Asic

Dicyclomine Hydrochloride:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Asic (Dicyclomine Hydrochloride) reviews

DESCRIPTION

Asic (Dicyclomine Hydrochloride) is an antispasmodic and anticholinergic (antimuscarinic) agent. Asic (Dicyclomine Hydrochloride) occurs as a fine, white, crystalline, practically odorless powder with a bitter taste. It is soluble in water, freely soluble in alcohol and chloroform, and very slightly soluble in ether.

Chemically, it is [Bicyclohexyl]-1-carboxylic acid, 2-(diethyl-amino) ethyl ester, hydrochloride with the following structural formula:

C₁₉H₃₅NO₂-HCI   345.95

Each capsule, for oral administration, contains 10 mg of Asic (Dicyclomine Hydrochloride).

Each tablet, for oral administration, contains 20 mg of Asic (Dicyclomine Hydrochloride).

This product contains the following inactive ingredients: colloidal silicon dioxide (tablets only), corn starch (tablets only), D&C red #28 (capsules only), FD&C blue #1 (capsules only), FD&C blue #1 lake (tablets only), FD&C red #40 (capsules only), gelatin (capsules only), hypromellose (tablets only), lactose monohydrate (tablets only), magnesium stearate (capsules only), pregelatinized starch, silicon dioxide (capsules only), sodium lauryl sulfate (capsules only), sodium starch glycolate (tablets only), and stearic acid (tablets only).

Asic (Dicyclomine Hydrochloride) Structural Formula

CLINICAL PHARMACOLOGY

Dicyclomine relieves smooth muscle spasm of the gastrointestinal tract. Animal studies indicate that this action is achieved via a dual mechanism: (1) a specific anticholinergic effect (antimuscarinic) at the acetylcholine- receptor sites with approximately 1/8 the milligram potency of atropine (in vitro, guinea pig ileum); and (2) a direct effect upon smooth muscle (musculotropic) as evidenced by dicyclomine's antagonism of bradykinin- and histamine-induced spasms of the isolated guinea pig ileum. Atropine did not affect responses to these two agonists. In vivo studies in cats and dogs showed dicyclomine to be equally potent against acetylcholine (ACh)- or barium chloride (BaCI₂)- induced intestinal spasm while atropine was at least 200 times more potent against effects of ACh than BaCI₂. Tests for mydriatic effects in mice showed that dicyclomine was approximately 1/500 as potent as atropine; antisialogogue tests in rabbits showed dicyclomine to be 1/300 as potent as atropine.

In man, dicyclomine is rapidly absorbed after oral administration, reaching peak values within 60-90 minutes. The principal route of elimination is via the urine (79.5% of the dose). Excretion also occurs in the feces, but to a lesser extent (8.4%). Mean half-life of plasma elimination in one study was determined to be approximately 1.8 hours when plasma concentrations were measured for 9 hours after a single dose. In subsequent studies, plasma concentrations were followed for up to 24 hours after a single dose, showing a secondary phase of elimination with a somewhat longer half-life. Mean volume of distribution for a 20 mg oral dose is approximately 3.65 L/kg suggesting extensive distribution in tissues.

In controlled clinical trials involving over 100 patients who received drug, 82% of patients treated for functional bowel/irritable bowel syndrome with Asic (Dicyclomine Hydrochloride) at initial doses of 160 mg daily (40 mg q.i.d.) demonstrated a favorable clinical response compared with 55% treated with placebo (p<.05). In these trials, most of the side effects were typically anticholinergic in nature and were reported by 61% of the patients.

Nine percent (9%) of patients were discontinued from the drug because of one or more of these side effects (compared with 2% in the placebo group). In 41% of the patients with side effects, side effects disappeared or were tolerated at the 160 mg daily dose without reduction. A dose reduction from 160 mg daily to an average daily dose of 90 mg was required in 46% of the patients with side effects who then continued to experience a favorable clinical response; their side effects either disappeared or were tolerated.

INDICATIONS AND USAGE

For the treatment of functional bowel/irritable bowel syndrome.

