SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Migril Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Ergotamine tartrate 2.0mg, cyclizine hydrochloride 50.0mg and caffeine equivalent to caffeine hydrate 100mg.

For excipients, see 6.1.

3 PHARMACEUTICAL FORM

Tablet

White, round, biconvex compression-coated tablets with a pink core, scored and impressed ‘CP A4A’.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Migril is indicated for the relief of acute migraine attack

4.2    Posology and method of administration

Adults: Migril should be taken as soon as possible after the first warning of an attack of migraine and repeated if necessary at the prescribed intervals.

The usual initial dose is one tablet.

Additional doses of a half to one tablet may then be required at half-hourly intervals.

No more than 3 tablets (6 mg ergotamine) should be taken in any 24 hours or 4 tablets (8mg ergotamine) during any one attack.

The recommended minimum interval between successive courses is 4 days.

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

No more than two courses of treatment should be administered in a month.

Use the minimum effective dosage of Migril necessary, since individual sensitivity to the arterial effects of ergotamine varies considerably.

Children: The use of Migril in children is not recommended.

Use in the elderly: There are no absolute contra-indications to the use of Migril in the elderly, but see Section 4.3 'Contra-indications' and Section 4.4 'Precautions'.

4.3 Contraindications

Co-administration of ergotamine with potent CYP3A4 inhibitors (ritonavir, nelfinavir, indinavir, amprenavir, azithromycin, erythromycin, clarithromycin) has been associated with acute ergot toxicity (ergotism) characterised by vasospasm and ischaemia of the extremities, with some cases resulting in amputation. There have been rare reports of cerebral ischaemia in patients on protease inhibitor therapy when ergotamine was co-administered, at least one resulting in death. Due to the increased risk for ergotism and other serious vasospastic adverse events, ergotamine use is contraindicated with these drugs and other potent inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole).

Ergotamine should not be used when sepsis, hyperthyroidism, hepatic or renal impairment or porphyria are present.

Migril is contra-indicated during pregnancy because of a direct effect of ergotamine on the uterus. In animals, ergotamine has been reported to inhibit implantation, cause peri-natal mortality and foetal retardation.

Migril is contra-indicated during lactation and breast-feeding; it may suppress milk production and may also be excreted in milk at levels high enough to cause pharmacological effects in breast-fed infants.

Migril is contra-indicated in pre-existing vascular disease including coronary disease, obliterative vascular disease, angina, claudication, peripheral ischaemia, Raynaud's syndrome and hypertension.

Migril should not be taken if there is a hypersensitivity to any of its constituents.

4.4 Special warnings and precautions for use

Migril should not be used for migraine prophylaxis or taken regularly, even if the dosage recommendations above are adhered to, because of the risk of inducing ergotism or ergotamine dependence (see also Section 4.8, undesirable Effects).

The use of ergotamine-containing compounds carries the risk of precipitating arterial constriction and other manifestations of ergotism. Co-administration of ergotamine with potent CYP3A4 inhibitors has been associated with serious adverse events (see Section 4.3 Contra-Indication).

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: grapefruit juice, saquinavir, nefazodone, fluoxetine, fluvoxamine metronidazole, fluconazole 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.

Discontinue the use of Migril if symptoms of arterial insufficiency develop, including coldness, numbness or tingling of the extremities.

Migril should be used with caution in patients with infective hepatitis because of an increased risk of precipitating peripheral ischaemia.

Migril should be used with caution in patients with cardiac disease (increased risk of caffeine-induced arrhythmias).

Caution is advised in patients with gastrointestinal tract obstructive disease, glaucoma, prostatic hypertrophy or urinary retention as these conditions may be aggravated by cyclizine.

Care should be taken in the elderly, as they may be especially susceptible to complications associated with ergotamine.

Ergotamine should be used with care when anaemia is present.

There have been a few reports of patients on ergotamine developing retroperitoneal and/or pleuropulmonary fibrosis. There have also been rare reports of fibrotic thickening of aortic, mitral, tricuspid and/or pulmonary valves with long-term continuous use of ergotamine.

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol : Increased sedative effect - alcohol and Migril should not be taken concomitantly. .

