Biowaiver monographs for immediate-release solid oral dosage forms: Zidovudine (azidothymidine).

Literature data on the properties of zidovudine relevant to waiver of in vivo bioequivalence (BE) testing requirements for the approval of immediate-release (IR) solid oral dosage forms containing zidovudine alone or in combination with other active pharmaceutical ingredients (APIs) are reviewed. Solubility, dissolution, and permeability data for zidovudine, along with its dosing schedule, therapeutic index and pharmacokinetic properties, and reports related to BE/bioavailability were all taken into consideration. Data for solubility and permeability suggest that zidovudine belongs to Class I according to the Biopharmaceutics Classification System. Also, zidovudine is not a narrow therapeutic index drug. Although five out of 13 formulations tested in vivo (mostly of unreported composition) failed to show BE, it appears that in vitro studies performed according to biowaiver methods could predict in vivo behavior. Nevertheless, it is highly recommended that if a biowaiver is to be applied, excipient choices be limited to those found in IR drug products approved in International Conference on Harmonisation (ICH) or associated countries in the same dosage form (Table 2 of this monograph), in their usual amounts. These conclusions apply to products containing zidovudine as the only API and also to fixed combination products containing zidovudine with respect to the zidovudine component of the formulation.

Biowaiver monographs for immediate release solid oral dosage forms: efavirenz.

Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate-release (IR) solid oral dosage forms containing efavirenz as the only active pharmaceutical ingredient (API) are reviewed. Because of lack of conclusive data about efavirenz's permeability and its failure to comply with the "high solubility" criteria according to the Biopharmaceutics Classification System (BCS), the API can be classified as BCS Class II/IV. In line with the solubility characteristics, the innovator product does not meet the dissolution criteria for a "rapidly dissolving product." Furthermore, product variations containing commonly used excipients or in the manufacturing process have been reported to impact the rate and extent of efavirenz absorption. Despite its wide therapeutic index, subtherapeutic levels of efavirenz can lead to treatment failure and also facilitate the emergence of efavirenz-resistant mutants. For all these reasons, a biowaiver for IR solid oral dosage forms containing efavirenz as the sole API is not scientifically justified for reformulated or multisource drug products.

Biowaiver monographs for immediate release solid oral dosage forms: metronidazole.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing metronidazole are reviewed. Metronidazole can be assigned to Biopharmaceutics Classification System Class I. Most BE studies that were identified reported the investigated formulations to be bioequivalent, indicating the risk of bioinequivalence to be low. Formulations showing differences in bioavailability showed dissimilarities in in vitro dissolution profiles. Furthermore, metronidazole has a wide therapeutic index. It is concluded that a biowaiver for solid IR formulations is justified, provided: (a) the test product and its comparator are both rapidly dissolving; (b) meet similarity of the dissolution profiles at pH 1.2, 4.5, and 6.8; (c) the test product contains only excipients present in IR drug products approved in International Conference on Harmonisation (ICH) or associated countries in the same dosage form; and (d) if the test product contains sorbitol, sodium laurilsulfate, or propylene glycol, the test product needs to be qualitatively and quantitatively identical to its comparator with respect to these excipients [corrected]..

Biowaiver monographs for immediate release solid oral dosage forms: levofloxacin.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing levofloxacin as the only active pharmaceutical ingredient (API) are reviewed. According to the current Biopharmaceutics Classification System, levofloxacin can be assigned to Class I. No problems with BE of IR levofloxacin formulations containing different excipients and produced by different manufacturing methods have been reported and hence the risk of bioinequivalence caused by these factors appears to be low. In addition, levofloxacin has a wide therapeutic index. On the basis of this evidence, a biowaiver is recommended for IR solid oral dosage forms containing levofloxacin as the single API provided that (a) the test product contains only excipients present in IR levofloxacin drug products that have been approved in International Conference on Harmonization (ICH) or associated countries and which have the same dosage form; (b) both the test and comparator dosage form are "very rapidly dissolving" or "rapidly dissolving" with similarity of the dissolution profiles demonstrated at pH 1.2, 4.5, and 6.8; and (c) if the test product contains polysorbates, it should be both qualitatively and quantitatively identical to its comparator in terms of polysorbate content.