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Invokamet Side Effects

Generic Name: canagliflozin / metformin

Note: This document contains side effect information about canagliflozin / metformin. Some of the dosage forms listed on this page may not apply to the brand name Invokamet.

In Summary

Common side effects of Invokamet 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.

For the Consumer

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

Warning

Oral route (Tablet; Tablet, Extended Release)

Lactic Acidosis:Postmarketing 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 (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 (eg, carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, 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 canagliflozin / metformin hydrochloride and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.Risk of Lower Limb Amputation:An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, a component of canagliflozin / metformin hydrochloride, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD. Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.Monitor patients receiving canagliflozin / metformin hydrochloride for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.

Side effects requiring immediate medical attention

Along with its needed effects, canagliflozin / metformin may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking canagliflozin / metformin:

More common

  • Bladder pain
  • bloody or cloudy urine
  • decreased appetite
  • diarrhea
  • difficult, burning, or painful urination
  • fast, shallow breathing
  • frequent urge to urinate
  • frequent urination
  • general feeling of discomfort
  • increased urge to urinate during the night
  • increased volume of pale, dilute urine
  • itching of the vagina or genitals
  • itching, stinging, or redness of the vaginal area
  • lower back or side pain
  • muscle pain or cramping
  • nausea
  • sleepiness
  • stomach discomfort
  • thick, white vaginal discharge with mild or no odor
  • unusual tiredness or weakness
  • waking to urinate at night

Less common

  • Dry mouth
  • increased thirst

Incidence not known

  • Anxiety
  • blurred vision
  • chills
  • clay-colored stools
  • cold sweats
  • confusion
  • cool, pale skin
  • depression
  • difficulty with swallowing
  • dizziness
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • fast heartbeat
  • fever
  • headache
  • hives, itching, skin rash
  • increased hunger
  • irregular heartbeat
  • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or genitals
  • loss of appetite
  • loss of consciousness
  • nightmares
  • numbness or tingling in the hands, feet, or lips
  • pain in the skin around the penis
  • pain, tenderness, redness, or swelling of the area between the anus and genitals
  • reddening of the skin, especially around the ears
  • redness, itching, or swelling of the penis
  • seizures
  • shakiness
  • slurred speech
  • stomach pain or tenderness
  • sweating
  • swelling of the eyes, face, or inside of the nose
  • swelling of the feet or lower legs
  • unpleasant breath odor
  • vomiting
  • vomiting of blood
  • weakness or heaviness of the legs
  • yellow eyes or skin

Side effects not requiring immediate medical attention

Some side effects of canagliflozin / metformin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

  • Difficulty having a bowel movement

For Healthcare Professionals

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

Postmarketing reports: Fournier's gangrene[Ref]

In the 5 years (2013 to 2018) since SGLT2 inhibitor approval, 12 cases of Fournier's gangrene have been reported. Reports were almost equal in men and women (men=7; women=5), ages ranged from 38 to 78 years, and the average time to onset after starting an SGLT2 inhibitor was 9.2 months (range 7 days to 25 months). All SGLT2 inhibitor drugs except ertugliflozin were included in the reports. Ertugliflozin being the most recently approved agent, is expected to have the same risk, but insufficient patient use to assess risk. All patients were hospitalized, all required surgery, all required surgical debridement, 5 required more than 1 surgery and 1 required skin grafting. Four cases were complicated by diabetic ketoacidosis, acute kidney injury, and septic shock, leading to prolonged hospitalization, and death in 1 case. In the general population, Fournier's gangrene occurs in about 1.6 out of 100,000 males annually, with the highest incidence in men 50 to 79 years. Since diabetes is a risk factor for Fournier's gangrene, a review of the FAERS database for the last 34 years was done and only 6 cases (all males, median age 57 years) were found with several other classes of antidiabetic drugs. Findings with SGLT2 inhibitors appear to show an association over a shorter time frame and involve both males and females.[Ref]

Cardiovascular

Canagliflozin:

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

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

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]

Canagliflozin:

Common (1% to 10%): Fatigue, asthenia, falls

Uncommon (0.1% to 1%): Leg and foot amputations[Ref]

Dermatologic

Canagliflozin:

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

Metformin:

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

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

Nervous system

Metformin:

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

References

1. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0

2. "Product Information. Invokamet (canagliflozin-metFORMIN)." Janssen Pharmaceuticals, Titusville, NJ.

3. FDA "FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes. Available from: URL: https://www.fda.gov/downloads/Drugs/DrugSafety/UCM618466.pdf." ([2018, Aug 29]):

4. FDA. U.S. Food and Drug Administration "FDA: SGLT2 inhibitors: Drug Safety Communication - FDA Warns Medicines May Result in a Serious Condition of Too Much Acid in the Blood Available from: URL: http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm44699" (2015 May 15):

5. FDA. U.S. Food and Drug Administration "FDA Drug Safety Communication: Interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate. Available from: URL: http://www.f" ([2016, May 18]):

6. US Food and Drug Administration "FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR) Available from: URL: https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm?source=govdelivery&" ([2017, May 16]):

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Some side effects may not be reported. You may report them to the FDA.