Ergotamine Tartrate
DRUG DESCRIPTION
ErgomarĀ® Sublingual Tablets
Ergotamine tartrate tablets USP. . . . 2 mg
Inactive Ingredients: Microcrystalline Cellulose NF, Natural Peppermint Flavor Powder, Crospovidone NF, Saccharin Sodium USP Powder, D&C Yellow #10 Lake, Magnesium Stearate NF, FD&C Blue #1 Aluminum Lake.
INDICATIONS
ErgomarĀ® is indicated as therapy to abort or prevent vascular headache, e.g., migraine, migraine variants or a so-called "histaminic cephalalgia".
DOSAGE AND ADMINISTRATION
Procedure
For best results, dosage should start at the first sign of an attack. Early Administration Gives Maximum Effectiveness. At the first sign of an attack or to relieve symptoms after onset of an attack, one 2 mg tablet is placed under the tongue. Another tablet should be taken at half-hour intervals thereafter, if necessary, but dosage must not exceed three tablets in any 24hour period. Total weekly dosage should not exceed five tablets (10 mg) in any one week. ErgomarĀ® Sublingual Tablets should not be used for chronic daily administration.
HOW SUPPLIED
ErgomarĀ® Sublingual Tablets, 2 mg
(ergotamine tartrate tablets USP)
ErgomarĀ® Sublingual Tablets are round, green tablets each containing 2 mg of ergotamine tartrate. They are debossed with the product identification code "LB2" on one side, and are supplied in individual foil strips packaged in a plastic child resistant canister containing 20 tablets (5 - 2 x 2 foil strips) NDC 10802-1202-0
SIDE EFFECTS
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
Neurological: paresthesias, numbness, weakness, and vertigo.
Allergic: Localized edema and itching.
Fibrotic Complications: (See WARNINGS).
Drug Abuse and Dependence
There have been reports of drug abuse and psychological dependence in patients on ergotamine tartrate therapy. Due to the chronicity of vascular headaches, it is imperative that patients be advised not to exceed recommended dosages with long-term use to avoid ergotism. (See PRECAUTIONS)
DRUG INTERACTIONS
CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease inhibitors)
See CONTRAINDICATIONS and WARNINGS.
ErgomarĀ® Sublingual Tablets (ergotamine tartrate tablets USP) should not be administered with other vasoconstrictors. Use with sympathomimetics (pressor agents) may cause extreme elevation of blood pressure. The beta-blocker lnderal (propranolol) has been reported to potentiate the vasoconstrictive action of ergotamine 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.
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 CONTRAINDIATIONS). 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. ErgomarĀ® Sublingual 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 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.
Pregnancy
Teratogenic Effects
Pregnancy Category X: There are no studies on the placental transfer or teratogenicity of ErgomarĀ®. Ergotamine crosses the placenta in small amounts, although it does not appear to be embryotoxic in this quantity. However, prolonged vasoconstriction of the uterine vessels and/or increased myometrial tone leading to reduced myometrial and placental blood flow may have contributed to fetal growth retardation observed in animals. (See CONTRAINDICATIONS)
Nonteratogenic Effects
ErgomarĀ® is contraindicated in pregnancy due to its oxytocic effects of ergotamine (See CONTRAINDICATIONS)
Labor and Delivery
ErgomarĀ® is contraindicated in pregnancy due to its oxytocic effect which is maximal in the third trimester. (See CONTRAINDICATIONS)
Nursing Mothers
Ergot drugs are known to inhibit prolactin but there are no reports of decreased lactation with ErgomarĀ®. Ergotamine is excreted in breast milk and may cause symptoms of vomiting diarrhea, weak pulse and unstable blood pressure in nursing infants. Because of the potential for serious adverse reactions in nursing infants from ErgomarĀ®, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
OVERDOSE
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. 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.
CONTRAINDICATIONS
Coadministration of ergotamine with potent CYP 3A4 inhibitors (ritonavir, nelfinavir, indinavir, erythromycin, clorithromycin 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 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).
