Invokana

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

Common side effects of Invokana include: vulvovaginal candidiasis, vaginal infection, vulvitis, vulvovaginitis, and mean glomerular filtration rate decreased. Other side effects include: balanitis, balanoposthitis, increased urine output, nocturia, polyuria, urinary urgency, and pollakiuria. See below for a comprehensive list of adverse effects.

Applies to canagliflozin: oral tablet

Along with its needed effects, canagliflozin (the active ingredient contained in Invokana) 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:

More common

• Bladder pain
• bloody or cloudy urine
• decreased frequency or amount of urine
• difficult, burning, or painful urination
• discharge with a strong odor from the penis
• frequent urge to urinate
• increased thirst
• itching of the vagina or outside of the genitals
• loss of appetite
• lower back or side pain
• nausea
• pain during sexual intercourse
• pain in the skin around the penis
• redness, itching, or swelling of the penis
• swelling of the face, fingers, or lower legs
• troubled breathing
• unusual tiredness or weakness
• vaginal discharge without odor or with mild odor
• vomiting
• weight gain

Less common

• Anxiety
• blurred vision
• chills
• cold sweats
• confusion
• cool, pale skin
• depression
• dizziness
• dry mouth
• fast or irregular heartbeat
• headache
• hives or welts, itching skin, rash
• increased hunger
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• nightmares
• redness of the skin
• seizures
• shakiness
• slurred speech
• unusual tiredness or weakness

Incidence not known

• Dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• flushed, dry skin
• frequent or painful urination
• frequent urge to urinate
• fruit-like breath odor
• increased urination
• loss of consciousness
• numbness or tingling in the hands, feet, or lips
• stomach pain
• sweating
• unexplained weight loss
• weakness or heaviness of the legs

Some side effects of canagliflozin 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
• lack or loss of strength
• pain or swelling in the arms or legs without an injury

Rare

• Increased sensitivity of the skin to sunlight
• redness or other discoloration of the skin
• severe sunburn

Applies to canagliflozin: oral tablet

The most commonly reported adverse reactions have included female genital mycotic infections, urinary tract infection, and increased urinary frequency.

In the CANVAS trial, amputations per 1000 patients per year in patients receiving canagliflozin (the active ingredient contained in Invokana) (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

Uncommon (0.1% to 1%): Bone fracture, upper extremity fracture

Frequency not reported: Loss of bone mineral density at hip and lower spine

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.

Very common (10% or more): Female genital mycotic infections including vulvovaginal mycotic infection, vulvovaginitis, vaginal infection, vulvitis, and genital infection fungal (up to 11.4%), recurrent male genital mycotic infections (22%)

Common (1% to 10%): Urinary tract infection, increased urination, male genital mycotic infections including balanitis, balanoposthitis, balanitis candida, and fungal genital infection

Uncommon (0.1% to 1%): Phimosis

Postmarketing reports: Urosepsis, pyelonephritis, Fournier's gangrene

Common (1% to 10%): Adverse reactions related to reduced intravascular volume (postural hypotension, orthostatic hypotension, hypotension, dehydration, and syncope)

Very common (10% or more): Hypoglycemia when combined with insulin or an insulin secretagogue (up to 49%), hyperkalemia (up to 27%)

Common (1% to 10%): Increased serum magnesium, increased serum phosphate, increased low-density lipoprotein (LDL-C)

Postmarketing reports: Acidosis including diabetic ketoacidosis, ketoacidosis, or ketosis

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%): Constipation, thirst, nausea, abdominal pain, pancreatitis

Common (1% to 10%): Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema

Frequency not reported: Serious hypersensitivity reaction

Postmarketing reports: Anaphylaxis

In a pooled analysis among patients with moderate renal impairment, the incidence of renal related adverse reactions such as increased serum creatinine, decreased eGFR, renal impairment, or acute renal failure, was 8.9% and 9.3% in patients receiving canagliflozin (the active ingredient contained in Invokana) 100 mg or 300 mg, compared with 3.7% in those receiving comparator drug or placebo.

From March 2013 to October 2015, the US FDA received 101 confirmable case reports of acute kidney injury (AKI) with use of canagliflozin (n=73) or dapagliflozin (n=28). Hospitalization was necessary for evaluation and management in 96 cases; admission to the intensive care unit occurred in 22 cases, and death occurred in 4 patients, of which 2 were cardiac-related. Dialysis was necessary in 15 patients, 3 of whom had a history of chronic kidney disease or previous AKI. In 58 cases, time to onset of AKI was within 1 month or less of initiating therapy. In 78 cases in which drug discontinuation was reported, 56 reported subsequent improvement; 3 patients recovered with sequelae, 11 patients did not recover (including the 4 deaths mentioned earlier). Median age was 57 years (range 28 to 78 years; based on 84 cases reporting age). Concomitant ACE inhibitor therapy was reported in 51 cases, diuretic use in 26 cases, and NSAID use in 6 cases. Almost half the patients reported a change in renal function at time of diagnosis (median elevation of serum creatinine from baseline 1.6 mg/dL [based on 32 cases reporting serum creatinine] and median decrease in eGFR 46 mL/min/1.73m2 [based on 13 cases reporting eGFR]).

Frequency not reported: Increases in serum creatinine, decreases in eGFR, renal impairment, acute renal failure

Postmarketing reports: Acute kidney injury

Uncommon (0.1% to 1%): Renal cell carcinoma

In the CANVAS trial (mean duration of follow-up of 5.7 years), the incidence of renal cell carcinoma was 0.29% (8/2716) in patients receiving this drug (placebo: 0.15% [2/1331]) excluding patients with less than 6 months of follow-up, less than 90 days of treatment, or a history of renal cell carcinoma.

Uncommon (0.1% to 1%): Photosensitivity reactions, rash, urticaria

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 (the active ingredient contained in Invokana) 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