1 Name of Medicine
Sumatriptan.
2 Qualitative and Quantitative Composition
(Sumatriptan) succinate equivalent to 50 mg sumatriptan is the therapeutically active ingredient in Imigran Migraine tablets.
Excipients with known effect.
Sugars (as lactose).3 Pharmaceutical Form
Imigran Migraine brand tablets 50 mg are pink, film-coated, capsule-shaped biconvex tablets engraved '50' on one face and plain on the other face.
4.1 Therapeutic Indications
Imigran Migraine tablets (2 tab pack) are indicated for the acute relief of migraine attacks in patients who have a stable, well-established pattern of symptoms.
4.2 Dose and Method of Administration
Migraine.
It is recommended to start the treatment at the first sign of a migraine headache or associated symptoms such as nausea, vomiting or photophobia. The efficacy of sumatriptan is independent of the duration of the attack when starting treatment. Administration during a migraine aura prior to other symptoms occurring may not prevent the development of a headache.
If a patient does not respond to the first dose of Imigran Migraine, a second dose should not be taken for the same attack. Imigran Migraine may be used for subsequent attacks.
Tablets.
The initial recommended adult dose of oral Imigran Migraine is 50 mg. The tablet should be swallowed whole with water. If symptoms recur, a further dose of 50 mg may be given. Maximum of 100 mg (2 tablets) in 24 hours.4.3 Contraindications
Imigran Migraine should not be used in patients who have:
Hypersensitivity to any component of the preparation (see Section 6.1 List of Excipients);
A history of myocardial infarction;
Peripheral vascular disease or symptoms or signs consistent with ischaemic heart disease;
Prinzmetal's angina/coronary vasospasm;
Uncontrolled hypertension;
Cerebrovascular accident or transient ischaemic attack;
Severe hepatic impairment.
Imigran Migraine should not be used within 24 hours of treatment with an ergotamine-containing or ergot-type medication such as dihydroergotamine or methysergide.
Imigran Migraine should not be given to patients receiving monoamine oxidase inhibitors (MAOIs) or within two weeks of discontinuation of MAOI therapy.
Imigran Migraine should not be administered to patients with hemiplegic, basilar or ophthalmoplegic migraine.
4.4 Special Warnings and Precautions for Use
Imigran Migraine should only be used where there is a clear diagnosis of migraine. However, if a patient does not respond to the first dose, the opportunity should be taken to review the diagnosis before a second dose is given. The recommended doses of Imigran Migraine should not be exceeded.
Drowsiness.
Drowsiness may occur as a result of migraine or its treatment with Imigran Migraine. Caution is recommended in patients performing skilled tasks, e.g. driving or operating machinery.
Use in hepatic or renal impairment.
Imigran Migraine should also be administered with caution to patients with diseases which may affect significantly the metabolism, absorption and excretion of the drug, such as impaired hepatic or renal function. Studies have shown reduced sumatriptan clearance in patients with hepatic impairment. Lower doses should be considered in these patients. If appropriate, the first dose should be given under supervision to these patients.
Hypersensitivity to sulphonamides.
Patients with known hypersensitivity to sulphonamides may exhibit an allergic reaction following administration of Imigran Migraine. 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.
Overuse.
Overuse of acute migraine treatments has been associated with the exacerbation of headache (medication overuse headache, MOH) in susceptible patients. Withdrawal of the treatment may be necessary.
Co-administration with 5-HT1 agonists.
Co-administration of sumatriptan within 24 hours of other 5-HT1 agonists is not recommended due to the potential for vasoconstrictive effects.
Cardiovascular precautions.
It is strongly recommended that sumatriptan not be given to patients in whom risk factors indicate a possibility of unrecognised coronary artery disease (CAD) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischaemic myocardial disease or other significant underlying cardiovascular disease. The risk factors include hypertension, hypercholesterolaemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best and, in extremely rare cases (less than 1 in 10,000), serious cardiac events have occurred in patients without underlying cardiovascular disease. If during the cardiovascular evaluation, the patient's medical history of electrocardiographic investigations reveal findings indicative of, or consistent with coronary artery vasospasm or myocardial ischaemia, sumatriptan should not be administered (see Section 4.3 Contraindications).
Imigran Migraine may cause short lived elevation of blood pressure and peripheral vascular resistance. Sumatriptan should therefore be administered with caution to patients with controlled hypertension. Transient increases in blood pressure and peripheral vascular resistance have been observed in a small proportion of patients.
