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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 XR.
Common side effects of Invokamet XR 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
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.
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:
Incidence not known
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:
Applies to canagliflozin / metformin: oral tablet, oral tablet extended release
-The most commonly reported adverse reactions included hypoglycemia in combination with insulin or a sulfonylurea, vulvovaginal candidiasis, urinary tract infection, polyuria or pollakiuria.
- The most commonly reported adverse reactions included diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.
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.
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
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
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.
Volume depletion-related reactions included hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration.
Common (1% to 10%): Volume depletion-related reactions
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
Very rare (less than 0.01%): Lactic acidosis, vitamin B12 deficiency
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.
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
Very rare (less than 0.01%): Liver function disorders, liver function tests abnormalities, hepatitis
Very common (10% or more): Hypoglycemia in combination with insulin or sulfonylurea
Hypersensitivity-related reactions included erythema, rash, pruritus, urticaria, and angioedema.
Common (1% to 10%): Hypersensitivity-related reactions
Postmarketing reports: Anaphylaxis, angioedema
Common (1% to 10%): Constipation, nausea, abdominal pain, thirst, pancreatitis
Common (1% to 10%): Increased hemoglobin
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.
Common (1% to 10%): Fatigue, asthenia, falls
Uncommon (0.1% to 1%): Leg and foot amputations
Rash includes erythematous, generalized, macular, maculopapular, papular, pruritic, pustular and vesicular rashes.
Uncommon (0.1% to 1%): Rash, urticaria, photosensitivity-related reactions
Very rare (less than 0.01%): Urticaria, erythema, pruritus
Common (1% to 10%): Taste disturbance
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