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).

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

In patients with volume depletion not previously treated with canagliflozin, normalize volume status before initiating INVOKAMET/INVOKAMET XR.

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. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., cationic drugs such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving INVOKAMET/INVOKAMET XR.

Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including canagliflozin. Fatal cases of ketoacidosis have been reported in patients taking canagliflozin.

Reports of necrotizing fasciitis of the perineum (Fournier’s gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.

Canagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKAMET/INVOKAMET XR particularly in patients with eGFR less than 60 mL/min/1.73 m², elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure.

Canagliflozin causes intravascular volume contraction and can cause acute kidney injury. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving canagliflozin; some reports involved patients younger than 65 years of age.

Before initiating INVOKAMET/INVOKAMET XR, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing INVOKAMET/ INVOKAMET XR in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue INVOKAMET/INVOKAMET XR promptly and institute treatment.

Canagliflozin can lead to hyperkalemia.

An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET/INVOKAMET XR, in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.

Amputations of the toe and midfoot were most frequent; however, amputation involving the leg were also observed. Some patients had multiple amputations, some involving both limbs. Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.

Discontinue INVOKAMET/INVOKAMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 45 and 60 mL/min/1.73 m^2, 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.

INVOKAMET/INVOKAMET XR is contraindicated in patients with:

• 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

Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. INVOKAMET/ INVOKAMET XR should be temporarily discontinued while patients have restricted food and fluid intake.

There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including canagliflozin.

Canagliflozin increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections.

Long-term treatment with metformin has been associated with a decrease in vitamin B12, which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anemia). Patients with inadequate vitamin B12 or calcium intake or absorption may be predisposed to developing subnormal vitamin B12 levels, and routine serum vitamin B12 measurement at 2- to 3-year intervals is recommended in these patients.

An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using canagliflozin.

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with INVOKAMET/INVOKAMET XR may increase the risk for lactic acidosis.

Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis.

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving INVOKAMET/ INVOKAMET XR.

Drugs that are eliminated by renal tubular secretion (e.g. cationic drugs such as cimetidine) have the potential for interaction with metformin by competing for common renal tubular transport systems, and may increase the accumulation of metformin and the risk for lactic acidosis.

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.

Rifampin lowered canagliflozin exposure which may reduce the efficacy of INVOKAMET/INVOKAMET XR.

Canagliflozin increased digoxin exposure.

Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glycemic control.

Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

Based on animal data showing adverse renal effects, INVOKAMET/INVOKAMET XR is not recommended during the second and third trimesters of pregnancy. Because of the potential for serious adverse reactions in a breastfed infant, advise women that use of INVOKAMET/INVOKAMET XR is not recommended while breastfeeding.

Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.

GoToSource 

• Daily dose of canagliflozin greater than 300 mg and daily dose of metformin HCl greater than 2,000 mg in patients with an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 m² or greater. GoToSource

• Type 1 diabetes or diabetic ketoacidosis. GoToSource

• Use in patients under the age of 18. GoToSource

• Weight loss. GoToSource

Increased risk of bone fractures and decreased bone mineral density. GoToSource

Increased risk of falls. GoToSource

Ketoacidosis (excess blood acids/ketone bodies). GoToSource

Hypotension (low blood pressure). GoToSource 

Genital tract infections. GoToSource

Hypoglycemia (low blood sugar). GoToSource

Kidney injury. GoToSource

Hyperkalemia (elevated potassium), increased LDL-C and vitamin B12 deficiency. GoToSource 

Severe hypersensitivity reactions (anaphylaxis and angioedema) and photosensitivity reactions. GoToSource 

Fournier’s gangrene. GoToSource

Leg and foot amputations. GoToSource

Lawsuits filed for bone fractures, decreased bone density, ketoacidosis, fournier’s gangrene and kidney failure.