(British Approved Name Modified, rINNM)
INNs in main languages (French, Latin, Russian, and Spanish):
Pharmacopoeias. In China, Europe , International, Japan and US.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Ergotamine Tartrate). Slightly hygroscopic, colourless crystals or a white or almost white crystalline powder. It may contain 2 molecules of methanol of crystallisation. Slightly soluble in alcohol. Aqueous solutions slowly become cloudy owing to hydrolysis; this may be prevented by the addition of tartaric acid. A 0.25% suspension in water has a pH of 4.0 to 5.5. Store in airtight glass containers at a temperature of 2° to 8°. Protect from light.
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Ergotamine Tartrate). Colourless odourless crystals or a white or yellowish-white crystalline powder. Soluble 1 in about 3200 of water, but soluble 1 in about 500 of water in the presence of a slight excess of tartaric acid; soluble 1 in 500 of alcohol. Store at a temperature not exceeding 8°. Protect from light.
The adverse effects of ergotamine may be attributed either to its effects on the CNS, or to vasoconstriction of blood vessels and possible thrombus formation.
After therapeutic doses nausea and vomiting commonly occur as a result of the direct emetogenic effect of ergotamine; some patients may also experience abdominal pain. Weakness and muscle pains in the extremities and numbness and tingling of the fingers and toes may occur. There may occasionally be localised oedema and itching in hypersensitive patients. Treatment should be stopped if symptoms of vasoconstriction develop. Susceptible patients, especially those with sepsis, liver disease, kidney disease, or occlusive peripheral vascular disease, may show signs of acute or chronic poisoning with normal doses of ergotamine.
Symptoms of acute overdosage include nausea, vomiting, diarrhoea, extreme thirst, coldness, tingling, and itching of the skin, a rapid and weak pulse, hypertension or hypotension, shock, confusion, convulsions, and unconsciousness; fatalities have been reported. Further symptoms of peripheral vasoconstriction or of cardiovascular disturbances, as seen in chronic ergotamine poisoning, may also occur but may be delayed.
In chronic poisoning or ergotism, resulting from therapeutic overdosage or the use of ergotamine in susceptible patients, severe circulatory disturbances may develop. The extremities, especially the feet and legs, become numb, cold, tingling, and pale or cyanotic, with muscle pain; there may be no pulse in the affected limb. Eventually gangrene develops in the toes and sometimes the fingers. Anginal pain, tachycardia or bradycardia, and hypertension or hypotension have been reported. Myocardial infarction has occurred rarely. Pleural and peritoneal fibrosis may occur with excessive use and there have been rare cases of fibrosis of the cardiac valves. Chronic, intractable headache (rebound headache) may occur and is also a major withdrawal symptom following the development of ergotamine dependence (see under Precautions, below). Other adverse effects include confusion and convulsions. On rare occasions symptoms of vasoconstriction of blood vessels in the brain, eye, intestines, and kidneys occur. Anorectal ulceration, sometimes leading to rectal necrosis and stenosis or rectovaginal fistula, has been reported after excessive use of suppositories containing ergotamine.
Effects on the cardiovascular system. Reports of adverse cardiovascular effects associated with ergotamine, including mention of fatalities.
Fibrosis. For reference to fibrosis associated with the use of ergotamine tartrate, see Methysergide Maleate.
Treatment of Adverse Effects
Treatment of acute poisoning with ergotamine is symptomatic. Although the benefit of gastric decontamination is uncertain, activated charcoal may be given to patients who present within 1 hour of ingesting a toxic dose (more than 125 micrograms/kg in adults) or any amount in a child or adult with peripheral vascular disease, ischaemic heart disease, severe infection, or hepatic or renal impairment. Alternatively, gastric lavage may be considered in adults within 1 hour of ingesting a potentially life-threatening overdose. In chronic poisoning, withdrawal of ergotamine may be all that is required in some patients. In both acute and chronic poisoning, attempts must be made to maintain an adequate circulation to the affected parts of the body in order to prevent the onset of gangrene. In severe arterial vasospasm vasodilators such as sodium nitroprusside by intravenous infusion have been given; heparin and dextran 40 have also been advocated to minimise the risk of thrombosis. Analgesics may be required for severe ischaemic pain.
Cardiovascular effects. Sodium nitroprusside has been used in severe ergotamine poisoning for its vasodilating and hypotensive actions; it should, however, be used with care if hypotension is a symptom of poisoning. It is usually given by intravenous infusion although there have also been reports of intra-arterial infusion for ergotamine-induced ischaemia; for details of precautions to be observed.
