What are the dangers / risks of Invokana?

Key Points

• The main risks of Invokana (canagliflozin) treatment include diabetic ketoacidosis, lower limb amputation, dehydration and low blood pressure, serious urinary tract infections, a rare genital infection called Fournier's gangrene, genital yeast infections, low blood sugar when combined with insulin, allergic reactions, and bone fractures.
• Invokana no longer carries a boxed warning. The FDA removed the amputation boxed warning on August 26, 2020, after newer trial data showed the risk was lower than first described. The amputation warning still appears in the label.
• The most common side effect is a genital yeast infection, in both women and men. Urinary tract infections and urinating more often are also common.
• Most serious side effects are uncommon. Invokana also lowers the risk of kidney failure, heart attack, and stroke in certain people, which is why doctors often weigh the risks and benefits.

Invokana (canagliflozin) is a prescription tablet used with diet and exercise to lower blood sugar in adults and children aged 10 and older with type 2 diabetes. It belongs to a group of medicines called SGLT2 inhibitors. It works by blocking a protein in the kidneys so your body flushes extra sugar out in your urine.

Update: the amputation boxed warning was removed

You may have seen that Invokana previously carried a boxed warning (the FDA's most serious type of warning) for leg and foot amputations. However, it has since been removed.

The FDA added that warning in 2017 based on two trials called CANVAS and CANVAS-R. In August 2020, the agency removed it. Later trials showed clear heart and kidney benefits, and newer safety data suggested the amputation risk, while still real, was lower than first described, especially when patients are monitored properly. The amputation risk is still described in the Warnings and Precautions section of the label, and it still deserves attention.

Serious risks of Invokana

Invokana carries several risks and warnings that you should know about. Discuss the full information with your healthcare professional.

Lower limb amputation

In the CANVAS and CANVAS-R trials, people taking Invokana had roughly twice the rate of leg and foot amputations compared with people taking a placebo. Toe and midfoot amputations were most common, but some involved the leg below or above the knee. Some people had more than one.

CREDENCE was a later trial in people with diabetic kidney disease, and it found almost no difference in amputation rates between Invokana and placebo. Researchers reviewing the evidence have noted that the doubled risk seen in CANVAS was not confirmed in CREDENCE, and that it remains unsettled whether this is a real drug effect. One analysis pooled four large US insurance databases covering more than 700,000 patients and found no increased risk of below-knee amputation with canagliflozin compared with non-SGLT2 diabetes drugs.

Your risk is highest if you have: a previous amputation, peripheral vascular disease (narrowed blood vessels in the legs), or nerve damage (neuropathy). In the trials, the events that most often led to an amputation were leg and foot infections, gangrene, and diabetic foot ulcers.

What to do: Check your feet daily and take foot care seriously. Call your doctor right away about any new pain, tenderness, sore, ulcer, or infection on your legs or feet. Your doctor may stop Invokana if these happen

Dehydration, low blood pressure, and sudden kidney problems

Invokana makes you urinate more, which can pull too much fluid out of your body. That can leave you dizzy, lightheaded, weak, or faint, especially when you stand up. It can also raise your risk of a fall.

In pooled trial data, about 2.3% of people on the 100 mg dose and 3.4% on the 300 mg dose had a dehydration-related reaction. For people 75 and older, those numbers rose to 4.9% and 8.7%.

You could be at risk of dehydration if you:

• have low blood pressure
• take medicine to lower your blood pressure
• are on a low sodium diet
• have kidney problems
• are 65 years of age or older.

Severe fluid loss can lead to sudden (acute) kidney injury. There have been reports of people needing hospital care or dialysis. Call your doctor if you are vomiting, have diarrhea, cannot keep fluids down, or are drinking or eating much less than usual. Discuss with your doctor how much fluid you should drink each day to help lower your risk for dehydration.

Genital yeast infections

Genital yeast infections are listed as a common side effect with SGLT2 inhibitors, including Invokana, and occur more frequently in women.

Symptoms of a vaginal yeast infection in women (also called vulvovaginitis or candidiasis):

• vaginal itching
• vaginal odor
• white or yellowish discharge that may be lumpy or look like cottage cheese
• vaginal burning discomfort or burning while urinating
• painful sexual intercourse.

In Invokana studies, the overall incidence of genital yeast infections in women was 10.6% (with the 100 mg dose), 11.6% (with the 300 mg dose) and 2.8% (inactive placebo). The number of women who had to stop treatment for this side effect was low: 0.7% of those receiving Invokana compared to 0% in the placebo group.

Symptoms of a yeast infection of the penis in men (balanitis or balanoposthitis):

• redness, itching, or swelling of the penis rash or sores on the penis
• foul smelling discharge from the penis
• pain in the skin around the penis
• tight, shiny skin on the head of your penis
• painful urination or not being able to urinate
• swollen glands near your groin.

Some men who are not circumcised may have swelling of the penis that makes it difficult to pull back the skin around the tip of the penis. Balanitis is most likely to occur in men who have a tight foreskin that is difficult to pull back, or who have poor hygiene. An allergy to condoms or spermicides may also worsen balanitis caused by yeast.

In men, genital yeast infections (e.g., candidal balanitis, balanoposthitis) occurred in 4.2% (with the 100 mg dose). 3.8% (with the 300 mg dose) and 0.7% (inactive placebo).

