Usual Adult Dose for Diabetes Type 2

Initial dose: Individualize dose based on patient's current regimen and renal function:

Canagliflozin-Metformin Immediate-Release tablets: Take orally twice a day with meals

• In patients not currently on canagliflozin or metformin: canagliflozin 50 mg-metformin 500 mg orally twice a day
• In patients on metformin: canagliflozin 50 mg plus one-half of the total daily metformin dose orally twice a day
• In patients on canagliflozin: one-half daily dose of canagliflozin plus metformin 500 mg orally twice a day
• In patients already on canagliflozin and metformin: Switch to canagliflozin-metformin at the same total daily dose divided into 2 doses taken orally twice a day

Canagliflozin-Metformin Extended-release (XR tablets): Take orally once a day with morning meal

• In patients not currently on canagliflozin or metformin: Initial dose: canagliflozin 100 mg-metformin 1000 mg orally once a day
• In patients on metformin: canagliflozin 100 mg plus total daily metformin dose (or nearest appropriate) orally once a day
• In patients on canagliflozin: current daily dose of canagliflozin plus metformin 1000 mg orally once a day
• In patients already treated with canagliflozin and metformin: Switch to canagliflozin-metformin at the same total daily dose (or nearest appropriate) orally once a day

Maintenance dose: Adjust based on efficacy and tolerability; canagliflozin may be increased from 100 mg/day to 300 mg/day in patients with an eGFR of 60 mL/min/1.73 m2 or greater; a gradual dose escalation of metformin will help to reduce gastrointestinal side effects.
Maximum dose: Canagliflozin 300 mg/day; Metformin 2000 mg/day

Comments:

• For patients with an eGFR less than 60 mL/min/1.73 m2, consult renal dose adjustments for dosing guidance.
• When used in combination with insulin or an insulin secretagogue, a lower dose of insulin or insulin secretagogue may be considered to reduce the risk of hypoglycemia.
• For patients taking an evening dose of metformin extended-release (XR) and switching to canagliflozin-metformin XR once a day, skip the last evening dose of metformin XR before starting canagliflozin-metformin XR the following morning.

Uses:

• 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.
• 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 and established cardiovascular disease.
• Canagliflozin is indicated to reduce the risk of end stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes and diabetic nephropathy with albuminuria greater than 300 mg/day.

Renal Dose Adjustments

eGFR 60 mL/min/1.73 m2 or greater: No adjustment recommended
eGFR 45 to less than 60 mL/min/1.73 m2: Maximum canagliflozin dose: 100 mg/day
eGFR 30 to less than 45 mL/min/1.73 m2: Assess benefit risk of continuing therapy; Maximum canagliflozin dose: 100 mg/day
eGFR less than 30 mL/min/1.73 m2: Contraindicated
Dialysis: Contraindicated

IODINATED CONTRAST PROCEDURE:

• Stop this drug at time of, or prior to, an iodinated contrast imaging procedure for patients with an eGFR less than 60 mL/min/1.73 m2; reevaluate eGFR 48 hours after the imaging procedure and restart drug if renal function is stable (see dose adjustment section for full instruction).

Liver Dose Adjustments

Metformin is not recommended in patients with clinical or laboratory evidence of hepatic disease.

IODINATED CONTRAST PROCEDURE:

• Stop this drug at time of, or prior to, an iodinated contrast imaging procedure for patients with a history of liver disease; reevaluate eGFR 48 hours after the imaging procedure and restart drug if renal function is stable (see dose adjustment section for full instruction).

Dose Adjustments

Elderly: Monitor renal function more frequently and adjust dose based on renal function.

Concomitant Use of Insulin and Insulin Secretagogues:

• A lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycemia.

Concomitant use with UDP-Glucuronosyl Transferase (UGT) Enzyme Inducers, AND:

• eGFR greater than 60 mL/min/1.73m2: Consider increasing total daily dose of canagliflozin to 200 mg/day in patients currently tolerating a dose of 100 mg/day; may increase to a maximum dose of 300 mg/day for patients tolerating a dose of 200 mg/day and requiring additional glycemic control
• eGFR less than 60 mL/min/1.73 m2: May increase dose of canagliflozin to 200 mg/day in patients tolerating canagliflozin at 100 mg/day

Concomitant use with drugs that increase the risk of metformin-associated lactic acidosis; impair renal function, result in significant hemodynamic changes, interfere with acid-base balance, and/or increase metformin accumulation should be undertaken with increased monitoring.

