IMPORTANT SAFETY INFORMATION for INVOKANA^®, INVOKAMET^®, and INVOKAMET^® XR

CONTRAINDICATIONS

INVOKANA^® is contraindicated in patients with:

• Serious hypersensitivity reaction to INVOKANA^®, such as anaphylaxis or angioedema
• Patients on dialysis

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 INVOKANA^® 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 INVOKANA^® use 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 INVOKANA^® 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 INVOKANA® 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: INVOKANA^® 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 INVOKANA^®. 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 INVOKANA^®/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 INVOKANA®. 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 INVOKANA^®. Before initiating INVOKANA^®/INVOKAMET^®/INVOKAMET^® XR, consider factors in patient history that may predispose to ketoacidosis. For patients who undergo scheduled surgery, consider temporarily discontinuing INVOKANA^®/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 INVOKANA^®/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 INVOKANA^®/INVOKAMET^®/INVOKAMET^® XR. 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. INVOKANA^®/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 INVOKANA^®/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 INVOKANA^®. Serious outcomes have included hospitalization, multiple surgeries, and death. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INVOKANA^®/INVOKAMET^®/INVOKAMET^® XR.

• Genital Mycotic Infections: INVOKANA^®/INVOKAMET^®/INVOKAMET^® XR 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 INVOKANA^®; these reactions generally occurred within hours to days after initiation. If reactions occur, discontinue INVOKANA^®/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 INVOKANA^®. 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

• 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
  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 INVOKANA^®/INVOKAMET^®/INVOKAMET^® XR
  UGT Enzyme Inducers
  Co-administration with rifampin lowered canagliflozin exposure, which may reduce the efficacy of INVOKANA^®/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 INVOKANA^®/INVOKAMET^®/INVOKAMET^® XR, increase the dose of canagliflozin to 200 mg once daily in patients currently tolerating 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 INVOKANA^®/INVOKAMET^®/INVOKAMET^® XR, increase the dose of canagliflozin  to 200 mg once daily in patients currently tolerating canagliflozin 100 mg. Consider adding another antihyperglycemic agent in patients who require additional glycemic control.

  Digoxin
  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: INVOKANA^®/INVOKAMET^®/INVOKAMET^® XR is not recommended in pregnant women, especially during the second and third trimesters.
• Lactation: INVOKANA^®/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 INVOKANA^®/INVOKAMET^®/INVOKAMET^® XR in patients <18 years of age have not been established.
• Geriatric Use: Frequently monitor renal function after initiating INVOKANA^®/INVOKAMET^®/INVOKAMET^® XR in elderly patients and adjust dose accordingly.
  INVOKANA^®
  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.
  Metformin HCl
  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 INVOKANA^® 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 INVOKANA^® for glycemic control may be more likely to experience hypotension and may be at a higher risk for acute kidney injury. INVOKANA^® is contraindicated in patients with ESKD on dialysis. INVOKAMET^®/INVOKAMET^® XR is contraindicated in severe renal impairment (eGFR <30 mL/min/1.73 m²) or in patients on dialysis.
• Hepatic Impairment: INVOKANA^® has not been studied in patients with severe hepatic impairment and is not recommended in this population.

  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.

OVERDOSAGE

• In the event of an overdose with INVOKANA^®/INVOKAMET^®/INVOKAMET^® XR, contact the Poison Control Center. Employ the usual supportive measures.

ADVERSE REACTIONS

• The most common (≥5%) adverse reactions with INVOKANA^® 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.

Please read full Prescribing Information and Medication Guide for INVOKANA^®.

Please read full Prescribing Information for INVOKAMET^® and INVOKAMET^® XR, including Boxed WARNING, and Medication Guide for INVOKAMET^® and INVOKAMET^® XR.

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