Ergotamine Tartrate and Caffeine

INDICATIONS AND USAGE Ergotamine tartrate and caffeine tablets are indicated as therapy to abort or prevent vascular headache; e.g., migraine, migraine variants or so-called “histaminic cephalalgia.”

DOSAGE AND ADMINISTRATION Procedure For best results, dosage should start at the first sign of an attack. Rectally Two suppositories is the maximum dose for an individual attack. Total weekly dosage should not exceed 5 suppositories. Ergotamine Tartrate and Caffeine Suppositories should not be used for chronic daily administration. In carefully selected patients, with due consideration of maximum dosage recommendations, administration of the drug at bedtime may be an appropriate short-term preventive measure. Maximum Adult Dosage: One suppository at start of attack; second suppository after 1 hour, if needed for full relief. Early administration gives maximum effectiveness.

WARNINGS - CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) Coadministration of ergotamine with potent CYP 3A4 inhibitors such as protease inhibitors or macrolide antibiotics has been associated with serious adverse events; for this reason, these drugs should not be given concomitantly with ergotamine (See CONTRAINDICATIONS ) . While these reactions have not been reported with less potent CYP 3A4 inhibitors, there is a potential risk for serious toxicity including vasospasm when these drugs are used with ergotamine. Examples of less potent CYP 3A4 inhibitors include: saquinavir, nefazodone, fluconazole, fluoxetine, grapefruit juice, fluvoxamine, zileuton, metronidazole, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with ergotamine. Fibrotic Complications There have been a few reports of patients on ergotamine tartrate and caffeine therapy developing retroperitoneal and/or pleuropulmonary fibrosis. There have also been rare reports of fibrotic thickening of the aortic, mitral, tricuspid, and/or pulmonary valves with long-term continuous use of ergotamine tartrate and caffeine. Ergotamine tartrate and caffeine tablets should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION ).

CONTRAINDICATIONS Coadministration of ergotamine with potent CYP 3A4 inhibitors (ritonavir, nelfinavir, indinavir, erythromycin, clarithromycin, and troleandomycin) has been associated with acute ergot toxicity (ergotism) characterized by vasospasm and ischemia of the extremities (see PRECAUTIONS : Drug Interactions ), with some cases resulting in amputation. There have been rare reports of cerebral ischemia in patients on protease inhibitor therapy when ergotamine tartrate and caffeine tablets was coadministered, at least one resulting in death. Because of the increased risk of ergotism and other serious vasospastic adverse events, ergotamine use is contraindicated with these drugs and other potent inhibitors of CYP 3A4 (e.g., ketoconazole, itraconazole) (see WARNINGS : CYP 3A4 Inhibitors ). Ergotamine tartrate and caffeine tablets may cause fetal harm when administered to pregnant women. Ergotamine tartrate and caffeine tablets is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this product, the patient should be apprised of the potential hazard to the fetus. Peripheral vascular disease, coronary heart disease, hypertension, impaired hepatic or renal function and sepsis. Hypersensitivity to any of the components.

Drug Interactions - CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) See CONTRAINDICATIONS and WARNINGS . Ergotamine tartrate and caffeine tablets should not be administered with other vasoconstrictors. Use with sympathomimetics (pressor agents) may cause extreme elevation of blood pressure. The beta-blocker Inderal (propranolol) has been reported to potentiate the vasoconstrictive action of ergotamine tartrate and caffeine tablets by blocking the vasodilating property of epinephrine. Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy. The blood levels of ergotamine-containing drugs are reported to be elevated by the concomitant administration of macrolide antibiotics and vasospastic reactions have been reported with therapeutic doses of the ergotamine-containing drugs when coadministered with these antibiotics.

ADVERSE REACTIONS Cardiovascular: Vasoconstrictive complications of a serious nature may occur at times. These include ischemia, cyanosis, absence of pulse, cold extremities, gangrene, precordial distress and pain, EKG changes and muscle pains. Although these effects occur most commonly with long-term therapy at relatively high doses, they have also been reported with short-term or normal doses. Other cardiovascular adverse effects include transient tachycardia or bradycardia and hypertension. Gastrointestinal: Nausea and vomiting; rectal or anal ulcer (from overuse of suppositories). Neurological: Paresthesias, numbness, weakness, and vertigo. Allergic: Localized edema and itching. Fibrotic Complications: (See WARNINGS ). To report SUSPECTED ADVERSE REACTIONS, contact Cosette Pharmaceuticals, Inc. at 1-800-922-1038 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CLINICAL PHARMACOLOGY Ergotamine is an alpha adrenergic blocking agent with a direct stimulating effect on the smooth muscle of peripheral and cranial blood vessels and produces depression of central vasomotor centers. The compound also has the properties of serotonin antagonism. In comparison to hydrogenated ergotamine, the adrenergic blocking actions are less pronounced and vasoconstrictive actions are greater. Caffeine, also a cranial vasoconstrictor, is added to further enhance the vasoconstrictive effect without the necessity of increasing ergotamine dosage. Many migraine patients experience excessive nausea and vomiting during attacks, making it impossible for them to retain any oral medication. In such cases, therefore, the only practical means of medication is through the rectal route where medication may reach the cranial vessels directly, evading the splanchnic vasculature and the liver. Pharmacokinetics Interactions : Pharmacokinetic interactions (increased blood levels of ergotamine) have been reported in patients treated orally with ergotamine and macrolide antibiotics (e.g., troleandomycin, clarithromycin, erythromycin), and in patients treated orally with ergotamine and protease inhibitors (e.g. ritonavir) presumably due to inhibition of cytochrome P450 3A metabolism of ergotamine (see CONTRAINDICATIONS ). Ergotamine has also been shown to be an inhibitor of cytochrome P450 3A catalyzed reactions. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known.