DICLEGIS

1 INDICATIONS AND USAGE DICLEGIS is indicated for the treatment of nausea and vomiting of pregnancy in women who do not respond to conservative management. Limitations of Use DICLEGIS has not been studied in women with hyperemesis gravidarum. DICLEGIS is a fixed dose combination drug product of doxylamine succinate, an antihistamine, and pyridoxine hydrochloride, a Vitamin B6 analog, indicated for the treatment of nausea and vomiting of pregnancy in women who do not respond to conservative management. ( 1 )

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: Somnolence [see Warnings and Precautions ( 5.1 ) ] Falls or other accidents resulting from the effect of the combined use of DICLEGIS with CNS depressants including alcohol [see Warnings and Precautions ( 5.1 ) ] The most common adverse reaction with DICLEGIS (≥5 percent and exceeding the rate in placebo) is somnolence. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Duchesnay Inc. at 1-855-722-7734 or medicalinfo@duchesnayusa.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety and efficacy of DICLEGIS were compared to placebo in a double-blind, randomized, multi-center trial 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

4 CONTRAINDICATIONS DICLEGIS is contraindicated in women with any of the following conditions: Known hypersensitivity to doxylamine succinate, other ethanolamine derivative antihistamines, pyridoxine hydrochloride or any inactive ingredient in the formulation Monoamine oxidase (MAO) inhibitors intensify and prolong the adverse central nervous system effects of DICLEGIS [ see Drug Interactions (7.1) ] . Known hypersensitivity to doxylamine succinate, other ethanolamine derivative antihistamines, pyridoxine hydrochloride or any inactive ingredient in the formulation ( 4 ) Monoamine oxidase (MAO) inhibitors ( 4 , 7 )

11 DESCRIPTION DICLEGIS (doxylamine succinate and pyridoxine hydrochloride) delayed-release tablets are round, white, film-coated, delayed-release tablets containing 10 mg of doxylamine succinate and 10 mg of pyridoxine hydrochloride. Tablets are imprinted on one side with the pink image of a pregnant woman. Inactive ingredients are as follows: 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. Doxylamine Succinate Doxylamine succinate is classified as an antihistamine. The chemical name for doxylamine succinate is ethanamine, N,N-dimethyl-2-[1-phenyl-1-(2-pyridinyl)ethoxy]-, butanedioate (1:1). The empirical formula is C 17 H 22 N 2 O • C 4 H 6 O 4 and the molecular mass is 388.46. The structural formula is: Doxylamine succinate is a white to creamy white powder that is very soluble in water and alcohol, freely soluble in chloroform and very slightly soluble in ether and benzene. Pyridoxine Hydrochloride Pyridoxine hydrochloride is a vitamin B6 analog. The chemical name for pyridoxine hydrochloride is 3,4-pyridinedimethanol, 5-hydroxy-6-methyl-, hydrochloride. The empirical formula is C 8 H 11 NO 3 • HCl and the molecular mass is 205.64. The structural formula is: Pyridoxine hydrochloride is a white or practically white crystalline powder that is freely soluble in water, slightly soluble in alcohol and insoluble in ether. structure-1 structure-2

2 DOSAGE AND ADMINISTRATION Take two tablets daily at bedtime. If symptoms are not adequately controlled, the dose can be increased to a maximum recommended dose of four tablets daily (one in the morning, one mid-afternoon and two at bedtime) as described in the full prescribing information. ( 2 ) 2.1 Dosage Information Initially, take two DICLEGIS delayed-release tablets orally at bedtime (Day 1). If this dose adequately controls symptoms the next day, continue taking two tablets daily at bedtime. However, if symptoms persist into the afternoon of Day 2, take the usual dose of two tablets at bedtime that night then take three tablets starting on Day 3 (one tablet in the morning and two tablets at bedtime). If these three tablets adequately control symptoms on Day 4, continue taking three tablets daily. Otherwise take four tablets starting on Day 4 (one tablet in the morning, one tablet mid-afternoon and two tablets at bedtime). The maximum recommended dose is four tablets (one in the 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.

10 OVERDOSAGE 10.1 Signs and Symptoms of Overdose DICLEGIS is a delayed-release formulation, therefore, signs and symptoms of intoxication may not be apparent immediately. 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. 10.2 Management of Overdose If treatment is needed, it consists of gastric lavage or activated charcoal, whole bowel irrigation and symptomatic treatment. For additional information about overdose treatment, call a poison control center ( 1‑800-222-1222 ).

7 DRUG INTERACTIONS Severe drowsiness can occur when used in combination with alcohol or other sedating medications. ( 7 ) 7.1 Drug Interactions Use of DICLEGIS is contraindicated in women who are taking monoamine oxidase inhibitors (MAOIs), which prolong and intensify the anticholinergic (drying) effects of antihistamines. Concurrent use of alcohol and other CNS depressants (such as hypnotic sedatives and tranquilizers) with DICLEGIS is not recommended. 7.2 Drug-Food Interactions A food-effect study 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 [see Dosage and Administration (2) , Clinical Pharmacology (12.3) ] . Therefore, DICLEGIS should be taken on an empty stomach with a glass of water [ see Dosage and Administration (2 )]. 7.3 False Positive Urine Tests for Methadone, Opiates and PCP False positive 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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of DICLEGIS is unknown. 12.3 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 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.