Serious cardiac events, including some that have been fatal, have occurred within a few hours following the use of Imigran Migraine Tablets. These events are extremely rare (less than 1 in 10,000) and the majority of these case reports were confounded by patients having pre-existing heart disease or risk factors for ischaemic heart disease and may reflect underlying disease and spontaneous events. Under these circumstances the specific contribution of Imigran Migraine cannot be determined. Events reported have included coronary artery vasospasm, transient myocardial ischaemia, myocardial infarction, and cardiac arrhythmias including ventricular tachycardia and ventricular fibrillation. Therefore, Imigran Migraine 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. Significant cardiovascular sequelae have been reported in patients in whom risk factors were not readily identifiable. There is no experience in patients with recent cardiac arrhythmias (especially tachycardias). Until further information is available, the use of Imigran Migraine is not recommended in these patients.
A myocardial infarct has been reported in a 14 year old male following the use of oral sumatriptan; clinical signs occurred within 1 day of drug administration.
Following administration, Imigran Migraine can be associated with transient symptoms, including chest pain and tightness, which may be intense and involve the throat. If symptoms consistent with ischaemic heart disease occur, appropriate investigations should be carried out and further doses should not be given until the results of these investigations are known. Patients should be advised to contact their doctor immediately if they experience symptoms consistent with ischaemic heart disease (see Section 4.3 Contraindications).
Cerebrovascular precautions.
Cerebral haemorrhage, subarachnoid haemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with oral sumatriptan, and some have resulted in fatalities. The relationship of sumatriptan to these events is uncertain. In a number of cases, it appears possible that the cerebrovascular events were primary, sumatriptan having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. Sumatriptan should not be administered if the headache being experienced is atypical of the patient. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g. cerebrovascular accident, transient ischaemia attack).
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.
Imigran Migraine should be used with caution in patients with a history of seizures or other risk factors which lower the seizure threshold.
There is no experience in patients with recent cerebrovascular accidents. Until further information is available, the use of Imigran Migraine is not recommended in these patients (see Section 4.3 Contraindications).
There is no information available on the use of Imigran Migraine in the treatment of ophthalmoplegic migraine.
Other vasospastic events.
Sumatriptan may cause vasospastic reactions other than coronary artery vasospasm. Both peripheral vascular ischaemia and colonic ischaemia with abdominal pain and bloody diarrhoea have been reported.
Use in adolescents (12-17 years).
The efficacy of oral sumatriptan has not been established in placebo-controlled trials carried out in 794 adolescent migraineurs. High placebo responses were found in these studies and there was a lack of statistically significant difference between placebo and oral doses ranging from 25 to 100 mg. The safety profile of oral sumatriptan is similar to that of adults.
Paediatric use.
The safety and effectiveness of sumatriptan in children under the age of 12 years has not been established.
Use in the elderly.
Experience of the use of Imigran Migraine in patients aged over 65 is limited. However, the pharmacokinetics do not differ significantly from a younger population. Until further clinical data are available, the use of Imigran Migraine in patients aged over 65 is not recommended.
Effects on laboratory tests.
No data available.4.5 Interactions with Other Medicines and Other Forms of Interactions
Pharmacodynamic.
Prolonged vasospastic reactions have been reported with ergotamine. As these effects may be additive, concomitant use of ergotamine or ergotamine derivatives and Imigran Migraine should be avoided. Twenty-four hours should elapse before Imigran Migraine is taken following any ergotamine containing preparation. Conversely, ergotamine containing preparations should not be taken until 6 hours have elapsed following Imigran Migraine administration (see Section 4.3 Contraindications).
Pharmacokinetic.
An interaction may occur between sumatriptan and MAOIs and concomitant administration is contraindicated (see Section 4.3 Contraindications). Rarely an interaction may occur between sumatriptan and selective serotonin reuptake inhibitors. There have been rare post marketing reports describing patients with serotonin syndrome (including altered mental status, autonomic instability, neuromuscular abnormalities, weakness, hyper-reflexia and incoordination) following the use of a SSRI. Serotonin syndrome has been reported following concomitant treatment with triptans and serotonin noradrenaline reuptake inhibitors (SNRIs).
If concomitant treatment with sumatriptan and an SSRI/SNRI is clinically warranted, appropriate observation of the patient is advised.
