Are Risk of Invokana and Invokamet Bone Fractures a Sign of Fractured Regulations?

Washington, DCA drug indicated for the treatment of type 2 diabetes already carries warnings for compelling adverse reactions including a heightened risk for lower limb amputations, kidney failure, diabetic ketoacidosis and cardiovascular injuries. To that end, the FDA warns of fracture risk with Invokana and Invokamet. Yet in spite of such serious side effects associated with Invokana (canagliflozin) and Invokamet (canagliflozin and metformin), the US Food and Drug Administration (FDA) approved, last year an expanded indication for Invokamet.

The latter was originally approved by the FDA in 2014. Last year, Invokamet XR was given the FDA’s blessing as an extended-release drug for the treatment of type 2 diabetes.

“Invokamet XR offers the convenience of once-daily dosing and provides physicians needed flexibility for tailoring treatment to the needs of type 2 diabetes patients, especially those with higher A1c levels,” said John Anderson, MD, with The Frist Clinic in Nashville, Tennessee, in a published statement on behalf of Invokamet XR manufacturer Janssen Pharmaceuticals that appeared in Formulary Watch (09/26/16). “As with Invokamet, physicians can prescribe the XR formulation to adults when they are first diagnosed with type 2 diabetes or as additional therapy for people whose A1c levels are not well controlled with either agent alone.”

However, there are Invokamet XR side effects that are similar to Invokamet and Invokana: for one, the FDA warns of fracture risk with both Invokana and Invokamet. That bone fracture risk includes metformin, which is part of the genetic makeup of Invokamet and Invokamet XR along with canagliflozin (Invokana). Invokamet and Invokamet XR are both comprised of a combination of canagliflozin and metformin.

With Invokamet XR there is also a boxed warning issued by the manufacturer and the FDA with regard to lactic acidosis, described as a rare but serious complication that can occur due to metformin accumulation. In addition, Invokamet XR should not be used in patients with type 1 diabetes, or for the treatment of diabetic ketoacidosis.

More recently, the FDA issued a black box warning with regard to Invokana and a higher risk for foot and leg amputation. That happened in May of this year, and is on top of existing concerns over the potential for kidney failure, diabetic ketoacidosis and cardiovascular injuries. Many an Invokana lawsuit alleges such injuries. The most recent FDA–mandated black box warning, issued on May 16, only exacerbates and deepens those concerns.

Combined with the black box warning issued at the time of FDA approval for Invokamet XR extended release metformin/canagliflozin, the suggestion that the benefits associated with Invokana and Invokamet / Invokamet XR come at a particularly high cost – in terms of adverse event risk – to the patient, or plaintiff.

Invokana, as of September last year, was reported as the most-prescribed sodium co-transporter 2 (SGLT2) inhibitor in its class, with in excess of 9 million prescriptions written in the US alone.

Invokamet and Invokamet XR (canagliflozin and metformin) are not alone in risk for bone fracture. Invokana (canagliflozin) was flagged with bone fracture risk within two years of its original approval by the FDA in 2013. The regulator warned that Invokana could increase bone fracture risk and decrease bone mineral density in type 2 diabetes patients.

In a post-marketing safety evaluation, 714 elderly participants were tested for changes to bone mineral density over two years. The results showed patients starting the drug suffered bone fractures as early as 12 weeks into treatment. Canagliflozin was seen to have caused loss of bone mineral density at the hip and lower spine. The data mined from the clinical trial confirmed fractures happened more frequently in patients with canagliflozin, especially in post-menopausal women.

The FDA operates under a mandate to approve, and maintain medications provided benefits outweigh risks for the intended patients. In leaving Invokana and Invokamet / XR on the market, the FDA is signaling that the SGLT-2 medications are considered not unsafe and carry benefits that still outweigh the risks.

Patients and plaintiffs considering Invokana or Invokamet / metformin lawsuits alleging bone fracture, amputation, kidney or cardiovascular injuries may beg to differ. Janssen is a division of Johnson & Johnson.