Doxylamine Succinate and Pyridoxine Hydrochloride

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 have not 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 B6 analog, indicated for the treatment of nausea and vomiting of pregnancy in women who do not respond to conservative management. ( 1 )

Doxylamine succinate and pyridoxine hydrochloride 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 )

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 )

Activities requiring mental alertness: Avoid engaging in activities requiring complete mental alertness, such as driving or operating heavy machinery, while using doxylamine succinate and pyridoxine hydrochloride delayed-release tablets until cleared to do so by a healthcare provider ( 5.1 ) Central nervous system (CNS) depressants: Concurrent use with alcohol or other CNS depressants is not recommended ( 5.1 ) Anticholinergic actions: Use with caution in patients with increased intraocular pressure, narrow angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction and urinary bladder-neck obstruction ( 5.2 ) Interference with urine drug screen: Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets may interfere with urine screening for methadone, opiates and PCP ( 5.3 )

5.1 Activities Requiring Mental Alertness Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets may cause somnolence due to the anticholinergic properties of doxylamine succinate, an antihistamine. Women should avoid engaging in activities requiring complete mental alertness, such as driving or operating heavy machinery, while using doxylamine succinate and pyridoxine hydrochloride delayed-release tablets until cleared to do so by their healthcare provider. Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets 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 Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets have 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)].

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 delayed-release tablets with CNS depressants including alcohol [ see Warnings and Precautions (5.1) ] The most common adverse reaction with doxylamine succinate and pyridoxine hydrochloride delayed-release tablets (≥5 percent and exceeding the rate in placebo) is somnolence. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Analog Pharma Inc. at 1-844-884-5505 or medicalinfo@analogpharma.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 doxylamine succinate and pyridoxine hydrochloride delayed-release tablets 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 delayed-release tablets 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 Delayed-Release Tablets (Only Those Adverse Reactions Occurring at an Incidence ≥ 5 Percent and at a Higher Incidence with Doxylamine Succinate and Pyridoxine Hydrochloride Delayed-Release Tablets than Placebo are Shown) Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets (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

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 delayed-release tablets 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 delayed-release tablets 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 delayed-release tablets 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 delayed-release tablets 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 delayed-release tablets 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 delayed-release tablets is not recommended.

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.

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