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Invokana Black Box Warning After Studies Show Higher Amputation Risk

Patient Loses Leg After Taking Invokana

Two recent clinical trials studying Invokana (canagliflozin) shed light on the diabetes drug’s alarming side effects. Canagliflozin is a type 2 sodium-glucose transport inhibitor (SGLT2 inhibitor) marketed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson. The medication works to lower blood sugar levels in the body by stopping the kidneys from reabsorbing blood glucose. Instead of the blood glucose staying in the body, it is removed with the body’s urine.

The clinical trials were named CANVAS and CANVAS-R, based on long scientific acronyms. The studies examined the effects of canagliflozin on patients with Type-2 diabetes. The trials discovered that leg and foot amputations occurred twice as often in patients taking canagliflozin as those treated with a placebo.

The risk for amputations broke down like this: 5.9 out of every 1,000 patients treated with canagliflozin suffered amputation, as compared to 2.8 out of every 1,000 patients treated with a placebo. Over a year’s time, the risk of amputation was 7.5 out of every 1,000 patients treated with canagliflozin, compared to 4.2 out of every 1,000 patients treated with a placebo. These are statistically significant results, meaning the risk of amputation for those people taking Invokana was large enough to cause alarm in the medical community.

In the clinical trials, amputations of the toe and middle of the foot were the most common; however, amputations of the leg, below and above the knee, also occurred. Some patients had more than one amputation.

Based on this new data, the FDA ordered new warnings, including a prominent boxed warning, to be added to the canagliflozin drug labels to explain and describe this risk.  

Black Box Warnings

A boxed warning is serious business. A “boxed warning” or “black box warning” is a warning that appears on the package insert for certain prescription drugs. It is given this name because the FDA requires that the warning be presented with a box or notable border around the text. The boxed warning is designed to call attention to serious or life-threatening risks that are possible when using the prescription drug.

In July 2017, the FDA required a boxed warning for the diabetes drug Invokana, which included these bullet points:

“Warning: Lower Limb Amputation”

  • 2-fold increased risk of lower limb amputations was observed in two studies of patients taking Invokana.
  • Amputations of the toe and midfoot were most frequent; amputations of the leg were also observed. Some patients had multiple amputations.
  • Before taking Invokana, 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 Invokana for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications

See FDA Website for the complete boxed warning.

In the drug package insert, which is easily accessible online, Janssen describes in more detail the troubling side-effects that can be caused by taking Invokana, including the greater risk of amputations. Section 5 of the insert is titled “Warnings and Precautions.” Here are the key warnings, which I have (gently) edited to make them (slightly) easier to read:

5.1 Lower Limb Amputation

An increased risk of lower limb amputations was associated with Invokana use.

Amputations of the toe and midfoot were the most frequent; however, amputations involving the leg, below and above the knee, were also observed. Some patients had multiple amputations, some involving both lower limbs.

The risk of amputation was highest in patients with a baseline history of prior amputation, vascular disease, and neuropathy.

. . . Other Side Effects of Taking Invokana . . .

Warning Label on Diabetes Drug Invokana

5.2 Hypotension

Invokana causes intravascular volume contraction. Hypotension can occur after initiating Invokana . . . particularly in patients with impaired renal function, elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system, or patients with low systolic blood pressure.

5.3 Ketoacidosis

Reports of ketoacidosis [a serious condition of diabetes that can occur when the body produces high levels of blood acids called ketones] . . . . have been identified in patients with type 1 and type 2 diabetes mellitus receiving Invokana (and other SGLT2 inhibitors). Fatal cases of ketoacidosis have been reported in patients taking Invokana.

5.4 Acute Kidney Injury and Impairment in Renal Function

Invokana can cause renal impairment [reduced kidney function]. There have been post-marketing reports of kidney injury, requiring hospitalization and dialysis, in patients receiving Invokana.

5.5 Hyperkalemia

Invokana can lead to hyperkalemia [high potassium levels in the blood].

5.6 Urosepsis and Pyelonephritis
There have been post-marketing reports of urinary tract infections including urosepsis and pyelonephritis in patients receiving SGLT2 inhibitors, including Invokana. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections.

5.7 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues are known to cause hypoglycemia [low blood sugar]. Invokana can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue.

5.8 Genital Mycotic Infections

Invokana can increase the risk of mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more prone to develop genital mycotic infections.

5.9 Hypersensitivity Reactions

Angioedema and anaphylaxis have been reported with Invokana. These reactions generally occurred within hours to days after initiating Invokana.

5.10 Bone Fracture

An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using Invokana. Consider factors that contribute to fracture risk prior to initiating Invokana.

5.11 Increases in Low-Density Lipoprotein (LDL-C)

Dose-related increases in LDL-C [this is sometimes referred to as the “bad cholesterol”] occur with Invokana.

5.12 Macrovascular Outcomes

There have been no studies establishing conclusive evidence of a macrovascular risk reduction with Invokana.


The bottom line: if you are taking Invokana for treatment of Type-2 diabetes, talk to your doctor about the risks and whether you should remain on the medication. For more information, consult the FDA website.