FDA Strengthens Fracture Warning for Canagliflozin

Miriam E. Tucker


September 10, 2015

The US Food and Drug Administration (FDA) has strengthened its warning for canagliflozin (Invokana, Invokamet, Johnson & Johnson/Janssen) related to the increased risk for bone fractures.

The "Adverse Reactions" section of the product label for canagliflozin had already mentioned the risk for bone fractures. Now, based on new confirmatory information from several clinical trials, the FDA has added further warning and precaution information. In the trials, the fractures affected the upper extremities, occurred as early as 12 weeks after starting the drug, and typically arose from minor trauma such as falling from a standing height.

The FDA has also added new information to the label about decreased bone mineral density at the hip and lower spine.

Healthcare professionals are advised to consider factors that contribute to fracture risk before starting patients on canagliflozin, and to counsel patients about factors that might contribute to bone fracture risk.

The new fracture warning is based on pooled data from nine clinical trials with a mean of 85 weeks' exposure to canagliflozin, in which the incidence rates of adjudicated bone fractures were between 1.1 and 1.5 per 100 patient-years of exposure.

Data on bone mineral density came from an FDA-mandated postmarketing safety trial involving 714 elderly patients with type 2 diabetes (mean age, 64 years; range, 55 - 80 years). At 2 years, patients randomly assigned to canagliflozin 100 mg and 300 mg had placebo-corrected declines in bone mineral density, as measured by dual-energy X-ray absorptiometry, of 0.9% and 1.2%, respectively, at the hip, and of 0.3% and 0.7%, respectively, at the lumbar spine.

In addition, placebo-adjusted bone mineral density declines of 0.1% were seen at the femoral neck for both canagliflozin doses, and of 0.4% at the distal forearm for patients taking the 300-mg canagliflozin dose (but no change was seen at the distal forearm with the 100-mg dose).

A Class Effect?

The FDA is also evaluating the possible risk for bone fractures for other drugs in the sodium glucose cotransporter 2 (SGLT2) inhibitor class, including dapagliflozin (Farxiga, Xigduo XR, AstraZeneca) and empagliflozin (Jardiance, Glyxambi, Synjardy, Lilly/Boehringer Ingelheim), to determine whether additional label changes or studies are needed. The label for Farxiga mentions a small number of cases of fractures in patients with renal impairment; the Jardiance prescribing information does not mention bone effects.

The topic of SGLT2 inhibitors and bone was discussed in an article published earlier this year in Lancet Diabetes and Endocrinology by Simeon I. Taylor, MD, professor of medicine at University of Maryland School of Medicine in Baltimore, and colleagues. They explain that SGLT2 inhibitors increase concentrations of phosphate in serum, probably via increased tubular reabsorption, which has the potential to adversely affect bone.

Furthermore, they say, SGLT2 inhibitors increase concentrations of parathyroid hormone (PTH). Sustained increases in PTH concentration enhance bone resorption and increase the risk for bone fractures.

"Although canagliflozin causes a small increase in mean PTH concentration (7.9%), the standard deviation is large. Thus, a substantial number of patients treated with canagliflozin might have a 50% or greater increase in PTH concentrations — a change that could be clinically significant," the authors write.

Dr Taylor told Medscape Medical News, "Although not proven, I believe that increased risk of bone fracture is likely a class effect. Nevertheless, individual drugs differ with respect to selectivity for SGLT2 vs SGLT1, and also with respect to where on the dose-response curve the approved dose falls. So, it is certainly possible that the magnitude of the risk could vary among individual SGLT2 inhibitors."

Healthcare professionals and patients are urged to report adverse effects involving canagliflozin or other SGLT2 inhibitors to the FDA MedWatch program.

Dr Taylor was employed by Bristol-Myers Squibb from 2002 to 2013, where, as vice president of cardiovascular and metabolic disease research, he participated in research and development leading to the approval of dapagliflozin (Farxiga), which is currently marketed by AstraZeneca.


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