Biowaiver Monograph for Fluoxetine Hydrochloride Immediate Release Solid Oral Dosage Forms

Background: Generic versions of an innovator pharmaceutical product must demonstrate similar safety and efficacy in order to qualify for interchangeability. Since 1960s, pivotal in vivo bioequivalence studies have emerged as the gold standards in proving similarity and interchangeability between bioequivalent products. The advent of the biopharmaceutical classification system (BCS) has revolutionized the drug approval process. The World Health Organization (WHO) has called for granting biowaivers for the orally administered drugs on its essential medicines list (WHO's EML). The International Pharmaceutical Federation (FIP) adopted this initiative and called researchers around the world to prepare biowaiver monographs and evaluate the possibility of granting a biowaiver for the orally administered drugs listed on the WHO's EML. Objectives: The present study was conducted in response to the WHO and FIP initiatives. The present monograph reviews data relevant to applying the biowaiver procedure for the approval of immediate-release (IR) multisource solid dosage forms containing fluoxetine hydrochloride (HCl) as the active pharmaceutical ingredient (API). Methods: Solubility studies were conducted to assign a correct BCS solubility class for fluoxetine HCl. Molecular descriptors and permeability data were evaluated to assign a BCS permeability class for fluoxetine HCl. Dissolution experiments were conducted on the innovator product and locally available generics. The consequences of granting a biowaiver decision for IR solid oral dosage forms containing fluoxetine HCl as an API were evaluated after collecting and evaluating all pertinent biopharmaceutical and clinical data. Results: Solubility studies revealed that fluoxetine HCl meets the “highly soluble” criteria according to the BCS criteria set by different regulatory authorities. Permeability data were inconclusive and it was not clear if fluoxetine HCl would be assigned a high or low permeability class. Innovator and generic formulations containing fluoxetine showed very rapid dissolution and released more than 85% of their fluoxetine HCl contents in less than 15 min. Conclusion: Our study concluded that IR solid oral formulations can be granted a biowaiver and similarity between test and reference products can be safely compared using in vitro dissolution testing. The main risks associated with a wrong fluoxetine biowaiver decision would be attributed to accumulating concentrations due to CYP2D6 deficiency in ultra-poor metabolizers. Taken together, our results suggest that fluoxetine HCl with manageable risks can be a candidate for waiver of in vivo bioequivalence studies. Keywords: absorption; bioavailability; bioequivalence; biopharmaceutical classification system (BCS); fluoxetine HCl; permeability; dissolution; solubility