 mg once daily1

Estimated GFR 45 to <60 mL/minute per 1.73 m2: consider alternative antidiabetic agent1

Probenecid

Increased canagliflozin AUC and peak plasma concentration

No adjustment of canagliflozin dosage necessary1

Rifampin

Concomitant administration decreased canagliflozin AUC and peak plasma concentration1

Possible decreased efficacy of canagliflozin1

Estimated GFR >60 mL/minute per 1.73 m2: if concomitant use cannot be avoided, increase canagliflozin to 300 mg once daily1

Estimated GFR 45 to <60 mL/minute per 1.73 m2: consider alternative antidiabetic agent1

Ritonavir

Possible decreased efficacy of canagliflozin1

Estimated GFR >60 mL/minute per 1.73 m2: if concomitant use cannot be avoided, increase canagliflozin to 300 mg once daily1

Estimated GFR 45 to <60 mL/minute per 1.73 m2: consider alternative antidiabetic agent1

Simvastatin

Increased simvastatin AUC and peak plasma concentration1

No adjustment of simvastatin dosage necessary1

Warfarin

Slightly increased R- and S-warfarin AUC and peak plasma concentrations1

No adjustment of warfarin dosage necessary1

Invokana Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations usually attained within 1–2 hours after oral dosing.1 12 Mean absolute oral bioavailability approximately 65%.1

Food

Administration with a high-fat meal had no effect on canagliflozin pharmacokinetics.1 However, based on the drug's potential to reduce postprandial plasma glucose excursions due to delayed intestinal glucose absorption, take canagliflozin with the first meal of the day.1

Specific Populations

Mild hepatic impairment (Child-Pugh class A): AUC and peak plasma concentration increased by 10 and 7%, respectively, compared with individuals with normal hepatic function.1

Moderate hepatic impairment (Child-Pugh class B): AUC increased by 11% and peak plasma concentration decreased by 4% compared with individuals with normal hepatic function.1

Mild renal impairment (estimated GFR 60 to <90 mL/minute per 1.73 m2): AUC increased by 15%, compared with healthy individuals following a single 200-mg dose of the drug.1

Moderate renal impairment (estimated GFR 30 to <60 mL/minute per 1.73 m2): AUC increased by 29% compared with healthy individuals following a single 200-mg dose of the drug.1

Severe renal impairment (estimated GFR <30 mL/minute per 1.73 m2): AUC was increased by 53% compared with healthy individuals following a single 200-mg dose of the drug.1

Distribution

Extent

Extensively distributes into tissues.1

Plasma Protein Binding

99% (mainly to albumin).1

Specific Populations

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

Elimination

Metabolism

Metabolized principally via O-glucuronidation by UGT1A9 and UGT2B4 to inactive metabolites.1

Elimination Route

41.5, 7, and 3% recovered in feces as canagliflozin, a hydroxylated metabolite, and an O-glucuronide metabolite, respectively.1

33% excreted in urine; 30.5% as O-glucuronide metabolite and <1% as unchanged drug.1

Half-life

Terminal elimination half-life was 10.6 and 13.1 hours for single doses of 100 and 300 mg, respectively.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Inhibits SGLT2, a transporter expressed in proximal renal tubules and responsible for majority of reabsorption of filtered glucose from tubular lumen.1 14

  • Reduces reabsorption of filtered glucose and lowers the renal threshold for glucose in a dose-dependent manner, leading to increased urinary glucose excretion.1 12 13

  • Increases glucose excretion independent of insulin secretion.14

  • May delay oral glucose absorption through transient inhibition of SGLT1 in the intestinal lumen.13 14

Advice to Patients

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

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

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

  • Importance of informing patients that yeast infection may occur (e.g., vulvovaginitis, balanitis, balanoposthitis).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).1 Advise patients of treatment options and when to seek medical advice.1

  • Importance of informing patients that due to the mechanism of action of canagliflozin, patients taking the drug will test positive for glucose in their urine.1

  • Risk of serious hypersensitivity reactions, such as urticaria and rash.1 If signs or symptoms of such a reaction or angioedema occur , importance of discontinuing canagliflozin and informing clinician promptly.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

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

  • Importance of taking canagliflozin exactly as directed by clinician.1 (See Administration under Dosage and Administration.)

