DOXYLAMINE SUCCINATE AND PYRIDOXINE HYDROCHLORIDE- doxylamine succinate and pyridoxine hydrochloride tablet, delayed release 
Actavis Pharma, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use DOXYLAMINE SUCCINATE AND PYRIDOXINE HYDROCHLORIDE DELAYED-RELEASE TABLETS safely and effectively. See full prescribing information for DOXYLAMINE SUCCINATE AND PYRIDOXINE HYDROCHLORIDE DELAYED-RELEASE TABLETS..

DOXYLAMINE succinate and PYRIDOXINE hydrochloride delayed-release tablets, for oral use.
Initial U.S. Approval: 1976

RECENT MAJOR CHANGES

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

INDICATIONS AND USAGE

Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets 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)

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)

DOSAGE FORMS AND STRENGTHS

Delayed-release tablets containing 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride. (3)

CONTRAINDICATIONS

  • 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)

WARNINGS AND PRECAUTIONS

  • 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 asthma, 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)

ADVERSE REACTIONS

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 Actavis at 1-800-272-5525 or www.actavis.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.


DRUG INTERACTIONS

  • Severe drowsiness can occur when used in combination with alcohol or other sedating medications. (7)

USE IN SPECIFIC POPULATIONS

Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets are intended for use in pregnant women. (8)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 1/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

RECENT MAJOR CHANGES

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Dosage Information

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Activities Requiring Mental Alertness

5.2 Concomitant Medical Conditions

5.3 Interference with Urine Screen for Methadone, Opiates and Phencyclidine Phosphate (PCP)

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Drug Interactions

7.2 Drug-Food Interactions

7.3 False Positive Urine Tests for Methadone, Opiates and PCP

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Lactation

8.4 Pediatric Use

10 OVERDOSAGE

10.1 Signs and Symptoms of Overdose

10.2 Management of Overdose

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage and Handling

17 PATIENT COUNSELING INFORMATION

Somnolence and Severe Drowsiness

Interference with urine drug screening

*
Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

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 have not been studied in women with hyperemesis gravidarum.

2 DOSAGE AND ADMINISTRATION

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, unscored, round, biconvex film coated tablets, plain on both sides containing 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride. The tablets are printed with “2132” on one side with black ink and plain on the other.

4 CONTRAINDICATIONS

Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets are contraindicated in women with any of the following conditions:

5 WARNINGS AND PRECAUTIONS

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: asthma, 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)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed elsewhere in the labeling:

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

7 DRUG INTERACTIONS

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.

 

8 USE IN SPECIFIC POPULATIONS

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 to 4% and 15 to 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.

8.3 Lactation

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.

10 OVERDOSAGE

10.1 Signs and Symptoms of Overdose

Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets 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).

11 DESCRIPTION

Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets are round, unscored, white to off white, biconvex film-coated, delayed-release tablets containing 10 mg of doxylamine succinate, USP and 10 mg of pyridoxine hydrochloride, USP. Tablets are printed with “2132” on one side with black ink and plain on the other.

Inactive ingredients are as follows: colloidal silicon dioxide, croscarmellose sodium, hypromellose, iron oxide black, magnesium stearate, magnesium trisilicate, methacrylic acid and ethyl acrylate copolymer, microcrystalline cellulose, polyethylene glycol, polysorbate, propylene glycol, talc, titanium dioxide.

Doxylamine Succinate

Doxylamine succinate, USP is classified as an antihistamine. The chemical name for doxylamine succinate, USP is ethanamine, N,N-dimethyl-2-[1-phenyl-1-(2-pyridinyl)ethoxy]-, butanedioate (1:1). The empirical formula is C17H22N2O • C4H6O4 and the molecular mass is 388.46. The structural formula is:

structural formula

Doxylamine succinate, USP 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, USP is a vitamin B6 analog. The chemical name for pyridoxine hydrochloride, USP is 3,4-pyridinedimethanol, 5-hydroxy-6-methyl-, hydrochloride. The empirical formula is C8H11NO3 • HCl and the molecular mass is 205.64. The structural formula is.

structural formula

Pyridoxine hydrochloride, USP is a white or practically white crystalline powder that is freely soluble in water, slightly soluble in alcohol and insoluble in ether.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

The pharmacokinetics of doxylamine succinate and pyridoxine hydrochloride delayed-release tablets 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 doxylamine succinate and pyridoxine hydrochloride delayed-release tablets 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 to 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 Cmax 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 Doxylamine Succinate and Pyridoxine Hydrochloride Delayed-release Tablets in Healthy Non-Pregnant Adult Women
  Single Dose Multiple Dose
 AUC0-inf
(ngh/mL)
Cmax
(ng/mL)
Tmax
(h)
AUC0-inf
(ngh/mL)
Cmax
(ng/mL)
Tmax
(h)
   
