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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 death (CV), 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.
WARNING: LACTIC ACIDOSIS
- Postmarketing 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/L); 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 (eg, carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
- Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information.
- If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET®/INVOKAMET® XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
INVOKAMET® and INVOKAMET® XR are contraindicated in patients with:
- Severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or on dialysis
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis
- Serious hypersensitivity reaction to canagliflozin or metformin HCl, such as anaphylaxis or angioedema
WARNINGS AND PRECAUTIONS
Lactic Acidosis: Postmarketing cases of metformin-associated lactic acidosis, including fatal cases, were reported. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis. Additional findings included elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate:pyruvate ratio, and metformin plasma levels generally >5 mcg/mL.
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of INVOKAMET®/INVOKAMET® XR. Prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin.
Educate patients and their families about the symptoms of lactic acidosis and if symptoms occur instruct them to discontinue INVOKAMET®/INVOKAMET® XR and report these symptoms to their healthcare provider.
Recommendations to reduce the risk include:
Renal Impairment: Obtain an eGFR before initiation and at least annually thereafter, and more frequently in patients at increased risk of renal impairment.
Drug Interactions: More frequent monitoring is recommended when administered with drugs that impair renal function, result in hemodynamic change, interfere with acid-base balance, or increase metformin accumulation (eg, cationic drugs).
Age 65 or Greater: Assess renal function more frequently in elderly patients.
Radiological Studies with Contrast: Stop INVOKAMET®/INVOKAMET® XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR <60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart INVOKAMET®/INVOKAMET® XR if renal function is stable.
Surgery and Other Procedures: Discontinue INVOKAMET®/INVOKAMET® XR while patients have restricted food and fluid intake.
Hypoxic States: Discontinue INVOKAMET®/INVOKAMET® XR in conditions associated with hypoxemia.
Excessive Alcohol Intake: Warn patients against excessive alcohol intake while receiving INVOKAMET®/INVOKAMET® XR.
Hepatic Impairment: Avoid use of INVOKAMET®/INVOKAMET® XR in patients with evidence of hepatic disease.
Lower-Limb Amputation: An increased risk of lower-limb amputations associated with canagliflozin, a component of INVOKAMET®/INVOKAMET® XR, versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1000 patient-years), two randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. The risk of lower-limb amputations was observed at both the 100-mg and 300-mg once-daily dosage regimens.
Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving canagliflozin in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving canagliflozin in the two trials). Some patients had multiple amputations, some involving both lower limbs.
Lower-limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy.
Before initiating, consider factors in the patient history that may predispose to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores, or ulcers involving the lower limbs, and discontinue if these complications occur.
- Volume Depletion: Canagliflozin can cause intravascular volume contraction, which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been postmarketing reports of acute kidney injury which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INVOKAMET®/INVOKAMET® XR in patients with one or more of these characteristics, assess and correct volume status. Monitor for signs and symptoms of volume depletion after initiating therapy.
- Ketoacidosis: Ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, has been identified in patients with type 1 and 2 diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. In placebo-controlled trials of patients with type 1 diabetes, the risk of ketoacidosis was increased in patients who received SGLT2 inhibitors compared to patients who received placebo. The risk of ketoacidosis may be greater with higher doses. Fatal cases of ketoacidosis have been reported in patients taking canagliflozin. Before initiating INVOKAMET®/INVOKAMET® XR, consider factors in patient history that may predispose to ketoacidosis. For patients who undergo scheduled surgery, consider temporarily discontinuing INVOKAMET®/INVOKAMET® XR for at least 3 days prior to surgery. Monitor for ketoacidosis and temporarily discontinue in other clinical situations known to predispose to ketoacidosis. Ensure risk factors for ketoacidosis are resolved prior to restarting therapy. Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue INVOKAMET®/INVOKAMET® XR and seek medical attention immediately if signs and symptoms occur.
- Urosepsis and Pyelonephritis: Serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization have been reported in patients receiving SGLT2 inhibitors, including canagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate for signs and symptoms and treat promptly.
Hypoglycemia With Concomitant Use of Sulfonylurea or Insulin: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKAMET®/ INVOKAMET® XR may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKAMET®/INVOKAMET® XR.
- Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Necrotizing fasciitis of the perineum, a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, has been identified in postmarketing surveillance in female and male patients with diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Serious outcomes have included hospitalization, multiple surgeries, and death. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INVOKAMET®/INVOKAMET® XR.
- Genital Mycotic Infections: Canagliflozin increases risk of genital mycotic infections, especially in uncircumcised males or patients with prior infections. Monitor and treat appropriately.
- Hypersensitivity Reactions: Hypersensitivity reactions, including angioedema and anaphylaxis, were reported with canagliflozin; these reactions generally occurred within hours to days after initiation. If reactions occur, discontinue INVOKAMET®/INVOKAMET® XR; treat and monitor until signs and symptoms resolve.
