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.

Warnings and Precautions

Lactic Acidosis: There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. 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.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue INVOKAMET/INVOKAMET XR and report these symptoms to their healthcare provider.

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.

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 INVOKAMET/INVOKAMET XR, 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 receiving INVOKAMET/INVOKAMET XR for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue INVOKAMET/INVOKAMET XR if these complications occur.

Ketoacidosis: Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in clinical trials and postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (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. INVOKAMET/INVOKAMET XR is not indicated for the treatment of patients with type 1 diabetes mellitus.

Before initiating INVOKAMET/INVOKAMET XR consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse.

For patients who undergo scheduled surgery, consider temporarily discontinuing INVOKAMET/INVOKAMET XR for at least 3 days prior to surgery.

Consider monitoring for ketoacidosis and temporarily discontinuing INVOKAMET/INVOKAMET XR in other clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery). Ensure risk factors for ketoacidosis are resolved prior to restarting INVOKAMET/INVOKAMET XR.

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.

Volume Depletion: Canagliflozin can cause intravascular volume contraction which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been post-marketing 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.

Urosepsis and Pyelonephritis: There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including canagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated.

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): 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.

Genital Mycotic Infections

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. Monitor and treat appropriately.

Hypersensitivity Reactions

Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with canagliflozin. These reactions generally occurred within hours to days after initiating canagliflozin. If hypersensitivity reactions occur, discontinue use of INVOKAMET/INVOKAMET XR; treat and monitor until signs and symptoms resolve.

Bone Fracture: An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using canagliflozin in the CANVAS trial. Consider factors that contribute to fracture risk prior to initiating INVOKAMET/INVOKAMET XR.

Vitamin B12 Levels: In metformin HCl clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin HCl or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2-to 3-year intervals in patients on INVOKAMET/INVOKAMET XR and manage any abnormalities.

DRUG INTERACTIONS

Carbonic Anhydrase Inhibitors: 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/INVOKAMET XR may increase the risk for lactic acidosis.

Consider more frequent monitoring of these patients.

Examples: Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide)

Drugs That Reduce Metformin Clearance: 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 could increase systemic exposure to metformin and may increase the risk for lactic acidosis.

Consider the benefits and risks of concomitant use.

Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine

Alcohol: Alcohol is known to potentiate the effect of metformin HCl on lactate metabolism.

Warn patients against excessive alcohol intake while receiving INVOKAMET/INVOKAMET XR.

UGT Enzyme Inducers:UGT enzyme inducers decrease canagliflozin exposure which may reduce the effectiveness of INVOKAMET/INVOKAMET XR

For patients with eGFR 60 mL/min/1.73 m²or greater, if an inducer of UGTs is co-administered with INVOKAMET/INVOKAMET XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating INVOKAMET/INVOKAMET XR with a total daily dose of canagliflozin 100 mg. The total daily dose of canagliflozin may be increased to 300 mg in patients currently tolerating canagliflozin 200 mg and who require additional glycemic control.

For patients with eGFR less than 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 in patients currently tolerating canagliflozin 100 mg.

Examples: Rifampin, phenytoin, phenobarbital, ritonavir

Insulin Secretagogues or Insulin: The risk of hypoglycemia is increased when INVOKAMET/INVOKAMET XR is used concomitantly with insulin secretagogues (e.g., sulfonylurea) or insulin.

Concomitant use may require a lower dosage of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

Drugs Affecting Glycemic Control: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.

When such drugs are administered to a patient receiving INVOKAMET/INVOKAMET XR, monitor for loss of blood glucose control. When such drugs are withdrawn from a patient receiving INVOKAMET/INVOKAMET XR, monitor for hypoglycemia.

Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.

Digoxin: Canagliflozin increases digoxin exposure.

Monitor patients taking INVOKAMET/INVOKAMET XR with concomitant digoxin for a need to adjust dose of digoxin.

Lithium: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.

Monitor serum lithium concentration more frequently during INVOKAMET/INVOKAMET XR initiation and dosage changes.

Positive Urine Glucose Test: SGLT2 inhibitors increase urinary glucose excretion which will lead to positive urine glucose tests.

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

Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.

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: Based on animal data showing adverse renal effects from canagliflozin, INVOKAMET/INVOKAMET XR is not recommended during the second and third trimesters of pregnancy.

Limited data with INVOKAMET, INVOKAMET XR or canagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin HCl use during pregnancy have not reported a clear association with metformin HCl and major birth defect or miscarriage risk. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.

Lactation: There is no information regarding the presence of INVOKAMET, INVOKAMET XR or canagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk. However, there is insufficient information on the effects of metformin HCl on the breastfed infant and no available information on the effects of metformin HCl on milk production. Canagliflozin is present in the milk of lactating rats. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.

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.

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 pediatric patients under 18 years of age have not been established.

Hepatic Impairment: Use of metformin HCl 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.

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

Gafacom

INVOKAMET® (canagliflozin and metformin hydrochloride tablets) Warnings and Precautions for use

CONTRAINDICATIONS