Many other drugs have been used in the treatment of circulatory disturbances induced by ergotamine. These include captopril by mouth, alprostadil by intra-arterial infusion, and glyceryl trinitrate by intravenous infusion.
Ergotamine tartrate is contra-indicated in patients with severe or uncontrolled hypertension, shock, severe or persistent sepsis, peripheral vascular disease, ischaemic heart disease, temporal arterrtis, hyperthyroidism, or hepatic or renal impairment. It is also contra-indicated in those with basilar or hemiplegic migraine. Ergotamine tartrate should be used with care in patients with anaemia. It is contra-indicated in pregnancy because of its oxytocic effect (see also below). Patients should be warned to keep within the recommended dosage. Some symptoms of overdosage may mimic those of migraine. Numbness or tingling of the extremities generally indicates that ergotamine should be stopped. Although ergotamine is used for limited periods in the prevention of episodic cluster headache, it should not be given prophylactically in other circumstances, as prolonged use may give rise to gangrene. Dependence has occurred with regular use of ergotamine tartrate even if dosage recommendations are adhered to (see below).
Dizziness and feelings of anxiety have been reported; if affected, patients should avoid driving or operating machinery.
Breast feeding. Although the American Academy of Pediatrics includes ergotamine among those drugs that may be given with caution to breast-feeding mothers, it notes that maternal use in doses equivalent to those given for the treatment of migraine has been associated with vomiting, diarrhoea, and convulsions in nursing infants. UK licensed product information recommends that ergotamine tartrate should be avoided during breast feeding; the distribution of unchanged drug and metabolites into breast milk presents a risk of ergotism in the infant and repeated doses of ergotamine may impair lactation.
Cardiovascular disorders. In the USA, dihydroergotamine is contra-indicated in patients with ischaemic heart disease and other cardiovascular disorders such as hypertension, peripheral arterial disease, or coronary artery vasospasm and it is also recommended that it should not be given to those with a family history of ischaemic heart disease, to postmenopausal women or men aged over 40, or to those with other ischaemic risk factors such as hypertension, hypercholesterolaemia, smoking, diabetes, or obesity, unless cardiovascular evaluation to exclude such disease has been carried out. Similar precautions and contra-indications, which resemble those that apply to serotonin (5-HT1) agonists such as sumatriptan, may be applicable to other ergot derivatives used in migraine such as ergotamine.
In other countries, warnings concerning the use of ergot derivatives in patients with risk factors for myocardial ischaemia appear to be less stringent, although caution is clearly advisable.
Dependence. Dependence can develop insidiously when ergotamine tartrate is used for more than 2 days each week, even if total daily or weekly dosage recommendations are observed. Individual reports indicate a state of addiction characterised by a predictable and irresistible pattern of drug usage, the development of tolerance to adverse effects, and a syndrome of withdrawal on stopping the drug. Ergotamine-dependentpatients suffer from daily, or almost daily, migraine headaches, often referred to as medication-overuse headaches or ‘rebound headaches’, which are only alleviated by ergotamine. Intensifying headache with autonomic disturbances occurs within 24 to 48 hours of withdrawal of ergotamine and may continue for 72 hours or longer. As with other medication-overuse headaches, supportive and symptomatic measures should be taken to treat the withdrawal syndrome.
Porphyria. Ergotamine tartrate has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.
Pregnancy. Ergotamine is contra-indicated in pregnancy because of its oxytocic effect. Accidental dosage of ergotamine in the form of a Cafergot suppository (ergotamine tartrate 2 mg and caffeine 100 mg) to a patient at 39 weeks of pregnancy caused uterine contractions and fetal tachycardia. An emergency cae-sarean section was undertaken because of suspected placental abruption but no clear signs of retroplacental haemorrhage were found. The neonate recovered quickly after delivery and had developed normally during the next 10 years.
Jejunal atresia has been reported in an infant born prematurely to a woman who had taken ergotamine tartrate 6 to 8 mg daily, as Cafergot tablets, throughout her pregnancy. Two cases of Mobius syndrome (a condition characterised by facial paralysis as a result of hypoplasia of cranial nerve nuclei) have been associated with exposure to ergotamine during the first trimester of pregnancy. In the first report the mother had inadvertently been given three Cafergot suppositories within a period of 1 to 2 hours and at the time had experienced uterine cramping and a bloody vaginal discharge. The second mother had used 2-mg ergotamine suppositories on a regular basis during the first 8 weeks of pregnancy.
