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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 cotransporter 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

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; 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, taken before first meal of day.1

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

Correct volume depletion in patients with this condition before initiation of canagliflozin therapy.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 (eGFR ≥60 mL/minute per 1.73 m2): No dosage adjustment necessary.1

Moderate renal impairment (eGFR 45 to <60 mL/minute per 1.73 m2): 100 mg once daily.1 Initiation not recommended if eGFR <45 mL/minute per 1.73 m2.1 Continued use not recommended in patients with eGFR persistently <45 mL/minute per 1.73 m2.1

Severe renal impairment (eGFR <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 (e.g., anaphylaxis, angioedema) to canagliflozin.1

  • Severe renal impairment (eGFR <30 mL/minute per 1.73 m2), end-stage renal disease, or on hemodialysis.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 canagliflozin therapy, consider factors that may predispose patients to ketoacidosis (e.g., pancreatic insulin deficiency, reduced caloric intake, alcohol abuse).1 50

Consider temporarily discontinuing SGLT2 inhibitor in patients with clinical situations known to predispose patients to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).1 50

Advise patients to monitor urine and/or plasma ketone levels if patients feel unwell (see Advice to Patients).1 40 42 50

Hypotension

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, patients receiving diuretics or drugs 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

Causes intravascular volume contraction and can cause renal impairment.1 51

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

Consider factors that may predispose patients to acute kidney injury, such as hypovolemia, chronic renal insufficiency, heart failure, concomitant medications (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIAs), prior to initiating canagliflozin therapy.1 51

Consider temporarily discontinuing canagliflozin in any setting of reduced oral intake (e.g., acute illness, fasting) or fluid losses (e.g., GI illness, excessive heat exposure).1 51

Monitor patients for acute kidney injury; monitor patients with an eGFR <60 mL/minute per 1.73 m2 more frequently.1 Discontinue canagliflozin and initiate appropriate treatment if such injury occurs.1 51

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

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 canagliflozin 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.1 43 Fractures observed as early as 12 weeks after initiation of canagliflozin treatment; more likely to affect the upper extremities and be associated with minor trauma (e.g., falls from no greater than standing height).1 43

Dose-related decreases in bone mineral density also observed in older adults (mean age: 64 years) receiving canagliflozin.1 43

Consider factors that contribute to fracture risk and counsel patients about such factors prior to initiating canagliflozin therapy.1 43

Effects on Lipoproteins

Dose-related increases in LDL-cholesterol can occur.1 Monitor serum lipid concentrations and treat if appropriate.1

Macrovascular Outcomes

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

Risk of Amputation

Interim analysis of data from an ongoing clinical study evaluating canagliflozin (Canagliflozin Cardiovascular Assessment Study [CANVAS]) revealed an increase in leg and foot amputations, mostly affecting the toes, in patients receiving the drug.52 53 A similar ongoing study has revealed no such increase in amputation risk.

FDA has not reached any conclusions about whether canagliflozin increases the risk of leg and foot amputations and is continuing to evaluate this potential risk.52

Instruct patients to seek medical attention if they experience new pain or tenderness, sores or ulcers, or infections in their legs or feet.52 (See Advice to Patients.)

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

Specific Populations

Pregnancy

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

Not recommended for use in the second or third trimesters of pregnancy.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 male genital mycotic infections,1 vulvovaginal pruritus,1 thirst,1 constipation,1 nausea.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 eGFR >60 mL/minute per 1.73 m2 who require additional glycemic control.1 Consider alternative antidiabetic agent in patients with an eGFR 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 and Laboratory Tests

Drug or Test

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 (see also Diuretics entry in this table.)

No dosage adjustment necessary1

Metformin

Increased canagliflozin and metformin AUCs and peak plasma concentrations1

No dosage adjustment necessary1

Phenobarbital

Possible decreased efficacy of canagliflozin1

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

For eGFR 45 to <60 mL/minute per 1.73 m2: consider alternative antidiabetic agent1

Phenytoin

Possible decreased efficacy of canagliflozin1

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

For eGFR 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

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

For eGFR 45 to <60 mL/minute per 1.73 m2: consider alternative antidiabetic agent1

Ritonavir

Possible decreased efficacy of canagliflozin1

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

For eGFR 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

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

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 (eGFR 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 (eGFR 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 (eGFR <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 17

  • 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 17

  • Importance of informing patients that ketoacidosis, which can be a life-threatening condition, has been reported with canagliflozin therapy.1 17 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 canagliflozin and seek medical attention immediately should they experience any such signs or symptoms.1 17 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 (i.e., <250 mg/dL).1 17 50

  • 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 17

  • Importance of informing patients that acute kidney injury has been reported with canagliflozin therapy.1 17 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 canagliflozin in those settings.1 51

  • Importance of informing patients that yeast infection may occur (e.g., vulvovaginitis, balanitis, balanoposthitis).1 17 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 17 Advise patients of treatment options and when to seek medical advice.1 17

  • Importance of informing patients of the potential for urinary tract infections, which may be serious.1 17 50 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 canagliflozin, patients taking the drug will test positive for glucose in their urine.1 Importance of not using urine glucose tests to monitor glycemic status.1

  • Risk of serious hypersensitivity reactions, such as rash, urticaria, and swelling of the face, lips, tongue, and throat that may result in difficulty breathing or swallowing.1 17 If signs or symptoms of such a reaction or anaphylaxis or angioedema occur , importance of discontinuing canagliflozin and informing clinician promptly.1 17

  • Importance of informing patients about the potential for bone fractures (e.g., hip, lumbar spine) and providing them with information about factors contributing to fracture risk.1 17 43

  • 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 17

  • Importance of seeking medical advice promptly during periods of stress such as fever, trauma, infection, or surgery as drug requirements may change.1 17

  • Instruct patients to notify their clinician if they experience new pain or tenderness, sores or ulcers, or infections involving their legs or feet and to seek medical attention should they experience such symptoms.

  • Importance of taking canagliflozin exactly as directed by clinician.1 17 Importance of patients not discontinuing canagliflozin without discussion with prescribing clinician.1 17 43

  • Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.1 17 Advise pregnant women and women of childbearing potential of the possible risk to a fetus with canagliflozin therapy.1 Advise women that breastfeeding is not recommended during canagliflozin therapy.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., diuretics, rifampin, phenytoin, phenobarbital, ritonavir, digoxin) and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1 17

  • Importance of informing patients of other important precautionary information.1 17 (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.

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 2017, Selected Revisions March 27, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Janssen Pharmaceuticals, Inc. Invokana (canagliflozin) tablets prescribing information. Titusville, NJ; 2016 May.

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]

17. Janssen Pharmaceuticals, Inc. Invokana (canagliflozin) tablets medication guide. Titusville, NJ; 2016 May.

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. 2015 May 15. 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.

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.

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.

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. Rosenstock J, Chuck L, González-Ortiz M et al. Initial Combination Therapy With Canagliflozin Plus Metformin Versus Each Component as Monotherapy for Drug-Naïve Type 2 Diabetes. Diabetes Care. 2016; 39:353-62. [PubMed 26786577]

50. US Food and Drug Administration. FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. From FDA website.

51. US Food and Drug Administration. FDA Drug Safety Communication: FDA strengthens kidney warnings for diabetes medicine canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). From FDA website.

52. US Food and Drug Administration. FDA Drug Safety Communication: Interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate. From FDA website.

53. Neal B, Perkovic V, de Zeeuw D et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)--a randomized placebo-controlled trial. Am Heart J. 2013; 166:217-223.e11. [PubMed 23895803]

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