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

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., diuretics, rifampin, phenytoin, phenobarbital, ritonavir, digoxin) and dietary or herbal supplements, as well as any concomitant illnesses.1

  • 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.

Canagliflozin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet, film-coated

100 mg (of anhydrous canagliflozin)

Invokana

Janssen

300 mg (of anhydrous canagliflozin)

Invokana

Janssen

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 25, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Janssen Pharmaceuticals, Inc. Invokana (canagliflozin) tablets prescribing information. Titusville, NJ; 2013 Mar.

2. Stenlöf K, Cefalu WT, Kim KA et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013; 15:372-82. [PubMed 23279307]

3. Cefalu WT, Leiter LA, Yoon KH et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013; :. [PubMed 23850055]

4. Fulcher G, Matthews DR, Perkovic V et al. Canagliflozin (CANA) in subjects with type 2 diabetes mellitus (T2DM) inadequately controlled on sulfonylurea (SU) monotherapy: a CANVAS study. Abstract presented at 73rd annual American Diabetes Association scientific sessions. Chicago, IL, 2013 June 21-5. Abstract No. 1124-P.

5. Wilding JP, Mathieu C, Vercruysse F et al. Canagliflozin (CANA), a sodium glucose co-transporter 2 inhibitor, improves glycemic control and reduced body weight in subjects with type 2 diabetes (T2D) inadequately controlled with metformin (MET) and sulfonylurea (SU). Abstract presented at 72rd annual American Diabetes Association scientific sessions. Philadelphia, PA, 2012 June 8-12. Abstract No. 1022-P.

6. Schernthaner G, Gross JL, Rosenstock J et al. Canagliflozin Compared With Sitagliptin for Patients With Type 2 Diabetes Who Do Not Have Adequate Glycemic Control With Metformin Plus Sulfonylurea: A 52-week randomized trial. Diabetes Care. 2013; :.

7. Forst T, Guthrie R, Goldenberg R, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes on metformin and pioglitazone. Abstract presented at 4th World Congress on controversies to consensus in diabetes, obesity, and hypertension (CODHy). Barcelona, Spain, 2012 Nov 8-11.

8. Bode B, Stenlöf K, Sullivan D et al. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract (1995). 2013; 41:72-84. [PubMed 23680739]

9. Yale JF, Bakris G, Cariou B et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013; 15:463-73. [PubMed 23464594]

10. Devineni D, Morrow L, Hompesch M et al. Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes Obes Metab. 2012; 14:539-45. [PubMed 22226086]

11. Inagaki N, Kondo K, Yoshinari T et al. Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, 12-week study. Diabetes Obes Metab. 2013; :. [PubMed 23782594]

12. Devineni D, Curtin CR, Polidori D et al. Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in subjects with type 2 diabetes mellitus. J Clin Pharmacol. 2013; 53:601-10. [PubMed 23670707]

13. Polidori D, Sha S, Mudaliar S et al. Canagliflozin Lowers Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption in Addition to Increasing Urinary Glucose Excretion: Results of a randomized, placebo-controlled study. Diabetes Care. 2013; 36:2154-61. [PubMed 23412078]

14. Riser Taylor S, Harris KB. The Clinical Efficacy and Safety of Sodium Glucose Cotransporter-2 Inhibitors in Adults with Type 2 Diabetes Mellitus. Pharmacotherapy. 2013; :. [PubMed 23744749]

15. Nomura S, Sakamaki S, Hongu M et al. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J Med Chem. 2010; 53:6355-60. [PubMed 20690635]

16. Rosenstock J, Aggarwal N, Polidori D et al. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care. 2012; 35:1232-8. [PubMed 22492586]

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