IMIGRAN™ Tablets
Sumatriptan (as the succinate salt) Tablets
Qualitative and Quantitative Composition
Imigran 50 Tablets: pink, capsule shaped, film-coated tablets, engraved with '50' on one side and 'Imigran' on the other. Each contains 50mg of sumatriptan base, as the succinate salt, to be taken orally. The 50mg tablets may also be marked with '50' on one side and blank on the other.
Imigran 100 Tablets: white, film-coated, biconvex, capsule shaped tablets of nominal dimensions 12 x 6.5mm, engraved 'Glaxo' on one side and 'Imigran' on the other. Each contains 100mg sumatriptan base, as the succinate salt, to be taken orally. The 100mg tablets may also be marked with '100' on one side and blank on the other.
Pharmaceutical Form
Tablets.
Clinical Particulars
Therapeutic Indications
Imigran Tablets are indicated for the acute relief of migraine attacks with or without aura.
Posology and Method of Administration
Imigran Tablets should not be used prophylactically.
It is advisable that Imigran be given as early as possible after the onset of a migraine headache. It is equally effective at whatever stage of the attack it is administered. The recommended adult dose of oral Imigran is a single 50mg tablet. Some patients may require 100mg.
If a patient does not respond to the first dose of Imigran, a second dose should not be taken for the same attack. Imigran may be taken for subsequent attacks.
If the patient has responded to the first dose, but the symptoms recur a second dose may be given in the next 24 hours, provided that not more than 300mg is taken in any 24 hour period.
The tablets should be swallowed whole with water.
Children
The safety and effectiveness of sumatriptan in children has not yet been established.
Elderly (over 65)
Experience of the use of sumatriptan in patients aged over 65 years is limited. The pharmacokinetics do not differ significantly from a younger population, but until further clinical data are available, the use of sumatriptan in patients aged over 65 years is not recommended.
Contra-indications
Hypersensitivity to any component of the preparation.
Sumatriptan should not be given to patients who have had a myocardial infarction or have ischaemic heart disease (IHD), Prinzmetal's angina/coronary vasospasm, peripheral vascular disease or patients who have symptoms or signs consistent with IHD.
Sumatriptan should not be administered to patients with a history of cerebrovascular accident (CVA) or transient ischaemic attack (TIA).
The use of sumatriptan in patients with uncontrolled hypertension is contraindicated.
Sumatriptan should not be administered to patients with severe hepatic impairment.
The concomitant use of ergotamine or derivatives of ergotamine (including methysergide) is contraindicated (see Interaction with Other Medicaments and Other Forms of Interaction).
Concurrent administration of monoamine oxidase inhibitors (MAOIs) and sumatriptan is contraindicated. Sumatriptan must not be used within two weeks of discontinuation of therapy with monoamine oxidase inhibitors.
Special Warnings and Special Precautions for Use
Imigran Tablets should only be used where there is a clear diagnosis of migraine.
Sumatriptan is not indicated for use in the management of hemiplegic, basilar or ophthalmoplegic migraine.
As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. It should be noted that migraineurs may be at increased risk of certain cerebrovascular events (eg. cerebrovascular accident, transient ischaemic attack).
Following administration, sumatriptan can be associated with transient symptoms including chest pain and tightness which may be intense and involve the throat (see Undesirable Effects). Where such symptoms are thought to indicate ischaemic heart disease appropriate evaluation should be carried out.
Sumatriptan should not be given to patients in whom unrecognised cardiac disease is likely without a prior evaluation for underlying cardiovascular disease. Such patients include postmenopausal women, males over 40 and patients with risk factors for coronary artery disease. However, these evaluations may not identify every patient who has cardiac disease and, in very rare cases, serious cardiac events have occurred in patients without underlying cardiovascular disease.
Sumatriptan should be administered with caution to patients with controlled hypertension as transient increases in blood pressure and peripheral vascular resistance have been observed in a small proportion of patients.
