|
INVOKAMET XR (canagliflozin and metformin hydrochloride extended-release) tablets
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use INVOKAMET ®XR safely and effectively. See full prescribing information for INVOKAMET XR.
INVOKAMET XR (canagliflozin and metformin hydrochloride extended-release) tablets, for oral use
Initial U.S. Approval – 2016
WARNING: LACTIC ACIDOSIS
See full prescribing information for complete boxed warning.
-
Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. (5.1)
-
Risk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, 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. (5.1)
-
If lactic acidosis is suspected, discontinue INVOKAMET XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. (5.1
INDICATIONS AND USAGE
INVOKAMET XR is a sodium-glucose co-transporter 2 (SGLT2) inhibitor and biguanide combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both canagliflozin and metformin is appropriate (1)
Limitation of use:
Not for treatment of type 1 diabetes or diabetic ketoacidosis (1)
DOSAGE AND ADMINISTRATION
-
Individualize based on the patient's current regimen (2.1)
-
Take two tablets once daily with the morning meal (2.1)
-
In patients currently not treated with either canagliflozin or metformin, initiate therapy with two INVOKAMET XR tablets, each tablet containing canagliflozin 50 mg and metformin 500 mg (2.1)
-
In patients already treated with canagliflozin and metformin, switch to two INVOKAMET XR tablets containing the same total daily dose of canagliflozin and the same, or nearest appropriate, total daily dose of metformin (2.1)
-
In patients that require additional glycemic control that are taking a total daily dose of canagliflozin 100 mg, the INVOKAMET XR dose can be increased to canagliflozin 300 mg once daily. Do not exceed a total daily canagliflozin dose of 300 mg (2.1)
-
Gradually escalate metformin dose to reduce the gastrointestinal side effects while not exceeding a total daily dose of 2000 mg (2.1)
-
Assess renal function before initiating and periodically thereafter (2.2)
-
INVOKAMET XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 45 mL/min/1.73 m2 (2.2)
-
Limit the dose of canagliflozin component to two tablets, each tablet containing 50 mg, daily in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 (2.2)
-
INVOKAMET XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.4)
-
Swallow whole. Never crush, cut, or chew (2.5)
DOSAGE FORMS AND STRENGTHS
Film-coated tablets:
-
Canagliflozin 50 mg and metformin hydrochloride 500 mg extended-release
-
Canagliflozin 50 mg and metformin hydrochloride 1,000 mg extended-release
-
Canagliflozin 150 mg and metformin hydrochloride 500 mg extended-release
-
Canagliflozin 150 mg and metformin hydrochloride 1,000 mg extended-release (3)
CONTRAINDICATIONS
-
Moderate to severe renal impairment (eGFR below 45 mL/min/1.73 m2), end stage renal disease or dialysis (4, 5.1, 5.4)
-
Metabolic acidosis, including diabetic ketoacidosis (1, 4, 5.1)
-
History of serious hypersensitivity reaction to canagliflozin or metformin (4, 5.9)
WARNINGS AND PRECAUTIONS
-
Lactic acidosis: See boxed warning (5.1)
-
Hypotension: Before initiating INVOKAMET XR, assess volume status and correct hypovolemia in patients with renal impairment, the elderly, in patients with low systolic blood pressure, or on diuretics, ACEi, or ARB. Monitor for signs and symptoms during therapy (5.2)
-
Ketoacidosis: Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue INVOKAMET XR, eva luate and treat promptly. Before initiating INVOKAMET XR, consider risk factors for ketoacidosis. Patients on INVOKAMET XR may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis (5.3)
-
Acute kidney injury and impairment in renal function: Consider temporarily discontinuing in settings of reduced oral intake or fluid losses. If acute kidney injury occurs, discontinue and promptly treat. Monitor renal function during therapy (5.4)
-
Hyperkalemia: Monitor potassium levels in patients with impaired renal function and in patients predisposed to hyperkalemia (2.2, 5.5, 6.1, 8.6)
-
Urosepsis and pyelonephritis: eva luate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (5.6)
-
Hypoglycemia: Consider a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia when used in combination with INVOKAMET XR (5.7)
-
Genital mycotic infections: Monitor and treat if indicated (5.8)
-
Hypersensitivity reactions: Discontinue INVOKAMET XR and monitor until signs and symptoms resolve (5.9)
-
Bone fracture: Consider factors that contribute to fracture risk before initiating INVOKAMET XR (5.10)
-
Vitamin B12 deficiency: Metformin may lower vitamin B12 levels. Monitor hematologic parameters annually (5.11)
-
Increased LDL-C: Monitor LDL-C and treat if appropriate (5.12)
-
Most common adverse reactions associated with canagliflozin (5% or greater incidence): female genital mycotic infections, urinary tract infection, and increased urination (6.1)
-
Most common adverse reactions associated with metformin (5% or greater incidence) are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
-
Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring (7.1)
-
Drugs that are eliminated by renal tubular secretion (e.g. cationic drugs such as cimetidine), may increase the accumulation of metformin. Consider more frequent monitoring (7.1)
-
Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake (7.1)
-
UGT inducers (e.g., rifampin): Canagliflozin exposure is reduced. Consider increasing canagliflozin from a total daily dose of 100 mg to a total daily dose of 300 mg once daily (2.3, 7.2)
-
Digoxin: Monitor digoxin levels (7.2)
USE IN SPECIFIC POPULATIONS
-
Pregnancy: Advise females of the potential risk to a fetus especially during the second and third trimesters (8.1)
-
Lactation: INVOKAMET XR is not recommended when breastfeeding (8.2)
-
Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy (8.3).
