Canagliflozin and metformin

WARNING: LACTIC ACIDOSIS

• Lactic acidosis is a rare but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure.
• The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.
• Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.
• If lactic acidosis is suspected, canagliflozin/metformin should be discontinued and the patient hospitalized immediately

Canagliflozin and metformin are oral diabetes medicines that help control blood sugar levels.

Canagliflozin and metformin is a combination medicine used with diet and exercise to improve blood sugar control in adults with type 2 diabetes.

Canagliflozin and metformin may also be used for purposes not listed in this medication guide.

Take the missed dose as soon as you remember (be sure to take the medicine with food). Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

In the U.S.

• Invokamet
• Invokamet XR

Available Dosage Forms:

• Tablet
• Tablet, Extended Release

Therapeutic Class: Antidiabetic

Pharmacologic Class: Sodium Glucose Co-Transporter 2 Inhibitor

Chemical Class: Metformin

Oral:

Immediate release: Administer twice daily with meals.

Extended release: Administer once daily with morning meal. Swallow tablets whole; do not crush, cut, or chew.

Store between 20°C and 25°C (68°F and 77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F). Store in original container.

Commonly reported side effects of canagliflozin/metformin include: lactic acidosis, vulvovaginal candidiasis, vaginal infection, vulvitis, and vulvovaginitis. Other side effects include: cyanocobalamin deficiency, balanitis, balanoposthitis, increased urine output, nocturia, polyuria, urinary urgency, and pollakiuria. See below for a comprehensive list of adverse effects.

Applies to canagliflozin / metformin: oral tablet, oral tablet extended release

General

Canagliflozin:
-The most commonly reported adverse reactions included hypoglycemia in combination with insulin or a sulfonylurea, vulvovaginal candidiasis, urinary tract infection, polyuria or pollakiuria.

Metformin:
- The most commonly reported adverse reactions included diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.[Ref]

Musculoskeletal

In the CANVAS trial, amputations per 1000 patients per year in patients receiving canagliflozin (100 mg or 300 mg per day) were 5.8 compared to 2.8 amputations per 1000 patients per year in the placebo group. In the CANVAS-R trials, these numbers were 7.5 and 4.2, respectively. The total number of amputations among canagliflozin-treated patients (n=5790) was 221 compared with 69 in the placebo group (n=4344). Amputations of the toe and midfoot were the most frequent; however, amputations involving the leg, below and above the knee, also occurred.

On September 10, 2015, the US Food and Drug Administration issued a drug safety communication regarding new information on bone fracture risk and decreased bone mineral density with use of canagliflozin. Based on updated data, fractures have occurred as early as 12 weeks after starting therapy with trauma that is usually minor, such as falling from standing height. Additionally, a 2-year study (n=714) has shown a greater loss of bone mineral density at the hip and lower spine in canagliflozin treated patients compared with placebo.[Ref]

Canagliflozin:
Common (1% to 10%): Lower limb amputations
Frequency not reported: Bone fracture, upper extremity fracture, loss of bone mineral density at hip and lower spine[Ref]

Genitourinary

Canagliflozin:
Very common (10% or more): Female genital mycotic infections (up to 11.4%)
Common (1% to 10%): Urinary tract infections, increased urination, male genital mycotic infections, vulvovaginal pruritus[Ref]

Cardiovascular

Volume depletion-related reactions included hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration.[Ref]

Canagliflozin:
Common (1% to 10%): Volume depletion-related reactions[Ref]

Metabolic

Canagliflozin:
Very common (10% or more): Elevated serum potassium, elevated serum magnesium, elevated serum phosphate
Common (1% to 10%): Increased low-density lipoprotein cholesterol, increased non-high-density lipoprotein cholesterol
Postmarketing reports: Acidosis including diabetic ketoacidosis, ketoacidosis, or ketosis

Metformin:
Very rare (less than 0.01%): Lactic acidosis, vitamin B12 deficiency[Ref]

