CLEMASTINE: 611 Adverse Event Reports & Safety Profile

DESCRIPTION Each teaspoonful (5 mL) of Clemastine Fumarate Syrup for oral administration contains clemastine 0.5 mg (present as clemastine fumarate, USP 0.67 mg). Other ingredients: alcohol 5.5% v/v, wild cherry flavor, fumaric acid, methylparaben, propylene glycol, propylparaben, purified water, saccharin sodium, sodium hydroxide, and sorbitol solution. Clemastine fumarate belongs to the benzhydryl ether group of antihistaminic compounds. The chemical name is (+)-(2R)-2-[2-[[(R)-p-Chloro-α-methyl-α-phenylbenzyl]- oxy]ethyl]-1-methylpyrrolidine fumarate and has the following structural formula: C 21 H 26 CINO.C 4 H 4 O 4 M.W.

459.97 CAS Registration Number 145976-57-9 Clemastine fumarate occurs as a colorless to faintly yellow, practically odorless, crystalline powder.

Clemastine Fumarate

Syrup is a clear, colorless liquid with wild cherry flavor and has an approximate pH of 6.2. "Image Description"

INDICATIONS AND USAGE Clemastine Fumarate Syrup is indicated for the relief of symptoms associated with allergic rhinitis such as sneezing, rhinorrhea, pruritus and lacrimation.

Clemastine Fumarate

Syrup is indicated for use in pediatric populations (age 6 years through 12) and adults (see DOSAGE AND ADMINISTRATION ). It should be noted that clemastine fumarate is indicated for the relief of mild uncomplicated allergic skin manifestations of urticaria and angioedema at the 2 mg dosage level only.

DOSAGE AND ADMINISTRATION DOSAGE SHOULD BE INDIVIDUALIZED ACCORDING TO THE NEEDS AND RESPONSE OF THE PATIENT. Pediatric: Children aged 6 to 12 years: For Symptoms Of Allergic Rhinitis -The starting dose is 1 teaspoonful (0.5 mg clemastine) twice daily. Since single doses of up to 2.25 mg clemastine were well tolerated by this age group, dosage may be increased as required, but not to exceed 6 teaspoonfuls daily (3 mg clemastine).

For

Urticaria and Angioedema -The starting dose is 2 teaspoonfuls (1 mg clemastine) twice daily, not to exceed 6 teaspoonfuls daily (3 mg clemastine). Adults and Children 12 years and Over: For Symptoms Of Allergic Rhinitis -The starting dose is 2 teaspoonfuls (1.0 mg clemastine) twice daily. Dosage may be increased as required, but not to exceed 12 teaspoonfuls daily (6 mg clemastine).

For

Urticaria and Angioedema -The starting dose is 4 teaspoonfuls (2 mg clemastine) twice daily, not to exceed 12 teaspoonfuls daily (6 mg clemastine).

CONTRAINDICATIONS Usage in Nursing Mothers Because of the higher risk of antihistamines for infants generally and for newborns and prematures in particular, antihistamine therapy is contraindicated in nursing mothers. Usage in Lower Respiratory Disease Antihistamines should not be used to treat lower respiratory tract symptoms including asthma. Antihistamines are also contraindicated in the following conditions: Hypersensitivity to clemastine fumarate or other antihistamines of similar chemical structure. Monoamine oxidase inhibitor therapy (see Drug Interactions section).

ADVERSE REACTIONS Transient drowsiness, the most common adverse reaction associated with clemastine fumarate, occurs relatively frequently and may require discontinuation of therapy in some instances.

Antihistaminic

Compounds It should be noted that the following reactions have occurred with one or more antihistamines and, therefore, should be kept in mind when prescribing drugs belonging to this class, including clemastine. The most frequent adverse reactions are italicized. General: Urticaria, drug rash, anaphylactic shock, photosensitivity, excessive perspiration, chills, dryness of the mouth, nose, and throat.

Cardiovascular

System: Hypotension, headache, palpitations, tachycardia, extrasystoles.

Hematologic

System: Hemolytic anemia, thrombocytopenia, agranulocytosis.

Nervous

System: Sedation, sleepiness, dizziness, disturbed coordination , fatigue, confusion, restlessness, excitation, nervousness, tremor, irritability, insomnia, euphoria, paresthesias, blurred vision, diplopia, vertigo, tinnitus, acute labyrinthitis, hysteria, neuritis, convulsions. GI System: Epigastric distress , anorexia, nausea, vomiting, diarrhea, constipation. GU System: Urinary frequency, difficult urination, urinary retention, early menses.

