Diclegis

White, round, film-coated tablet with a pink image of a pregnant woman on one side.
Each gastro-resistant tablet contains 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride.
Excipient(s) with known effect: Each tablet contains trace amounts of azo colouring agent E129.
Excipients/Inactive Ingredients: Tablet core: Microcrystalline cellulose, Magnesium trisilicate, Croscarmellose sodium, Magnesium stearate, Colloidal anhydrous silica.
Coating: Hypromellose (E464), Macrogol (400) (E1521), Macrogol (8000), Methacrylic acid-ethyl acrylate copolymer (1:1), Talc, Colloidal anhydrous silica, Sodium hydrogen carbonate, Sodium lauryl sulfate, Triethyl citrate, Polydimethylsiloxane, Polyethylene glycol sorbitan tristearate, Silica gel, Methylcellulose, Dimethyl siloxane hydroxyl-terminated, Glycerides C14-18 mono and di, Sulfuric acid, sorbic acid, benzoic acid, Titanium dioxide (E171), Polysorbate 80 (E433).
Waxing: Carnauba Wax.
Printing ink: Shellac (E904), Allura Red AC aluminum lake (E129), Propylene glycol (E1520), Indigo carmine aluminum lake (E132), n-Butyl alcohol, Ammonium hydroxide, Isopropyl alcohol, Simeticone.

Pharmacotherapeutic group: Aminoalkyl ethers. ATC code: R06AA59.
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).

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Paediatric 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).

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Multiple-dose administration resulted 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 1.0 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.)

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The 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 C_max and AUC by approximately 50% compared to fasting conditions. In contrast, food slightly increases pyridoxal 5'-phosphate C_max 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.)

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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.
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).

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Hepatic 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.

Diclegis is indicated for the treatment of nausea and vomiting of pregnancy in women who do not respond to conservative management.

Posology: The recommended starting dose is two tablets at bedtime (Day 1). If this dose adequately controls symptoms the next day, the patient can continue taking two tablets at bedtime. However, if symptoms persist into the afternoon of Day 2, the patient should continue the usual dose of two tablets at bedtime (Day 2) and on Day 3 take three tablets (one tablet in the morning and two tablets at bedtime). If these three tablets do not adequately control symptoms on Day 3, the patient can take four tablets starting on Day 4 (one tablet in the morning, one tablet mid-afternoon and two tablets at bedtime).
The maximum recommended daily dose is four tablets (one in the morning, one in the mid-afternoon and two at bedtime).
Diclegis should be taken as a daily prescription and not on an as needed basis. Continued need for Diclegis should be reassessed as the pregnancy progresses.
To prevent a sudden return of nausea and vomiting of pregnancy symptoms, a gradual tapering dose of Diclegis is recommended at the time of discontinuation.
Paediatric population: Diclegis is not indicated for use in children under 18 years of age. The safety and efficacy of Diclegis has not been established in that population (see Pharmacology: Pharmacodynamics under Actions). No data are available.
Method of administration: Diclegis should be administered on an empty stomach with a glass of water (see Interactions). The tablets should be swallowed whole and should not be crushed, split or chewed.

Diclegis is a delayed-release formulation; therefore, signs and symptoms may not be apparent immediately.
Symptoms: Signs and symptoms of overdose may include restlessness, dryness of mouth, dilated pupils, sleepiness, vertigo, mental confusion and tachycardia.
At toxic doses, doxylamine exhibits anticholinergic effects, including seizures, rhabdomyolysis, acute renal failure and death.
Management: In the event of an overdose, treatment consists of gastric lavage or activated charcoal, whole bowel irrigation and symptomatic treatment. Management should be in accordance with established treatment guidelines.
Paediatric population: Fatalities have been reported from doxylamine overdose in children. The overdose cases have been characterized by coma, grand mal seizures and cardiorespiratory arrest. Children appear to be at a high risk for cardiorespiratory arrest. A toxic dose for children of more than 1.8 mg/kg has been reported. A 3-year-old child died 18 hours after ingesting 1,000 mg doxylamine succinate. However, there is no correlation between the amount of doxylamine ingested, the doxylamine plasma level and clinical symptomatology.

Hypersensitivity to doxylamine succinate, other ethanolamine derivative antihistamines, pyridoxine hydrochloride or any of the excipients listed in Description.
Concomitant use with monoamine oxidase inhibitors (MAOIs) (see Interactions).

