10.6 35.1 ±
8.5 38.9 ±
19.3 0.8
(0.3-4.3) 0.4 ±
0.2
Fed 22.8 ±
9.9 27.0 ±
10.1 12.7 ±
5.7 8.0
(1.0-21.0) 1.2 ±
2.4
Pyridoxal‡
Mean±SD Fasted 209.4 ±
30.0 244.0 ±
32.5 62.0 ±
17.8 2.3
(0.8-5.0) 8.0 ±
1.7
Fed 204.2 ±
25.7 249.2 ±
43.0 33.1 ±
6.1 6.0
(1.0-21.0) 12.5 ±
7.6
Pyridoxal 5′-phosphate‡
Mean±SD Fasted 1021.7 ±
318.5 --- 27.4 ±
7.7 5.0
(3.0-71.8) ---
Fed 1064.6 ±
386.9 --- 30.2 ±
10.0 16.0
(6.0-22.0) ---
Distribution
Pyridoxine is highly protein bound, primarily to albumin. Its main active metabolite, pyridoxal 5′-phosphate (PLP) accounts for at least 60% of circulating vitamin B6 concentrations.
Metabolism
Doxylamine is biotransformed in the liver by N-dealkylation to its principle metabolites N-desmethyl-doxylamine and N, N-didesmethyldoxylamine.
Pyridoxine is a prodrug primarily metabolized in the liver.
Excretion
The principle metabolites of doxylamine, N-desmethyl-doxylamine and N, N-didesmethyldoxylamine, are excreted by the kidney.
The terminal elimination half-life of doxylamine and pyridoxine are 11.9 hours and 0.4 hours, respectively (see Table 5).
Table 5 – Terminal Elimination Half-Life (T1/2el) for BONJESTA Administered as a Single Dose under Fasting Conditions in Healthy Premenopausal Women
* N=12 † Baseline corrected value
BONJESTA
T1/2el (h)
Doxylamine 11.9 ± 2.2
Pyridoxine 0.4 ± 0.2*
Pyridoxal 8.0 ± 1.7†
Use in Specific Populations
Race: No pharmacokinetic studies have been conducted related to race.
Hepatic Impairment: No pharmacokinetic studies have been conducted in hepatic impaired patients.
Renal Impairment: No pharmacokinetic studies have been conducted in renal impaired patients.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility
Carcinogenicity
Two-year carcinogenicity studies in rats and mice have been conducted with doxylamine succinate. Doxylamine succinate is not likely to have human carcinogenic potential. The carcinogenic potential of pyridoxine hydrochloride has not been eva luated.
14 CLINICAL STUDIES
There have been no efficacy and safety trials conducted with BONJESTA.
A double-blind, randomized, multi-center, placebo-controlled study was conducted to support the safety and efficacy of 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride tablets (a different formulation and dosage strength than BONJESTA) in the treatment of nausea and vomiting of pregnancy. Adult women 18 years of age or older and 7 to 14 weeks gestation (median 9 weeks of gestation) w
