Xonvea 10 mg/10 mg gastro-resistant tablets

Gastro-resistant tablet White, round, film-coated tablet with a pink image of a pregnant woman on one side.

4.1 Therapeutic indications Xonvea is indicated for the treatment of nausea and vomiting of pregnancy (NVP) in pregnant women ≥18 years who do not respond to conservative management (i.e., lifestyle and diet change).4.2 Posology and method of administration **Posology** The recommended starting dose is two tablets (Total dose: 20 mg doxylamine succinate/20 mg pyridoxine hydrochloride) 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). Xonvea should be taken as a daily prescription and not on an as needed basis. Continued need for Xonvea should be reassessed as the pregnancy progresses. To prevent a sudden return of nausea and vomiting of pregnancy symptoms, a gradual tapering dose of Xonvea is recommended at the time of discontinuation. **Paediatric population** Xonvea is not indicated for use in children under 18 years of age. The safety and efficacy of Xonvea has not been established in that population (see section 5.1). No data are available. **Method of administration** Xonvea should be administered on an empty stomach with a glass of water (see section 4.5). Gastro-resistant tablets should be swallowed whole and should not be crushed, split or chewed to preserve the gastro-resistant properties.4.3 Contraindications Hypersensitivity to doxylamine succinate, other ethanolamine-derivative antihistamines, pyridoxine hydrochloride or any of the excipients listed in section 6.1. Concomitant use with monoamine oxidase inhibitors (MAOIs) (see section 4.5).4.4 Special warnings and precautions for use Xonvea may cause somnolence due to the anticholinergic properties of doxylamine succinate, an antihistamine (see section 4.8). Use of Xonvea is not recommended if a woman is concurrently using central nervous system (CNS) depressants including alcohol (see section 4.5). Xonvea 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. Xonvea contains pyridoxine hydrochloride, a vitamin B6 analog, therefore additional levels from diet and vitamin B6 supplements should be assessed. 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 section 4.5). *Excipients* This medicinal product contains the azo colouring agent Allura red AC aluminium lake (E 129) which may cause allergic reactions. This medicinal product contains 0.02 micrograms benzoic acid (E 210) in each gastro-resistant tablet. This medicinal product contains less than 1 mmol sodium (23 mg) per gastro-resistant tablet, that is to say essentially 'sodium-free'.4.5 Interaction with other medicinal products and other forms of interaction **Monoamine oxidase inhibitors** Monoamine oxidase inhibitors (MAOIs) prolong and intensify the anticholinergic effects of antihistamines and concomitant treatment with MAOIs is contraindicated (see section 4.3). **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 (see section 4.8). **Food** A food-effect study has demonstrated that the delay in the onset of action of Xonvea may be further delayed, and a reduction in absorption may occur when tablets are taken with food. Therefore, Xonvea should be taken on an empty stomach with a glass of water (see section 4.2). + **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.4.6 Fertility, pregnancy and lactation **Pregnancy** Xonvea is intended for use in pregnant women. A large amount of data on pregnant women, including two meta-analyses with over 168,000 patients and 18,000 exposures to the doxylamine/pyridoxine combination during first trimester, 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 Xonvea 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 Xonvea therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. **Fertility** Xonvea caused no impairment of fertility or reproductive performance in rats (see section 5.3). No human data available.4.7 Effects on ability to drive and use machines Xonvea 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 Xonvea until cleared to do so by their healthcare provider.4.8 Undesirable effects **a. Summary of the safety profile** Adverse event information is derived from clinical trials and worldwide post-marketing experience. There has been clinical experience regarding the use of the Xonvea combination (doxylamine succinate and pyridoxine hydrochloride). 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. **b. 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 events is qualified as "not known". | | | | | --- | --- | --- | | **System Organ Class** | **Undesirable Effect** | **Frequency** | | Immune system disorders | hypersensitivity | Not known | | Psychiatric disorders | anxiety, disorientation, insomnia, nightmares | Not known | | Nervous system disorders | somnolence | Very common | | dizziness | Common | | headache, migraines, paresthesia, psychomotor hyperactivity | Not known | | Eye disorders | vision blurred, visual disturbances | Not known | | Ear and labyrinth disorders | vertigo | Not known | | Cardiac disorders | dyspnea, palpitation, tachycardia | Not known | | Gastrointestinal disorders | dry mouth | Common | | abdominal distention, abdominal pain, constipation, diarrhoea | Not known | | Skin and subcutaneous tissue disorders | hyperhidrosis, pruritus, rash, rash maculo-papular | Not known | | Renal and urinary disorders | dysuria, urinary retention | Not known | | General disorders and administration site conditions | fatigue | Common | | chest discomfort, irritability, malaise | Not known | **c. Description of selected adverse reactions** Severe drowsiness may occur if Xonvea is taken along with CNS depressants including alcohol (see sections 4.4 and 4.5). Anticholinergic effects of Xonvea may be prolonged and intensified by monoamine oxidase inhibitors (MAOIs) (see sections 4.3 and 4.5). 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. **Reporting of suspected adverse reactions** Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose Xonvea is a delayed-release formulation; therefore, signs and symptoms may not be apparent immediately. **Symptoms** Signs and symptoms of overdosage 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 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.