Respiratory

System: Thickening of bronchial secretions, tightness of chest and wheezing, nasal stuffiness.

WARNINGS Antihistamines should be used with considerable caution in patients with: narrow angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, symptomatic prostatic hypertrophy, and bladder neck obstruction. Usage in Children Safety and efficacy of clemastine fumarate have not been established in children under the age of 12 years. Usage in Pregnancy Experience with this drug in pregnant women is inadequate to determine whether there is exists a potential for harm to the developing fetus. Usage with CNS Depressants Clemastine has additive effects with alcohol and other CNS depressants (hypnotics, sedatives, tranquilizers, etc.). Usage in Activities Requiring Mental Alertness Patients should be warned about engaging in activities requiring mental alertness such as driving a car or operating appliances, machinery, etc. Usage in the Elderly (approximately 60 years or older) Antihistamines are more likely to cause dizziness, sedation, and hypotension in elderly patients.

PRECAUTIONS General Clemastine fumarate should be used with caution in patients with: history of bronchial asthma, increased intraocular pressure, hyperthyroidism, cardiovascular disease, and hypertension. Information for Patients Patients taking antihistamines should receive the following information and instructions: Antihistamines are prescribed to reduce allergic symptoms. Patients should be questioned regarding a history of glaucoma, peptic ulcer, urinary retention, or pregnancy before starting antihistamine therapy. Patients should be told not to take alcohol, sleeping pills, sedatives, or tranquilizers while taking antihistamines. Antihistamines may cause drowsiness, dizziness, dry mouth, blurred vision, weakness, nausea, headache, or nervousness in some patients. Patients should avoid driving a car or working with hazardous machinery until they assess the effects of this medicine. Patients should be told to store this medicine in a tightly closed container in a dry, cool place away from heat or direct sunlight and out of the reach of children.

Drug Interactions

Additive CNS depression may occur when antihistamines are administered concomitantly with other CNS depressants including barbiturates, tranquilizers, and alcohol. Patients receiving antihistamines should be advised against the concurrent use of other CNS depressant drugs. Monoamine oxidase (MAO) inhibitors prolong and intensify the anticholinergic effects of antihistamines. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis In a 2-year oral study in the rat at a dose of 84 mg/kg (about 500 times the adult human dose) and an 85-week oral study in the mouse at 206 mg/kg (about 1300 times the adult human dose), clemastine fumarate showed no evidence of carcinogenesis. No mutagenic studies have been conducted with clemastine fumarate. Impairment of Fertility Oral doses of clemastine fumarate in the rat produced a decrease in mating ability of the male at 312 times the adult human dose. This effect was not found at 156 times the adult human dose.

Pregnancy Teratogenic Effects Pregnancy

Category B Oral reproduction studies performed with clemastine fumarate in rats and rabbits at doses up to 312 and 188 times the adult human doses respectively, have revealed no evidence of teratogenic effects. There are no adequate and well-controlled studies of clemastine fumarate in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed.

Nursing Mothers

Although quantitative determinations of antihistaminic drugs in breast milk have not been reported, qualitative tests have documented the excretion of diphenhydramine, pyrilamine, and tripelennamine in human milk. Because of the potential for adverse reactions in nursing infants from antihistamines, a decision should be made whether to discontinue nursing or to discontinue the drug.

Pediatric Use

The safety and efficacy of Clemastine Fumarate Syrup has been confirmed in the pediatric population (age 6 years through 12). Safety and dose tolerance studies have confirmed pediatric patients 6 through 11 years tolerated dosage ranges of 0.75 to 2.25 mg clemastine. In pediatric patients particularly, antihistamines in overdosage may produce hallucinations, convulsions and death. Symptoms of antihistamine toxicity in pediatric patients may include fixed dilated pupils, flushed face, dry mouth, fever, excitation, hallucinations, ataxia, incoordination, athetosis, tonic- lonic convulsions, and postictal depression (see OVERDOSAGE ).

Drug Interactions Additive CNS depression may occur when antihistamines are administered concomitantly with other CNS depressants including barbiturates, tranquilizers, and alcohol. Patients receiving antihistamines should be advised against the concurrent use of other CNS depressant drugs. Monoamine oxidase (MAO) inhibitors prolong and intensify the anticholinergic effects of antihistamines.