Pharmacology: Pharmacodynamics: Ergotamine aborts attacks of migraine with or without aura by its specific vasotonic action on distended extracranial arteries.
Caffeine accelerates and increases the enteral absorption of ergotamine.
Pharmacokinetics: Studies using tritium-labelled ergotamine indicate that 62% of an oral dose is absorbed from the gastrointestinal tract. Peak plasma levels are reached about 2 hours after ingestion. Ergotamine is extensively metabolized in the liver. In terms of unchanged drug its absolute bioavailability is about 2% when given orally. It has been suggested that the therapeutic effects of the drug are partially due to active metabolites. Protein binding amounts to 98%. Parent drug and metabolites are mainly excreted in the bile. Their elimination from plasma is biphasic, with half-lives of 2.7 and 21 hours, respectively. Caffeine is rapidly and almost completely absorbed; it is metabolized to a large extent. The metabolites are excreted mainly in the urine. Plasma elimination half-life is about 3.5 hours, protein binding 35%.
Toxicology: Preclinical safety data: Acute toxicity: LD50 values after single intravenous injection of Cafergot (ergotamine/caffeine 1:50) were found to be 40 mg/kg in rabbits, 124 mg/kg in rats, and 111 mg/kg in mice. After single oral administration in mice, LD50 was 474 mg/kg.
Chronic and subchronic toxicity: In a 26-week oral safety study in beagle dogs, ergotamine induced vomiting, salivation and decreased heart rate. In addition, superficial necrosis at the ear margin was observed, which is a common finding in lop-eared dogs and is due to the marked vasoconstrictor effect of the drug.
Carcinogenicity: There are no data about the carcinogenic potential of ergotamine.
Reproductive toxicity: Ergotamine showed no evidence for embryonal mortality or teratogenic effects in rabbits at 1, 3 and 10 mg/kg per day, and in rats at up to 3 mg/kg per day. However, in rats given 10 mg/kg per day, maternal weight increase was inhibited, fetal ossification retarded and prenatal mortality increased. High ergotamine doses constricted the uterine vessels, reduced blood supply and thus induced hypoxia which is known to be responsible for teratogenic effects in the offspring.
The combination of ergotamine and caffeine (1:100) revealed no teratogenic potential in rats and rabbits.
In a reproductive performance study in male rats, fertility was not impaired. In a reproductive performance study and a peri-/post-natal study in female rats, an increased number of stillbirth and/or peri-/post-natal mortality was observed.
In animal studies, caffeine was found to be teratogenic only at very high doses.