Cafergot

CAFERGOT- ergotamine tartrate and caffeine tablet, film coated
Sandoz Inc

Rx Only

WARNING

Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of Cafergot (ergotamine tartrate and caffeine tablets, USP) with potent CYP 3A4 inhibitors including protease inhibitors and macrolide antibiotics. Because CYP 3A4 inhibition elevates the serum levels of Cafergot (ergotamine tartrate and caffeine tablets, USP), the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities is increased. Hence, concomitant use of these medications is contraindicated (see also Contraindications and Warnings section).

DESCRIPTION

Each tablet for oral administration contains 1 mg ergotamine tartrate, USP, and 100 mg caffeine, USP.

ERGOTAMINE TARTRATE:

ErgotamineTartrateChemicalStructure
(click image for full-size original)

Ergotaman-3′,6′,18-trione, 12′-hydroxy-2′-methyl- 5′-(phenyl-methyl) -,(5′ α) -, [ R-(R*,R*)] -2,3-dihydroxy-butanedioate (2:1) (salt).

CAFFEINE:

CaffeineChemicalStructure

1H -Purine-2,6-dione, 3,7-dihydro-1,3,7- trimethyl-.

Inactive ingredients include black iron oxide, compressible sugar, iron oxide red, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, sodium starch glycolate, talc, titanium dioxide and yellow iron oxide.

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.

INDICATIONS AND USAGE

Cafergot (ergotamine tartrate and caffeine tablets, USP) is indicated as therapy to abort or prevent vascular headache, e.g., migraine, migraine variants, or so-called “histaminic cephalalgia”.

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 Cafergot (ergotamine tartrate and caffeine tablets, USP) was coadministered, at least one resulting in death. Because of the increased risk for 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).

Cafergot (ergotamine tartrate and caffeine tablets, USP) may cause fetal harm when administered to pregnant women. Cafergot (ergotamine tartrate and caffeine tablets, USP) 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.

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).

PRECAUTIONS

General

Although signs and symptoms of ergotism rarely develop even after long-term intermittent use of the orally administered drug, care should be exercised to remain within the limits of recommended dosage.

Ergotism is manifested by intense arterial vasoconstriction, producing signs and symptoms of peripheral vascular ischemia. Ergotamine induces vasoconstriction by a direct action on vascular smooth muscle. In chronic intoxication with ergot derivatives, headache, intermittent claudication, muscle pains, numbness, coldness and pallor of the digits may occur. If the condition is allowed to progress untreated, gangrene can result.

While most cases of ergotism associated with ergotamine treatment result from frank overdosage, some cases have involved apparent hypersensitivity. There are few reports of ergotism among patients taking doses within the recommended limits or for brief periods of time. In rare instances, patients, particularly those who have used the medication indiscriminately over long periods of time, may display withdrawal symptoms consisting of rebound headache upon discontinuation of the drug.

Information for Patients

Patients should be advised that two tablets of Cafergot (ergotamine tartrate and caffeine tablets, USP) should be taken at the first sign of a migraine headache. No more than 6 tablets should be taken for any single migraine attack. No more than 10 tablets should be taken during any 7-day period. Administration of ergotamine tartrate and caffeine tablets should not exceed the dosing guidelines and should not be used for chronic daily administration (see Dosage and Administration). Cafergot (ergotamine tartrate and caffeine tablets, USP) should be used only for migraine headaches. It is not effective for other types of headaches and it lacks analgesic properties. Patients should be advised to report to the physician immediately any of the following: numbness or tingling in the fingers and toes, muscle pain in the arms and legs, weakness in the legs, pain in the chest or temporary speeding or slowing of the heart rate, swelling or itching.

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