CONTRAINDICATIONS

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  Obstructive uropathy
  

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  Obstructive disease of the gastrointestinal tract
  

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  Severe ulcerative colitis
  

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  Reflux esophagitis
  

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  Unstable cardiovascular status in acute hemorrhage
  

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  Glaucoma
  

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  Myasthenia gravis
  

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  Evidence of prior hypersensitivity to Asic (Dicyclomine Hydrochloride) or other ingredients of these formulations
  

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  Infants less than 6 months of age
  

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  Nursing Mothers.
  

WARNINGS

In the presence of a high environmental temperature, heat prostration can occur with drug use (fever and heat stroke due to decreased sweating). If symptoms occur, the drug should be discontinued and supportive measures instituted.

Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance, treatment with this drug would be inappropriate and possibly harmful.

Dicyclomine may produce drowsiness or blurred vision. The patient should be warned not to engage in activities requiring mental alertness, such as operating a motor vehicle or other machinery or performing hazardous work while taking this drug.

Psychosis has been reported in sensitive individuals given anticholinergic drugs. CNS signs and symptoms include confusion, disorientation, short-term memory loss, hallucinations, dysarthria, ataxia, coma, euphoria, decreased anxiety, fatigue, insomnia, agitation and mannerisms, and inappropriate affect. These CNS signs and symptoms usually resolve within 12 to 24 hours after discontinuation of the drug.

There are reports that administration of dicyclomine syrup to infants has been followed by serious respiratory symptoms (dyspnea, shortness of breath, breathlessness, respiratory collapse, apnea, asphyxia), seizures, syncope, pulse rate fluctuations, muscular hypotonia, and coma. Death has been reported. No causal relationship between these effects observed in infants and dicyclomine administration has been established. DICYCLOMINE IS CONTRAINDICATED IN INFANTS LESS THAN 6 MONTHS OF AGE AND IN NURSING MOTHERS..

Safety and efficacy of Asic (Dicyclomine Hydrochloride) in pediatric patients have not been established.

PRECAUTIONS

General

Use with caution in patients with:

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  Autonomic neuropathy
  

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  Hepatic or renal disease
  

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  Ulcerative colitis-large doses may suppress intestinal motility to the point of producing a paralytic ileus and the use of this drug may precipitate or aggravate the serious complication of toxic megacolon
  

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  Hyperthyroidism
  

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  Hypertension
  

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  Coronary heart disease
  

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  Congestive heart failure
  

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  Cardiac tachyarrhythmia
  

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  Hiatal hernia
  

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  Known or suspected prostatic hypertrophy.
  

Investigate any tachycardia before administration of Asic (Dicyclomine Hydrochloride), since it may increase the heart rate.

With overdosage, a curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis).

Information For Patients

Dicyclomine may produce drowsiness or blurred vision. The patient should be warned not to engage in activities requiring mental alertness, such as operating a motor vehicle or other machinery or to perform hazardous work while taking this drug.

Dicyclomine is contraindicated in infants less than 6 months of age and in nursing mothers..

In the presence of a high environmental temperature, heat prostration can occur with drug use (fever and heat stroke due to decreased sweating).

If symptoms occur, the drug should be discontinued and a physician contacted.

Drug Interactions

The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of Class I, antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity.

Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids.

Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of the drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided.

The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion.

Carcinogenesis, Mutagenesis, Impairment of Fertility

There are no known human data on long-term potential for carcinogenicity or mutagenicity.

Long-term studies in animals to determine carcinogenic potential are not known to have been conducted.

In studies in rats at doses of up to 100 mg/kg/day, dicyclomine produced no deleterious effects on breeding, conception, or parturition.

Pregnancy

Teratogenic Effects

Pregnancy Category B.

Reproduction studies have been performed in rats and rabbits at doses up to 33 times the maximum recommended human dose based on 160 mg/day and have revealed no evidence of impaired fertility or harm to the fetus due to dicyclomine. Epidemiologic studies in pregnant women with products containing Asic (Dicyclomine Hydrochloride) (at doses up to 40 mg/day) have not shown that dicyclomine increases the risk of fetal abnormalities if administered during the first trimester of pregnancy. There are, however, no adequate and well-controlled studies in pregnant women at the recommended doses (80-160 mg/day). Because animal reproduction studies are not always predictive of human response, dicyclomine as indicated for functional bowel/irritable bowel syndrome should be used during pregnancy only if clearly needed.