The vasoconstrictor effects of ergotamine are enhanced by sympathomimetics such as adrenaline. There is also an increased risk of peripheral vasoconstriction during use of ergotamine with beta blockers. Ergotamine is metabolised by the cytochrome P450 isoenzyme CYP3 A4 and consequently it should not be given with potent inhibitors of this isoenzyme; elevated ergotamine concentrations sufficient to cause ergotism may occur with azole antifungals, macrolide antibacterials such as erythromycin and clarithromycin, and HIV-protease inhibitors including indinavir and ritonavir. Use of tetracycline with ergotamine may also increase the risk of ergotism and should be avoided.
Ergotamine should not be used with or given until several hours after stopping a serotonin (5-HT1) agonist, since there is an additional risk of prolonged vasospastic reactions; at least 6 hours is advised for almotriptan, rizatriptan, sumatriptan, and zolmitriptan, and at least 24 hours for eletriptan and frovatriptan. Conversely, a delay is advised before starting a serotonin agonist in patients who have been receiving ergotamine: almotriptan, eletriptan, frovatriptan, rizatriptan, sumatriptan, or zolmitriptan should not be given until at least 24 hours after stopping the use of preparations containing ergotamine.
Antibacterials. Acute reactions ranging from minor ergotism to severe vasospasm have been reported in patients given erythromycin in addition to ergotamine. There are also reports of acute ergotism in patients receiving ergotamine tartrate and clarithromycin or troleandomycin The theoretical possibility exists that there may be a similar interaction with azithromycin. Ergotism has also been reported in patients receiving erythromycin or troleandomycin with dihydroergotamine.
Antidepressants. There have been isolated case reports of the serotonin syndrome in patients receiving dihydroergotamine with amitriptyline, imipramine, paroxetine, or sertraline.
Antimigraine drugs. Arterial occlusion has been reported in 2 patients given methysergide with a high parenteral dosage of ergotamine for cluster headache; the combination should be avoided. Use of ergotamine as supplementary antimigraine medication in patients receiving dihydroergotamine is not recommended.
For reports of arterial vasoconstriction in patients taking beta blockers and antimigraine drugs, see below. See also Interactions, above for a comment on the risk of vasospastic reactions with serotonin (5-HT1) agonists such as sumatriptan.
Antivirals. There have been reports of ergotism in patients who received ergotamine and combination antiviral treatment for HIV infection. It was suggested that the ergotism might have been caused by inhibition of ergotamine metabolism by ritonavir in 4 cases, indinavir in one, and nelfinavir in another. One of the patients receiving ritonavir, who had taken three 1-mg tablets of ergotamine tartrate over the 4 days before presentation, also developed signs of cerebrovascular involvement and eventually went into an irreversible coma.
The metabolism of ergot alkaloids may be inhibited by delavirdine or efavirenz.
Beta blockers. Peripheral vasoconstriction was reported in a patient with migraine after addition of propranolol to regular use of Cafergot (ergotamine and caffeine) suppositories twice daily. This combination has been used without complication by others, who suggested that excessive dosage of ergotamine tartrate, rather than an interaction between ergotamine and propranolol, was responsible. However, arterial vasoconstriction has been reported after use of methysergide with propranolol and oxprenolol with ergotamine. Such combinations should therefore be used with caution.
Glyceryl trinitrate. Glyceryl trinitrate has been reported to increase the oral bioavailability and plasma concentrations of dihydroergotamine in patients with orthostatic hypotension.
Tacrolimus. Ergotamine may inhibit the metabolism of tacrolimus by cytochrome P450 isoenzymes.
Absorption of ergotamine from the gastrointestinal tract is poor and may be further decreased by the occurrence of gastric stasis during migraine attacks. Bioavailability is also diminished by a high first-pass hepatic metabolism. Ergotamine has been given rectally or by inhalation in an attempt to overcome these effects, with some improvement in absorption, but bioavailability is still about 5% or less. Absorption of sublingual ergotamine is very poor. There is considerable interindividual variation in the bioavailability of ergotamine, regardless of the route. Caffeine is sometimes included in oral and rectal preparations of ergotamine to improve the latter’s absorption, although whether it does so is not clear. Drugs such as metoclopramide are sometimes given with the aim of alleviating gastric stasis and thus improve the absorption of ergotamine. Plasma protein binding is about 93 to 98%. Ergotamine is metabolised extensively in the liver via the cytochrome P450 isoenzyme CYP3A4; the majority of metabolites are excreted in the bile. About 4% of a dose is excreted in the urine. Some of the metabolites are pharmacologically active. The elimination of ergotamine is biphasic; half-lives of about 2 and 21 hours have been reported for the 2 phases, respectively. Ergotamine or its metabolites have been detected in breast milk.