12.1 Mechanism of Action The mechanism of action of DICLEGIS is unknown.

12.3 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 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.

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3 DOSAGE FORMS AND STRENGTHS DICLEGIS delayed-release tablets are white, round, film coated tablets containing 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride. The tablets are imprinted with the pink image of a pregnant woman on one side. Delayed-release tablets containing 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride. ( 3 )

DICLEGIS doxylamine succinate and pyridoxine hydrochloride AMMONIA BUTYL ALCOHOL SILICON DIOXIDE CROSCARMELLOSE SODIUM D&C RED NO. 27 FD&C BLUE NO. 2 HYPROMELLOSES ISOPROPYL ALCOHOL MAGNESIUM STEARATE MAGNESIUM TRISILICATE POLYETHYLENE GLYCOL 400 POLYETHYLENE GLYCOL 8000 POLYSORBATE 80 PROPYLENE GLYCOL TALC TITANIUM DIOXIDE CELLULOSE, MICROCRYSTALLINE CARNAUBA WAX ALCOHOL METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A SHELLAC DIMETHICONE SODIUM BICARBONATE SODIUM LAURYL SULFATE TRIETHYL CITRATE DOXYLAMINE SUCCINATE DOXYLAMINE PYRIDOXINE HYDROCHLORIDE PYRIDOXINE

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility Carcinogenicity Two-year carcinogenicity studies in rats and mice have been conducted with doxylamine succinate. Doxylamine succinate is not likely to have human carcinogenic potential. The carcinogenic potential of pyridoxine hydrochloride has not been evaluated.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility Carcinogenicity Two-year carcinogenicity studies in rats and mice have been conducted with doxylamine succinate. Doxylamine succinate is not likely to have human carcinogenic potential. The carcinogenic potential of pyridoxine hydrochloride has not been evaluated.

NDA021876

DICLEGIS

doxylamine succinate and pyridoxine hydrochloride

55494-100

HUMAN PRESCRIPTION DRUG

ORAL

Package/Label Display Panel Bottle Label-Outside Front Cover with Imprint Area for Lot & Expiry Bottle Label – Inside Cover Bottle Label-Outside Front Cover with Imprint Area for Lot & Expiry Bottle Label – Inside Cover

Warnings and Precautions, Concomitant Medical Conditions ( 5.2 ) 10/2022

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) Somnolence and Severe Drowsiness Inform women to avoid engaging in activities requiring complete mental alertness, such as driving or operating heavy machinery, while using DICLEGIS until cleared to do so. Inform women of the importance of not taking DICLEGIS with alcohol or sedating medications, including other antihistamines (present in some cough and cold medications), opiates and sleep aids because somnolence could worsen leading to falls or other accidents. Interference with urine drug screening Inform women that use of DICLEGIS may result in false positive urine drug screening for methadone, opiates and PCP. DICLEGIS ® is a registered trademark of Duchesnay Inc. U.S. Patent Nos. 6,340,695 & 7,560,122. Distributed by: Duchesnay USA, Inc. Princeton, NJ 08540 Tel: 1-855-722-7734 Fax: 1-888-588-8508 www.duchesnayusa.com ©2018, Duchesnay Inc. All rights reserved.

14 CLINICAL STUDIES 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 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]

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.

8.1 Pregnancy Risk Summary DICLEGIS is intended for the treatment of nausea and vomiting of pregnancy in women who do not respond to conservative management. Maternal risks are discussed throughout the labeling. No increased risk for congenital malformations has been reported in epidemiologic studies in pregnant women. In the U.S. general population, the estimated background risks for major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Data Human Data The combination of doxylamine succinate and pyridoxine hydrochloride has been the subject of many epidemiological studies (cohort, case control and meta-analyses) designed to detect possible teratogenicity. A meta-analysis of 16 cohort and 11 case-control studies published between 1963 and 1991 reported no increased risk for malformations from first trimester exposures to doxylamine succinate and pyridoxine 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 USE IN SPECIFIC POPULATIONS DICLEGIS is intended for use in pregnant women. ( 8.1 ) 8.1 Pregnancy Risk Summary DICLEGIS is intended for the treatment of nausea and vomiting of pregnancy in women who do not respond to conservative management. Maternal risks are discussed throughout the labeling. No increased risk for congenital malformations has been reported in epidemiologic studies in pregnant women. In the U.S. general population, the estimated background risks for major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Data Human Data The combination of doxylamine succinate and pyridoxine hydrochloride has been the subject of many epidemiological studies (cohort, case control and meta-analyses) designed to detect possible teratogenicity. A meta-analysis of 16 cohort and 11 case-control studies published between 1963 and 1991 reported no increased risk for malformations from first trimester exposures to doxylamine succinate and pyridoxine 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How supplied DICLEGIS delayed-release tablets are supplied in a high-density polyethylene bottle with a polypropylene child-resistant cap and a silica gel desiccant canister. Each white, round, film-coated, delayed-release tablet contains 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride, and is imprinted on one side with the pink image of a pregnant woman. DICLEGIS tablets are provided as follows: NDC 55494-100-10 Bottles of 100. 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Keep bottle tightly closed and protect from moisture. Do not remove desiccant canister from bottle.