Safety

Invokamet (canagliflozin and metformin HCl) Tablets

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)

May 2016

Summary View

BOXED WARNING

WARNING: LACTIC ACIDOSIS

  • 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.
  • 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 and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

CONTRAINDICATIONS

  • Moderate to severe renal impairment (eGFR below 45 mL/min/1.73 m2), end stage renal disease (ESRD), or patients on dialysis.

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. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.
  • If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of INVOKAMET. In INVOKAMET-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.
  • Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue INVOKAMET and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney.

  • Before initiating INVOKAMET, obtain an estimated glomerular filtration rate (eGFR).
  • INVOKAMET is contraindicated in patients with an eGFR less than 45 mL/minute/1.73 m2.
  • Obtain an eGFR at least annually in all patients taking INVOKAMET. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

Drug Interactions: The concomitant use of INVOKAMET with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g. cationic drugs) [see Drug Interactions (7)]. Therefore, consider more frequent monitoring of patients.

Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.

Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop INVOKAMET 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 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 if renal function is stable.

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

Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotemia. When such events occur, discontinue INVOKAMET.

Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving INVOKAMET.

Hepatic Impairment: Patients with hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of INVOKAMET in patients with clinical or laboratory evidence of hepatic disease.

Acute Kidney Injury and Impairment in Renal Function
  • Canagliflozin causes intravascular volume contraction and can cause renal impairment. 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, 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 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 promptly and institute treatment.
  • Canagliflozin increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKAMET [see Adverse Reactions (6.1)]. Renal function should be evaluated prior to initiation of INVOKAMET and monitored periodically thereafter. Dosage adjustment and more frequent renal function monitoring are recommended in patients with an eGFR below 60 mL/min/1.73 m2. INVOKAMET is contraindicated in patients with an eGFR below 45 mL/min/1.73 m2 .
Postmarketing Experience

Acute Kidney Injury and Impairment in Renal Function

DRUG INTERACTIONS

Drug Interactions with Metformin

Drugs That Reduce Metformin Clearance

  • 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. Consider more frequent monitoring of these patients.

Alcohol

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

 

March 2016

Summary View

CONTRAINDICATIONS

  • History of a serious hypersensitivity reaction to canagliflozin or metformin, such as anaphylaxis or angioedema

WARNINGS AND PRECAUTIONS

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; treat and monitor until signs and symptoms resolve

ADVERSE REACTIONS

Postmarketing Experience
  • Anaphylaxis, Angioedema

 

September 2015

Summary View

WARNINGS AND PRECAUTIONS

Bone Fracture
  • An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using canagliflozin. Consider factors that contribute to fracture risk prior to initiating Invokamet

ADVERSE REACTIONS

Clinical Studies Experience

Falls

  • In a pool of nine clinical trials with mean duration of exposure to canagliflozin of 85 weeks, the proportion of patients who experienced falls was 1.3%, 1.5%, and 2.1% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. The higher risk of falls for patients treated with canagliflozin was observed within the first few weeks of treatment.

Bone Fracture

  • The occurrence of bone fractures was evaluated in a pool of nine clinical trials with a mean duration of exposure to canagliflozin of 85 weeks. The incidence rates of adjudicated bone fractures were 1.1, 1.4, and 1.5 per 100 patient-years of exposure in the comparator, canagliflozin 100 mg, and canagliflozin 300 mg groups, respectively. Fractures were observed as early as 12 weeks after treatment initiation and were more likely to be low trauma (e.g., fall from no more than standing height), and affect the upper extremities

USE IN SPECIFIC POPULATIONS

Renal Impairment

*Section edited to read:

  • The efficacy and safety of canagliflozin were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m2). These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR greater than or equal to 60 mL/min/1.73 m2). Dose-related, transient mean increases in serum potassium were observed early after initiation of canagliflozin  (i.e., within 3 weeks) in this trial. Increases in serum potassium of greater than 5.4 mEq/L and 15% above baseline occurred in 16.1%, 12.4%, and 27.0% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Severe elevations (greater than or equal to 6.5 mEq/L) occurred in 1.1%, 2.2%, and 2.2% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. The efficacy and safety of canagliflozin have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), with ESRD, or receiving dialysis. Canagliflozin is not expected to be effective in these patient populations.

 

March 2015

Summary View

ADVERSE REACTIONS

Clinical Studies Experience

Genital Mycotic Infections

  • Added...In females, discontinuation due to genital mycotic infections occurred in 0% and 0.7% of patients treated with placebo and canagliflozin, respectively.
  • Added...In males, discontinuations due to genital mycotic infections occurred in 0% and 0.5% of patients treated with placebo and canagliflozin, respectively.

 

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