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DOXYLAMINE SUCCINATE AND PYRIDOXINE HYDROCHLORIDE

doxylamine succinate and pyridoxine hydrochloride

Post-LOE

ORAL · TABLET, DELAYED RELEASE

12.1 Mechanism of Action The mechanism of action of doxylamine succinate and pyridoxine hydrochloride is unknown. 12.3 Pharmacokinetics The pharmacokinetics of doxylamine succinate and pyridoxine hydrochloride has been characterized in healthy non-pregnant adult women. Pharmacokinetic results for doxylamine and pyridoxine, including its vitamin B 6 metabolites, pyridoxal, pyridoxal 5'-phosphate, pyridoxamine and pyridoxamine 5'-phosphate, are summarized in Tables 2 to 5. Absorption A single-dose (two tablets) and multiple-dose (four tablets daily), open-label study was conducted to assess the safety and pharmacokinetic profile of doxylamine succinate and pyridoxine hydrochloride administered in healthy non-pregnant adult women. Single-doses (two tablets at bedtime) were administered on Days 1 and 2. Multiple-doses (one tablet in the morning, one tablet in the afternoon and two tablets at bedtime) were administered on Days 3 to 18. Blood samples for pharmacokinetic analysis were collected pre-and post-dose on Days 2 and 18 as well as pre-dose prior to bedtime dose only (trough) on Days 9, 10, 11, 16, 17, and 18. Doxylamine and pyridoxine are absorbed in the gastrointestinal tract, mainly in the jejunum. The C max of doxylamine and pyridoxine are achieved within 7.5 hours and 5.5 hours, respectively (see Table 2). Table 2: Single-Dose and Multiple-Dose Pharmacokinetics of Doxylamine Succinate and Pyridoxine Hydrochloride in Healthy Non-Pregnant Adult Women Single Dose Multiple Dose AUC 0-inf C max T max AUC 0-inf C max T max (ng•h/mL) (ng/mL) (h) (ng•h/mL) (ng/mL) (h) Doxylamine 1,280.9 ± 369.3 83.3 ± 20.6 7.2 ± 1.9 3,721.5 ± 1,318.5 168.6 ± 38.5 7.8 ± 1.6 Pyridoxine 43.4 ± 16.5 32.6 ± 15.0 5.7 ± 1.5 64.5 ± 36.4 46.1 ± 28.3 5.6 ± 1.3 Pyridoxal 211.6 ± 46.1 74.3 ± 21.8 6.5 ± 1.4 1,587.2 ± 550.0 210.0 ± 54.4 6.8 ± 1.2 Pyridoxal 5`Phosphate 1,536.4 ± 721.5 30.0 ± 10.0 11.7 ± 5.3 6,099.7 ± 1,383.7 84.9 ± 16.9 6.3 ± 6.6 Pyridoxamine 4.1 ± 2.7 0.5 ± 0.7 5.9 ± 2.1 2.6 ± 0.8 0.5 ± 0.2 6.6 ± 1.4 Pyridoxamine 5'-Phosphate 5.2 ± 3.8 0.7 ± 0.5 14.8 ± 6.6 94.5 ± 58.0 2.3 ± 1.7 12.4 ± 11.2 Multiple-dose administration of doxylamine succinate and pyridoxine hydrochloride results in increased concentrations of doxylamine as well as increases in doxylamine C max and AUC 0-last of absorption. The time to reach the maximum concentration is not affected by multiple doses. The mean accumulation index is more than 1 suggesting that doxylamine accumulates following multiple dosing (see Table 3). Although no accumulation was observed for pyridoxine, the mean accumulation index for each metabolite (pyridoxal, pyridoxal 5'-phosphate, and pyridoxamine 5'-phosphate) is more than 1 following multiple-dose administration of doxylamine succinate and pyridoxine hydrochloride. The time to reach the maximum concentration is not affected by multiple doses (see Table 2). Table 3: Pharmacokinetics of Doxylamine and Pyridoxine Following Single Dose and Multiple Dose Administration of D

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