Antiarrhythmics: Mexiletine may reduce clearance of caffeine.

Antibacterials: The blood levels of ergotamine-containing drugs are reported to be elevated by the concomitant administration of macrolide antibiotics (e.g. clarithromycin, erythromycin) and their concomitant use is contraindicated (see 4.3 Contraindications). Quinoline antibacterials such as ciprofloxacin may reduce caffeine clearance . Increased risk of ergotism with tetracycline antibacterials.

Antidepressants: Reduced clearance of caffeine by fluvoxamine . Concomitant tricyclic or MAOI antidepressants may increase sedative effects and antimuscarinic effects of cyclizine.

Antiepileptics: Increased clearance of caffeine by phenytoin.

Antimuscarinincs: Increased antimuscarinic effects, e.g. with atropine or drugs with antimuscarinic activity .

Antimigraine drugs: Increased risk of arterial occlusion with methysergide and vasospasm with 5-HT1 agonists. Ergotamine should be avoided for six hours after almotriptan, , sumatriptan, rizatriptan and zolmitriptan, and for 24 hours after eletriptan. Almotriptan, eletriptan, sumatriptan and rizatriptan should be avoided for 24 hours, and zolmitriptan for six hours, after ergotamine.

Antivirals: The concomitant use of certain HIV-protease inhibitors which are potent CYP 3A4 inhibitors (amprenavir, indinavir, nelfinavir, ritonavir) is contraindicated, due to an increased risk of ergotism (see 4.3 Contraindications).

Anxiolytics and hypnotics: Increased sedative effects,although sedative effects of diazepam may be reduced by caffeine.

Beta-blockers: Increased risks of peripheral vasoconstriction.

Disulfiram: Reduced clearance of caffeine.

Lithium: Caffeine may increase clearance of lithium.

Nicotine: Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischaemic response to ergot therapy.

Nitrates: Concomitant administration of ergot alkaloids including ergotamine may oppose the anti-anginal effects of glycerol trinitrate.

Oestrogens and progesterones: May reduce clearance of caffeine.

Sympathomimetics (pressor agents): Concomitant use may cause extreme elevation of blood pressure and vasoconstriction, including ergotism.

Phenylpropanolamine may also increase serum caffeine levels causing excess stimulation. Manic psychosis and hypertensive crises have been reported.

Theophylline: Possibility of increased plasma theophylline levels and caffeine levels during concomitant use.

Vasoconstrictors: Migril should not be administered with other vasoconstrictors.

4.6 Pregnancy and lactation

See Contra-indications (Section 4.3)

4.7 Effects on ability to drive and use machines

Cyclizine, in common with other antihistamines, may cause sedation; patients should be cautioned about driving or operating machinery.

4.8 Undesirable Effects

Habitual use of ergotamine-containing preparations should be avoided (see 4.4 Special Warnings and Precautions for Use). Ergotamine dependence can develop insidiously when ergotamine tartrate is used for more than two days in a week, even if the total daily or weekly dosage recommendations are observed. Ergotamine dependence can produce a syndrome of daily or almost daily non-migrainous “analgesic-induced” or “rebound headaches”, which are only relieved by ergotamine. An intensifying headache with autonomic disturbances occurs within 24-48 hours of ergotamine withdrawal and may continue for 72 hours or longer. Headache is also a recognised symptom of caffeine withdrawal.

Side-effects seen with Migril are usually due to the ergotamine component of the preparation and are more common if the dosage recommendations are exceeded.

Cardiovascular disorders: Raised blood pressure, hypotension, rapid and weak pulse, palpitations, arrhythmias including bradycardia and tachycardia, precordial pain, coronary infarction, fibrotic thickening of the heart valves (see

4.4 Special Warnings and Precautions for Use).

Cerebrovascular disorders: Cerebral ischaemia and thrombosis.

Disorders of the eye: Blurred vision.

Disorders of the immune system: Hypersensitivity reactions.

Gastrointestinal disorders: Dry mouth, nausea, vomiting, diarrhoea, constipation, , abdominal pain.

