FDA: Lotronex, approved generics no longer require REMS to ensure benefits outweigh risks

Agency experts explain why

FDA has eliminated the Risk Evaluation and Mitigation Strategy (REMS) programs for Lotronex (alosetron hydrochloride) and approved generics.

The REMS are no longer necessary to ensure the benefits of the drugs outweigh the risks of ischemic colitis (IC) and serious complications of constipation (CoC), adverse reactions associated with the drugs.

Laura Zendel

Lotronex (alosetron hydrochloride) is an FDA-approved drug indicated for women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have chronic IBS symptoms (generally lasting 6 months or longer), had anatomic or biochemical abnormalities of the gastrointestinal (GI) tract excluded, and have not responded adequately to conventional therapy. Alosetron is associated with infrequent but serious GI adverse reactions, such as IC and serious CoC. Because of these safety concerns, alosetron hydrochloride should only be used in patients with severe diarrhea-predominant IBS for whom the benefits exceed the risks.

Although the risks of IC and serious CoC still exist, FDA has determined the REMS for Lotronex and approved generics are no longer necessary to ensure the benefits of Lotronex/alosetron hydrochloride outweigh the risks. However, the prescribing information will continue to include the boxed warning to highlight and mitigate the known serious risks, as well as a medication guide.

Joyce Korvick

Lotronex, originally approved in February 2000, was voluntarily withdrawn by the manufacturer in November 2000 due to serious postmarketing adverse events, including at least 49 cases of IC and 21 cases of serious CoC, some of which were fatal, or required surgery or blood transfusions. It was reintroduced to the market in June 2002 with a risk management program (RMP) with restricted distribution. FDA identified Lotronex as a product deemed to have in effect an approved REMS following the passage of the Food and Drug Administration Amendments Act of 2007, and in 2010, FDA approved a restrictive REMS for Lotronex that required prescriber training and enrollment and safe-use conditions that included a form that was signed by the patient acknowledging the risks. The Lotronex REMS also required that pharmacies could only dispense Lotronex if the prescriber affixed an RMP sticker on a hard copy prescription, which intended to indicate prescriber compliance with the requirements. The first generic for alosetron hydrochloride was approved in 2015. In 2016, FDA approved modifications to the Lotronex REMS and the alosetron REMS programs to make prescriber training voluntary.

Evidence to support eliminating the REMS

Elimination of the Lotronex and alosetron REMS programs are supported by the following:

1. Recent REMS assessment reports indicate that surveyed prescribers understand the risks, the indicated patient population and the need to counsel patients despite an ongoing downward trend in the number of prescribers who complete the voluntary training program.
2. Surveyed patients understand the actions to take if they experience symptoms that may indicate IC, serious CoC, or both.
3. Reporting of IC and CoC adverse events associated with alosetron to the FDA Adverse Event Reporting System) has been stable since 2002, and an increase in severe outcomes has not been observed since the REMS programs were modified in 2016 to eliminate the restrictions. Additionally, an analysis of new female users of alosetron hydrochloride in FDA’s Sentinel Distributed Database from 2016 to 2020 found the rate of IC to be consistent with that listed in the prescribing information.
4. There has not been an observed increase in drug utilization since approval of the generic version of alosetron hydrochloride. Overall, there has been an ongoing downward trend in the estimated total number of patients receiving prescriptions for all alosetron hydrochloride products. Because the availability of approved therapeutic alternatives, drug use is not expected to increase with removal of the REMS.

Conclusion

Alosetron is associated with the risks of IC and serious CoC, which can be managed by following the recommendations in the prescribing information and the medication guide. FDA will continue to monitor the risks through use of a pharmacovigilance strategy that includes the review of adverse event reporting and an evaluation of drug utilization.

Patients can continue to be prescribed or take Lotronex and alosetron hydrocholoride. Prescribers and patients should continue to follow the recommendations in the prescribing information, which includes a boxed warning for the risks and the medication guide to mitigate risks.

FDA prioritizes patient safety and will continue to monitor these drugs for safety risks.