"The U.S. Food and Drug Administration today approved Diclegis (doxylamine succinate and pyridoxine hydrochloride) to treat pregnant women experiencing nausea and vomiting.
Diclegis is a delayed-release tablet intended for women who have"...
Mechanism of Action
The mechanism of action of DICLEGIS is unknown.
The pharmacokinetics of DICLEGIS has been characterized in healthy non-pregnant adult women. Pharmacokinetic results for doxylamine and pyridoxine, including its vitamin B6 metabolites, pyridoxal, pyridoxal 5'-phosphate, pyridoxamine and pyridoxamine 5'-phosphate, are summarized in Tables 2 to 5.
A single-dose (two tablets) and multiple-dose (four tablets daily), open-label study was conducted to assess the safety and pharmacokinetic profile of DICLEGIS 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 3-18.
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.
The Cmax of doxylamine and pyridoxine are achieved within 7.5 and 5.5 hours, respectively (see Table 2).
Table 2 : Single-Dose and Multiple-Dose
Pharmacokinetics of DICLEGIS in Healthy Non-Pregnant Adult Women
|Single Dose||Multiple Dose|
|AUCO-inf (ng•h/mL)||Cmax (ng/mL)||Tmax (h)||AUC0-inf (ng•h/mL)||Cmax (ng/mL)||Tmax (h)|
|Doxylamine||1280.9 ± 369.3||83.3 ± 20.6||7.2 ± 1.9||3721.5 ± 1318.5||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||1587.2 ± 550.0||i 210.0 ± 54.4||6.8 ± 1.2|
|Pyridoxal 5'Phosphate||1536.4 ± 721.5||30.0 ± 10.0||11.7 ± 5.3||6099.7 ± 1383.7||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|
Single Dose Multiple Dose Multiple-dose administration of DICLEGIS results in increased concentrations of doxylamine as well as increases in doxylamine Cmax and AUC0-last of absorption. The time to reach the maximum concentration is not affected by multiple doses. The mean accumulation index is more than 1.0 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 1.0 following multiple-dose administration of DICLEGIS. 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 DICLEGIS
to Healthy Non-Pregnant Adult Women
|AUC0-last (ng•h/mL)||AUC0-inf (ng•h/mL)||Cmax (ng/mL)||Tmax (h)||T1/2el (h)|
|Doxylamine Mean±SD||Single||911.4 ± 205.6||1280.9 ± 369.3||83.3 ± 20.6||7.2 ± 1.9||10.1 ± 2.1|
|N=18||Multiple||3661.3 ± 1279.2||3721.5 ± 1318.5||168.6 ± 38.5||7.8 ± 1.6||11.9 ± 3.3|
The administration of food delays the absorption of both doxylamine and pyridoxine. This delay is associated with a lower peak concentration of doxylamine, but the extent of absorption is not affected (see Table 4).
The effect of food on the peak concentration and the extent of absorption of the pyridoxine component is more complex because the pyridoxal, pyridoxamine, pyridoxal 5'-phosphate and pyridoxamine 5'-phosphate metabolites also contribute to the biological activity. Food significantly reduces the bioavailability of pyridoxine, lowering its Cmax and AUC by approximately 50% compared to fasting conditions. Similarly, food significantly reduces pyridoxal AUC and reduces its Cmax by 50% compared to fasting conditions. In contrast, food slightly increases pyridoxal 5'-phosphate Cmax and extent of absorption. As for pyridoxamine and pyridoxamine 5'-phosphate, the rate and extent of absorption seem to decrease under fed conditions.
