Invokamet (Canagliflozin, Metformin Hydrochloride)

WHAT IS INVOKAMET?

• Improves glycemic control in adults with type 2 diabetes mellitus (T2DM) in addition to diet and exercise
• Decreases the risk of serious cardiovascular events (e.g. death, myocardial infarction, stroke) in adults with T2DM and cardiovascular disease (CVD)
• Decreases the risk of developing end-stage kidney disease (ESKD), serum creatinine doubling, death from cardiovascular causes, and hospitalization for heart failure in adults with T2DM and diabetic nephropathy with albuminuria over 300 mg/day

Controlling hyperglycemia prevents downstream complications such as kidney damage, loss of limbs, blindness, heart attack, stroke, or nerve problems. Cardiovascular and renal events in diabetes can also be detrimental. It is important that diabetes and related events remain controlled to lessen the chance of related complications. Invokamet is not indicated for the treatment of type 1 diabetes.

HOW DOES INVOKAMET WORK?

Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor. SGLT2 is a transporter that reabsorbs filtered glucose in the proximal renal tubules. Invokamet inhibits SGLT2, decreasing renal reabsorption of glucose and lessening the renal glucose threshold, which elevates the amount of glucose excreted into the urine. By preventing SGLT2-dependent reabsorption of glucose and sodium, Invokamet also increases the amount of sodium getting to the distal tubule. This elevates tubuloglomerular feedback and decreases intraglomerular pressure. Metformin is a biguanide that lowers the production of hepatic glucose, lowers absorption of glucose in the intestine, and improves insulin sensitivity through increasing peripheral glucose. Insulin release does not change with metformin, however, fasting levels of insulin and day-long plasma insulin response can be lowered.

SIDE EFFECTS

Common side effects include:

• Yeast infection
• Urination changes (e.g. increased urgency, increased frequency)
• Urinary tract infection
• Low blood sugar
• Hypersensitivity reactions
• Increased hemoglobin
• Limb injury
• Increased thirst
• Abdominal pain
• Constipation
• Diarrhea
• Flatulence
• Nausea and vomiting

WARNINGS AND PRECAUTIONS

Lower Limb Amputation

In clinical trials, there was a higher risk of lower limb amputations in the group treated with canagliflozin compared to the group treated with placebo. This risk occurred at both the 100 mg and 300 mg doses. The most common amputations were those of the toe and midfoot, however, amputations of the leg also occurred. A few patients also had to undergo multiple amputations.

Patients with a history of previous amputation, peripheral vascular disease, diabetic foot ulcers, or neuropathy should use caution when starting Invokamet. Patients should be counseled on preventative foot care and common signs of infection. If patients experience symptoms of infection, pain, ulcers, or sores in the lower limbs, Invokamet should be stopped.

Volume Depletion

Canagliflozin has been known to cause intravascular volume contraction which presents as hypotension or short-term changes to creatinine. Volume depletion has been shown to cause acute kidney injury (AKI) resulting in hospitalization and sometimes dialysis. Invokamet should be used with caution in patients with eGFR of less than 60 mL/min/1.73 m², elderly patients, or patients taking loop diuretics. These patients could have an elevated risk of developing hypotension and volume depletion. Providers should monitor patients for signs of volume depletion throughout treatment with Invokamet.

Ketoacidosis

Canagliflozin has been reported to cause ketoacidosis. Ketoacidosis is a severe, life-threatening event that needs immediate hospitalization and could be fatal. The risk of developing ketoacidosis is elevated with higher doses of SGLT2 inhibitors such as Invokamet.

Patients with symptoms associated with metabolic acidosis should be evaluated for the possibility of ketoacidosis without regard to blood glucose levels. Ketoacidosis can still be present despite blood glucose levels less than 250 mg/dL. Symptoms include signs of dehydration and metabolic acidosis, such as vomiting, nausea, malaise, shortness of breath, and abdominal pain. If suspected, Invokamet should be stopped, and the patient should be assessed and treated appropriately with insulin, carbohydrate replacement, and fluid.