General disorders: Sleep disturbances including insomnia, dizziness, drowsiness, vertigo, retroperitoneal and/or pleuropulmonary fibrosis (see 4.4 Special warnings and precautions for use).

Haemopoetic disorders: Blood disorders including agranulcytosis, leucopenia, haemolytic anaemia, thrombocytopenia.

Musculoskeletal: muscle cramps, joint pains.

Neurological disorders: Dysaesthesia, paraesthesiae, formication, tremor, convulsions, headache, extrapyramidal effects.

Peripheral vascular disorders: Doses of ergotamine as small as 2mg have caused signs of arterial insufficiency but this is a very rare occurrence. Intermittent claudication, thrombophlebitis, peripheral arterial thrombosis, coldness and whiteness of the extremities, cyanosis and gangrene. Arterial vasospasm severe enough to threaten the viability of the limbs has been reported after routine therapy but it is more normally to be expected after prolonged overdosage.

Psychiatric disorders: Anxiety, depression, confusion, hallucinations, psychomotor impairment.

Renal and urinary disorders: Urinary retention. Repeated doses of ergotamine have occasionally been associated with renal artery spasm and loss of renal function.

Respiratory disorders: Dyspnoea

Skin and subcutaneous tissue disorders: Localised oedema, pruritus.

The side effects described above have mostly occurred following habitual chronic use exceeding the recommended dose; they may occasionally occur however at the therapeutic dose.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

4.9 Overdose

Acute overdosage: Symptoms: Acute overdosage with an ergotamine-containing preparation is characterised by nausea, vomiting, diarrhoea, extreme thirst, coldness, weakness, tingling and itching of the skin, a rapid and weak pulse, hypotension, shock, confusion, convulsions and unconsciousness. Blood pressure may be difficult to measure; fatalities have been reported. Further symptoms of peripheral vasoconstriction or of cardiovascular disturbances, as seen in chronic ergotamine poisoning, may also occur but be delayed.

Treatment of acute overdosage: If vomiting has not occurred, efforts should be made to clear the stomach contents. Activated charcoal may be used to reduce absorption. General supportive measures should be applied and intravenous vasodilators, such as sodium nitroprusside infusion may be necessary to relieve vasospasm.

Peritoneal dialysis and forced diuresis may help to eliminate ergotamine from the body.

Chronic overdosage: Symptoms: Chronic overdosage with ergotamine-containing preparations usually presents as peripheral ischaemia threatening the viability of the affected limb. 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. Chronic, intractable headache (rebound headache) may occur and is also a major withdrawal symptom following the development of ergotamine dependence. Other adverse effects include confusion and convulsions. On rare occasions symptoms of vasoconstriction of blood vessels in the brain, eye, intestines and kidneys occur.

Treatment of chronic overdosage: Withdraw Migril immediately.

Intravenous vasodilators such as nitroprusside and nitroglycerin may be used to re-establish normal blood flow. Captopril has also been used to reverse the effects of chronic overdosage with ergotamine.

Re-establishment of blood flow may be associated with intense burning sensations in the affected areas but these usually resolve after several weeks.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

None stated

Pharmacokinetic properties

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. Ergotamine has also been shown to be an inhibitor of cytochrome P450 3A catalysed reactions. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known.

5.3    Preclinical safety data

No additional data of relevance.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Maize starch

Liquid glucose Amaranth,

Dioctyl sodium sulphosuccinate or docusate sodium

Magnesium stearate

Lactose

Glucose

Gelatin

Sodium metabisulphate

Industrial methylated spirit or ethanol, purified water and sulphurous acid solution are all used in the manufacturing process but are not detected in the final formulation.

6.2 Incompatibilities

None stated.

6.3    Shelf life

36 months

6.4    Special precautions for storage

Do not store above 25 °C.

Keep the container tightly closed. Store in the original container.

6.5 Nature and contents of container

Amber glass bottles containing 100 tablets with low density polyethylene snap fit closures.

6.6 Special precautions for disposal

None stated

7    MARKETING AUTHORISATION HOLDER

Wockhardt UK Ltd Ash Road North Wrexham LL13 9UF UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 29831/0090

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

26/02/2009

10    DATE OF REVISION OF THE TEXT

23/09/2015