Diclegis may cause somnolence due to the anticholinergic properties of doxylamine succinate, an antihistamine (see Adverse Reactions).
Use of Diclegis is not recommended if a woman is concurrently using central nervous system (CNS) depressants including alcohol (see Interactions).
Diclegis has anticholinergic properties and, therefore, should be used with caution in patients with: asthma, increased intraocular pressure, narrow angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction and bladder-neck obstruction.
Diclegis contains pyridoxine hydrochloride, a vitamin B6 analog, therefore additional levels from diet and vitamin B6 supplements should be assessed.
Diclegis contains traces of the azo colouring agent Allura Red AC Aluminium Lake (E129) which may cause allergic reactions.
There is limited evidence in cases of hyperemesis gravidarum for the combination doxylamine/pyridoxine. These patients should be treated by a specialist.
There have been reports of false positive urine screening tests for methadone, opiates, and phencyclidine phosphate (PCP) with doxylamine succinate/pyridoxine hydrochloride use (see Interactions).
Effects on ability to drive and use machines: Diclegis has a moderate to major influence on the ability to drive and use machines.
Women should avoid engaging in activities requiring complete mental alertness, such as driving or operating heavy machinery, while using Diclegis until cleared to do so by their healthcare provider.

Pregnancy: Diclegis is intended for use in pregnant women.
A large amount of data on pregnant women indicates no malformative nor feto/neonatal toxicity of doxylamine succinate and pyridoxine hydrochloride.
Breast-feeding: The molecular weight of doxylamine succinate is low enough that passage into breast milk can be expected. Excitement, irritability and sedation have been reported in nursing infants presumably exposed to doxylamine succinate through breast milk. Infants with apnoea or other respiratory syndromes may be particularly vulnerable to the sedative effects of Diclegis resulting in worsening of their apnoea or respiratory conditions.
Pyridoxine hydrochloride is excreted into breast milk. There have been no reports of adverse events in infants presumably exposed to pyridoxine hydrochloride through breast milk.
A risk to breastfed infants cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Diclegis therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Fertility: Diclegis caused no impairment of fertility or reproductive performance in rats (see Pharmacology: Toxicology: Preclinical safety data under Actions). No human data available.

Summary of the safety profile: Adverse event information is derived from clinical trials and worldwide post-marketing experience.
There has been a vast clinical experience regarding the use of Diclegis combination (doxylamine succinate and pyridoxine hydrochloride). In a double-blind, randomized, placebo-controlled trial of 15 days duration, 261 women with nausea and vomiting of pregnancy were included of which 128 were treated with placebo and 133 with doxylamine succinate/pyridoxine hydrochloride. The mean gestational age at enrolment was 9.3 weeks; gestation range was from 7 to 14 weeks. The incidence of treatment-emergent adverse events was similar for both treatment and placebo groups. The most frequently reported adverse reaction (≥5% and exceeding the rate in placebo) was somnolence.
Tabulated list of adverse reactions: The following listing of adverse reactions is based on clinical trial experience and/or post-marketing use.
Undesirable effects are displayed by MedDRA System Organ Classes and use the following conventions for frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse reactions is qualified as "not known". (See Table 6.)

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Description of selected adverse reactions: Severe drowsiness may occur if Diclegis is taken along with CNS depressants including alcohol (see Precautions and Interactions).
Anticholinergic effects of Diclegis may be prolonged and intensified by monoamine oxidase inhibitors (MAOIs) (see Contraindications and Interactions).
Possible adverse anticholinergic effects associated with the use of antihistamines as a class in general include: dryness of mouth, nose and throat; dysuria; urinary retention; vertigo, visual disturbances, blurred vision, diplopia, tinnitus; acute labyrinthitis; insomnia; tremors, nervousness; irritability; and facial dyskinesia. Tightness of chest, thickening of bronchial secretions, wheezing, nasal stuffiness, sweating, chills, early menses, toxic psychosis, headache, faintness and paresthesia have occurred.
Rarely, agranulocytosis, haemolytic anaemia, leukopenia, thrombocytopenia, and pancytopenia have been reported in a few patients receiving some antihistamines. Increased appetite and/or weight gain also occurred in patients receiving antihistamines.

Monoamine oxidase inhibitors: Monoamine oxidase inhibitors (MAOIs) prolong and intensify the anticholinergic effects of antihistamines.
Central nervous system depressants: Concurrent use with central nervous system (CNS) depressants including alcohol, hypnotic sedatives and tranquilizers is not recommended. The combination may result in severe drowsiness.
Food: A food-effect study has demonstrated that the delay in the onset of action of Diclegis may be further delayed, and a reduction in absorption may occur when tablets are taken with food. Therefore, Diclegis should be taken on an empty stomach with a glass of water (see Dosage & Administration).
Interference with urine screen for Methadone, Opiates and PCP: False positive urine drug screens for methadone, opiates, and PCP can occur with doxylamine succinate/pyridoxine hydrochloride use. Confirmatory tests, such as Gas Chromatography Mass Spectrometry (GC-MS), should be used to confirm the identity of the substance in the event of a positive immunoassay result.

Incompatibilities: Not applicable.

Store below 30°C.
Shelf life: 24 months.

Antiemetics

R06AA59 - doxylamine, combinations ; Belongs to the class of aminoalkyl ethers used as systemic antihistamines.

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