Nursing Mothers

Since dicyclomine has been reported to be excreted in human milk, Asic (Dicyclomine Hydrochloride) IS CONTRAINDICATED IN NURSING MOTHERS..

Pediatric Use

DICYCLOMINE IS CONTRAINDICATED IN INFANTS LESS THAN 6 MONTHS OF AGE.

Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS

Controlled clinical trials have provided frequency information for reported adverse effects of Asic (Dicyclomine Hydrochloride) listed in a decreasing order of frequency.

Not all of the following adverse reactions have been reported with Asic (Dicyclomine Hydrochloride). Adverse reactions are included here that have been reported for pharmacologically similar drugs with anticholinergic/antispasmodic action.

Gastrointestinal: dry mouth, nausea, vomiting, constipation, bloated feeling, abdominal pain, taste loss, anorexia

Central Nervous System: dizziness, light-headedness, tingling, headache, drowsiness, weakness, nervousness, numbness, mental confusion and/or excitement (especially in elderly persons), dyskinesia, lethargy, syncope, speech disturbance, insomnia

Ophthalmologic: blurred vision, diplopia, mydriasis, cycloplegia, increased ocular tension

Dermatological/Allergic: rash, urticaria, itching, and other dermal manifestations; severe allergic reaction or drug idiosyncrasies including anaphylaxis

Genitourinary: urinary hesitancy, urinary retention

Cardiovascular: tachycardia, palpitations

Respiratory: Dyspnea, apnea, asphyxia

Other: decreased sweating, nasal stuffiness or congestion, sneezing, throat congestion, impotence, suppression of lactation

DRUG ABUSE AND DEPENDENCE

Abuse of and/or dependence on dicyclomine for anticholinergic effects have been rarely reported.

OVERDOSAGE

Signs and Symptoms

The signs and symptoms of overdosage are headache; nausea; vomiting; blurred vision; dilated pupils; hot, dry skin; dizziness; dryness of the mouth; difficulty in swallowing; and CNS stimulation. A curare-like action may occur.

A 37-year-old female reported numbness on the left side, cold fingertips, blurred vision, abdominal and flank pain, decreased appetite, dry mouth, and nervousness following ingestion of 320 mg daily (four 20 mg tablets QID) for four days. These events resolved after discontinuing the dicyclomine.

Oral LD₅₀

The acute oral LD₅₀ of the drug is 625 mg/kg in mice.

Minimum Human Lethal Dose/Maximum Human Dose Recorded

The amount of drug in a single dose that is ordinarily associated with symptoms of overdosage or that is Iikely to be life threatening, has not been defined. The maximum human oral dose recorded was 600 mg by mouth in a 10-month-old child and approximately 1500 mg in an adult, each of whom survived.

In three of the infants who died following administration of Asic (Dicyclomine Hydrochloride), the blood concentrations of drug were 200, 220, and 505 ng/mL, respectively.

Dialysis

It is not known if dicyclomine is dialyzable.

Treatment

Treatment should consist of gastric lavage, emetics, and activated charcoal. Sedatives (e.g., short-acting barbiturates, benzodiazepines) may be used for management of overt signs of excitement. If indicated, an appropriate parenteral cholinergic agent may be used as an antidote.

DOSAGE AND ADMINISTRATION

DOSAGE MUST BE ADJUSTED TO INDIVIDUAL PATIENT NEEDS.

The only oral dose clearly shown to be effective is 160 mg per day (in 4 equally divided doses). Since this dose is associated with a significant incidence of side effects, it is prudent to begin with 80 mg per day (in 4 equally divided doses). Depending upon the patient's response during the first week of therapy, the dose should be increased to 160 mg per day unless side effects limit dosage escalation.