Uses and Administration
Ergotamine is an alkaloid derived from ergot. It has marked vasoconstrictor effects, and a partial agonist action at serotonin (5-HT) receptors; it also has a powerful oxytocic action on the uterus, although less so than ergometrine. It is used in migraine and cluster headache, and has been tried in orthostatic hypotension.
Ergotamine is commonly used as the tartrate. It is usually given orally, but has also been given sublingually, rectally, and by oral inhalation. It was formerly given by subcutaneous or intramuscular injection. Caffeine is sometimes given with ergotamine tartrate with the intention of improving the latter’s absorption, although whether it does so is not clear. Antiemetics such as cyclizine hydrochloride are sometimes included in combination preparations with ergotamine tartrate. Ergotamine is used in migraine unresponsive to non-opioid analgesics. However, its adverse effects limit its use and prevent use for prophylaxis. It is most effective when given as early as possible in a migraine attack, preferably during the prodromal phase. The usual oral dose is 1 to 2 mg of ergotamine tartrate, repeated, if necessary, half an hour later. Usually not more than 6 mg should be given in 24 hours, although some manufacturers recommend not more than 4 mg in 24 hours and others not more than 8 mg per attack. The recommended minimum interval between successive 24-hour courses is 4 days, and the total weekly dose is limited to a maximum of 12 mg, although again some manufacturers recommend a lower weekly limit of 8 mg. It is also recommended that patients should receive no more than 2 courses per month. Similar doses may be given sublingually.
Ergotamine tartrate may also be given rectally as suppositories, especially if the oral route is not effective or not practicable. The rectal dose of ergotamine tartrate is 2 mg repeated, if necessary, one hour later. Usually, not more than 4 mg should be given in 24 hours and not more than 8 mg in one week with an interval of at least 4 days between successive 24-hour courses. A more rapid onset of action may be achieved by oral inhalation. One dose containing 360 micrograms of ergotamine tartrate has been inhaled at the onset of the attack and repeated, if necessary, at 5-minute intervals. Not more than 6 inhalation doses should be taken in 24 hours and not more than 12 in one week, with an interval of at least 4 days between successive 24-hour courses.
Ergotamine is used in patients with cluster headache to treat individual attacks of headache but since such attacks are short-lived oral inhalation may be preferable to oral, sublingual, or rectal routes. Doses used are similar to those given to treat migraine. It has also been used to prevent headache attacks during cluster periods, when it is usually given daily in low doses for up to 2 weeks, either orally or rectally (see below).
Migraine and cluster headache. Ergotamine was formerly one of the main drugs used to treat acute attacks of migraine unresponsive to non-opioid analgesics, but triptan serotonin (5-HT1) agonists such as sumatriptan are now preferred. Since ergotamine may exacerbate the nausea and vomiting that commonly develops as a migraine attack progresses it is often necessary to give an antiemetic as well. Poor oral bioavailability may be reduced further during a migraine attack and ergotamine has sometimes been given sublingually, rectally, or by inhalation. Adverse effects limit the dose that can be used for an individual attack and prevent the long-term use that would be required for migraine prophylaxis.
Ergotamine may be used similarly in cluster headache to treat individual headaches during a cluster period. Ergotamine is also used in low doses given by mouth or rectally for limited periods of up to 2 weeks in the prophylaxis of headache attacks during a cluster period. Regimens that have been tried for such prophylaxis include 1 to 2 mg of ergotamine tartrate given 1 to 2 hours before an expected attack or 1 to 2 hours before bedtime for nocturnal attacks. The total maximum dose of ergotamine tartrate that may be given weekly for the prevention of cluster headache is less well established than for the treatment of migraine. Ergotamine is often given for only 5 to 6 days in each week, which allows the patient to assess whether the cluster period has ended.
Orthostatic hypotension. Ergotamine and dihydroergotamine may be of use in patients with refractory orthostatic hypotension. Ergotamine is believed to be less selective than dihydroergotamine in its actions and affects both venous capacitance and peripheral resistance. However, the oral bioavailability of ergotamine is greater than that of dihydroergotamine and there have also been some reports of successful treatment with inhaled or rectal ergotamine.
British Pharmacopoeia 2008; Ergotamine Sublingual Tablets;
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2: Ergotamine Tartrate and Caffeine Suppositories; Ergotamine Tartrate and Caffeine Tablets; Ergotamine Tartrate Inhalation Aerosol; Ergotamine Tartrate Injection; Ergotamine Tartrate Tablets.