There have been rare postmarketing reports describing patients with weakness, hyper-reflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised (see Interaction with Other Medicaments and Other Forms of Interaction).
Sumatriptan should be administered with caution to patients with conditions which may affect significantly the absorption, metabolism or excretion of the drug, eg. impaired hepatic or renal function.
Sumatriptan should be used with caution in patients with a history of epilepsy or structural brain lesions which lower their convulsion threshold.
Patients with known hypersensitivity to sulphonamides may exhibit an allergic reaction following administration of sumatriptan. Reactions may range from cutaneous hypersensitivity to anaphylaxis. Evidence of cross sensitivity is limited, however, caution should be exercised before using sumatriptan in these patients.
The recommended dose of Imigran should not be exceeded.
Pregnancy and Lactation
No teratogenic effects have been seen in rats or rabbits and sumatriptan had no effect on the post-natal development of rats.
When administered to pregnant rabbits throughout the period of organogenesis sumatriptan has occasionally caused embryolethality at doses which were sufficiently high to produce maternal toxicity.
Caution should be exercised by considering the expected benefit to the mother against possible risk to the foetus.
Post-marketing data from multiple prospective pregnancy registries have documented the pregnancy outcomes in over 1,000 women exposed to sumatriptan. Although there is insufficient information to draw definitive conclusions, the findings have not detected an increase in the frequency of birth defects nor a consistent pattern of birth defects, amongst women exposed to sumatriptan compared with the general population.
It has been demonstrated that following subcutaneous administration sumatriptan is excreted into breast milk. Infant exposure can be minimised by avoiding breast feeding for 24 hours after treatment.
Effects on Ability to Drive and Use Machines
Drowsiness may occur as a result of migraine or its treatment with sumatriptan.
Caution is recommended in patients performing skilled tasks, eg. driving or operating machinery.
Interaction with other medicaments and other forms of interaction
There is no evidence of interactions with propanolol, flunarizine, pizotifen or alcohol.
Prolonged vasospastic reactions have been reported with ergotamine. As these effects may be additive, 24 hours should elapse before sumatriptan can be taken following any ergotamine containing preparation.
Conversely, ergotamine containing preparations should not be taken until 6 hours have elapsed following sumatriptan administration.
An interaction may occur between sumatriptan and MAOIs and concomitant administration is contraindicated (see Contraindications). Rarely an interaction may occur between sumatriptan and SSRIs (see Special Warnings and Special Precautions for Use).
Undesirable Effects
General
The following symptoms are usually transient and may be intense and can affect any part of the body including the chest and throat.
- Pain, sensations of tingling, heat, heaviness, pressure or tightness.
The following symptoms are mostly mild to moderate in intensity and transient:
- Flushing, dizziness and feelings of weakness.
- Fatigue and drowsiness have been reported.
Although direct comparisons are not available, nausea, vomiting and fatigue appear to be less frequent with subcutaneous administration of Imigran Injection than with tablets.
Conversely, flushing and sensations of tingling, heat, pressure and heaviness may be more common after Imigran Injection.
Cardiovascular
- Hypotension
- Bradycardia
- Tachycardia
- Palpitations
Transient increases in blood pressure arising soon after treatment have been recorded.
Cardiac arrhythmias, transient ischaemic ECG changes, coronary artery vasospasm, and myocardial infarction have been reported rarely (see Contraindications and Warnings and Precautions).
There have been rare reports of Raynaud's phenomenon and ischaemic colitis.
Gastrointestinal
Nausea and vomiting occurred in some patients but the relationship to sumatriptan is not clear.
CNS
There have been rare reports of seizures, following use of sumatriptan. Although some have occurred in patients with either a history of seizures or concurrent conditions predisposing to seizures there are also reports in patients where no such predisposing factors are apparent.
Eye
Patients treated with Imigran rarely exhibit visual disorders like flickering and diplopia. Additionally cases of nystagmus, scotoma and reduced vision have been observed. Very rarely loss of vision has occurred, which is usually transient. However, visual disorders may also occur during a migraine attack itself.
