In an alert yesterday from the FDA (here), the Agency indicated that it was changing the TE code of Accord Healthcare’s product (ANDA 091195) from AB (substitutable) to BX (“not sufficient information to demonstrate that Accord Healthcare Inc.’s tacrolimus oral capsules provide the same therapeutic effect as Prograf (tacrolimus) oral capsules”). Tacrolimus is used for the prevention of organ rejection after organ transplant procedures.
The Agency notes that, while there does not appear to be an issue with the Accord product’s efficacy, recent studies conducted for the Agency raised concern “that the peak blood concentration of tacrolimus for Accord Healthcare Inc.’s generic tacrolimus oral capsules may be increased compared to the brand-name drug, Prograf (tacrolimus), creating a risk of toxicity. However, according to the new data, there were no significant differences in the trough blood levels, indicating no increased risk for organ rejection.”
The Agency updated its recommendation for bioequivalence testing in the product-specific bioequivalence guidance for tacrolimus in 2012 after it classified tacrolimus as a narrow therapeutic index drug. The FDA alert says that “[T]his change led to concerns from the transplant community regarding the substitutability of FDA-approved generic tacrolimus oral capsules that were approved prior to 2012, for both their therapeutic equivalence to the brand-name drug, Prograf (tacrolimus) and other approved generics.” Subsequent to those concerns, the FDA funded multiple studies to evaluate the issue and found that the Accord product had higher Cmax values that could lead to tacrolimus toxicity. The data lead the FDA to fund an additional bioequivalence study that confirmed the Accord product has a higher maximum concentration than the brand-name Prograf product, which could lead to potential signs or symptoms of tacrolimus toxicity. This finding led the FDA to change the TE code, as noted above, for the Accord product. However, the Agency also noted that it “is not aware of post-marketing issues regarding safety or efficacy for Accord Healthcare Inc.’s tacrolimus oral capsules.”
The notice cited above provides additional detail regarding the Agency’s action and has links for questions and answers that further explain this action (here), as well as the Agency’s response to a Citizen Petition filed by Belcher Pharmaceuticals, LLC (here) asking the Agency to take certain actions regarding all generic tacrolimus products that were approved prior to 2012 (when the PSG was revised). The Petition was denied in part and granted in part.
The Accord product remains approved, but it is now not considered interchangeable with Prograf, which means it cannot be automatically substituted in the pharmacy or by pharmacists. The FDA advises that “patients currently taking Accord Healthcare Inc.’s tacrolimus oral capsules should not make changes to their treatment, except in consultation with their health care professional. Patients should also inform their health care professional if they have experienced any problems that may be related to taking Accord Healthcare Inc.’s tacrolimus oral capsules.”