The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed
Australia: Ergodryl Mono¤; Lingraine¤; Medihaler-Ergotamine¤; Austria: Ergokapton; Ergotartrat¤; Brazil: Enxak¤; Gynergene¤; Canada: Ergomar¤; Gynergen¤; Medihaler-Ergotamine¤; Chile: Jaquedryl; Germany: Clavigrenin akut¤; ergo sanol SL¤; ergo sanol spezial N; Ergo-Kranit akut; Gynergen¤; Migrexa¤; RubieNex mono¤; Hungary: Ergam; Ireland: Lingraine¤; Italy: Ergotan; Gynergen¤; Netherlands: Gynergeen¤; South Africa: Ergate¤; Spain: Gynergeno¤; Switzerland: Ergosanol SL¤; Thailand: Ergosia; Gynaemine; United Kingdom: Lingraine¤; Medihaler-Ergotamine¤; United States: Ergomar; Ergostat¤; Medihaler-Ergotamine¤
Argentina: Cafergot; Cefalex; Ibu-Tetralgin; Ibumar Migra; Ibupirac Migra; Integrobe Plus; Jaquedryl; Migra Dioxadol; Migra Dorixina; Migral Compositum; Migral II; Migral; Mikesan; Solacil; Tetralgin Novo; Tetralgin; Zilactin-E¤; Australia: Cafergot-PB¤; Cafergot; Ergodryl¤; Migral¤; Austria: Avamigran; Cafergot; Lenticor¤; Medium¤; Migril; Pansecoff¤; Secokapton; Synkapton; Belgium: Cafergot-PB¤; Cafergot; Migril¤; Brazil: Cafergot¤; Migrane; Ormigrein; Canada: Bellergal; Cafergot-PB¤; Cafergot; Ergodryl; Gravergol¤; Megral¤; Wigraine¤; Chile: Bellergal Retardado¤; Cafergot-PB; Cefalmin; Cinabel; Clonalgin Compuesto; Ergobelan; Ergonef; Fredol; Migra-Nefersil; Migragesic; Migranol; Migratam; Ultrimin; Czech Republic: Bellaspon; Denmark: Ergokoffin; Gynergen Comp; Finland: Anervan; France: Bellergal¤; Gynergene Cafeine; Migwell¤; Germany: Avamigran N¤; bella sanol¤; Bellaravil-retard¤; Bellergal¤; Cafergot N¤; Cafergot-PB¤; Celetil¤; Circovegetalin compositum¤; ergo sanol spezial¤; ergo sanol¤; Ergo-Kranit¤; Ergoffin¤; Migrane-Dolviran¤; Migrane-Kranit spezial N¤; Migranex spezial N¤; Migratan S; Praecimal¤; Regium¤; RubieNex spezial¤; Greece: Cafergot; Hong Kong: Cafergot; Gravergol¤; Migril¤; Hungary: Kefalgin; India: Migranil; Ireland: Cafergot¤; Migranat; Migril¤; Israel: Cafergot; Temigran; Italy: Bellergil¤; Cafergot; Distonium¤; Virdex; Malaysia: Cafergot; Mexico: Cafergot; Caftar; Ergocaf; Sydolil; Trinergot; Netherlands: Cafergot; Cranimal¤; Ercycof; Migril¤; Neo-Cranimal¤; Norway: Anervan; Cafergot Comp¤; Cafergot¤; New Zealand: Cafergot; Ergodryl¤; Migril¤; Portugal: Avamigran; Migretil; South Africa: Bellergal¤; Cafergot-PB; Cafergot; Migril; Singapore: Cafergot; Migril¤; Spain: Bellergal¤; Cafergot-PB¤; Cafergot; Distovagal¤; Hemicraneal; Igril¤; Lasa Infantil¤; Sweden: Anervan; Cafergot; Switzerland: Bellagotin; Bellergal¤; Cafergot-PB; Cafergot; Ergosanol a la cafeine¤; Ergosanol special a la cafeine¤; Ergosanol special¤; Migrexa¤; Migril¤; Thailand: Avamigran; Bellergal¤; Benera; Cafergot; Degran; Neuramizone; Poligot-CF; Polygot; United Kingdom: Cafergot; Migril; United States: Bel-Phen-Ergot S; Bellamine; Bellergal-S; Cafatine-PB; Cafatine; Cafergot-PB¤; Cafergot; Cafetrate¤; Ercaf; Folergot-DF; Migergot¤; Phenerbel-S; Wigraine¤; Venezuela: Cafergot; Traveget