If efficacy is not achieved within 2 weeks or side effects require doses below 80 mg per day, the drug should be discontinued. Documented safety data are not available for doses above 80 mg daily for periods longer than 2 weeks.

The intramuscular dosage form is to be used temporarily when the patient cannot take oral medication. Intramuscular injection is about twice as bioavailable as oral dosage forms; consequently, the recommended intramuscular dose is 80 mg daily (in 4 equally divided doses).

Oral Asic (Dicyclomine Hydrochloride) should be started as soon as possible and the intramuscular form should not be used for periods longer than 1 or 2 days.

HOW SUPPLIED

Asic Capsules USP and Asic (Dicyclomine Hydrochloride) Tablets USP are supplied as follows:

10 mg capsules: Clear Dark Blue cap/Clear Dark Blue body hard gelatin capsules, imprinted with white ink WATSON over 794 on cap and 10 mg on the body, in bottles of 100 and 1000.

20 mg tablets: Blue, round, unscored, flat-faced, beveled-edge tablets, debossed WATSON and 795 on the periphery on one side and plain on the other side, in bottles of 100 and 1000.

Storage

Store at controlled room temperature 15°-30°C (59°-86°F).

Dispense in a well-closed container as defined in USP/NF.

Manufactured for:

Watson Laboratories, Inc.

Corona, CA 92880 USA

Manufactured by:

Patheon Pharmaceuticals Inc.

Cincinnati, OH 45215 USA

Doxylamine Succinate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Patient package insert
• Asic (Doxylamine Succinate) reviews

1 INDICATIONS AND USAGE

Asic (Doxylamine Succinate) is indicated for the treatment of nausea and vomiting of pregnancy in women who do not respond to conservative management.

Limitations of Use

Asic (Doxylamine Succinate) has not been studied in women with hyperemesis gravidarum.

Asic (Doxylamine Succinate) is a fixed dose combination drug product of Asic (Doxylamine Succinate) 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)

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 as described in the full prescribing information. (2)

2.1 Dosage Information

Initially, take two Asic (Doxylamine Succinate) 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 Asic (Doxylamine Succinate) tablets.

Take as a daily prescription and not on an as needed basis. Reassess the woman for continued need for Asic (Doxylamine Succinate) as her pregnancy progresses.

3 DOSAGE FORMS AND STRENGTHS

Asic (Doxylamine Succinate) delayed-release tablets are white, round, film coated tablets containing 10 mg Asic (Doxylamine Succinate) 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 Asic (Doxylamine Succinate) succinate and 10 mg pyridoxine hydrochloride. (3)

4 CONTRAINDICATIONS

Asic (Doxylamine Succinate) is contraindicated in women with any of the following conditions:

• Known hypersensitivity to Asic (Doxylamine Succinate) 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 Asic (Doxylamine Succinate) .

• Known hypersensitivity to Asic (Doxylamine Succinate) succinate, other ethanolamine derivative antihistamines, pyridoxine hydrochloride or any inactive ingredient in the formulation (4)
• Monoamine oxidase (MAO) inhibitors (4, 7)

5 WARNINGS AND PRECAUTIONS

• Activities requiring mental alertness: Avoid engaging in activities requiring complete mental alertness, such as driving or operating heavy machinery, while using Asic 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)

5.1 Activities Requiring Mental Alertness

Asic (Doxylamine Succinate) may cause somnolence due to the anticholinergic properties of Asic (Doxylamine Succinate) succinate, an antihistamine. Women should avoid engaging in activities requiring complete mental alertness, such as driving or operating heavy machinery, while using Asic (Doxylamine Succinate) until cleared to do so by their healthcare provider.

Asic (Doxylamine Succinate) 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 .

