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«WARNINGS AND PRECAUTIONS - HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use  Activities ...»

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------------------------ WARNINGS AND PRECAUTIONS ---------------------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

 Activities requiring mental alertness: Avoid engaging in activities

DICLEGIS safely and effectively. See full prescribing information for

requiring complete mental alertness, such as driving or operating heavy

DICLEGIS.

machinery, while using DICLEGIS until cleared to do so by a healthcare DICLEGIS (doxylamine succinate and pyridoxine hydrochloride) provider (5.1) delayed-release tablets, for oral use.

 Central nervous system (CNS) depressants: Concurrent use with alcohol Initial U.S. Approval: 1976 or other CNS depressants is not recommended (5.1)

---------------------------- INDICATIONS AND USAGE --------------------------  Anticholinergic actions: Use with caution in patients with asthma, DICLEGIS is a fixed dose combination drug product of doxylamine succinate, increased intraocular pressure, narrow angle glaucoma, stenosing peptic an antihistamine, and pyridoxine hydrochloride, a Vitamin B6 analog, ulcer, pyloroduodenal obstruction and urinary bladder-neck obstruction indicated for the treatment of nausea and vomiting of pregnancy in women (5.2) who do not respond to conservative management. (1)

------------------------------- ADVERSE REACTIONS ----------------------------

----------------------- DOSAGE AND ADMINISTRATION ---------------------- The most common adverse reaction with DICLEGIS (≥5 percent and Take two tablets daily at bedtime. If symptoms are not adequately controlled, exceeding the rate in placebo) is somnolence. (6) the dose can be increased to a maximum recommended dose of four tablets To report SUSPECTED ADVERSE REACTIONS, contact Duchesnay daily (one in the morning, one mid-afternoon and two at bedtime) as described Inc. at 1-855-722-7734 or medicalinfo@duchesnayusa.com or FDA at in the

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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.

2 DOSAGE AND ADMINISTRATION

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.

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.

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)].

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5.1 Activities Requiring Mental Alertness DICLEGIS 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 DICLEGIS until cleared to do so by their healthcare provider.

DICLEGIS 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 DICLEGIS 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.

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)]





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.

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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

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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)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Pregnancy Category A DICLEGIS 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.

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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) 6-15) 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 22-50). 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.

8.3 Nursing Mothers 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.

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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).

11 DESCRIPTION DICLEGIS (doxylamine succinate and pyridoxine hydrochloride) delayed-release tablets are round, white, filmcoated, 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, talc, titanium dioxide.

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

C17H22N2O • C4H6O4 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.

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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 C8H11NO3 • 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.

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.



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