Hypersensitivity/Skin
Hypersensitivity reactions ranging from cutaneous hypersensitivity to rare cases of anaphylaxis.
Laboratory values
Minor disturbances in liver function tests have occasionally been observed.
Overdose
Patients have received single injections of up to 12mg subcutaneously without significant adverse effects. Doses in excess of 16mg subcutaneously and 400mg orally were not associated with side effects other than those mentioned.
If overdosage occurs, the patient should be monitored for at least ten hours and standard supportive treatment applied as required.
It is unknown what effect haemodialysis or peritoneal dialysis has on the plasma concentrations of sumatriptan.
Pharmacological Properties
Pharmacodynamic Properties
Sumatriptan has been demonstrated to be a selective vascular 5-hydroxytryptamine-1-(5HT1D) receptor agonist with no effect at other 5HT receptor (5HT2 -5HT7) subtypes. The vascular 5HT1D receptor is found predominantly in cranial blood vessels and mediates vasoconstriction.
In animals sumatriptan selectively constricts the carotid arterial circulation, but does not alter cerebral blood flow. The carotid arterial circulation supplies blood to the extracranial and intracranial tissues such as the meninges and dilatation and/or oedema formation in these vessels is thought to be the underlying mechanism of migraine in man. In addition, experimental evidence suggests that sumatriptan inhibits trigeminal nerve activity. Both these actions may contribute to the anti-migraine action of sumatriptan in humans.
Clinical response begins 10-15 minutes following a 6mg subcutaneous injection, 15 minutes following a 20mg dose given by intra-nasal administration and around 30 minutes following a 100mg oral dose.
Although the recommended dose of oral Imigran is 50mg, migraine attacks vary in severity both within and between patients. Doses of 25-100mg have shown greater efficacy than placebo in clinical trials, but 25mg is statistically significantly less effective than 50 and 100mg.
Pharmacokinetic Properties
Following subcutaneous injection sumatriptan has a high mean bioavailability (96%) with peak serum concentrations occurring in 25 minutes. Average peak serum concentration after a 6mg subcutaneous dose is 72ng/mL. The elimination half life is approximately 2 hours. After oral administration, sumatriptan is rapidly absorbed, 70% of maximum concentration occurring at 45 minutes. After 100mg dose the mean maximum plasma concentration is 54ng/mL. Mean absolute oral bioavailability is 14% partly due to presystemic metabolism and partly due to incomplete absorption. Plasma protein binding is low (14-21%), the mean total volume of distribution is 170 litres. Mean total plasma clearance is approximately 1160mL/min and the mean renal plasma clearance is approximately 260mL/min. Non-renal clearance accounts for about 80% of the total clearance. Sumatriptan is eliminated primarily by oxidative metabolism mediated by monoamine oxidase A. The major metabolite, the indole acetic acid analogue of sumatriptan is mainly excreted in urine, where it is present as a free acid and the glucuronide conjugate. It has no known 5HT1 or 5HT2 activity. Minor metabolites have not been identified. The pharmacokinetics of oral sumatriptan do not appear to be significantly affected by migraine attacks.
Preclinical Safety Data
Sumatriptan was devoid of genotoxic and carcinogenic activity in in-vitro systems and animal studies.
In a rat fertility study oral doses of sumatriptan resulting in plasma levels approximately 200 times those seen in man after a 100mg oral dose were associated with a reduction in the success of insemination.
This effect did not occur during a subcutaneous study where maximum plasma levels achieved approximately 150 times those in man by the oral route.
Pharmaceutical Particulars
Incompatibilities
None reported.
Shelf Life
Imigran 50 36 months
Imigran 100 48 months
Special Precautions for Storage
Imigran Tablets should be stored below 30°C.
Package Quantities
Imigran Tablets are packed in double foil blister packs in cartons. Each carton also contains a Patient Information Leaflet.
Imigran 50 4 × 50mg tablets
Imigran 100 2 × 100mg tablets
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