Talk to your doctor about what to do if you should get a yeast infection. This is treatable and few patients stop treatment due to this side effect. Oral prescription or over-the-counter topical antifungal treatment may be treatment options.

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Diabetic ketoacidosis

Ketoacidosis happens when your blood builds up too many ketones and becomes too acidic. It is serious, often needs hospital treatment, and can be fatal. The FDA has received reports of deaths from ketoacidosis in people with type 2 diabetes taking SGLT2 inhibitors

Stop taking Invokana and contact your doctor right away if you get any of the following symptoms:

• nausea
• tiredness
• vomiting
• trouble breathing
• stomach area (abdominal) pain.

If you get any of these symptoms during treatment with Invokana, if possible, check for ketones in your urine, even if your blood sugar is less than 250 mg/dL.

Serious urinary tract infections

Invokana raises the risk of urinary tract infections. In some cases these become severe such as a kidney infection (pyelonephritis) or a bloodstream infection (urosepsis) and require hospital care.

In clinical studies, UTIs occurred in 5.9% of patients receiving the 100 mg dose of Invokana, 4.4% of patients receiving the 300 mg dose and 3.8% of those on the inactive placebo.

Before you start treatment with Invokana, tell your doctor if you have a history of urinary tract infections or problems with urination. If you get any of the following symptoms, tell your doctor immediately:

• burning feeling when passing urine
• a need to urinate often
• the need to urinate right away pain in the lower part of your stomach (pelvis)
• blood in your urine
• a fever, back pain, nausea, or vomiting.

Low blood sugar (hypoglycemia)

On its own, Invokana rarely causes low blood sugar. The risk goes up sharply when you combine it with insulin or a sulfonylurea such as glipizide or glimepiride. Your doctor may lower the dose of those medicines when you start Invokana.

Signs and symptoms of low blood sugar may include:

• headache
• drowsiness
• weakness
• confusion
• dizziness
• irritability
• hunger
• fast heartbeat
• sweating
• shaking or feeling jittery

Fournier's gangrene

Fournier’s Gangrene is a rare but serious bacterial infection that causes damage to the tissue under your skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). This can happen in both women and men. It can require hospitalization, multiple surgeries, and may lead to death.

Seek medical attention immediately if you have fever or if you are feeling very weak, tired or uncomfortable and you have these symptoms in the area between and around your anus and genitals:

• pain
• tenderness
• swelling
• redness of the skin (erythema)

Serious allergic reactions

Reactions including anaphylaxis and angioedema (swelling under the skin around the eyes, lips, tongue, throat, hands, or feet) have been reported, usually within hours to days of starting the drug.

Stop taking Invokana and get emergency help if you have trouble breathing or swelling of your face, lips, tongue, or throat.

Bone fractures and falls

In the CANVAS trial, broken bones happened more often on Invokana, and the difference showed up as early as 12 weeks after starting. Fractures were usually low-impact and tended to affect the wrists, arms, ankles, and feet.

Falls were also slightly more common, and the higher risk appeared in the first few weeks of treatment. That is a good reason to be careful about standing up quickly early on.

Other effects to know about

• Higher potassium in people with reduced kidney function, which can affect the heart.
• Higher LDL cholesterol. The 300 mg dose raised LDL by about 8 mg/dL on average.
• Positive urine sugar tests. Invokana will make you test positive for glucose in your urine, so urine tests are not a reliable way to track your diabetes control.

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Drug interactions

Invokana is also associated with some drug interactions. Some interactions can affect your dose of Invokana and you may need a dose adjustment. Be sure to tell your doctor and pharmacist about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor and pharmacist if you take:

• diuretics (water pills)
• insulin or sulfonylureas
• rifampin (for tuberculosis)
• phenytoin or phenobarbital (for seizures)
• ritonavir (for HIV infection)
• lithium
• digoxin (for heart problems).

Pregnancy and breastfeeding

Tell your doctor if you are pregnant or plan to become pregnant while taking Invokana. Invokana may harm your unborn baby.

Invokana may also pass into your breast milk. Do not breastfeed while taking Invokana.

Talk with your doctor about the best way to control your blood sugar while you are pregnant. Also discuss the best way to feed your baby if you are taking Invokana.

Stop Invokana before surgery

The FDA label says Invokana may be withheld at least 3 days before surgery or any procedure that involves a long stretch without eating. Fasting while taking Invokana raises your risk for ketoacidosis.

You typically restart once you are stable and eating normally again. Tell every doctor, surgeon, dentist, and anesthesiologist that you take Invokana, and bring it up as soon as a procedure gets scheduled.

Bottom Line

• There are many important warnings and side effects to consider before you start treatment with Invokana. Some of the top concerns include amputations, dehydration, low blood pressure, and genital yeast infections.
• Your pharmacist will give you a Medication Guide when you fill your prescription for Invokana. You should re-read it with each new refill in case of new or updated information.
• Always talk to your doctor before you start treatment with any medication about warnings, side effects and drug interactions that could affect your health.

This is not all the information you need to know about Invokana (canagliflozin) for safe and effective use. Review the full Invokana information here, and speak to your health care provider if you have questions or concerns.

Read next

See also:

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Drug information

• Invokana Information for Consumers
• Invokana prescribing info & package insert (for Health Professionals)
• Side Effects of Invokana (detailed)
• Invokana user reviews (257)

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