A patient’s history should be evaluated prior to starting Invokamet, as pancreatic insulin deficiency, caloric restriction, and alcohol abuse could predispose an individual to ketoacidosis. Patients undergoing surgery should stop Invokamet 3 days prior to the surgery. If patients anticipate a clinical situation known to cause ketoacidosis, such as surgery or prolonged fasting, providers should consider stopping Invokamet.

Urosepsis and Pyelonephritis

Canagliflozin has caused cases of severe urinary tract infections involving urosepsis and pyelonephritis. Occurrences have sometimes required hospitalization. If a patient presents with signs of a urinary tract infection, they should be treated appropriately.

Hypoglycemia with Concomitant Use of Insulin Products

Invokamet can cause hypoglycemia when used in combination with other products that lower blood glucose, such as insulin. Dose adjustments to insulin may be required to prevent development of hypoglycemia. Patients should be counseled on common signs and symptoms of hypoglycemia.

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

Necrotizing fasciitis of the perineum, also known as Fournier’s gangrene, is a rare but potentially fatal infection that requires immediate intervention with surgery. Occurrences can result in hospitalization, surgeries, and death. Patients should be aware of the signs and symptoms associated with necrotizing fasciitis, such as pain, erythema, tenderness, or swelling of the genital or perineal area. Symptoms can also include malaise or fever.

If necrotizing fasciitis is suspected, providers should treat with broad-spectrum antibiotics and possibly surgical debridement. Invokamet should be stopped and blood glucose levels should be monitored.

Genital Mycotic Infections

Canagliflozin has been shown to elevate the risk of genital mycotic infections. Patients who have had genital mycotic infections in the past or who are uncircumcised males have a higher likelihood of developing genital mycotic infections. If suspected, providers should monitor and treat the patient appropriately.

Hypersensitivity Reactions

Canagliflozin has been shown to cause severe hypersensitivity reactions, including anaphylaxis and angioedema, within hours or days of starting therapy. If anaphylaxis or angioedema should occur, Invokamet should be stopped and the patient should seek medical attention.

Bone Fracture

Patients have an elevated risk of bone fracture after starting canagliflozin. This risk can be increased as early as 12 weeks after starting treatment. Providers should assess a patient’s risk factors for developing a fracture before starting Invokamet.

DRUG INTERACTIONS

Carbonic Anhydrase Inhibitors (CAI)

Carbonic anhydrase inhibitors can lower serum bicarbonate and cause non-anion gap metabolic acidosis. When used concomitantly with metformin, this combination can elevate an individual’s risk for developing lactic acidosis. Patients that are taking these drugs in combination should be frequently monitored. Examples of CAIs include topiramate and acetazolamide.

Alcohol

Patients should avoid excessive alcohol intake. Alcohol has been shown to increase metformin’s effect on lactate metabolism, causing increased risk for lactic acidosis.

UGT Enzyme Inducers

UGT inducers include drugs such as rifampin, ritonavir, phenobarbital, and phenytoin. In patients who are on a UGT inducer and have an eGFR of less than 60 mL/min/1.73 m², increase the dose of Invokamet to 200 mg daily in those already tolerating 100 mg.

Digoxin

When co-administered with digoxin, Invokamet has been shown to increase digoxin concentrations. Use caution when taking concomitantly and monitor appropriately to avoid digoxin toxicity.

Positive Urine Glucose Test

SGLT2 inhibitors such as Invokamet can elevate glucose excretion in the urine. This phenomenon will cause positive urine glucose tests if administered. Therefore, do not use urine glucose tests to monitor glycemic control in patients taking Invokamet.

Interference with 1,5-anhydroglucitol (1,5-AG) Assay

The 1,5-AG assay is not a reliable form of glycemic control monitoring in patients taking Invokamet. Other methods should be implemented to monitor glucose control in patients taking SGLT2 inhibitors.