 Doxylamine1280.9 ± 369.383.3 ± 20.67.2 ± 1.93721.5 ± 1318.5168.6 ± 38.57.8 ± 1.6
 Pyridoxine43.4 ± 16.532.6 ± 15.05.7 ± 1.564.5 ± 36.446.1 ± 28.35.6 ± 1.3
 Pyridoxal211.6 ± 46.174.3 ± 21.86.5 ± 1.41587.2 ± 550.0210.0 ± 54.46.8 ± 1.2
 Pyridoxal
 5`Phosphate
1536.4 ± 721.530.0 ± 10.011.7 ± 5.36099.7 ± 1383.784.9 ± 16.96.3 ± 6.6
 Pyridoxamine4.1 ± 2.70.5 ± 0.75.9 ± 2.12.6 ± 0.80.5 ± 0.26.6 ± 1.4
 Pyridoxamine
 5'-phosphate
5.2 ± 3.80.7 ± 0.514.8 ± 6.694.5 ± 58.02.3 ± 1.712.4 ± 11.2

Multiple-dose administration of doxylamine succinate and pyridoxine hydrochloride delayed-release tablets results in increased concentrations of doxylamine as well as increases in doxylamine Cmax and AUC0-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 doxylamine succinate and pyridoxine hydrochloride delayed-release tablets. 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 Doxylamine Succinate and Pyridoxine Hydrochloride Delayed-release Tablets to Healthy Non-Pregnant Adult Women
 AUC0-last
(ngh/mL)
AUC0-inf
(ngh/mL)
Cmax
(ng/mL)
Tmax
(h)
T1/2el
(h)
 Doxylamine
 
Mean±SD
 N=18
 Single911.4 ± 205.61280.9 ± 369.383.3 ± 20.67.2 ± 1.910.1 ± 2.1
  Multiple3661.3 ± 1279.23721.5 ± 1318.5168.6 ± 38.57.8 ± 1.611.9 ± 3.3
 Pyridoxine
 
Mean±SD
 N=18
 Single39.3 ± 16.543.4 ± 16.532.6 ± 15.05.7 ± 1.50.5 ± 0.2
  Multiple59.3 ± 33.964.5 ± 36.446.1 ± 28.35.6 ± 1.30.5 ± 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 Cmax and AUC by approximately 50% compared to fasting conditions. Similarly, food significantly reduces pyridoxal AUC and reduces its Cmax by 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.

Table 4 – Pharmacokinetics of Doxylamine and Pyridoxine Following Administration of Doxylamine Succinate and Pyridoxine Hydrochloride Delayed-release Tablets Under Fed and Fasted Conditions in Healthy Non-Pregnant Adult Women
  AUC0-t
(ngh/mL)
 AUC0-inf
(ngh/mL)
 Cmax
(ng/mL)
 Tmax
(h)
 T1/2el
(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 ±
 422.7a
 75.7 ±
 16.6
 14.9 ±
 7.4
 12.5±
 2.9a
 Pyridoxine Mean±SD
N=42
 Fasted 33.8 ±
 13.7
 39.5±
 12.9c
 35.5 ±
 21.4
 2.5 ±
 0.9
 0.4 ±
 0.2c
  Fed 18.3 ±
 14.5
 24.2±
 14.0b
 13.7 ±
 10.8
 9.3 ±
 4.0
 0.5 ±
 0.2b

aN=37; bN=18; cN=31

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 principle metabolites N-desmethyl-doxylamine and N, N-didesmethyldoxylamine.

Pyridoxine is a prodrug primarily metabolized in the liver.

Excretion

The principle 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 (T1/2el) for Doxylamine Succinate and Pyridoxine Hydrochloride Delayed-release Tablets Administered as a Single Dose of Two Tablets under Fasting Conditions in Healthy Non-Pregnant Adult Women
  T1/2el
(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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, 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.

14 CLINICAL STUDIES

A double-blind, randomized, multi-center, placebo-controlled study was conducted to support the safety and efficacy of doxylamine succinate and pyridoxine hydrochloride delayed-release tablets 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 doxylamine succinate and pyridoxine hydrochloride delayed-release tablets or placebo. Two tablets of doxylamine succinate and pyridoxine hydrochloride delayed-release tablets 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 doxylamine succinate and pyridoxine hydrochloride delayed-release tablets-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 doxylamine succinate and pyridoxine hydrochloride delayed-release tablets 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 doxylamine succinate and pyridoxine hydrochloride delayed-release tablets 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* Doxylamine Succinate
+ Pyri
doxine
H
ydrochloride
 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]

*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.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets 100 bottle count is supplied in a high-density polyethylene bottle with a polypropylene child-resistant cap and a silica gel desiccant canister. Each white to off white, unscored, round, biconvex film-coated, delayed-release tablet contains 10 mg doxylamine succinate, USP and 10 mg pyridoxine hydrochloride, USP and is printed with “2132” on one side with black ink and plain on the other.

Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets are provided as follows:

NDC 0591-2132-01 Bottles of 100.

16.2 Storage and Handling

Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Keep bottle tightly closed and protect from moisture. Do not remove desiccant canister from bottle.

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 doxylamine succinate and pyridoxine hydrochloride delayed-release tablets until cleared to do so.

Inform women of the importance of not taking doxylamine succinate and pyridoxine hydrochloride delayed-release tablets 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 doxylamine succinate and pyridoxine hydrochloride delayed-release tablets may result in false positive urine drug screening for methadone, opiates and PCP.

