FDA Strengthens Warnings on Bone Fracture Risk With Canagliflozin (Invokana, Invokamet)

Commentary by Heather P. Whitley, PharmD

Woman Reading Warning LabelsThe U.S. Food and Drug Administration (FDA) has strengthened the warning regarding an increased risk for bone fractures and decreased bone mineral density for the type 2 diabetes medication canagliflozin (Invokana, Invokamet). To address these concerns, the FDA added a new item to Warnings and Precautions section and revised the Adverse Reactions section of the prescribing information for Invokana and Invokamet.

“Certainly, SGLT2 inhibitors appear to be effective across the entire disease state, from people who are newly diagnosed to people who have long-standing diabetes,” commented Heather P. Whitley, PharmD, Associate Clinical Professor, Department of Pharmacy Practice, Auburn University Harrison School of Pharmacy, Montgomery, Alabama. “However, we need to be more thoughtful in who we prescribe canagliflozin for, as it relates to bone health in our patient population with type 2 diabetes,” Dr. Whitley said.

The additional item in the Warnings and Precautions section states that an increased risk of bone fracture was observed as early as 12 weeks in studies involving patients using canagliflozin and that healthcare professionals should “consider factors that contribute to fracture risk before initiating Invokana/Invokamet.”

Factors that contribute to this risk include a history of fracture, and diagnosis of osteoporosis or osteopenia, Dr. Whitley said. Other people at risk for fracture include those who are older in age, are perimenopausal or postmenopausal, have eating disorders (particularly anorexia and bulimia), have a history of fractures from nontraumatic events, with frequent use of oral or injectable steroids, or who smoke or abuse alcohol, Dr. Whitley noted.

Changes to Adverse Reactions Section
Information about the risk for bone fracture was already included in the Adverse Reactions section of the drug’s prescribing information when the agent was approved. However, based on additional data from 9 clinical trials confirming that fractures occur more often with canagliflozin than with placebo, the FDA revised the Adverse Reactions section to:

“The occurrence of bone fractures was evaluated in a pool of nine clinical trials with a mean duration of exposure to canagliflozin of 85 weeks. The incidence rates of adjudicated bone fractures were 1.1, 1.4, and 1.5 per 100 patient-years of exposure in the comparator, canagliflozin 100 mg, and canagliflozin 300 mg groups, respectively. Fractures were observed as early as 12 weeks after treatment initiation and were more likely to be low trauma (eg, fall from no more than standing height), and affect the upper extremities.”

The FDA also added information about a risk for decreased bone mineral density to the Adverse Reactions section. The information is based on data from a postmarketing study that evaluated changes in bone mineral density over 2 years in 714 older adults (mean age, 64 years) showed placebo-corrected decreases in bone mineral density at the total hip (0.9% and 1.2% with 100 mg and 300 mg canagliflozin, respectively) and lower spine (0.3% and 0.7% with 100 mg and 300 mg canagliflozin, respectively).

Is This a Class Effect?
“One of the big questions that arises from a labeling change such as this is: is this a unique effect of canagliflozin or is it a class effect?,” Dr. Whitley noted. “At present, we just don’t know. This information will be forthcoming as more studies of a longer duration come out, as have been requested by the FDA,” Dr. Whitley said.

The FDA stated that it is evaluating the risk of bone fractures among other drugs in this class—including dapagliflozin (Farxiga, Xigduo XR) and empaglifozin (Jardiance, Glyxambi, Synjardy)—to determine if additional label changes or studies are needed.

“For the moment, stay tuned as more evidence becomes available,” Dr. Whitley concluded. “At present, I would be cautious about prescribing any agents in the SGLT2 class, for those individuals at increased risk for fracture.

 

September 24, 2015

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