BONJESTA Dailymed

Initially, take one BONJESTA extended-release tablet orally at bedtime (Day 1). If this dose adequately controls symptoms the next day, continue taking one tablet daily at bedtime only. However, if symptoms persist on Day 2, increase the daily dose to one tablet in the morning and one tablet at bedtime. The maximum recommended dose is two tablets per day, one in the morning and one at bedtime. Take on an empty stomach with a glass of water [see Clinical Pharmacology (12.3)]. Swallow tablets whole. Do not crush, chew, or split BONJESTA tablets. Take daily and not on an as needed basis. Reassess the woman for continued need for BONJESTA as her pregnancy progresses.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety and efficacy of combination 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride tablets compared to placebo was studied in a double-blind, randomized, multi-center trial in 261 women with nausea and vomiting of pregnancy. The mean gestational age at enrollment was 9.3 weeks, range 7 to 14 weeks gestation [see Clinical Studies (14)]. Adverse reactions that occurred at an incidence ≥5 percent and exceeded the incidence for placebo are summarized in Table 1. Table 1: Number (Percent) of Women with ≥ 5 Percent Adverse Reactions in a 15-Day Placebo-Controlled Trial of Combination 10 mg Doxylamine Succinate and 10 mg Pyridoxine Hydrochloride Tablets (Only Those Adverse Reactions Occurring at an Incidence ≥ 5 Percent and at a Higher Incidence than Placebo are Shown) Adverse Reaction Combination 10 mg Doxylamine Succinate and 10 mg Pyridoxine Hydrochloride Tablets (N = 133) Placebo (n = 128) Somnolence 19 (14.3%) 15 (11.7%)



Risk Summary BONJESTA is intended for the treatment of nausea and vomiting of pregnancy in women who do not respond to conservative management. Maternal risks are discussed throughout the labeling. No increased risk for congenital malformations has been reported in epidemiologic studies in pregnant women. In the U.S. general population, the estimated background risks for major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Data ​Human Data The combination of doxylamine succinate and pyridoxine hydrochloride has been the subject of many epidemiological studies (cohort, case control and meta-analyses) designed to detect possible teratogenicity. A meta-analysis of 16 cohort and 11 case-control studies published between 1963 and 1991 reported no increased risk for malformations from first trimester exposures to doxylamine succinate and pyridoxine hydrochloride, with or without dicyclomine hydrochloride. A second meta-analysis of 12 cohort and 5 case-control studies published between 1963 and 1985 reported no statistically significant relationships between fetal abnormalities and the first trimester use of the combination of doxylamine succinate and pyridoxine hydrochloride with or without dicyclomine hydrochloride.

The pharmacokinetics of BONJESTA has been characterized in healthy non-pregnant adult women.