Manufactured by:
Actavis Laboratories FL, Inc.
Fort Lauderdale, FL. 33314 USA

Distributed by:
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA

Rev: A 1/2019

Patient Information

Doxylamine Succinate (dox il′ a meen sux′ i nate) and Pyridoxine Hydrochloride (pir′′ i dox′ een hye′′ droe klor′ ide) Delayed-release Tablets

What are  doxylamine succinate and pyridoxine hydrochloride delayed-release tablets?

Who should not take  doxylamine succinate and pyridoxine hydrochloride delayed-release tablets?

Do  not take doxylamine succinate and pyridoxine hydrochloride delayed-release tablets if you:

Before taking doxylamine succinate and pyridoxine hydrochloride delayed-release tablets, tell your healthcare  provider about  all of your medical conditions, including if you;

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 doxylamine succinate and pyridoxine hydrochloride delayed-release tablets?

If you take too much doxylamine succinate and pyridoxine hydrochloride delayed-release tablets (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 doxylamine succinate and pyridoxine hydrochloride delayed-release tablets, 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 doxylamine succinate and pyridoxine hydrochloride delayed-release tablets?

Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets  may cause serious side effects, including drowsiness.

Drowsiness is a common side effect when taking doxylamine succinate and pyridoxine hydrochloride delayed-release tablets, but can also be severe:

Doxylamine succinate and pyridoxine hydrochloride delayed-release tablets may cause false positive urine drug screening test for methadone, opiates and PCP.
These are not all the possible side effects of doxylamine succinate and pyridoxine hydrochloride delayed-release tablets.

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 doxylamine succinate and pyridoxine hydrochloride delayed-release tablets?

Keep doxylamine succinate and pyridoxine hydrochloride delayed-release tablets and all medicines out  of the reach  of children.

General informationabout the  safe and effective use of doxylamine succinate and pyridoxine hydrochloride delayed-release tablets.
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 doxylamine succinate and pyridoxine hydrochloride delayed-release tablets that is written for health professionals. Do not use doxylamine succinate and pyridoxine hydrochloride delayed-release tablets for a condition for which it was not prescribed. Do not give doxylamine succinate and pyridoxine hydrochloride delayed-release tablets to other people, even if they have the same symptoms that you have. It may harm them.      

What are the ingredients in doxylamine succinate and pyridoxine hydrochloride delayed-release tablets?
Active ingredient: doxylamine succinate (an antihistamine) and pyridoxine hydrochloride (vitamin B6).
Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, iron oxide black, magnesium stearate, magnesium trisilicate, methacrylic acid and ethyl acrylate copolymer, microcrystalline cellulose, polyethylene glycol, polysorbate, propylene glycol, talc, titanium dioxide. 

Manufactured by:
Actavis Laboratories FL, Inc.
Fort Lauderdale, FL. 33314 USA

Distributed by: 
Actavis Pharma Inc.
Parsippany, NJ 07054 USA 

This Patient Information has been approved by the U.S. Food and Drug Administration             Rev: A 1/2019                           

Principal Display Panel

NDC 0591-2132-01

Doxylamine Succinate and Pyridoxine Hydrochloride Delayed-Release Tablets

10 mg/10 mg

PHARMACIST: Dispense with the accompany Patient Information to each patient.

WARNING: Swallow tablets whole.
Do not crush, chew, or split the tablets.

100 Tablets
Rx Only

updated lbl
DOXYLAMINE SUCCINATE AND PYRIDOXINE HYDROCHLORIDE 
doxylamine succinate and pyridoxine hydrochloride tablet, delayed release
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0591-2132
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
DOXYLAMINE SUCCINATE (UNII: V9BI9B5YI2) (DOXYLAMINE - UNII:95QB77JKPL) DOXYLAMINE SUCCINATE10 mg
PYRIDOXINE HYDROCHLORIDE (UNII: 68Y4CF58BV) (PYRIDOXINE - UNII:KV2JZ1BI6Z) PYRIDOXINE HYDROCHLORIDE10 mg
Inactive Ingredients
Ingredient NameStrength
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
HYPROMELLOSES (UNII: 3NXW29V3WO)  
FERROSOFERRIC OXIDE (UNII: XM0M87F357)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
MAGNESIUM TRISILICATE (UNII: C2E1CI501T)  
METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A (UNII: NX76LV5T8J)  
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
TALC (UNII: 7SEV7J4R1U)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
Product Characteristics
ColorWHITE (white to off white) Score2 pieces
ShapeROUNDSize8mm
FlavorImprint Code 2132
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:0591-2132-01100 in 1 BOTTLE; Type 0: Not a Combination Product06/21/2019
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA20581106/21/2019
Labeler - Actavis Pharma, Inc. (119723554)

Revised: 1/2019
Document Id: 3dd1b394-c75c-4bb1-9016-56f75d764e7e
Set id: 3670d66e-c1e4-42ce-8760-c3d5accad925
Version: 5
Effective Time: 20190115
 
Actavis Pharma, Inc.