Twenty reports of acidosis have been identified in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database during the period March 2013 through 06 June 2014. All patients required emergency room treatment or hospitalization. These cases were not typical of ketoacidosis or diabetic ketoacidosis (DKA) in that they occurred in patients with type 2 diabetes and their blood sugar levels were only slightly increased. Some factors identified as potentially triggering the acidosis included major illness, reduced food and fluid intake, and reduced insulin dose.[Ref]

Renal

Canagliflozin:
Common (1% to 10%): Renal function decline
Frequency not reported: Increased serum creatinine increases, decreased GFR
Postmarketing reports: Acute kidney injury, renal function impairment, urosepsis, pyelonephritis[Ref]

Hepatic

Metformin:
Very rare (less than 0.01%): Liver function disorders, liver function tests abnormalities, hepatitis[Ref]

Endocrine

Canagliflozin:
Very common (10% or more): Hypoglycemia in combination with insulin or sulfonylurea[Ref]

Hypersensitivity

Hypersensitivity-related reactions included erythema, rash, pruritus, urticaria, and angioedema.[Ref]

Canagliflozin:
Common (1% to 10%): Hypersensitivity-related reactions
Postmarketing reports: Anaphylaxis, angioedema[Ref]

Gastrointestinal

Canagliflozin:
Common (1% to 10%): Constipation, nausea, abdominal pain, thirst, pancreatitis[Ref]

Hematologic

Canagliflozin:
Common (1% to 10%): Increased hemoglobin[Ref]

Other

Canagliflozin:
Common (1% to 10%): Fatigue, asthenia, falls
Uncommon (0.1% to 1%): Leg and foot amputations[Ref]

Final results from 2 clinical trials, the CANVAS (Canagliflozin Cardiovascular Assessment Study) and the CANVAS-R (A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants with Type 2 Diabetes Mellitus) have shown leg and foot amputations occurred almost twice as often in canagliflozin treated patients compared with placebo treated patients. Amputations of the toe and middle of the foot were most common, however some amputations involved the leg, below and above the knee. Some patients had more than 1 amputation; some involved both limbs.

The risk of amputation calculated from the CANVAS trial showed 5.9 per 1000 patients per year for canagliflozin treated patients compared to 2.8 per 1000 patients per year for placebo patients. The CANVAS-R trial showed 7.5 per 1000 patients per year compared to 4.2 per 1000 patients per year for canagliflozin treated patients and placebo patients, respectively.[Ref]

Dermatologic

Rash includes erythematous, generalized, macular, maculopapular, papular, pruritic, pustular and vesicular rashes.[Ref]

Canagliflozin:
Uncommon (0.1% to 1%): Rash, urticaria, photosensitivity-related reactions

Metformin:
Very rare (less than 0.01%): Urticaria, erythema, pruritus[Ref]

Nervous system

Metformin:
Common (1% to 10%): Taste disturbance[Ref]

Some side effects of canagliflozin / metformin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Initial dose: Individualize dose based on patient's current regimen:

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; a gradual dose escalation of metformin will help to reduce gastrointestinal side effects.
Maximum dose: Canagliflozin 300 mg/day; Metformin 2000 mg/day

Comments:
-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) switching to canagliflozin-metformin XR once a day, skip the last evening dose of metformin XR before starting canagliflozin-metformin XR the following morning.

Use: 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.

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

Animal studies have revealed that canagliflozin may affect renal development and maturation with drug exposure that correspond to the late second and third trimester of human development. Co-administration of canagliflozin and metformin in animals demonstrated that neither was embryolethal nor teratogenic, but minor skeletal abnormalities (delayed-ossification) in fetuses were observed. There are no controlled data in human pregnancy. US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

Use is not recommended. This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus. Risk Summary: Based on animal data, this drug is not recommended during the second and third trimester of pregnancy. US FDA pregnancy category: Not Assigned