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INVOKAMET (Canagliflozin and Metformin Hydrochloride)

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INVOKAMET (Canagliflozin and Metformin Hydrochloride) HIGHLIGHTS OF PRESCRIBING INFORMATION ---------------------------WARNINGS AND PRECAUTIONS-------------------­ These highlights do not include all the information needed to use • Lactic acidosis: Warn against excessive alcohol use. INVOKAMET is not INVOKAMET® safely and effectively. See full prescribing information recommended in hepatic impairment or hypoxic states. Ensure normal renal for INVOKAMET. function before initiating and at least annually thereafter (5.1, 5.4, 5.7, 5.13, 5.14) INVOKAMET (canagliflozin and metformin hydrochloride) tablets, for • Hypotension: Before initiating INVOKAMET, assess volume status and oral use correct hypovolemia in patients with renal impairment, the elderly, in Initial U.S. Approval – 2014 patients with low systolic blood pressure, or on diuretics, ACEi, or ARB. Monitor for signs and symptoms during therapy (5.2) WARNING: LACTIC ACIDOSIS • Ketoacidosis: Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If See full prescribing information for complete boxed warning. suspected, discontinue INVOKAMET, evaluate and treat promptly. Before initiating INVOKAMET, consider risk factors for ketoacidosis. Patients on • Lactic acidosis can occur due to metformin accumulation. The risk INVOKAMET may require monitoring and temporary discontinuation of increases with conditions such as renal impairment, sepsis, therapy in clinical situations known to predispose to ketoacidosis (5.3) dehydration, excess alcohol intake, hepatic impairment, and acute • congestive heart failure (5.1) Impairment in renal function: Monitor renal function during therapy (5.4) • Radiological studies and surgical procedures: Temporarily discontinue for • Symptoms include malaise, myalgias, respiratory distress, increasing radiologic studies with intravascular administration of iodinated contrast somnolence, and nonspecific abdominal distress. Laboratory materials or any surgical procedures necessitating restricted intake of food abnormalities include low pH, increased anion gap, and elevated blood and fluids (5.4) lactate (5.1) • Hyperkalemia: Monitor potassium levels in patients with impaired renal function and in patients predisposed to hyperkalemia (2.2, 5.5, 6.1, 8.6) • If acidosis is suspected, discontinue INVOKAMET and hospitalize the • Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of patient immediately (5.1) urinary tract infections and treat promptly, if indicated (5.6) • Hypoglycemia: Consider a lower dose of insulin or the insulin -------------------------RECENT MAJOR CHANGES----------------------------­ secretagogue to reduce the risk of hypoglycemia when used in combination Contraindications (4) 03/2016 with INVOKAMET (5.8) Warnings and Precautions (5.3) 12/2015 • Genital mycotic infections: Monitor and treat if indicated (5.9) Warnings and Precautions (5.6) 12/2015 • Hypersensitivity reactions: Discontinue INVOKAMET and monitor until Warnings and Precautions (5.10) 03/2016 signs and symptoms resolve (5.10) Warnings and Precautions (5.11) 09/2015 • Bone fracture: Consider factors that contribute to fracture risk before initiating INVOKAMET (5.11) ----------------------------INDICATIONS AND USAGE--------------------------­ • Vitamin B12 deficiency: Metformin may lower vitamin B12 levels. Monitor INVOKAMET is a sodium-glucose co-transporter 2 (SGLT2) inhibitor and hematologic parameters annually (5.12) biguanide combination product indicated as an adjunct to diet and exercise to • Increased LDL-C: Monitor LDL-C and treat if appropriate (5.15) improve glycemic control in adults with type 2 diabetes mellitus who are not adequately controlled on a regimen containing metformin or canagliflozin or ------------------------------ADVERSE REACTIONS---------------------------­ in patients already being treated with both canagliflozin and metformin (1) • Most common adverse reactions associated with canagliflozin (5% or greater incidence): female genital mycotic infections, urinary tract Limitation of use: infection, and increased urination (6.1) Not for treatment of type 1 diabetes or diabetic ketoacidosis (1) • Most common adverse reactions associated with metformin (5% or greater incidence) are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, -----------------------DOSAGE AND ADMINISTRATION----------------------­ abdominal discomfort, and headache (6.1) • Individualize based on the patient’s current regimen (2) • Take twice daily with meals, with gradual dose escalation to reduce the To report SUSPECTED ADVERSE REACTIONS, contact Janssen gastrointestinal side effects due to metformin (2.1) Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or • Do not exceed a daily dose of metformin 2,000 mg and canagliflozin www.fda.gov/medwatch. 