ErgomarĀ® Sublingual Tablets may cause fetal harm when administered to pregnant women. ErgomarĀ® Sublingual Tablets are 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.
CLINICAL PHARMACOLOGY
Ergotamine is a 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.
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.
PATIENT INFORMATION
Patients should be advised that one ErgomarĀ® Sublingual Tablet should be taken at the first sign of a migraine headache. No more than 2 tablets should be taken for any single migraine attack. No more than 5 tablets should be taken during any 7-day period. Administration of ErgomarĀ® Sublingual Tablets should not exceed the dosing guidelines and should not be used for chronic daily administration (See DOSAGE AND ADMINISTRATION). ErgomarĀ® Sublingual Tablets 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.
Ergotamine Tartrate
Indications: Cephalgia, histaminic; Headache, migraine; Headache, vascular
DESCRIPTION:
Each Ergotamine Tartrate sublingual tablet contains 2 mg ergotamine tartrate, USP. Also contains hydroxypropyl cellulose, NF; FD & C yellow No. 6 Al lake; lactose, NF; magnesium stearate, NF; mannitol, USP; artificial peppermint flavor; pregelatinized starch, NF; saccharin, NF; saccharin sodium, USP; and corn starch, NF.
Pharmacological Category: Vasoconstrictor, uterine stimulant, alpha adrenoreceptor antagonist.
Therapeutic Class: Antimigraine.
Chemical Name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(phenylmethyl)-(5'a )-,(R-(R*,R *) )-2,3-dihydroxybutanedioate (2:1) (salt).
Molecular weight: 1313.43
CLINICAL PHARMACOLOGY:
The pharmacological properties of ergotamine are extremely complex; some of its actions are unrelated to each other, and even mutually antagonistic. The drug has partial agonist and/or antagonist activity against tryptaminergic, dopaminergic and alpha adrenergic receptors depending upon their site, and it is a highly active uterine stimulant. It causes constriction of peripheral and cranial blood vessels and produces depression of central vasomotor centers. The pain of a migraine attack is believed to be due to greatly increased amplitude of pulsations in the cranial arteries, especially the meningeal branches of the external carotid artery. Ergotamine reduces extracranial blood flow, causes a decline in the amplitude of pulsation in the cranial arteries, and decreases hyperperfusion of the territory of the basilar artery. It does not reduce cerebral hemispheric blood flow. Long-term usage has established the fact that ergotamine tartrate is effective in controlling up to 70% of acute migraine attacks, so that it is now considered specific for the treatment of this headache syndrome. Ergotamine produces constriction of both arteries and veins. In doses used in the treatment of vascular headaches, ergotamine usually produces only small increases in blood pressure, but it does increase peripheral resistance and decrease blood flow in various organs. Small doses of the drug increase the force and frequency of uterine contraction; larger doses increase the resting tone of the uterus also. The gravid uterus is particularly sensitive to these effects of ergotamine. Although specific teratogenic effects attributable to ergotamine have not been found, the fetus suffers if ergotamine is given to the mother. Retarded fetal growth and an increase in intrauterine death and resorption have been seen in animals. These are thought to result from ergotamine-induced increases in uterine motility and vasoconstriction in the placental vascular bed.
The bioavailability of sublingually administered ergotamine has not been determined.
Ergotamine is metabolized in the liver by largely undefined pathways, and 90% of the metabolites are excreted in the bile. The unmetabolized drug is erratically secreted in the saliva, and only traces of unmetabolized drug appear in the urine and feces. Ergotamine is secreted into breast milk. The elimination half-life of ergotamine from plasma is about 2 hours, but the drug may be stored in some tissues, which would account for its long-lasting therapeutic and toxic actions.
INDICATIONS AND USAGE:
Ergotamine tartrate is indicated as therapy to abort or prevent vascular headache, e.g., migraine, migraine variants, or so called "histaminic cephalalgia".