5.2 Concomitant Medical Conditions

Asic (Doxylamine Succinate) 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
• Falls or other accidents resulting from the effect of the combined use of Asic (Doxylamine Succinate) with CNS depressants including alcohol

The most common adverse reaction with Asic (Doxylamine Succinate) (≥5 percent and exceeding the rate in placebo) is somnolence. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Duchesnay Inc. at 1-855-722-7734 or medicalinfoAsic (Doxylamine Succinate)duchesnayusa.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 Asic (Doxylamine Succinate) 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 Asic (Doxylamine Succinate) 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 Asic (Doxylamine Succinate) (Only Those Adverse Reactions Occurring at an Incidence ≥ 5 Percent and at a Higher Incidence with Asic (Doxylamine Succinate) than Placebo are Shown)

6.2 Postmarketing Experience

The following adverse events, listed alphabetically, have been identified during post-approval use of the combination of 10 mg Asic (Doxylamine Succinate) 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

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

7.1 Drug Interactions

Use of Asic (Doxylamine Succinate) 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 Asic (Doxylamine Succinate) is not recommended.

7.2 Drug-Food Interactions

A food-effect study demonstrated that the delay in the onset of action of Asic (Doxylamine Succinate) may be further delayed, and a reduction in absorption may occur when tablets are taken with food . Therefore, Asic (Doxylamine Succinate) should be taken on an empty stomach with a glass of water [ see Dosage and Administration (2)].

8 USE IN SPECIFIC POPULATIONS

Pregnancy Category A. Asic is intended for use in pregnant women. (8.1)

8.1 Pregnancy

Pregnancy Category A

Asic (Doxylamine Succinate) is intended for use in pregnant women.

The combination of Asic (Doxylamine Succinate) 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 Asic (Doxylamine Succinate) 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 Asic (Doxylamine Succinate) succinate and pyridoxine hydrochloride with or without dicyclomine hydrochloride.

Animal Data

The effects of Asic (Doxylamine Succinate) succinate and pyridoxine hydrochloride on embryofetal development have been studied in rats and monkeys.

Once daily treatment of pregnant rats with Asic (Doxylamine Succinate) 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 Asic (Doxylamine Succinate) 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 Asic (Doxylamine Succinate) 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 Asic.

The molecular weight of Asic (Doxylamine Succinate) 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 Asic (Doxylamine Succinate) succinate through breast milk. Infants with apnea or other respiratory syndromes may be particularly vulnerable to the sedative effects of Asic (Doxylamine Succinate) 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 Asic (Doxylamine Succinate) in children under 18 years of age have not been established.

Fatalities have been reported from Asic (Doxylamine Succinate) 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 Asic (Doxylamine Succinate) succinate. However, there is no correlation between the amount of Asic (Doxylamine Succinate) ingested, the Asic (Doxylamine Succinate) plasma level and clinical symptomatology.

10 OVERDOSAGE

10.1 Signs and Symptoms of Overdose

Asic 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, Asic (Doxylamine Succinate) 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

Asic (Doxylamine Succinate) (doxylamine succinate and pyridoxine hydrochloride) delayed-release tablets are round, white, film-coated, delayed-release tablets containing 10 mg of Asic (Doxylamine Succinate) 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 8000, polysorbate 80, propylene glycol, shellac glaze, simethicone, sodium bicarbonate, sodium lauryl sulfate, talc, titanium dioxide, triethyl citrate.

Asic (Doxylamine Succinate) Succinate

Asic (Doxylamine Succinate) succinate is classified as an antihistamine. The chemical name for Asic (Doxylamine Succinate) 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:

Asic (Doxylamine Succinate) 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.

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 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.

structure-1 structure-2

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of Asic is unknown.

12.3 Pharmacokinetics

The pharmacokinetics of Asic (Doxylamine Succinate) has been characterized in healthy non-pregnant adult women. Pharmacokinetic results for Asic (Doxylamine Succinate) 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 Asic (Doxylamine Succinate) 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.

Asic (Doxylamine Succinate) and pyridoxine are absorbed in the gastrointestinal tract, mainly in the jejunum.

The C_max of Asic (Doxylamine Succinate) and pyridoxine are achieved within 7.5 and 5.5 hours, respectively.

Multiple-dose administration of Asic (Doxylamine Succinate) results in increased concentrations of Asic (Doxylamine Succinate) as well as increases in Asic (Doxylamine Succinate) C_max and AUC_0-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 Asic (Doxylamine Succinate) accumulates following multiple dosing.