Table 4 : Pharmacokinetics of Doxylamine and
Pyridoxine Following Administration of DICLEGIS Under Fed and Fasted Conditions
in Healthy Non-Pregnant Adult Women
|AUC0-t (ng•h/mL)||AUC0-inf (ng•h/mL)||Cmax (ng/mL)||Tmax (h)||T1/2el (h)|
|Doxylamine||Fasted||1407.2 ± 336.9||1447.9 ± 332.2||94.9 ± 18.4||5.1 ± 3.4||12.6 ± 3.4|
|Mean±SD N=42||Fed||1488.0 ± 463.2||1579.0 ± 422.7*||75.7 ± 16.6||14.9 ± 7.4||12.5 ± 2.9*|
|Pyridoxine||Fasted||33.8 ± 13.7||39.5 ± 12.9†||35.5 ± 21.4||2.5 ± 0.9||0.4 ± 0.2†|
|Mean±SD N=42||Fed||18.3 ± 14.5||24.2 ±14.0‡||13.7 ± 10.8||9.3 ± 4.0||0.5 ± 0.2‡|
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.
Doxylamine is biotransformed in the liver by N-dealkylation to its principle metabolites N-desmethyl-doxylamine and N, Ndidesmethyldoxylamine.
Pyridoxine is a prodrug primarily metabolized in the liver.
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 12.5 hours and 0.5 hours, respectively (see Table 5).
Table 5 : Terminal Elimination Half-Life (T 1/2el) for
DICLEGIS Administered as a Single Dose of Two Tablets under Fasting Conditions
in Healthy Non-Pregnant Adult Women
|Doxylamine||12.6 ± 3.4|
|Pyridoxine||0.4 ± 0.2|
|Pyridoxal||2.1 ± 2.2|
|Pyridoxal 5'-Phosphate||81.6 ± 42.2|
|Pyridoxamine||3.1 ± 2.5|
|Pyridoxamine 5'-Phosphate||66.5 ± 51.3|
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.
A double-blind, randomized, multi-center, placebo-controlled study was conducted to support the safety and efficacy of DICLEGIS 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) with nausea and vomiting of pregnancy were randomized to 14 days of DICLEGIS or placebo. Two tablets of DICLEGIS were administered at bedtime on Day 1. If symptoms of nausea and vomiting persisted into the afternoon hours of Day 2, the woman was directed to take her usual dose of two tablets at bedtime that night and, beginning on Day 3, to take one tablet in the morning and two tablets at bedtime. Based upon assessment of remaining symptoms at her clinic visit on Day 4 (± 1 day), the woman may have been directed to take an additional tablet mid-afternoon. A maximum of four tablets (one in the morning, one in the mid-afternoon and two at bedtime) were taken daily.
Over the treatment period, 19% of DICLEGIS-treated patients remained on 2 tablets daily, 21% received 3 tablets daily, and 60% received 4 tablets daily.
The primary efficacy endpoint was the change from baseline at Day 15 in the Pregnancy Unique-Quantification of Emesis (PUQE) score. The PUQE score incorporates the number of daily vomiting episodes, number of daily heaves, and length of daily nausea in hours, for an overall score of symptoms rated from 3 (no symptoms) to 15 (most severe).
At baseline, the mean PUQE score was 9.0 in the DICLEGIS arm and 8.8 in the placebo arm. There was a 0.7 (95% confidence interval 0.2 to 1.2 with p-value 0.006) mean decrease (improvement in nausea and vomiting symptoms) from baseline in PUQE score at Day 15 with DICLEGIS compared to placebo (see Table 6).
Table 6 : Change from Baseline in the Primary
Endpoint, Pregnancy Unique-Quantification of Emesis (PUQE) Score at Day 15.
(Intent-to-Treat Population with Last-Observation Carried Forward)
|PUQE Score*||Doxylamine Succinate + Pyridoxine Hydrochloride||Placebo||Treatment Difference [95% Confidence Interval]|
|Baseline||9.0 ± 2.1||8.8 ± 2.1|
|Change from baseline at Day 15||-4.8 ± 2.7||-3.9 ± 2.6||-0.7 [-1.2, -0.2]|
|*The Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) score incorporated the number of daily vomiting episodes, number of daily heaves, and length of daily nausea in hours, for an overall score of symptoms rated from 3 (no symptoms) to 15 (most severe). Baseline was defined as the PUQE score completed at the enrollment visit.|
Last reviewed on RxList: 10/11/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Diclegis Information
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