Canagliflozin and Metformin

INVOKAMET INVOKAMET is a combination of canagliflozin and metformin HCl immediate-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. INVOKAMET XR INVOKAMET XR is a combination of canagliflozin and metformin HCl extended-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. Canagliflozin Canagliflozin, when used as a component of INVOKAMET or INVOKAMET XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of: Major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD).

Canagliflozin SGLT2, expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RT G ), and thereby increases urinary glucose excretion (UGE). Canagliflozin increases the delivery of sodium to the distal tubule by blocking SGLT2-dependent glucose and sodium reabsorption. This is believed to increase tubuloglomerular feedback and reduce intraglomerular pressure. Metformin HCl Metformin HCl is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose.

Assess renal function before initiating and as clinically indicated. Assess volume status and correct volume depletion before initiating. Individualize starting dose based on the patient's current regimen and renal function. See Table 1 in the full prescribing information for recommended starting dosages based on the current regimen. The maximum recommended total daily dosage is 300 mg of canagliflozin and 2,000 mg of metformin HCl. Initiation of INVOKAMET or INVOKAMET XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m 2, due to the metformin HCl component. INVOKAMET: take one tablet orally twice daily with meals. INVOKAMET XR: take two tablets orally once daily with the morning meal. Swallow whole. Never crush, cut, or chew.

INVOKAMET or INVOKAMET XR is contraindicated in patients with: Severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ). Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Serious hypersensitivity reaction to canagliflozin or metformin HCl, such as anaphylaxis or angioedema. Severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ). Metabolic acidosis, including diabetic ketoacidosis. Serious hypersensitivity reaction to canagliflozin or metformin HCl

Boxed warning (lactic acidosis): Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue INVOKAMET or INVOKAMET XR if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. Lower Limb Amputation: Monitor patients for infection or ulcers of lower limb and institute appropriate treatment.

The following important adverse reactions are also discussed elsewhere in the labeling: Lactic Acidosis Diabetic Ketoacidosis in Patients with Type 1 Diabetes and Other Ketoacidosis Lower Limb Amputation Volume Depletion Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Hypersensitivity Reactions Bone Fracture Vitamin B 12 Deficiency Most common adverse reactions associated with canagliflozin (5% or greater incidence): female genital mycotic infections, urinary tract infection, and increased urination. Most common adverse reactions associated with metformin HCl (5% or greater incidence) are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.

Table 8: Clinically Significant Drug Interactions with INVOKAMET or INVOKAMET XR Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with INVOKAMET or INVOKAMET XR may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients.

Store at 20 °C to 25 °C (68 °F to 77 °F), excursions permitted between 15 °C to 30°C (59 °F to 86 °F). Store and dispense in the original container. Storage in a pill box or pill organizer is allowed for up to 30 days.