Doxylamine Succinate and Pyridoxine Hydrochloride

RECENT MAJOR CHANGES Warnings and Precautions, Interference with Urine Screen for Methadone, Opiates and Phencyclidine Phosphate (PCP) (5.3) 06/2018

1 INDICATIONS AND USAGE Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets are indicated for the treatment of nausea and vomiting of pregnancy in women who do not respond to conservative management. Limitations of Use Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets havenot been studied in women with hyperemesis gravidarum. Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets are a fixed dose combination drug product of doxylamine succinate, an antihistamine, and pyridoxine hydrochloride, a Vitamin B 6 analog, indicated for the treatment of nausea and vomiting of pregnancy in women who do not respond to conservative management. ( 1 )

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 doxylamine succinate and pyridoxine hydrochloride 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 doxylamine succinate and pyridoxine hydrochloride delayed-release tablets. Take as a daily prescription and not on an as needed basis. Reassess the woman for continued need for doxylamine succinate and pyridoxine hydrochloride delayed-release tablets as her pregnancy progresses.

2.1 Dosage Information Initially, take two doxylamine succinate and pyridoxine hydrochloride 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 doxylamine succinate and pyridoxine hydrochloride delayed-release tablets. Take as a daily prescription and not on an as needed basis. Reassess the woman for continued need for doxylamine succinate and pyridoxine hydrochloride delayed-release tablets as her pregnancy progresses.

3 DOSAGE FORMS AND STRENGTHS Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets are white to off white, round, biconvex film coated tablets, plain on both sides containing 10 mg doxylamine succinate, USP and 10 mg pyridoxine hydrochloride, USP. The tablets are printed with “ 2132 ” on one side with black ink and plain on the other. Delayed-release tablets containing 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride. ( 3 )

4 CONTRAINDICATIONS Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets are 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 doxylamine succinate and pyridoxine hydrochloride delayed-release tablets [ 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 )

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 doxylamine succinate and pyridoxine hydrochloride with CNS depressants including alcohol [see Warnings and Precautions (5.1)] The most common adverse reaction with doxylamine succinate and pyridoxine hydrochloride (≥5 percent and exceeding the rate in placebo) is somnolence. (6) To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical at 1-800-828-9393 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 doxylamine succinate and pyridoxine hydrochloride 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 doxylamine succinate and pyridoxine hydrochloride 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 Doxylamine Succinate and Pyridoxine Hydrochloride (Only Those Adverse Reactions Occurring at an Incidence ≥ 5 Percent and at a Higher Incidence with Doxylamine Succinate and Pyridoxine Hydrochloride than Placebo are Shown) Doxylamine Succinate and Pyridoxine Hydrochloride (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

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 doxylamine succinate and pyridoxine hydrochloride 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 doxylamine succinate and pyridoxine hydrochloride 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 Doxylamine Succinate and Pyridoxine Hydrochloride (Only Those Adverse Reactions Occurring at an …

7 DRUG INTERACTIONS Severe drowsiness can occur when used in combination with alcohol or other sedating medications. (7) 7.1 Drug Interactions Use of doxylamine succinate and pyridoxine hydrochloride 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 doxylamine succinate and pyridoxine hydrochloride is not recommended. 7.2 Drug-Food Interactions A food-effect study demonstrated that the delay in the onset of action of doxylamine succinate and pyridoxine hydrochloride 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, doxylamine succinate and pyridoxine hydrochloride 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.

7.1 Drug Interactions Use of doxylamine succinate and pyridoxine hydrochloride 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 doxylamine succinate and pyridoxine hydrochloride is not recommended.

7.2 Drug-Food Interactions A food-effect study demonstrated that the delay in the onset of action of doxylamine succinate and pyridoxine hydrochloride 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, doxylamine succinate and pyridoxine hydrochloride 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.

8 USE IN SPECIFIC POPULATIONS Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets are intended for use in pregnant women. ( 8.1 ) 8.1 Pregnancy Risk Summary Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets are 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 ​Risk Summary Women should not breastfeed while using doxylamine succinate and pyridoxine hydrochloride delayed-release tablets. 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 doxylamine succinate and pyridoxine hydrochloride delayed-release tablets 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 doxylamine succinate and pyridoxine hydrochloride delayed-release tablets 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.

12.1 Mechanism of Action The mechanism of action of doxylamine succinate and pyridoxine hydrochloride delayed-release tablets is unknown.

11 DESCRIPTION Doxylamine Succinate and Pyridoxine Hydrochloride Delayed-Release Tablets 10 mg/10 mg are white, round, biconvex, film-coated, delayed-release tablet imprinted on one side with “186” in black color. Inactive ingredients are as follows: ammonium hydroxide, black iron oxide, colloidal anhydrous silica, colloidal silicon dioxide, croscarmellose sodium, dicalcium phosphate anhydrous, hypromellose, isopropyl alcohol, magnesium stearate, magnesium trisilicate, methacrylic acid copolymer type C, microcrystalline cellulose, n-butanol, polyethylene glycol/macrogol, polysorbate 80, propylene glycol, shellac glaze, sodium bicarbonate, sodium lauryl sulphate, talc, titanium dioxide and 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 or almost 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 to practically white crystals or crystalline powder that is freely soluble in water, slightly soluble in alcohol and acetone, soluble in chloroform, insoluble in ether. Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets

10 OVERDOSAGE 10.1 Signs and Symptoms of Overdose Doxylamine succinate and pyridoxine hydrochloride 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 ).

10.1 Signs and Symptoms of Overdose Doxylamine succinate and pyridoxine hydrochloride 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 ).

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Doxylamine Succinate and Pyridoxine Hydrochloride Delayed-Release Tablets 10 mg/10 mg are supplied in a high-density polyethylene bottle with a polypropylene child-resistant cap and a silica gel desiccant canister. Each white, round, biconvex, film-coated, delayed-release tablet contains 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride, and is imprinted on one side with “186” in black color. Doxylamine succinate and pyridoxine hydrochloride tablets are provided as follows: NDC 49884-186-01 Bottles of 100. 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. Keep bottle tightly closed and protect from moisture. Do not remove desiccant canister from bottle.

16.1 How Supplied Doxylamine Succinate and Pyridoxine Hydrochloride Delayed-Release Tablets 10 mg/10 mg are supplied in a high-density polyethylene bottle with a polypropylene child-resistant cap and a silica gel desiccant canister. Each white, round, biconvex, film-coated, delayed-release tablet contains 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride, and is imprinted on one side with “186” in black color. Doxylamine succinate and pyridoxine hydrochloride tablets are provided as follows: NDC 49884-186-01 Bottles of 100.

16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. Keep bottle tightly closed and protect from moisture. Do not remove desiccant canister from bottle.