-
Geriatrics: Higher incidence of adverse reactions related to reduced intravascular volume. Assess renal function more frequently (5.2, 6.1, 8.5)
-
Renal impairment: Higher incidence of adverse reactions related to reduced intravascular volume and renal function (2.2, 5.4, 8.6)
-
Hepatic Impairment: Avoid use in patients with hepatic impairment (8.7)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 9/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
INVOKAMET XR (canagliflozin and metformin hydrochloride extended release) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both canagliflozin and metformin is appropriate.
Limitations of Use
INVOKAMET XR is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
-
Individualize the starting dose of INVOKAMET XR (canagliflozin and metformin hydrochloride extended-release), taken once-daily with the morning meal, based on the effectiveness and tolerability of the patient's current regimen:
-
–
-
In patients currently not treated with either canagliflozin or metformin, initiate therapy with two INVOKAMET XR tablets, each tablet containing canagliflozin 50 mg and metformin 500 mg [see Clinical Studies (14.1)].
-
–
-
In patients on metformin, switch to two INVOKAMET XR tablets, where two tablets equal a starting dose of canagliflozin 100 mg daily and the patient's current total daily dose (or nearest appropriate) of metformin.
-
–
-
In patients on canagliflozin, switch to two INVOKAMET XR tablets, where two tablets equal the patient's current total daily dose of canagliflozin and a starting dose of metformin 1000 mg daily.
-
–
-
In patients already treated with canagliflozin and metformin, switch to two INVOKAMET XR tablets containing the same total daily dose of canagliflozin and the same, or nearest appropriate, total daily dose of metformin.
-
In patients that require additional glycemic control that are taking a total daily dose of canagliflozin 100 mg, the INVOKAMET XR dose can be increased to canagliflozin 300 mg once daily [see Dosage Forms and Strengths (3) and Clinical Studies (14.1)].
-
The dose of metformin should be gradually escalated to reduce the gastrointestinal side effects due to metformin [see Dosage Forms and Strengths (3) and Clinical Studies (14.1)].
-
Patients taking an evening dose of metformin XR should skip their last dose before starting INVOKAMET XR the following morning.
-
In patients with volume depletion not previously treated with canagliflozin, correct this condition before initiating INVOKAMET XR [see Warnings and Precautions (5.2), Use in Specific Populations (8.5, 8.6), and Patient Counseling Information (17)].
-
Adjust dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of metformin 2000 mg and canagliflozin 300 mg in patients with an eGFR of 60 mL/min/1.73 m2 or greater [see Dosage and Administration (2.2)].
2.2 Recommended Dosage for Patients with Renal Impairment
-
Assess renal function before initiating INVOKAMET XR and periodically thereafter.
-
INVOKAMET XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 45 mL/min/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.1, 5.3)].
-
Limit the dose of INVOKAMET XR to two tablets, each tablet containing canagliflozin 50 mg, in patients with moderate renal impairment with an eGFR of 45 to less than 60 mL/min/1.73 m2.
2.3 Concomitant Use with UDP-Glucuronosyl Transferase (UGT) Enzyme Inducers
If an inducer of UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) is co-administered with INVOKAMET XR, consider increasing the dose of canagliflozin to a total daily dose of 300 mg once daily in patients currently tolerating INVOKAMET XR with 100 mg canagliflozin once daily who have an eGFR of 60 mL/min/1.73 m2 or greater and require additional glycemic control [see Drug Interactions (7.2)].
Consider another antihyperglycemic agent in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer.
2.4 Discontinuation for Iodinated Contrast Imaging Procedures
Discontinue INVOKAMET XR 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 liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-eva luate eGFR 48 hours after the imaging procedure; restart INVOKAMET XR if renal function is stable [see Warnings and Precautions (5.1)].
2.5 Important Administration Instructions
3 DOSAGE FORMS AND STRENGTHS
INVOKAMET XR (canagliflozin and metformin hydrochloride extended-release) film-coated tablets for oral administration are available in the following strengths:
-
Canagliflozin 50 mg and metformin hydrochloride 500 mg extended-release tablets are oblong, biconvex, almost white to light orange film-coated tablets with "CM1" on one side. A thin line on the tablet side may be visible.
-
Canagliflozin 50 mg and metformin hydrochloride 1,000 mg extended-release tablets are oblong, biconvex, pink, film-coated tablets with "CM3" on one side. A thin line on the tablet side may be visible.
-
Canagliflozin 150 mg and metformin hydrochloride 500 mg tablets extended-release are oblong, biconvex, orange, film-coated tablets with "CM2" on one side. A thin line on the tablet side may be visible.
-
Canagliflozin 150 mg and metformin hydrochloride 1,000 mg extended-release tablets are oblong, biconvex, reddish brown, film-coated tablets with "CM4" on one side. A thin line on the tablet side may be visible.
4 CONTRAINDICATIONS
INVOKAMET XR is contraindicated in patients with:
5 WARNINGS AND PRECAUTIONS
5.1 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 XR. In INVOKAMET XR-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 XR 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 [see Clinical Pharmacology (12.3)].
-
Before initiating INVOKAMET XR, obtain an estimated glomerular filtration rate (eGFR).
-
INVOKAMET XR 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 XR. 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 XR 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 [see Use in Specific Populations (8.5)].
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 XR 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-eva luate eGFR 48 hours after the imaging procedure, and restart INVOKAMET XR 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 XR 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 |
|