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 Asic (Doxylamine Succinate). The time to reach the maximum concentration is not affected by multiple doses.

Food Effect

The administration of food delays the absorption of both Asic (Doxylamine Succinate) and pyridoxine. This delay is associated with a lower peak concentration of Asic (Doxylamine Succinate), but the extent of absorption is not affected.

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 C_max and AUC by approximately 50% compared to fasting conditions. Similarly, food significantly reduces pyridoxal AUC and reduces its C_max by 50% compared to fasting conditions. In contrast, food slightly increases pyridoxal 5’-phosphate C_max and extent of absorption. As for pyridoxamine and pyridoxamine 5’-phosphate, the rate and extent of absorption seem to decrease under fed conditions.

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

Asic (Doxylamine Succinate) 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 Asic (Doxylamine Succinate), N-desmethyl-doxylamine and N, N-didesmethyldoxylamine, are excreted by the kidney.

The terminal elimination half-life of Asic (Doxylamine Succinate) and pyridoxine are 12.5 hours and 0.5 hours, respectively.

Table 5 – Terminal Elimination Half-Life (T_1/2el) for Asic (Doxylamine Succinate) Administered as a Single Dose of Two Tablets under Fasting Conditions in Healthy Non-Pregnant Adult Women

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 Asic (Doxylamine Succinate) succinate. Asic (Doxylamine Succinate) 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 Asic (Doxylamine Succinate) 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 Asic (Doxylamine Succinate) or placebo. Two tablets of Asic (Doxylamine Succinate) 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 DICLEGIS-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 Asic (Doxylamine Succinate) 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 Asic (Doxylamine Succinate) compared to placebo.

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)

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How supplied

Asic delayed-release tablets are supplied in a high-density polyethylene bottle with a polypropylene child-resistant cap and a silica gel desiccant canister. Each white, round, film-coated, delayed-release tablet contains 10 mg Asic (Doxylamine Succinate) succinate and 10 mg pyridoxine hydrochloride, and is imprinted on one side with the pink image of a pregnant woman. Asic (Doxylamine Succinate) tablets are provided as follows:

NDC 55494-100-10 Bottles of 100.

16.2 Storage and Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Keep bottle tightly closed and protect from moisture. Do not remove desiccant canister from bottle.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling

17.1 Somnolence and Severe Drowsiness

Inform women to avoid engaging in activities requiring complete mental alertness, such as driving or operating heavy machinery, while using Asic (Doxylamine Succinate) until cleared to do so.

Inform women of the importance of not taking Asic (Doxylamine Succinate) 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.

Asic (Doxylamine Succinate)^® is a registered trademark of Duchesnay Inc.

U.S. Patent Nos. 6,340,695 & 7,560,122.

Distributed by:

Duchesnay USA, Inc.

Bryn Mawr, PA, 19010

Tel: 1-855-722-7734

Fax: 1-888-588-8508

www.duchesnayusa.com

©2013, Duchesnay Inc. All rights reserved.

Patient Package Insert

Patient Information

Asic (Doxylamine Succinate) (dye-CLEE-gis)

(doxylamine succinate and pyridoxine hydrochloride) delayed-release tablets

What is Asic (Doxylamine Succinate)?

- Asic (Doxylamine Succinate) is a prescription medicine used to treat nausea and vomiting of pregnancy in

women who have not improved with change in diet or other non-medicine treatments.

- It is not known if Asic (Doxylamine Succinate) is safe and effective in children under 18 years of age.

Who should not take Asic (Doxylamine Succinate)?

Do not take Asic (Doxylamine Succinate) if you:

- are allergic to Asic (Doxylamine Succinate) succinate, other ethanolamine derivative antihistamines, pyridoxine hydrochloride or any of the ingredients in Asic (Doxylamine Succinate). See the end of this leaflet for a complete list of ingredients in Asic (Doxylamine Succinate).