5.1 Pharmacodynamic properties Pharmacotherapeutic group: aminoalkyl ethers, ATC code: R06AA59 **Mechanism of action** Xonvea 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 Xonvea were compared to placebo in a double-blind, randomised, multi-centre 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 Xonvea 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 Xonvea-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 Xonvea 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 Xonvea compared to placebo (see Table 1). **Table 1 - Change from Baseline in the Primary Endpoint, Pregnancy Unique-Quantification of Emesis (PUQE) Score at Day 15\** | | | | | | --- | --- | --- | --- | | **PUQE Score\\** | **Doxylamine Succinate +Pyridoxine Hydrochloride** | **Placebo** | **Treatment Difference [95% Confidence Interval]** | | Baseline Change from baseline at Day 15 | 9.0 ± 2.1 -4.8 ± 2.7 | 8.8 ± 2.1 -3.9 ± 2.6 | -0.9 [-1.2, -0.2]§ | \ Intent-to-Treat Population with Last-Observation Carried Forward \\ 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 form 3 (no symptoms) to 15 (most severe). Baseline was defined as the PUQE score completed at the enrolment visit. § Calculated Cohen's d coefficient = 0.34. The difference in mean PUQE score reduction is considered a “medium-size effect” as per Cohen's d coefficient (of 0.34) where >0.20 = medium effect. **Paediatric population** The European Medicines Agency has waived the obligation to submit the results of studies with Xonvea in all subsets of the paediatric population in treatment of nausea and vomiting of pregnancy (see section 4.2 for information on paediatric use).5.2 Pharmacokinetic properties The pharmacokinetics of Xonvea has been characterised in healthy non-pregnant adult women. A single-dose (two tablets) and multiple-dose (four tablets daily), open-label study was conducted to assess the safety and pharmacokinetic profile of Xonvea 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. **Absorption** Doxylamine and pyridoxine are absorbed in the gastrointestinal tract, mainly in the jejunum. The maximum plasma concentration Cmax of doxylamine and pyridoxine are achieved within 7.5 and 5.5 hours, respectively. Multiple-dose administration resulted in increased concentrations of doxylamine as well as increases in doxylamine Cmax and AUC 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. Although no accumulation was observed for pyridoxine, the mean accumulation index for some metabolites (pyridoxal, pyridoxal 5'-phosphateand 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. 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. The effect of food on the peak concentration and the extent of absorption of the pyridoxine component is more complex because its 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. **Distribution** Doxylamine is a low protein binding (fraction unbound of 28.7% in rat), highly permeable, and it is not a substrate of P-glycoprotein, leading to a wide distribution into tissues. Doxylamine crosses the blood-brain barrier and has a high affinity for H1 receptors in the brain. Pyridoxine is highly protein bound, primarily to albumin. Its metabolites pyridoxal and pyridoxal 5'-phosphate are, respectively, partially and almost completely bound to albumin in plasma. 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 primarily by the cytochrome P450 enzymes CYP2D6, CYP1A2, and CYP2C9, to its principle metabolites N-desmethyl-doxylamine and N,N-didesmethyldoxylamine. Pyridoxine is a prodrug primarily metabolised in the liver, with a high first pass effect. The metabolic scheme for pyridoxine is complex, with formation of primary and secondary metabolites along with interconversion back to pyridoxine. Pyridoxine and its metabolites, pyridoxal, pyridoxamine, pyridoxal 5'-phosphate and pyridoxamine 5'-phosphate contribute to the biologic activity. **Elimination** The principle metabolites of doxylamine, N-desmethyl-doxylamine and N,N-didesmethyldoxylamine, are excreted by the kidney. Renal elimination is also the main pathway of excretion of derivatives of pyridoxine metabolism (reported to be 74% of a 100 mg intravenous dose of pyridoxine), mainly as the inactive form 4-pyridoxic acid. The terminal elimination half-life of doxylamine and pyridoxine are 12.6 hours and 0.4 hours, respectively. *Hepatic Impairment:* No pharmacokinetic studies have been conducted in hepatic impaired patients. *Renal Impairment:* No pharmacokinetic studies have been conducted in renal impaired patients.5.3 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.

6.1 List of excipients **Tablet core** Microcrystalline cellulose Magnesium trisilicate Croscarmellose sodium Magnesium stearate Colloidal anhydrous silica **Coating** Hypromellose (E 464) Macrogol (E 1521) Methacrylic acid-ethyl acrylate copolymer (1:1) Talc (E 553b) Colloidal anhydrous silica Sodium hydrogen carbonate (E 500) Sodium lauril-sulfate (E 487) Triethyl citrate Simethicone emulsion (contains benzoic acid (E 210) Titanium dioxide (E 171) Polysorbate 80 (E 433) **Waxing** Carnauba wax **Printing ink** Shellac Allura red AC aluminum lake (E 129) Propylene glycol (E 1520) Indigo carmine aluminum lake (E 132) Simethicone6.2 Incompatibilities Not applicable6.3 Shelf life 42 months6.4 Special precautions for storage This medicinal product does not require any special storage conditions.6.5 Nature and contents of container PVC/aluminium blisters. Pack sizes of 20, 30 and 40 gastro-resistant tablets. Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling No special requirements. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.