Ergotamine/ Cyclizine/ Caffeine

Registered South African indications:

• Relief of acute migraine attacks

Registered South African contraindications

• Hypersensitivity to ergotamine tartrate, cyclizine hydrochloride, caffeine anhydrous or to any of the inactive ingredients
• Pregnancy
• Lactation
• Not recommended for use in children
• Pre-existing vascular disease including
  - Coronary disease
  - Obliterative vascular disease
  - Angina
  - Claudication
  - Peripheral ischaemia
  - Raynaud's Syndrome
  - Severe high blood pressure
  - Recent or contemplated angioplasty or vascular surgery
• Hyperthyroidism
• Sepsis
• Kidney and liver disease
• Porphyria
• Malnutrition
• Anaemia
• Contraindicated in conditions such as glaucoma, bladder neck obstruction, urinary retention, prostatic hypertrophy (enlarged prostate gland), and pyloroduodenal obstruction (intestinal blockage) as the formulation contains cyclizine hydrochloride
• Contraindicated in patients with anxiety disorders, severe cardiac disease, insomnia or peptic ulcer as the formulation contains caffeine
• Coadministration with potent CYP3A4 inhibitors (ritonavir, nelfinavir, indinavir, amprenavir, azithromycin, erythromycin, clarithromycin, ketoconazole, itraconazole) due to increased risk for ergotism and other serious vasospastic adverse events

South African recommendations

Ergotamine/cyclizine/caffeine usage

• Avoid regular usage or use for migraine prophylaxis due to risk of ergotism or ergotamine dependence

Ergotamine dependence

• Monitor for symptoms of dependence and discontinue ergotamine/cyclizineyclizine/caffeine if observed

Coadministration with potent CYP3A4 inhibitors

• Can cause serious adverse events. Also, avoid coadministration with less potent CYP3A4 inhibitors due to potential risk of toxicity

Symptoms of arterial insufficiency

• Discontinue therapy if symptoms such as coldness, numbness or tingling of the extremities occur

Infective hepatitis

• Use ergotamine/cyclizine/caffeine with caution in patients with infective hepatitis due to increased risk of precipitating peripheral ischaemia

Elderly

• Use with caution in elderly patients, as they may be more susceptible to ergotamine-related complications

Anaemic patients

• Ergotamine should be used with care when anaemia is present

Smokers

• The administration of ergotamine to a patient who smokes heavily may increase the risk of peripheral ischaemia

Fibrotic complications

• Monitor for development of retroperitoneal, pleuropulmonary fibrosis or fibrotic thickening of heart valves with long-term ergotamine use

Caffeine

• May inhibit sleep, and should be used cautiously in patients with cardiac disease
• Patients should avoid caffeine 12 hours before dipyridamole-assisted myocardial perfusion studies

Contains lactose

• Ergotamine/cyclizine/caffeine is not suitable for patients with certain hereditary conditions of galactose intolerance (e.g., galactosaemia, Lapp lactase deficiency, glucose-galactose malabsorption, or fructose intolerance)

Contains glucose

• Ergotamine/cyclizine/caffeine may affect glycaemic control in patients with diabetes mellitus

Effects on ability to drive and use machines

• Ergotamine/cyclizine/caffeine may cause drowsiness and impaired concentration, which can be aggravated by alcohol or other central nervous system depressants. Avoid operating hazardous machinery, driving motor vehicles, or performing potentially hazardous tasks where loss of concentration may lead to accidents

Forms avail. in SA and covered in this monograph: tab

South African registered indications and dosages

Relief of acute migraine attacks

Ergotamine/ Cyclizine/ Caffeine
2/50/100 (mg)

• Oral (tab): 1 tab, taken at the onset of an attack; Then: ½-1 tab, every 30min as needed; Max: 4 tab/migraine attack (8mg ergotamine/migraine attack), 6 tabs/week (12mg ergotamine/week)

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Ergotamine/cyclizine/caffeine should not be used for migraine prophylaxis or taken regularly, even if the dosage recommendations are adhered to because of the risk of inducing ergotism or ergotamine dependence

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The smallest effective dose should be used to minimize side effects. The number of tablets used to relieve a previous attack may be taken as one dose in subsequent attacks

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Ergotamine/cyclizine/caffeine does not result in tolerance, thus the efficacy will not diminish with continued use provided that the adequate dosage is employed. However, ergotamine dependence can develop with habitual use and a syndrome of non-migrainous rebound headache can develop, in which case the combination agent should be discontinued

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It is recommended that the patient should lie down in a quiet, darkened room after taking the medication, as it facilitates relief of symptoms

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No more than 4 tablets (8mg ergotamine) should be given in any one attack. No more than 6 tablets (12mg ergotamine) should be given in any one week

Contraindicated

Pregnancy

South African recommendations

• Contraindicated

Breastfeeding

South African recommendations

• Contraindicated

Fertility

South African recommendations

• No data available

Renal Impairment

South African recommendations

• Contraindicated

Hepatic Impairment

South African recommendations

• Contraindicated

Elderly

South African recommendations

• Caution; no dose adjustment recommended
  There have been no specific studies of ergotamine/cyclizine/caffeine in the elderly, however caution is recommended in elderly patients, who may be more susceptible to complications associated with vasospasm and hypothermia

