Doxyla-B6 Forte

Doxyla-B6 Forte is indicated for the treatment of nausea and vomiting of pregnancy in women who do not respond to conservative management.

Limitations of Use

Doxyla-B6 Forte has not been studied in women with hyperemesis gravidarum.

Dosage Information

Initially, take two Doxyla-B6 Forte 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. Swallow tablets whole. Do not crush, chew, or split Doxyla-B6 Forte tablets.

Take as a daily prescription and not on an as needed basis. Reassess the woman for continued need for Doxyla-B6 Forte as her pregnancy progresses.

Doxyla-B6 Forte 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 Doxyla-B6 Forte.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Activities Requiring Mental Alertness

Doxyla-B6 Forte 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 Doxyla-B6 Forte until cleared to do so by their healthcare provider.

Doxyla-B6 Forte 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.

Concomitant Medical Conditions

Doxyla-B6 Forte has 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.

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 Doxyla-B6 Forte until cleared to do so.

Inform women of the importance of not taking Doxyla-B6 Forte 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.

Nonclinical Toxicology

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.

Use In Specific Populations

Pregnancy

Pregnancy Category A

Doxyla-B6 Forte is intended for use in pregnant women.

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.

Animal Data

The effects of doxylamine succinate and pyridoxine hydrochloride on embryofetal development have been studied in rats and monkeys.

Once daily treatment of pregnant rats with doxylamine succinate and pyridoxine hydrochloride during organogenesis (gestational day (GD) 615) resulted in increased fetal resorptions, decreased fetal body weight and increased skeletal variations with reduced ossification at doses 60 to 100 times the highest clinical dose based on body surface area.

Pregnant cynomolgus monkeys were treated once daily with doxylamine succinate and pyridoxine hydrochloride during organogenesis (GD 2250). At birth, there were no observed malformations, and no evidence of embryo, fetal or maternal toxicity at doses up to 3.2 times the highest proposed clinical dose based on body surface area. In a similarly designed study in pregnant cynomolgus and rhesus monkeys and baboons, ventricular septal defects (VSDs) were observed in the preterm (GD 100) fetuses. Doses used in this study were 0.5-20 times higher than the clinical dose based on body surface area, with no relationship between dose and incidence of VSD. There were no VSDs in infant monkeys at term. No VSDs were observed at GD 100 in cynomolgus monkeys administered the combination of doxylamine succinate and pyridoxine hydrochloride for 4-day periods between 22 and 41 days of gestation.

Nursing Mothers

Women should not breastfeed while using Doxyla-B6 Forte.

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 Doxyla-B6 Forte 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.

Pediatric Use

The safety and effectiveness of Doxyla-B6 Forte 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 following adverse reactions are discussed elsewhere in the labeling:

• Somnolence
• Falls or other accidents resulting from the effect of the combined use of Doxyla-B6 Forte with CNS depressants including alcohol

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 Doxyla-B6 Forte 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. Adverse reactions for Doxyla-B6 Forte 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 Doxyla-B6 Forte (Only Those Adverse Reactions Occurring at an Incidence ≥ 5 Percent and at a Higher Incidence with DIGLEGIS than Placebo are Shown)

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

Signs and Symptoms of Overdose

Doxyla-B6 Forte 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.

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).

The pharmacokinetics of Doxyla-B6 Forte 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 Doxyla-B6 Forte 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 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 Doxyla-B6 Forte in Healthy Non-Pregnant Adult Women

Single Dose Multiple Dose Multiple-dose administration of Doxyla-B6 Forte 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 Doxyla-B6 Forte. 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 Doxyla-B6 Forte to Healthy Non-Pregnant Adult Women

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 Doxyla-B6 Forte Under Fed and Fasted Conditions in Healthy Non-Pregnant Adult Women

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, Ndidesmethyldoxylamine.

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 (T 1/2el) for Doxyla-B6 Forte Administered as a Single Dose of Two Tablets under Fasting Conditions in Healthy Non-Pregnant Adult Women