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Pharmacology: Pharmacodynamics: Mechanism of action: Diclegis provides the action of two unrelated compounds. Doxylamine succinate (an antihistamine) and pyridoxine hydrochloride (vitamin B6) provide anti-nauseant and antiemetic activity.
Doxylamine succinate, an ethanolamine, first-generation antihistamine crosses the blood-brain barrier and exerts an antiemetic action by selectively binding to H1 receptors in the brain.
Pyridoxine hydrochloride, a water-soluble vitamin, is converted to pyridoxal, pyridoxamine, pyridoxal 5'-phosphate and pyridoxamine 5'-phosphate. Although pyridoxal 5'-phosphate is the main active antiemetic metabolite, the other metabolites also contribute to the biological activity.
The mechanism of action of the combination of doxylamine succinate and pyridoxine hydrochloride to treat nausea and vomiting of pregnancy has not been established.
Clinical efficacy and safety: The safety and efficacy of Diclegis were compared to placebo in a double-blind, randomized, multi-center trial in 261 adult women 18 years of age or older. The mean gestational age at enrolment was 9.3 weeks, range 7 to 14 weeks gestation. 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 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 two tablets daily, 21% three tablets daily, and 60% received four 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 0.9 (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 this medicinal product compared to placebo (see Table 1).
Click on icon to see table/diagram/imagePaediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with Diclegis in all subsets of the paediatric population in treatment of nausea and vomiting of pregnancy (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: 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.
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 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.
Doxylamine and pyridoxine are absorbed in the gastrointestinal tract, mainly in the jejunum.
The Cmax of doxylamine and pyridoxine are achieved within 7.5 and 5.5 hours, respectively (see Table 2).
Click on icon to see table/diagram/imageMultiple-dose administration resulted 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. The time to reach the maximum concentration is not affected by multiple doses (see table 2 as previously mentioned). (See Table 3.)
Click on icon to see table/diagram/imageThe administration of food delays the absorption of both doxylamine and pyridoxine. This delay is associated with a lower peak concentration of doxylamine, but 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 and pyridoxal lowering their Cmax and AUC by approximately 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. (See Table 4.)
Click on icon to see table/diagram/imageDistribution: 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.
Biotransformation: 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 metabolised in the liver.
Elimination: 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 12.6 hours and 0.4 hours, respectively (see Table 5).
Click on icon to see table/diagram/imageHepatic Impairment: No pharmacokinetic studies have been conducted in hepatic impaired patients.
Renal Impairment: No pharmacokinetic studies have been conducted in renal impaired patients.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on available data of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.
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