CONTRAINDICATIONS:
Ergotamine is contraindicated in peripheral vascular disease (thromboangiitis obliterans, luetic arteritis, severe arteriosclerosis, thrombophlebitis, Raynaud's disease), coronary heart disease, hypertension, impaired hepatic or renal function, severe pruritus, and sepsis. It is also contraindicated in patients who are hypersensitive to any of its components. Ergotamine may cause fetal harm when administered to a pregnant woman by virtue of its powerful uterine stimulant actions. It is contraindicated in women who are, or may become, pregnant.
PRECAUTIONS:
General: Although signs and symptoms of ergotism rarely develop even after long-term intermittent use of ergotamine, care should be exercised to remain within the limits of recommended dosage.
Carcinogenesis: No studies have been performed to investigate ergotamine tartrate for carcinogenic effects.
Pregnancy Category X: See CONTRAINDICATIONS.
Nursing Mothers: Ergotamine is secreted into human milk. It can reach the breast-fed infant by this route and exert pharmacologic effects in it. Caution should be exercised when ergotamine is administered to a nursing woman. Excessive dosing or prolonged administration of ergotamine may inhibit lactation.
DRUG INTERACTIONS:
The effects of ergotamine tartrate may be potentiated by triacetyloleandomycin which inhibits the metabolism of ergotamine. The pressor effects of ergotamine and other vasoconstrictor drugs can combine to cause dangerous hypertension.
ADVERSE REACTIONS:
Nausea and vomiting occur in up to 10% of patients after ingestion of therapeutic doses of ergotamine. Weakness of the legs and pain in limb muscles are also frequent complaints. Numbness and tingling of the fingers and toes, precordial pain, transient changes in heart rate and localized edema and itching may also occur, particularly in patients who are sensitive to the drug.
DRUG ABUSE AND DEPENDENCE:
Patients who take ergotamine for extended periods of time may become dependent upon it and require progressively increasing doses for relief of vascular headaches, and for prevention of dysphoric effects which follow withdrawal of the drug.
OVERDOSAGE:
Overdosage with ergotamine causes nausea, vomiting, weakness of the legs, pain in limb muscles, numbness and tingling of the fingers and toes, precordial pain, tachycardia or bradycardia, hypertension or hypotension and localized edema and itching together with signs and symptoms of ischemia due to vasoconstriction of peripheral arteries and arterioles. The feet and hands become cold, pale and numb. Muscle pain occurs while walking and later at rest also. Gangrene may ensue. Confusion, depression, drowsiness, and convulsions are occasional signs of ergotamine toxicity. Overdosage is particularly likely to occur in patients with sepsis or impaired renal or hepatic function. Patients with peripheral vascular disease are especially at risk of developing peripheral ischemia following treatment with ergotamine. Some cases of ergotamine poisoning have been reported in patients who have taken less than 5 mg of the drug. Usually, however, toxicity is seen at doses of ergotamine tartrate in excess of about 15 mg in 24 hours or 40 mg in a few days.
Treatment of ergotamine overdosage consists of the withdrawal of the drug followed by symptomatic measures including attempts to maintain an adequate circulation in the affected parts. Anticoagulant drugs, low molecular weight dextran and potent vasodilator drugs may all be beneficial. Intravenous infusion of sodium nitroprusside has also been reported to be successful. Vasodilators must be used with special care in the presence of hypotension.
Nausea and vomiting may be relieved by atropine or antiemetic compounds of the phenothiazine group. Ergotamine is dialyzable.
DOSAGE AND ADMINISTRATION:
All efforts should be made to initiate therapy as soon as possible after the first symptoms of the attack are noted, because success is proportional to rapidity of treatment, and lower dosages will be effective. At the first sign of an attack or to relieve the symptoms of the full-blown attack, one sublingual tablet (2 mg) is placed under the tongue. Another sublingual tablet (2 mg) should be placed under the tongue at half-hourly intervals thereafter, if necessary, for a total of three tablets (6 mg). Dosage must not exceed three tablets (6 mg) in any 24-hour period. Limit dosage to not more than five tablets (10 mg) in any one week.
Store at controlled room temperature 15-30Ā°C (59-86Ā°F). Protect from moisture and light.