ylamine 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.

legis until cleared to do so by their healthcare provider. diclegis use is not recommended if a woman is concurrently using central nervous system (cns) depressants including alcohol. the combination may result in severe drowsiness leading to falls or accidents [ see drug interactions (7.1) ] . 5.2 concomitant medical conditions diclegis has anticholinergic properties and, therefore, should be used with caution in women with: increased intraocular pressure, narrow angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction and urinary bladder-neck obstruction. 5.3 interference with urine screen for methadone, opiates and phencyclidine phosphate (pcp) there have been reports of false positive urine screening tests for methadone, opiates, and pcp with doxylamine succinate/pyridoxine hydrochloride use [see drug interactions ( 7.3 )].

morning, one in the mid-afternoon and two at bedtime) daily. take on an empty stomach with a glass of water [ see clinical pharmacology (12.3) ]. swallow tablets whole. do not crush, chew, or split diclegis tablets. take as a daily prescription and not on an as needed basis. reassess the woman for continued need for diclegis as her pregnancy progresses.

l 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 for diclegis that occurred at an incidence ≥5 percent and exceeded the incidence for placebo are summarized in table 1. table 1: number (percent) of subjects with ≥ 5 percent adverse reactions in a 15‑day placebo-controlled study of diclegis (only those adverse reactions occurring at an incidence ≥ 5 percent and at a higher incidence with diclegis than placebo are shown) diclegis (n = 133) placebo (n = 128) somnolence 19 (14.3%) 15 (11.7%) 6.2 postmarketing experience the following adverse events, listed alphabetically, have been identified during post-approval use of the combination of 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure . cardiac disorders : dyspnea, palpitation, tachycardia ear and labyrinth disorders : vertigo eye disorders : vision blurred, visual disturbances gastrointestinal disorders : abdominal distension, abdominal pain, constipation, diarrhea general disorders and administration site conditions : chest discomfort, fatigue, irritability, malaise immune system disorders : hypersensitivity nervous system disorders : dizziness, headache, migraines, paresthesia, psychomotor hyperactivity psychiatric disorders : anxiety, disorientation, insomnia, nightmares renal and urinary disorders : dysuria, urinary retention skin and subcutaneous tissue disorders : hyperhidrosis, pruritus, rash, rash maculo-papular

ylamine 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.

ridoxine 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 doxylamine succinate and pyridoxine hydrochloride with or without dicyclomine hydrochloride. 8.2 lactation women should not breastfeed while using diclegis. 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 apnea or other respiratory syndromes may be particularly vulnerable to the sedative effects of diclegis resulting in worsening of their apnea 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. 8.4 pediatric use the safety and effectiveness of diclegis in children under 18 years of age have not been established. 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.

sis 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 doxylamine succinate and pyridoxine hydrochloride with or without dicyclomine hydrochloride.

