FDA drug safety program mitigates prenatal exposure to phentermine-topiramate

Key takeaways:

• Phentermine-topiramate is approved for weight loss, but topiramate’s association with birth defects is well established.
• An FDA safety program successfully reduced prenatal exposure to the drug combination.

Prenatal exposure to topiramate — which has been linked to birth defects — was lower among those using it in combination with phentermine than those taking topiramate alone, data show.

Researchers attributed the finding to an FDA-mandated drug safety program that warns prescribers, pharmacists and patients about the risks associated with topiramate. The program only applies to the combination product phentermine-topiramate, not topiramate alone.

In 2012, the FDA approved the fixed-dose combination drug phentermine-topiramate for long-term obesity management, Amir Sarayani, PharmD, MPH, PhD, a graduate assistant at the University of Florida College of Pharmacy, and colleagues wrote in Annals of Internal Medicine. To prevent prenatal exposure, the FDA also required adding phentermine-topiramate to its Risk Evaluation and Mitigation Strategy (REMS) program.

However, topiramate, which is also used for epilepsy and migraine prevention, never had any such requirement “to avoid burden on patients and providers managing” those conditions, Sarayani and colleagues wrote.

The researchers conducted a retrospective cohort study to assess the rates of pregnancy testing, contraceptive use and prenatal exposure in patients receiving phentermine-topiramate compared with topiramate or other anti-obesity medications (AOMs).

Sarayani and colleagues used information from the MarketScan Commercial Claims Research Database, a nationwide health insurance claims database that offers deidentified billing records for privately insured people in the United States. The researchers evaluated data for 156,280 treatment episodes among women aged 12 to 55 years who had no sterilization procedure, no infertility diagnosis and no other indications for topiramate.

There were three exposure groups in the study: phentermine-topiramate; topiramate; and AOM (liraglutide, lorcaserin, or bupropion-naltrexone).

Sarayani and colleagues found that prenatal exposure to phentermine and topiramate extended-release capsules appeared to be much lower among phentermine-topiramate users than for those who used topiramate alone or other AOMs. In fact, those who used phentermine-topiramate had about 50% fewer prenatal exposures than those who used AOM or topiramate. However, the difference in prenatal exposure between AOM and topiramate was small.

The adjusted prevalence of pregnancy at treatment initiation for phentermine–topiramate vs. topiramate was 0.9 vs. 1.6 per 1,000 episodes, and the prevalence ratio was 0.54 (95% CI, 0.31-0.95). During treatment, the incidence rate of conception was 9.1 vs. 15 per 1,000 person-years (rate ratio = 0.61; 95% CI, 0.40-0.91) for phentermine-topiramate vs. topiramate.

Sarayani and colleagues noted that contraceptive use and pregnancy testing seemed to be inadequate for everyone — a finding that they wrote warrants attention to prevent remaining potential exposures. Overall, 20% of patients used contraceptives before and during treatment, and fewer than one in 20 patients had pregnancy tests before medication initiation.

“Pregnancy testing before and during treatment seemed to be significantly higher among phentermine–topiramate users, albeit at low absolute levels, likely contributing to lower prenatal exposures,” the researchers wrote. “However, contraceptive use patterns seemed unchanged, requiring further research to understand patients' experiences with these recommendations and potential modification of the REMS to facilitate behavior change.”

The researchers additionally looked at the role age may play in prenatal exposure. Younger patients, they found, used more pregnancy tests and contraceptives than older patients, but they also faced a higher absolute risk for prenatal exposures.

“Prenatal exposure was generally low among older women across study cohorts but substantially higher in women younger than 40 years. However, patients using phentermine–topiramate under a REMS program had less prenatal exposure than topiramate and AOM users,” Sarayani and colleagues wrote. “Still, potential exposures were detected, suggesting the need for further clinical vigilance and risk mitigation.”