300 mg; INVOKAMET is limited to canagliflozin 50 mg twice daily in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 (2.1, 2.2) ------------------------------DRUG INTERACTIONS-----------------------------­ • Assess renal function before initiating INVOKAMET. Do not initiate or • Cationic drugs: May reduce metformin elimination (7.1) continue INVOKAMET if creatinine levels are greater than or equal to • UGT inducers (e.g., rifampin): Canagliflozin exposure is reduced. Consider 1.5 mg/dL for males or 1.4 mg/dL for females, or if eGFR is persistently increasing canagliflozin dose from 50 mg to 150 mg twice daily (2.3, 7.2) below 45 mL/min/1.73 m2 (2.2, 4) • Digoxin: Monitor digoxin levels (7.2) --------------------DOSAGE FORMS AND STRENGTHS---------------------­ Film-coated tablets: -----------------------USE IN SPECIFIC POPULATIONS----------------------­ • Pregnancy: Use during pregnancy only if the potential benefit justifies the • Canagliflozin 50 mg and metformin hydrochloride 500 mg potential risk to the fetus (8.1) • Canagliflozin 50 mg and metformin hydrochloride 1,000 mg • Nursing mothers: Discontinue drug or nursing (8.3) • Canagliflozin 150 mg and metformin hydrochloride 500 mg • Geriatrics: Higher incidence of adverse reactions related to reduced • Canagliflozin 150 mg and metformin hydrochloride 1,000 mg (3) intravascular volume (5.2, 6.1, 8.5) • Renal impairment: Higher incidence of adverse reactions related to reduced -------------------------------CONTRAINDICATIONS-----------------------------­ intravascular volume and renal function (2.2, 5.4, 8.6) • Renal impairment, ESRD, or on dialysis (4, 5.1, 5.4) • Metabolic acidosis, including diabetic ketoacidosis (1, 4, 5.1) See 17 for PATIENT COUNSELING INFORMATION and Medication • History of serious hypersensitivity reaction to canagliflozin or Guide. metformin (4, 5.10) Revised: 03/2016 2.2 Recommended Dosage for Patients with Renal FULL PRESCRIBING INFORMATION: CONTENTS* Impairment WARNING: LACTIC ACIDOSIS 2.3 Concomitant Use with UDP-Glucuronosyl 1 INDICATIONS AND USAGE Transferase (UGT) Enzyme Inducers 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 2.1 Recommended Dosage 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 1 Reference ID: 3907899 5.1 Lactic Acidosis 11 DESCRIPTION 5.2 Hypotension 12 CLINICAL PHARMACOLOGY 5.3 Ketoacidosis 12.1 Mechanism of Action 5.4 Impairment in Renal Function 12.2 Pharmacodynamics 5.5 Hyperkalemia 12.3 Pharmacokinetics 5.6 Urosepsis and Pyelonephritis 13 NONCLINICAL TOXICOLOGY 5.7 Impaired Hepatic Function 13.1 Carcinogenesis, Mutagenesis, Impairment of 5.8 Hypoglycemia with Concomitant Use of Fertility Sulfonylurea or Insulin 13.2 Animal Toxicology and/or Pharmacology 5.9 Genital Mycotic Infections 14 CLINICAL STUDIES 5.10 Hypersensitivity Reactions 14.1 Canagliflozin as Add-on Combination Therapy 5.11 Bone Fracture with Metformin 5.12 Vitamin B12 Levels 14.2 Canagliflozin Compared to Glimepiride, Both as 5.13 Alcohol Intake Add-on Combination Therapy with Metformin 5.14 Hypoxic States 14.3 Canagliflozin as Add-on Combination Therapy 5.15 Increases in Low-Density Lipoprotein (LDL-C) with Metformin and Sulfonylurea 5.16 Macrovascular Outcomes 14.4 Canagliflozin Compared to Sitagliptin, Both as 6 ADVERSE REACTIONS Add-on Combination Therapy with Metformin and 6.1 Clinical Studies Experience Sulfonylurea 6.2 Postmarketing Experience 14.5 Canagliflozin as Add-on Combination Therapy 7 DRUG INTERACTIONS with Metformin and Pioglitazone 7.1 Drug Interactions with Metformin 14.6 Canagliflozin as Add-on Combination Therapy 7.2 Drug Interactions with Canagliflozin with Insulin (With or Without Other 8 USE IN SPECIFIC POPULATIONS Anti-Hyperglycemic Agents, Including Metformin) 8.1 Pregnancy 16 HOW SUPPLIED/STORAGE AND HANDLING 8.3 Nursing Mothers 17 PATIENT COUNSELING INFORMATION 8.4 Pediatric Use 8.5 Geriatric Use *Sections or subsections omitted from the full prescribing information are 8.6 Renal Impairment not listed. 10 OVERDOSAGE 2 Reference ID: 3907899 FULL PRESCRIBING INFORMATION WARNING: LACTIC ACIDOSIS • Lactic acidosis is a rare but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure. • The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. • Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. • If lactic acidosis is suspected, INVOKAMET® should be discontinued and the patient hospitalized immediately [see Warnings and Precautions
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