The pharmacokinetics of BONJESTA has been characterized in healthy non-pregnant adult women. Absorption In a single-dose, crossover clinical trial conducted in 48 healthy, premenopausal women under fasting conditions, one BONJESTA (20 mg doxylamine succinate and 20 mg pyridoxine) tablet was bioequivalent to two combination tablets of 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride based on the exposure (AUC) and peak concentration (Cmax) of doxylamine and baseline corrected pyridoxal 5′-phosphate. Mean ± SD plasma (whole blood for pyridoxal) pharmacokinetic (PK) parameters are summarized in Table 2. Table 2 – Mean ± SD Single-Dose Pharmacokinetics of BONJESTA in Healthy Premenopausal Adult Women BONJESTA Mean±SD AUC0-t (ng•h/mL) AUC0-inf (ng•h/mL) AUC0-72 (ng•h/mL) Cmax (ng/mL) Tmax Median (range) (h) Doxylamine N=48 1367.0 ±356.7 1425.8 ±405.1 --- 92.3 ±15.7 4.5(2.5-5.5) Pyridoxine N=47 42.3 ±14.7 42.5 ±14.7 --- 47.1 ±18.7 0.5(0.5-4.7) PyridoxalBaseline corrected values N=48N=46 for AUC0-inf 203.7 ±51.7 233.6 ±55.9 --- 58.9 ±17.0 3.0(0.8-5.0) Pyridoxal 5′-Phosphate N=48 --- --- 1076.2 ±382.2 30.1 ±9.2 9.0(3.0-16.0) In a multiple-dose, crossover clinical trial conducted in 31 healthy, premenopausal women, one BONJESTA (20 mg doxylamine succinate and 20 mg pyridoxine) tablet given twice daily for 11 days was bioequivalent to one combination tablet of 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride given three times daily (1 tablet in the morning, 1 tablet in the afternoon and 2 tablets at bedtime), based on the exposure (AUC) and peak concentration (Cmax) of doxylamine and baseline corrected pyridoxal 5′-phosphate. Mean ± SD plasma (whole blood for pyridoxal) PK parameters are summarized in Table 3. Table 3 – Mean ± SD Multiple-Dose (Day 11) Pharmacokinetic Parameters of BONJESTA (given twice daily) in Healthy Premenopausal Adult Women BONJESTA Mean±SD AUC0-24 (ng•h/mL) AUC0-12 (ng•h/mL) AUC0-6 (ng•h/mL) Cmax (ng/mL) Tmax Median (range) (h) Doxylamine N=34 2879.4 ±696.0 1573.2 ±406.5 883.6 ±228.5 173.6 ±45.5 3.5(1.0-20.0) Pyridoxine N=34 80.0 ±22.7 46.3 ±15.4 45.3 ±16.3 48.2 ±23.7 1.5(0.3-16.5) PyridoxalBaseline corrected values N=34 1511.3 ±300.0 848.1 ±183.6 647.2 ±149.6 189.6 ±48.3 3.0(2.0-15.0) Pyridoxal 5′-Phosphate N=34 1742.3 ±554.3 831.7 ±274.5 426.2 ±144.0 85.9 ±26.2 15.0(2.0-24.0) Food Effect In a single-dose, crossover clinical trial conducted in 23 healthy, premenopausal women, the administration of a high fat, high calorie meal delayed the absorption of doxylamine, pyridoxine, and pyridoxine metabolites. This delay is associated with lower peak concentrations of doxylamine, pyridoxine, and pyridoxal. The extent of absorption for pyridoxine was decreased. The effect of food on the peak concentration and the extent of absorption of the pyridoxine component is more complex because the pyridoxine metabolites such as pyridoxal, pyridoxamine, pyridoxal 5′-phosphate, and pyridoxamine 5′-phosphate also contribute to the biological activity. Food significantly reduces the bioavailability of pyridoxine, lowering its Cmax and AUC by approximately 67% and 37%, respectively, compared to fasting conditions. Similarly, food significantly reduces pyridoxal Cmax by approximately 46% compared to fasting conditions. In contrast, food did not affect pyridoxal 5′-phosphate Cmax and AUC. Table 4 – Mean ± SD Pharmacokinetic Parameters of Doxylamine and Pyridoxine Metabolites Following a Single Dose Administration of BONJESTA Under Fed and Fasted Conditions in Healthy Premenopausal Adult Women BONJESTAN=23 AUC0-t (ng•h/mL) AUC0-inf (ng•h/mL) Cmax (ng/mL) Tmax Profile of Subject 20 was excluded , Median (range) (h) T1/2el (h) Doxylamine Mean±SD Fasted 1273.7 ±276.2 1321.9 ±315.5 85.9 ±10.6 3.5(2.5-5.5) 11.9 ±2.2 Fed 1242.8 ±254.0 1281.4 ±282.9 64.5 ±15.2 6.5(2.0-24.0) 12.7 ±2.60 Pyridoxine Mean±SD Fasted 34.7 ±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 PyridoxalBaseline corrected values 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 principal metabolites N-desmethyl-doxylamine and N, N-didesmethyldoxylamine.  Pyridoxine is a prodrug primarily metabolized in the liver.  Excretion The principal 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 Adult Women (N=23) BONJESTAT1/2el  (h)  Doxylamine 11.9 ± 2.2  Pyridoxine 0.4 ± 0.2N=12  Pyridoxal 8.0 ± 1.7Baseline corrected value 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.

BONJESTA extended-release tablets are supplied in a high-density polyethylene bottle with a polypropylene child-resistant cap and a silica gel desiccant canister. Each pink, round, film-coated, extended-release tablet contains 20 mg doxylamine succinate and 20 mg pyridoxine hydrochloride, and is imprinted on one side with the pink image of a pregnant woman and a "D" on the other side. BONJESTA tablets are provided as follows:

BONJESTA extended-release tablets are supplied in a high-density polyethylene bottle with a polypropylene child-resistant cap and a silica gel desiccant canister. Each pink, round, film-coated, extended-release tablet contains 20 mg doxylamine succinate and 20 mg pyridoxine hydrochloride, and is imprinted on one side with the pink image of a pregnant woman and a "D" on the other side. BONJESTA tablets are provided as follows: NDC 55494-120-60 Bottles of 60NDC 55494-120-10 Bottles of 100