) on days 9, 10, 11, 16, 17, and 18. doxylamine and pyridoxine are absorbed in the gastrointestinal tract, mainly in the jejunum. the c max 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 auc 0-inf c max t max auc 0-inf c max t max (ng•h/ml) (ng/ml) (h) (ng•h/ml) (ng/ml) (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 ± 550.0 210.0 ± 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 multiple-dose administration of diclegis results 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 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 auc 0-last (ng•h/ml) auc 0-inf (ng•h/ml) c max (ng/ml) t max (h) t 1/2el (h) doxylamine mean±sd n=18 single 911.4 ± 205.6 1280.9 ± 369.3 83.3 ± 20.6 7.2 ± 1.9 10.1 ± 2.1 multiple 3661.3 ± 1279.2 3721.5 ± 1318.5 168.6 ± 38.5 7.8 ± 1.6 11.9 ± 3.3 pyridoxine mean±sd n=18 single 39.3 ± 16.5 43.4 ± 16.5 32.6 ± 15.0 5.7 ± 1.5 0.5 ± 0.2 multiple 59.3 ± 33.9 64.5 ± 36.4 46.1 ± 28.3 5.6 ± 1.3 0.5 ± 0.1 food effect 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 c max and auc by approximately 50% compared to fasting conditions. similarly, food significantly reduces pyridoxal auc and reduces its c max by 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. table 4 – pharmacokinetics of doxylamine and pyridoxine following administration of diclegis under fed and fasted conditions in healthy non-pregnant adult women auc 0-t (ng•h/ml) auc 0-inf (ng•h/ml) c max (ng/ml) t max (h) t 1/2el (h) doxylamine mean±sd n=42 fasted 1407.2 ± 336.9 1447.9 ± 332.2 94.9 ± 18.4 5.1 ± 3.4 12.6 ± 3.4 fed 1488.0 ± 463.2 1579.0 ± 422.7 n=37 75.7 ± 16.6 14.9 ± 7.4 12.5 ± 2.9 pyridoxine mean±sd n=42 fasted 33.8 ± 13.7 39.5 ± 12.9 n=31 35.5 ± 21.4 2.5 ± 0.9 0.4 ± 0.2 fed 18.3 ± 14.5 24.2 ±14.0 n=18 13.7 ± 10.8 9.3 ± 4.0 0.5 ± 0.2 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 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 t 1/2el (h) 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.

l tract, mainly in the jejunum. the c max 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 auc 0-inf c max t max auc 0-inf c max t max (ng•h/ml) (ng/ml) (h) (ng•h/ml) (ng/ml) (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 ± 550.0 210.0 ± 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 multiple-dose administration of diclegis results 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 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 auc 0-last (ng•h/ml) auc 0-inf (ng•h/ml) c max (ng/ml) t max (h) t 1/2el (h) doxylamine mean±sd n=18 single 911.4 ± 205.6 1280.9 ± 369.3 83.3 ± 20.6 7.2 ± 1.9 10.1 ± 2.1 multiple 3661.3 ± 1279.2 3721.5 ± 1318.5 168.6 ± 38.5 7.8 ± 1.6 11.9 ± 3.3 pyridoxine mean±sd n=18 single 39.3 ± 16.5 43.4 ± 16.5 32.6 ± 15.0 5.7 ± 1.5 0.5 ± 0.2 multiple 59.3 ± 33.9 64.5 ± 36.4 46.1 ± 28.3 5.6 ± 1.3 0.5 ± 0.1 food effect 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 c max and auc by approximately 50% compared to fasting conditions. similarly, food significantly reduces pyridoxal auc and reduces its c max by 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. table 4 – pharmacokinetics of doxylamine and pyridoxine following administration of diclegis under fed and fasted conditions in healthy non-pregnant adult women auc 0-t (ng•h/ml) auc 0-inf (ng•h/ml) c max (ng/ml) t max (h) t 1/2el (h) doxylamine mean±sd n=42 fasted 1407.2 ± 336.9 1447.9 ± 332.2 94.9 ± 18.4 5.1 ± 3.4 12.6 ± 3.4 fed 1488.0 ± 463.2 1579.0 ± 422.7 n=37 75.7 ± 16.6 14.9 ± 7.4 12.5 ± 2.9 pyridoxine mean±sd n=42 fasted 33.8 ± 13.7 39.5 ± 12.9 n=31 35.5 ± 21.4 2.5 ± 0.9 0.4 ± 0.2 fed 18.3 ± 14.5 24.2 ±14.0 n=18 13.7 ± 10.8 9.3 ± 4.0 0.5 ± 0.2 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 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 t 1/2el (h) 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.

