Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Amoxicillin Trihydrate

Abstract

Literature and experimental data relevant to waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release solid oral dosage forms containing amoxicillin trihydrate are reviewed. Solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), therapeutic uses, therapeutic index, excipient interactions, as well as dissolution and BE and bioavailability studies were taken into consideration. Solubility and permeability studies indicate that amoxicillin doses up to 875 mg belong to BCS class I, whereas 1000 mg belongs to BCS class II and doses of more than 1000 mg belong to BCS class IV. Considering all aspects, the biowaiver procedure can be recommended for solid oral products of amoxicillin trihydrate immediate-release preparations containing amoxicillin as the single active pharmaceutical ingredient at dose strengths of 875 mg or less, provided (a) only the excipients listed in this monograph are used, and only in their usual amounts, (b) the biowaiver study is performed according to the World Health Organization-, U.S. Food and Drug Administration-, or European Medicines Agency-recommended method using the innovator as the comparator, and (c) results comply with criteria for "very rapidly dissolving" or "similarly rapidly dissolving." Products containing other excipients and those containing more than 875 mg amoxicillin per unit should be subjected to an in vivo BE study.

Is the demonstration of bioequivalence for clavulanic acid required in amoxicillin–clavulanic acid orally administered immediate-release products?

“…Clavulanic acid is also free of serious side effects. Over 3 decades of successful use bears the testimony to the Co‐amoxiclav combination's exceptional tolerability . The majority of the adult and paediatric patients have received the combination well and only minority group of patients has reported mild adverse effects related to gastrointestinal disturbance such as diarrhoea, nausea and vomiting (SPC, Co‐amoxiclav 1000 mg/200 mg).…”

“…Due to its excellent stability characteristics especially in acidic medium, amoxicillin trihydrate form is most commonly used in manufacturing oral dosage formulations and further, it does not exhibit polymorphism . The solubility of amoxicillin reported in pH 1.2, 4.5 and 6.8 media is 7.69, 3.55 and 5.4 mg/ml, respectively . Doses up to 875 mg are highly soluble.…”

“…Whilst amoxicillin is excreted in the urine mostly unmetabolised with 50–85% of the dose found in the urine 6 h after an oral dose, clavulanate on the other hand undergoes appreciable hepatic metabolism and the products are excreted via faeces, urine and lungs. Post 6 h of an oral dose, only 20–60% of the clavulanate dose appears unchanged in urine …”

“…On the other hand, FIP (International Pharmaceutical Federation), BCS (Biopharmaceutics Classification System) and Biowaiver Focus Group have recommended favourably for biowaiver of doses up to 875 mg of amoxicillin solid dosage formulations owing to its high solubility and high permeability. Moreover, amoxicillin is a high therapeutic index drug and therefore, the risk to patients due to the sub‐ or the suprabioavailable product was deemed low . However, amoxicillin doses higher than 875 are considered ‘not highly soluble’ and consequently, biowaiver is not recommended for doses higher than 875.…”

Differences in drug quality between South Africa and Germany

“…The release of amoxicillin is slower in this medium than at lower pH values, and it is therefore considered more suitable for detecting differences between drug products . Furthermore, degradation at the pH of SIF sp (6.8) is negligible compared to degradation in more acidic media, eliminating a potential source of variability in the results . The product marketed in Germany shows a faster release of amoxicillin than the South African product in SIF sp .…”