- Bone Fracture: Increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using canagliflozin. Prior to initiation, consider factors that contribute to fracture risk.
- Vitamin B12 Levels: Metformin HCl may lower vitamin B12 levels. Measure hematological parameters annually and vitamin B12 at 2- to 3-year intervals and manage any abnormalities.
Drug Interactions With Metformin
Carbonic Anhydrase Inhibitors
Topiramate or other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, or dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce lactic acidosis. Consider more frequent monitoring of these patients.
Drugs That Reduce Metformin Clearance
Drugs that are eliminated by renal tubular secretion (eg, cationic drugs such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase accumulation of metformin and risk for lactic acidosis.
Alcohol is known to potentiate the effect of metformin HCl on lactate metabolism. Warn patients against excessive alcohol intake while receiving INVOKAMET®/INVOKAMET® XR.
Drugs Affecting Glycemic Control
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. When such drugs are administered to a patient receiving INVOKAMET®/INVOKAMET® XR, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving INVOKAMET®/INVOKAMET® XR, the patient should be observed closely for hypoglycemia.
Drug Interactions With Canagliflozin
UGT Enzyme Inducers
Co-administration with rifampin lowered canagliflozin exposure, which may reduce the efficacy of INVOKAMET®/INVOKAMET® XR. For patients with eGFR ≥60 mL/min/1.73 m2, if an inducer of UGTs (eg, rifampin, phenytoin, phenobarbital, ritonavir) is co-administered with INVOKAMET®/INVOKAMET® XR, increase the dose of canagliflozin to 200 mg once daily in patients currently tolerating INVOKAMET®/INVOKAMET® XR with a total daily dose of canagliflozin 100 mg. The dose may be increased to 300 mg once daily in patients currently tolerating canagliflozin 200 mg and who require additional glycemic control.
For patients with eGFR <60 mL/min/1.73 m2, if an inducer of UGTs is co-administered with INVOKAMET®/INVOKAMET® XR, increase the total daily dose of canagliflozin to 200 mg once daily in patients currently tolerating canagliflozin 100 mg.
Canagliflozin increased digoxin exposure. Monitor patients with concomitant digoxin and adjust doses appropriately.
Drug/Laboratory Test Interference
Positive Urine Glucose Test
Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
Interference With 1,5-Anhydroglucitol (1,5-AG) Assay
Monitoring glycemic control with 1,5-AG assay is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
USE IN SPECIFIC POPULATIONS
- Pregnancy: INVOKAMET®/INVOKAMET® XR is not recommended in pregnant women, especially during the second and third trimesters.
- Lactation: INVOKAMET®/INVOKAMET® XR is not recommended while breastfeeding.
- Females and Males of Reproductive Potential: Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin HCl may result in ovulation in some anovulatory women.
- Pediatric Use: Safety and effectiveness of INVOKAMET®/INVOKAMET® XR in patients <18 years of age have not been established.
Geriatric Use: Frequently monitor renal function after initiating INVOKAMET®/INVOKAMET® XR in elderly patients and adjust dose accordingly.
Patients ≥65 years had a higher incidence of adverse reactions related to reduced intravascular volume, particularly with the 300-mg dose; more prominent increase in the incidence was seen in patients who were ≥75 years. Smaller reductions in HbA1c relative to placebo were seen in patients ≥65 years compared to younger patients.
The initial and maintenance dosing of metformin HCl should be conservative in elderly patients due to potential decreased renal function. Adjust dose based on assessment of renal function.
Renal Impairment: The efficacy and safety of canagliflozin for glycemic control were evaluated in a trial that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/1.73 m2). These patients had less overall glycemic efficacy, and patients treated with 300 mg per day had increases in serum potassium, which were transient and similar by the end of the study. Patients with renal impairment using canagliflozin for glycemic control may be more likely to experience hypotension and may be at a higher risk for acute kidney injury. Canagliflozin is contraindicated in patients with ESKD on dialysis and in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2) who are being treated for glycemic control.
INVOKAMET®/INVOKAMET® XR is contraindicated in severe renal impairment (eGFR <30 mL/min/1.73 m2) or in patients on dialysis.
- Hepatic Impairment: Metformin HCl use in patients with hepatic impairment has been associated with some cases of lactic acidosis. INVOKAMET®/INVOKAMET® XR is not recommended in patients with hepatic impairment.
- In the event of an overdose with INVOKAMET®/INVOKAMET® XR, contact the Poison Control Center. Employ the usual supportive measures.
- The most common (≥5%) adverse reactions associated with canagliflozin were female genital mycotic infections, urinary tract infections, and increased urination.
- The most common (≥5%) adverse reactions due to initiation of metformin HCl are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.