- take monoamine oxidase inhibitors (MAOIs) (Marplan, Nardil, Emsam, Eldepryl, Zelapar, Parnate)

Before taking Asic (Doxylamine Succinate), tell your healthcare provider about all of your medical conditions, including;

- if you are breastfeeding or plan to breastfeed. Asic (Doxylamine Succinate) can pass into your breast milk and may harm your baby. You should not breastfeed while using Asic (Doxylamine Succinate).

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 Asic (Doxylamine Succinate)?

- Talk to your healthcare provider about how much Asic (Doxylamine Succinate) to take and when to take it.

- Take Asic (Doxylamine Succinate) everyday as prescribed by your healthcare provider. Do not stop taking Asic (Doxylamine Succinate) without talking to your healthcare provider first.

- See the following schedule for the usual way you should start taking Asic (Doxylamine Succinate):

- Day 1- Take 2 tablets, by mouth at bedtime.

- Day 2- Take 2 tablets at bedtime. If your nausea and vomiting is better or controlled on Day 2, continue to take 2 tablets every night at bedtime. This will be your usual dose unless your healthcare provider tells you otherwise.

- Day 3- If you still had nausea and vomiting on Day 2, take 3 tablets on Day 3 (1 tablet in the morning and 2 tablets at bedtime).

- Day 4- If your nausea and vomiting was better or controlled on Day 3, continue to take 3 tablets each day (1 tablet in the morning and 2 tablets at bedtime). If you still had nausea and vomiting on Day 3, start taking 4 tablets each day (1 tablet in the morning, 1 tablet in the afternoon, and 2 tablets at bedtime).

- Do not take more than 4 tablets (1 in the morning, 1 in the mid-afternoon, and 2 at bedtime) in 1 day.

- Take Asic (Doxylamine Succinate) on an empty stomach with a glass of water.

- Take Asic (Doxylamine Succinate) tablets whole. Do not crush, chew, or break Asic (Doxylamine Succinate) tablets before swallowing. If you cannot swallow Asic (Doxylamine Succinate) tablets whole, tell your healthcare provider.

- If you take too much Asic (Doxylamine Succinate) (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 Asic (Doxylamine Succinate), 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 Asic (Doxylamine Succinate)?

Asic (Doxylamine Succinate) may cause serious side effects, including drowsiness.

- Do not drive, operate heavy machinery, or other activities that need your full attention unless your healthcare provider says that you may do so.

- Do not drink alcohol, or take other central nervous system depressants such as cough and cold medicines, certain pain medicines, and medicines that help you sleep while you take Asic (Doxylamine Succinate). Severe drowsiness can happen or become worse causing falls or accidents.

These are not all the possible side effects of Asic (Doxylamine Succinate).

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 Asic (Doxylamine Succinate)?

- Store Asic (Doxylamine Succinate) between 68°F to 77°F (20°C to 25°C).

- Keep Asic (Doxylamine Succinate) tablets dry, in a tightly closed container, and out of the light.

- Safely throw away medicine that is out of date or no longer needed.

Keep Asic (Doxylamine Succinate) and all medicines out of the reach of children.

General information about the safe and effective use of Asic (Doxylamine Succinate).

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 Asic (Doxylamine Succinate) that is written for health professionals. Do not use Asic (Doxylamine Succinate) for a condition for which it was not prescribed. Do not give Asic (Doxylamine Succinate) to other people, even if they have the same symptoms that you have. It may harm them.

What are the ingredients in Asic (Doxylamine Succinate)?

Active ingredient: Asic (Doxylamine Succinate) succinate (an antihistamine) and pyridoxine hydrochloride (vitamin B₆)

Inactive ingredients: 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 8000, polysorbate 80, propylene glycol, shellac glaze, simethicone, sodium bicarbonate, sodium lauryl sulfate, talc, titanium dioxide, triethyl citrate.

Distributed by: Duchesnay USA, Inc., Bryn Mawr, PA, 19010,

www.duchesnayusa.com or call 1-855-722-7734.

This Patient Information has been approved by the U.S. Food and Drug Administration

Issued: 05/2013

Bottle Label-Outside Front Cover with Imprint Area for Lot & Expiry

Bottle Label – Inside Cover