ASIA MIGRAINE

Ergotamine Tartrate and Caffeine Suppository ergotamine tartrate USP 2 mg caffeine USP 100 mg Inactive Ingredients: tartaric acid NF, and hard fat NF Ergotamine Tartrate and Caffeine Suppositories are for rectal administration only.

Suppositories are sealed in foil to afford protection from leakage.

If an unavoidable period of exposure to heat softens the suppository, it should be chilled in ice-cold water to solidify it before removing the foil.

Indicated as therapy to abort or prevent vascular headache, e.g., migraine, migraine variants or so-called “histaminic cephalalgia”.

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.

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.

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.

Nausea and vomiting; rectal or anal ulcer (from overuse of suppositories).

Paresthesias, numbness, weakness, and vertigo.

Localized edema and itching.

Complications: See WARNINGS.

To report SUSPECTED ADVERSE

REACTIONS, contact Cosette Pharmaceuticals, Inc.fda.gov/medwatch.

The toxic effects of an acute overdosage of ergotamine tartrate and caffeine are due primarily to the ergotamine component.

The amount of caffeine is such that its toxic effects will be overshadowed by those of ergotamine.

Symptoms include vomiting, numbness, tingling, pain and cyanosis of the extremities associated with diminished or absent peripheral pulses; hypertension or hypotension; drowsiness, stupor, coma, convulsions and shock.

A case has been reported of reversible bilateral papillitis with ring scotomata in a patient who received five times the recommended daily adult dose over a period of 14 days.

Treatment consists of removal of the offending drug by enema.

Maintenance of adequate pulmonary ventilation, correction of hypotension, and control of convulsions and blood pressure are important considerations.

Treatment of peripheral vasospasm should consist of warmth, but not heat, and protection of the ischemic limbs.

Vasodilators may be beneficial but caution must be exercised to avoid aggravating an already existent hypotension.

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.

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 suppositories should not be used for chronic daily administration See DOSAGE AND ADMINISTRATION.

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, 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 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.

Ergotamine tartrate and caffeine may cause fetal harm when administered to pregnant women.

Ergotamine tartrate and caffeine 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.

For best results, dosage should start at the first sign of an attack.

Two suppositories is the maximum dose for an individual attack.

Total weekly dosage should not exceed 5 suppositories.

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.

One suppository at start of attack; second suppository after 1 hour, if needed for full relief.

Early administration gives maximum effectiveness.

USP are supplied in boxes of 12 foil wrapped suppositories.

NDC 0713-0166-12.

The suppositories should be refrigerated at 2° to 8°C (36° to 46°F).

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Plainfield, NJ 07080 8-0166CPLNC1 Iss. 06/2020 VC7420.