Porphyria Information

South African recommendations

• Contraindicated

Drugs in Sport

• Permitted - No warnings

Blood and lymphatic system disorders

• Blood disorders including agranulocytosis (Less frequent)
• Leucopenia (Less frequent)
• Haemolytic anaemia (Less frequent)
• Thrombocytopenia (Less frequent)

Immune system disorders

• Hypersensitivity reactions (Less frequent)

Psychiatric disorders

• Anxiety (Frequency unknown)
• Depression (Frequency unknown)
• Confusion (Frequency unknown)
• Hallucinations (Frequency unknown)
• Psychomotor impairment (Frequency unknown)

Nervous system disorders

• Dizziness (Frequent)
• Drowsiness (Frequent)
• Headache (Frequent)
• Dysaesthesia (Frequency unknown)
• Paraesthesiae (Frequency unknown)
• Formication (Frequency unknown)
• Tremor (Frequency unknown)
• Convulsions (Frequency unknown)
• Extrapyramidal effects (Frequency unknown)

Eye disorders

• Blurred vision (Frequent)
• Ocular vasospasm (changes in vision, miosis) (Less frequent)

Cardiac disorders

• Coronary vasospasm-induced angina pectoris (Less frequent)
• Dysrhythmias including bradycardia and tachycardia (Less frequent)
• Increase or decrease in blood pressure (Less frequent)
• Rapid, weak pulse (Less frequent)
• Myocardial infarction (Less frequent)
• Cerebral infarction (Less frequent)
• Precordial pain (Less frequent)
• Coronary infarction (Less frequent)
• Fibrotic thickening of the heart valves (Less frequent)

Vascular disorders

• Cerebral ischaemia (anxiety, confusion) (Less frequent)
• Peripheral, vasospasm-induced ischaemia (Less frequent)
  - Itching of skin
  - Numbness and tingling of fingers, toes or face
  - Pain in the arms, legs or lower back, especially pain in the calves and/or heels on exertion
  - Pale, bluish-coloured or cold hands or feet
  - Weak or absent pulses
  - Weakness in legs, gangrene, thrombotic complications
• Arterial insufficiency (Less frequent)
• Intermittent claudication (Frequency unknown)
• Thrombophlebitis (Frequency unknown)
• Peripheral arterial thrombosis (Frequency unknown)
• Arterial vasospasm (Frequency unknown)

Respiratory, thoracic and mediastinal disorders

• Apnoea (shortness of breath) (Frequency unknown)

Gastrointestinal disorders

• Diarrhoea (Frequent)
• Nausea and vomiting (Frequent)
• Stomach pain or bloating (Frequent)
• Dryness of the mouth, nose and throat (Frequent)

Skin and subcutaneous tissue disorders

• Localised oedema (Frequent)
• Pruritus (Less frequent)

Musculoskeletal, connective tissue and bone disorders

• Muscle cramps (Frequency unknown)
• Joint pains (Frequency unknown)

Renal and urinary disorders

• Urinary retention (Frequent)
• Renal artery spasm (Less frequent)
• Loss of renal function (Less frequent)

General disorders and administration site conditions

• Dizziness (Frequent)
• Drowsiness (Frequent)
• Sleep disturbances including insomnia (Frequency unknown)
• Retroperitoneal and/or pleuropulmonary fibrosis (Frequency unknown)

Investigations

• Positive results of skin tests may be suppressed (Frequency unknown)

Ergotamine

• Beta-blocking agents
• Macrolide antibacterial agents
• Clarithromycin
• Erythromycin ethylsuccinate
• Tetracycline antibacterials
• Systemic vasoconstrictors
• Local anaesthetic solutions containing vasoconstrictors
• Nitroglycerine
• Antimigraine drugs
• Methysergide
• 5-HT1 agonists
• Almotriptan
• Sumatriptan
• Rizatriptan
• Zolmitriptan
• Eletriptan
• Antivirals (HIV-protease inhibitors)
• Amprenavir
• Indinavir
• Nelfinavir
• Ritonavir
• Antimuscarinics
• Atropine
• Nicotine
• Sympathomimetics (pressor agents)

Cyclizine

• Alcohol
• Central nervous system depressants
• Hypnotics
• Tranquillisers
• Anticholinergic medicines
• Antidepressants
• Tricyclic antidepressants
• Monoamine-oxidase inhibitors (MAOI)

Caffeine

• CNS stimulating medications
• Monoamine-oxidase inhibitors (MAOI)
• Antiarrhythmics
• Mexiletine
• Quinoline antibacterials
• Ciprofloxacin
• Antidepressants
• Fluvoxamine
• Antiepileptics
• Phenytoin
• Anxiolytics and hypnotics
• Diazepam
• Disulfiram
• Lithium
• Oestrogens and progesterones
• Phenylpropanolamine
• Theophylline

None routine 

Ergotamine exerts a marked vasoconstrictor effect by direct action on vascular smooth muscle. This is the suggested basis of its therapeutic effect in the treatment of vascular headaches, especially migraine. In addition ergotamine depresses the central vasomotor centres and blocks peripheral adrenergic receptors. Cyclizine is an H1-receptor blocking antihistamine which possesses anticholinergic and antiemetic properties. Caffeine acts primarily by increasing both the rate and extent of absorption of ergotamine.

COMBINATION PREPARATIONS

Ergotamine/ Cyclizine/ Caffeine

Tablet 2mg/50mg/100mg

• Migril (iNova) originator