Clemastine Fumarate

Drug Induced Liver Injury Rank (DILIrank 2.0)

Clemastine fumarate

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DOI:10.1016/j.drudis.2016.02.015

Reproduction studies in rats and rabbits using oral clemastine fumarate dosages up to 312 and 188 times the usual human adult dosage, respectively, have not revealed evidence of harm to the fetus. Reproduction studies in rats and rabbits using oral clemastine fumarate and phenylpropanolamine hydrochloride in a fixed combination ratio of 1:49 and at oral dosages up to 100 (in rats) and 67 (in rabbits) times the usual human dosage have not revealed evidence of teratogenic effects. Impaired maternal weight gain and death at 33 times the usual human dosage, and reduced fetal weight and slight increases in preimplantation loss and prenatal death at 100 times the usual human dosage were attributed to phenylpropanolamine in rats. Increased maternal death at dosages 20 and 67 times the usual human dosage, and maternal weight loss and a slight (but within normal limits) increase in prenatal death at a dosage 67 times the usual human dosage were attributed to phenylpropanolamine in rabbits.

Oral dosage of clemastine fumarate 312 times the usual human adult dosage have decreased mating ability in male rats, but dosages 156 times the usual human adult dosage had no effect on mating.

There was no evidence of carcinogenesis in rats receiving clemastine fumarate at an oral dosage of 84 mg/kg (about 500 times the usual human adult dosage) for 2 years or in mice receiving 206 mg/kg (about 1300 times the usual human adult dosage) for 85 weeks. The carcinogenic potential of clemastine fumarate in fixed combination with phenylpropanolamine has not been determined.

Since there is no specific antidote for overdose with antihistamines, treatment is symptomatic and supportive with possible utilization of the following: 1) Induction of emesis (syrup of ipecac recommended); however, precaution against aspiration necessary, especially in infants and children. 2) Gastric lavage (isotonic or 0.45% sodium chloride solution) if patient unable to vomit within three hours of ingestion. 3) Saline cathartics (milk of magnesia) are sometimes used. 4) Vasopressors to treat hypotension; however, epinephrine should not be used since it may further lower blood pressure. 5) Oxygen and intravenous fluids. 6) Precaution against use of stimulants (analeptic agents) because they may cause seizures. /Antihistamines/

LD50 Mouse oral 730 mg/kg

LD50 Mouse iv 43 mg/kg

LD50 Rat oral 3550 mg/kg

LD50 Rat iv 82 mg/kg

In 12 healthy subjects given clemastine fumarate by mouth peak plasma concentrations occurred after 3 to 5 hr. After intravenous injection in 3 subjects a rapid decline in plasma concentration during the first 30 minutes occurred followed by a slow rise to peak concentration 2 to 3 hours after administraton. In 5 subjects given clemastine fumarate the ability to inhibit histamine flares correlated well with plasma concentation.

Clemastine fumarate is rapidly and almost completely absorbed from the GI tract. Peak plasma concentrations of the drug are attained within 2-5 hours after a single oral dose. Following oral administration of clemastine fumarate, the antihistaminic effect of the drug (as measured by suppression of the wheal response induced by intradermal injection of histamine) is maximal within 5-7 hours and persists for 10-12 and, in some individuals, up to 24 hours.

Distribution of clemastine into human body fluids and tissues has not been fully characterized, but the drug has been shown to distribute into milk. Following oral administration of 2.68 mg of clemastine fumarate daily for 3 days in one nursing woman, a milk clemastine concentration of about 5-10 ug/ml occurred 20 hours after the last dose of the drug and was about 25-50% of the stimultaneous maternal plasma drug concentration; clemastine was undetectable in milk 6 days after discontuance of the drug.

Clemastine and its metabolites are eliminated principally in urine.