Iodinated Contrast Imaging Procedures:

• Stop this drug at time of, or prior to, an iodinated contrast imaging procedure for patients with an eGFR below 60 mL/min/1.73 m2; for patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast.
• Reevaluate eGFR 48 hours after the imaging procedure and only restart this drug if renal function is stable.

Precautions

US BOXED WARNINGS: LACTIC ACIDOSIS:
Lactic Acidosis:

• Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin associated lactic acidosis is characterized by elevated blood lactate levels (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally greater than 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 or older, radiological study with contrast, surgery and other procedures, hypoxic states (e.g. 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 this drug and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

CONTRAINDICATIONS:

• Severe renal impairment (eGFR below 30 mL/min/1.73 m2), or on dialysis
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis
• Serious hypersensitivity reaction to canagliflozin or metformin, such as anaphylaxis or angioedema

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Contraindicated

Other Comments

Administration advice:
Canagliflozin-Metformin Immediate-Release Tablets:

• Take orally twice a day with meals

Missed Dose: If a dose is missed, patients should skip missed dose; patients should be advised not to take 2 doses at the same time

Canagliflozin-Metformin Extended-Release Tablets:

• Take orally once a day after breakfast
• Swallow whole; do not crush, chew, or cut
• Inactive ingredients may occasionally appear in the feces as a soft mass; if a patient reports seeing tablets in feces, adequacy of glycemic control should be assessed

Missed dose: If a dose is missed, patients should take as soon as remembered unless it is almost time for the next dose, in which case, they should skip the missed dose and take at the next regularly scheduled time; patients should be advised not to take 2 doses at the same time

Storage requirements:

• Store in the original container to protect from moisture
• May store in pill box or pill organizer for up to 30 days.

General

• This drug should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis
• Correct volume depletion prior to initiating treatment
• Assess renal function using eGFR.
• Stop this drug at time of, or prior to, an iodinated contrast imaging procedure for patients with an eGFR between less than 60 mL/min/1.73m2 ; for patients with a history of liver disease, alcoholism, or heart failure; for patients who will be administered intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after the imaging procedure and only restart this drug if renal function is stable.

Monitoring:

• Assess fluid status prior to initiation and monitor for signs and symptoms of volume depletion during therapy
• Verify renal function at baseline, repeat at least annually and more often as clinically indicated
• Monitor serum potassium levels periodically, especially in patients with impaired renal function and those predisposed to hyperkalemia due to medications or other medical conditions.
• Measure hematologic parameters annually; consider obtaining a serum Vitamin B12 every 2 to 3 years
• Monitor glycemic control
• Evaluate for the presence of acidosis, including ketoacidosis in symptomatic patients.
• Monitor for genital mycotic infections.
• Monitor for any new pain, tenderness, sores, ulcers, or infections in feet and legs.

Patient advice:

• Read the US FDA-approved patient labeling (Medication Guide).
• Patients should be instructed to keep tablets in the original bottle and not place into pill boxes or pill organizers.
• Patients should be told this drug will cause the urine to test positive for glucose.
• Patients should be instructed to maintain adequate fluid intake to avoid adverse reactions related to volume depletion such as orthostatic hypotension.
• Patients should be reminded that during periods of stress medical management of diabetes may change and they should know when to contact their health care provider.
• Inform patients that genital mycotic infections, urinary tract infections, and hypersensitivity reactions may occur; they should contact their health care professional if these occur.
• Patients should be instructed to seek immediate medical attention for symptoms of tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, especially if they have a fever and are feeling unwell.
• Patients experiencing symptoms of ketoacidosis such as difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue, or sleepiness should be instructed to seek immediate medical attention.
• Inform patients about the risk of lactic acidosis, conditions that might predispose them to its occurrence, and symptoms to watch for and report.
• Advise patients that this drug may need to be temporarily stopped if undergoing radiologic studies with intravascular iodinated contrast materials or surgical procedures that will limit food or fluid intake.
• Advise patients on the risks of excessive alcohol intake.
• Tell patients that while gastrointestinal symptoms might be common when initiating treatment, gastrointestinal problems after initiation should be reported.
• Patients should be instructed to report any new pain, tenderness, sores or ulcers, or infections of legs and feet; patients should be receiving routine preventative foot care.