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 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. 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 -0.7 [-1.2, -0.2]

sure if you take an maoi, including marplan, nardil, emsam, eldepryl, zelapar, and parnate. before taking diclegis, tell your healthcare provider about all of your medical conditions, including if you: have eye problems called increased intraocular pressure or narrow angle glaucoma. have a stomach problem called stenosing peptic ulcer or pyloroduodenal obstruction. have a bladder problem called urinary bladder-neck obstruction. are breastfeeding or plan to breastfeed. diclegis can pass into your breast milk and may harm your baby. you should not breastfeed while using diclegis. tell your healthcare provider about all the medicines you take , including prescription or over-the-counter medicines, vitamins, or herbal supplements. how should i take diclegis? talk to your healthcare provider about how much diclegis to take and when to take it. take diclegis everyday as prescribed by your healthcare provider. do not stop taking diclegis without talking to your healthcare provider first. see the following schedule for the usual way you should start taking diclegis: day 1- take 2 tablets, by mouth at bedtime. day 2- take 2 tablets at bedtime. if your nausea and vomiting is better or controlled on day 2, continue to take 2 tablets every night at bedtime. this will be your usual dose unless your healthcare provider tells you otherwise. day 3- if you still had nausea and vomiting on day 2, take 3 tablets on day 3 (1 tablet in the morning and 2 tablets at bedtime). day 4- if your nausea and vomiting was better or controlled on day 3, continue to take 3 tablets each day (1 tablet in the morning and 2 tablets at bedtime). if you still had nausea and vomiting on day 3, start taking 4 tablets each day (1 tablet in the morning, 1 tablet in the afternoon, and 2 tablets at bedtime). do not take more than 4 tablets (1 in the morning, 1 in the mid-afternoon, and 2 at bedtime) in 1 day. take diclegis on an empty stomach with a glass of water. take diclegis tablets whole. do not crush, chew, or break diclegis tablets before swallowing. if you cannot swallow diclegis tablets whole, tell your healthcare provider. if you take too much diclegis (overdose), you may have the following symptoms: restlessness, dry mouth, the pupils of your eyes become larger (dilated), sleepiness, dizziness, confusion, fast heart rate, seizures, muscle pain or weakness, and sudden and severe kidney problems. if you have these symptoms and they are severe, they may lead to death. stop taking diclegis, call your healthcare provider or go to the nearest hospital emergency room right away. for more information about overdose treatment, call your poison control center at 1-800-222-1222. what are the possible side effects of diclegis? diclegis may cause serious side effects, including drowsiness. drowsiness is a common side effect when taking diclegis, but can also be severe: do not drive, operate heavy machinery, or other activities that need your full attention unless your healthcare provider says that you may do so. do not drink alcohol, or take other central nervous system depressants such as cough and cold medicines, certain pain medicines, and medicines that help you sleep while you take diclegis. severe drowsiness can happen or become worse causing falls or accidents. diclegis may cause false positive urine drug screening test for methadone, opiates and pcp. these are not all the possible side effects of diclegis. call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088. how should i store diclegis? store diclegis between 68°f to 77°f (20°c to 25°c). keep diclegis tablets dry, in a tightly closed container, and out of the light. safely throw away medicine that is out of date or no longer needed. keep diclegis and all medicines out of the reach of children. general information about the safe and effective use of diclegis. medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. you can ask your pharmacist or healthcare provider for information about diclegis that is written for health professionals. do not use diclegis for a condition for which it was not prescribed. do not give diclegis to other people, even if they have the same symptoms that you have. it may harm them. what are the ingredients in diclegis? active ingredient: doxylamine succinate (an antihistamine) and pyridoxine hydrochloride (vitamin b 6 ). inactive ingredients: ammonium hydroxide, n-butanol, carnauba wax powder, colloidal silicon dioxide, croscarmellose sodium, d&c red#27, denatured alcohol, fd&c blue #2, hypromellose, isopropyl alcohol, magnesium stearate, magnesium trisilicate, methacrylic acid copolymer, microcrystalline cellulose 102, peg 400, peg 8000, polysorbate 80, propylene glycol, shellac glaze, simethicone, sodium bicarbonate, sodium lauryl sulfate, talc, titanium dioxide, triethyl citrate. distributed by: duchesnay usa, inc., bryn mawr, pa, 19010, www.duchesnayusa.com or call 1-855-722-7734. this patient information has been approved by the u.s. food and drug administration issued: october 2022