INVOKAMET® (canagliflozin and metformin HCl)

INVOKAMET^®(canagliflozin and metformin HCl) and INVOKAMET^®XR (canagliflozin and metformin hydrochloride extended-release tablets) contain canagliflozin and metformin HCl.

Canagliflozin

Canagliflozin is an inhibitor of sodium-glucose co-transporter 2 (SGLT2), the transporter responsible for reabsorbing the majority of glucose filtered by the kidney. Canagliflozin is chemically known as (1S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4methylphenyl]-D-glucitol hemihydrate and its molecular formula and weight are C₂₄H₂₅FO₅S•1/2 H₂O and 453.53, respectively.

Metformin HCl

Metformin HCl is a biguanide chemically known as 1,1-Dimethylbiguanide hydrochloride and its molecular formula and weight are C₄H₁₁N₅● HCl and 165.62, respectively.

INDICATIONS AND USAGE

INVOKAMET and INVOKAMET XR are a combination of canagliflozin and metformin hydrochloride (HCl) indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Canagliflozin is indicated 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 is indicated to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day.

Limitations of Use

INVOKAMET/INVOKAMET XR is not recommended in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients.

Mechanism of Action

Canagliflozin

Sodium-glucose co-transporter 2 (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 (RTG), 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. Metformin HCl decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

DOSAGE AND ADMINISTRATION

Assess renal function before initiating INVOKAMET/INVOKAMET XR and as clinically indicated.
In patients with volume depletion, correct this condition before initiating INVOKAMET/INVOKAMET XR.

Dosage Overview

INVOKAMET dosing is one tablet, twice daily with meals.
INVOKAMET XR dosing is two tablets, once daily with the morning meal. Swallow each tablet whole and never crush, cut, or chew.
The starting and maintenance dose of INVOKAMET/INVOKAMET XR is based on the patient’s current regimen and renal function.
The maximum recommended daily dose is canagliflozin 300 mg and metformin HCl 2,000 mg in patients with an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 m²or greater.

Starting Dose Based on Patient’s Current Regimen

Individualize the starting dose of INVOKAMET/INVOKAMET XR based on the patient’s current regimen and renal function:

Patients Currently not Treated with Either Canagliflozin or Metformin HCl

INVOKAMET: One tablet, twice daily, each tablet containing canagliflozin 50 mg and metformin HCl 500 mg;
INVOKAMET XR: Two tablets, once daily, each tablet containing canagliflozin 50 mg and metformin HCl 500 mg.

Patients on Metformin HCl

INVOKAMET: One tablet, twice daily, where the total daily dose contains canagliflozin 100 mg and the same, or nearest appropriate, daily dose of metformin HCl;
INVOKAMET XR: Two tablets, once daily, where the total daily dose contains canagliflozin 100 mg and the patient’s same, or nearest appropriate, daily dose of metformin HCl.

Patients on Canagliflozin

INVOKAMET: One tablet, twice daily, where the total daily dose contains the same daily dose of canagliflozin and metformin HCl 1,000 mg;
INVOKAMET XR: Two tablets, once daily, where the total daily dose contains the patient’s same daily dose of canagliflozin and metformin HCl 1,000 mg.

Patients Already Treated with Canagliflozin and Metformin HCl

INVOKAMET: One tablet, twice daily, where the total daily dose contains the same daily dose of canagliflozin and the same, or nearest appropriate, daily dose of metformin HCl;
INVOKAMET XR: Two tablets, once daily, where the total daily dose contains the same daily dose of canagliflozin and the same, or nearest appropriate, daily dose of metformin HCl.

Patients with eGFR of 60 mL/min/1.73 m²or Greater and Require Additional Glycemic Control

INVOKAMET: For patients tolerating canagliflozin 50 mg twice daily, increase the dose of canagliflozin to 150 mg twice daily, with gradual metformin HCl dose escalation based on tolerability;
INVOKAMET XR: For patients tolerating a daily dose of canagliflozin 100 mg, increase the dose to 300 mg once daily, with gradual metformin HCl dose escalation based on tolerability

Patients on Evening Dose of Metformin HCl Extended-Release Tablets

Patients taking an evening dose of metformin HCl extended-release tablets should skip their last dose before starting INVOKAMET/INVOKAMET XR the following morning.

Recommended Dosage for Patients with Renal Impairment

Initiation of INVOKAMET or INVOKAMET XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m², due to the metformin component.

estimated Glomerular Filtration Rate eGFR (mL/min/1.73 m2)	Recommended Dosage
eGFR 60 or greater	See Dosage and Administration.
eGFR 45 to less than 60	Limit the dose of canagliflozin component to 100 mg daily (two 50 mg tablets).
eGFR 30 to less than 45	Assess the benefit risk of continuing INVOKAMET or INVOKAMET XR; limit the dose of canagliflozin component to 100 mg daily (two 50 mg tablets).
eGFR less than 30	Contraindicated; discontinue INVOKAMET or INVOKAMET XR.
On dialysis	Contraindicated.

Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue INVOKAMET/INVOKAMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR of less than 60 mL/min/1.73 m²; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart INVOKAMET/INVOKAMET XR if renal function is stable.

CONTRAINDICATIONS

INVOKAMET/INVOKAMET XR is contraindicated in patients:

With severe renal impairment (eGFR less than 30 mL/min/1.73 m²) or on dialysis.
With acute or chronic metabolic acidosis, including diabetic ketoacidosis.
With serious hypersensitivity reaction to canagliflozin or metformin HCl, such as anaphylaxis or angioedema.

OVERDOSAGE

Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin HCl use has been established. Lactic acidosis has been reported in approximately 32% of metformin HCl overdose cases.

In the event of an overdose with INVOKAMET/INVOKAMET XR, contact the Poison Control Center. Employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful partly for removal of accumulated metformin from patients in whom INVOKAMET/INVOKAMET XR overdosage is suspected.

KEYWORDS

canagliflozin/metformin
invokamet uses
canagliflozin/metformin dose
invokamet 150 mg/1000 mg
invokamet 150 mg/500 mg
invokamet dosage

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INVOKAMET® (canagliflozin and metformin HCl) Uses and Dosing

INVOKAMET® (canagliflozin and metformin HCl)