FDA Cites Active Ingredient Issue With Riluzole For Treatment of Amyotrophic Lateral Sclerosis


The complete response letter cited issues with an active pharmaceutical ingredient used in the Biohaven 2017 bioequivalence study that was manufactured between 2014 and 2016 in an Apotex facility.

Dr Robert Berman

Robert Berman, MD, biohaven

Robert Berman, MD

The FDA has issued a complete response letter to Biohaven Pharmaceuticals for the 505(b)2 application seeking approval for a sublingual form of riluzole, previously known as BHV-0223, for treatment of amyotrophic lateral sclerosis.

The issue identified in the letter concerns the use of an active pharmaceutical ingredient, manufactured by Apotex Pharmachem India Private Limited (Apotex) between 2014 and 2016, used in the drug product supplies for the bioequivalence study in 2017. Concerns with Apotex manufacturing led to the withdrawal of 31 Apotex drug products from the U.S. market July 10, 2019.1

“We are doing everything possible to work with the FDA and active pharmaceutical ingredient manufacturer to resolve this matter, which we believe to be more technical in nature,” Robert Berman, MD, chief medical officer, riluzole development lead, Biohaven, said in a statement.2 “We believe that the quality issues surrounding the Apotex manufacturing facility do not affect the conclusions of our bioequivalence study, but will work collaboratively with the FDA to resolve this matter as quickly as possible.”

The FDA provided recommendations to Apotex regarding the information needed to qualify previous active pharmaceutical ingredient batches manufactured at Apotex during the period in question. Apotex did not provide Biohaven with notice of the FDA communication either during the bioequivalence trial or during the submission of the 505(b)2 application for riluzole.1

The agency did not cite any additional concerns in the complete response letter regarding riluzole.

According to Biohaven, the active pharmaceutical ingredient commercial supply of riluzole is currently sourced from another supplier. They were eventually informed by Apotex that they had an exemption from the FDA to supply riluzole to the U.S. market during that time period.

Biohaven is working with the FDA to resolve the matter and has already submitted additional information to the FDA regarding the issue and will re-deploy the associated funds for riluzole commercialization to other commercial needs of the organization.

In November 2018, the FDA accepted the new drug application filing of the novel, low dose formulation of riluzole. The new drug application submission is backed by data from multiple studies and clinical trials that evaluated the bioequivalence of riluzole to riluzole oral tablets as well its the safety and tolerability.

The main data from the clinical program designed to demonstrate pharmacokinetic equivalence of sublingual riluzole compared to oral riluzole confirmed that sublingual administration of BHV-0223 (40 mg) achieved similar blood exposures to orally ingested riluzole (50 mg) but with a 20% lower total daily drug burden.3 The results were reported in a bioequivalence study where 138 healthy volunteers were administered BHV-0223 and oral riluzole under fasted conditions. In the pre-specified primary analysis, BHV-0223 achieved area-under-the-curve and peak exposures of approximately 90% and 113%, respectively, compared to those generated by oral riluzole.3 BHV-0223 was generally well tolerated and participants reported that the sublingual formulation was easy to use. Based on the study results and reduced drug exposure to the liver, BHV-0223 may have a lessened risk for causing liver test elevations.


1. Apotex, Inc.; Withdrawal of Approval of 31 Abbreviated New Drug Applications. Federal Register website. https://www.federalregister.gov/documents/2019/07/10/2019-14660/apotex-inc-withdrawal-of-approval-of-31-abbreviated-new-drug-applications. Published July 10, 2019. Accessed July 22, 2019.

2, Biohaven's Nurtec (riluzole) 505(b)2 Application for Amyotrophic Lateral Sclerosis Affected by Issues Related to Apotex Plant: Complete Response Letter (CRL) Received From FDA Related to Isolated Drug Substance Supply Used in Bioequivalence Study [news release]. New Haven, CT: Biohaven Pharmaceuticals; July 19, 2019. https://www.prnewswire.com/news-releases/biohavens-nurtec-riluzole-505b2-application-for-amyotrophic-lateral-sclerosis-affected-by-issues-related-to-apotex-plant-complete-response-letter-crl-received-from-fda-related-to-isolated-drug-substance-supply-used-in-bioe-300888242.html. Accessed July 22, 2019.

3. Biohaven Announces Positive Results from Bioequivalence Study with Sublingual BHV-0223 Zydis Orally Dissolving Tablet [news release]. New Haven, Conn.: Biohaven Pharmaceutical Holding Company Ltd.; 2018. https://www.biohavenpharma.com/investors/news-events/press-releases/01-09-2018. Accessed Nov. 26, 2018.

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