The concomitant administration of any triptan/5-HT1 agonist with sumatriptan is not recommended.
There is no evidence of interactions with propranolol, flunarizine, pizotifen or alcohol.
Although there is no clear evidence, it is possible that an interaction may occur between serotonin 5-HT1 agonists and the herbal remedy St John's Wort (Hypericum perforatum), which may result in an increase in side effects.4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
No data available.
(Category B3)
No obvious teratogenic effects have been seen in rats given oral doses of 500 mg/kg and intravenous doses up to 12.5 mg/kg or in rabbits given oral doses up to 100 mg/kg and intravenous doses up to 8 mg/kg during organogenesis (although it is noted that the number of pregnant rabbits investigated was limited).
Reproduction studies in rats have not revealed any clear evidence of impaired fertility (oral doses up to 500 mg/kg, subcutaneous doses up to 60 mg/kg, given before and during mating) or of impaired post-natal pup development (oral doses up to 1000 mg/kg, subcutaneous doses up to 81 mg/kg, given during the peri and post-natal period). In the rabbit embryotoxicity cannot be ruled out. After oral administration, at doses of 5, 25 and 100 mg/kg on days 8-20 of gestation (severe maternal toxicity at 100 mg/kg) there was evidence of a small, increasing dose-related trend in post-implantation intrauterine death with a similar, and significant trend being recorded after intravenous treatment (0.5 to 8 mg/kg, days 8-20 of gestation).
Term foetuses from Dutch Stride rabbits treated during the period of organogenesis with oral sumatriptan exhibited an increased incidence of cervicothoracic vascular defects and skeletal abnormalities.
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.
Administration of this drug should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.
Sumatriptan is excreted in breast milk in animals. In rats given oral sumatriptan at 1000 mg/kg during the lactation period, 3 dams out of 20 showed total litter loss whilst in another litter, only 9/15 survived to the end of nursing. It has been demonstrated that following subcutaneous administration sumatriptan is excreted into breast milk. Infant exposure can be minimised by avoiding breastfeeding for 24 hours after treatment. Caution should be exercised when considering the administration of sumatriptan to a breastfeeding woman.4.7 Effects on Ability to Drive and Use Machines
No studies on the effects on the ability to drive and use machines have been performed. Drowsiness may occur as a result of migraine or its treatment with sumatriptan. This may influence the ability to drive and to operate machinery.
4.8 Adverse Effects (Undesirable Effects)
The most common side effects associated with treatment with Imigran Migraine are:
Pain, sensations of tingling, heat or cold, heaviness, pressure or tightness. These are usually transient and may be intense and can affect any part of the body including the chest and throat.
Flushing, dizziness and feelings of weakness. These are mostly mild to moderate in intensity and transient.
Fatigue, drowsiness, sensory disturbance including paraesthesia and hypoaesthesia have been reported.
Nausea and vomiting occurred in some patients but the relationship to Imigran Migraine is not clear.
Transient increases in blood pressure arising soon after treatment have been recorded.
Dyspnoea.
Serious coronary events have been reported (see Section 4.4 Special Warnings and Precautions for Use). Other cardiovascular adverse reactions include hypotension, bradycardia, tachycardia and palpitations. Very rarely (less than 1 in 10,000) Raynaud's phenomenon, angina and ischaemic colitis have been reported.
There have been rare (less than 1 in 1,000) reports of seizures following migraine attacks treated with 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.
Patients treated with Imigran Migraine very rarely (less than 1 in 10,000) 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 reactions ranging from cutaneous hypersensitivity (e.g. rash, urticaria, pruritus or erythema) to, in rare (less than 1 in 10,000) cases, anaphylaxis have been recorded (see Section 4.4 Special Warnings and Precautions for Use).
Minor disturbances of liver function tests have occasionally been observed. There is no evidence that clinically significant abnormalities occurred more frequently than with placebo.
In the clinical trial programme, decreased lymphocyte count post treatment was observed in a number of patients receiving oral Imigran Migraine. This effect was not dose-related and was also observed in patients receiving placebo. The significance of these findings is uncertain.
In the clinical trial programme, a similar profile of clinical adverse events was reported in the adolescent and adult populations taking Imigran Migraine tablets or nasal spray.
Post-marketing data.
In addition to the drug-related adverse reactions reported from clinical trials, the following serious spontaneous events, reported to be possibly, probably or almost certainly caused use of oral sumatriptan in patients less than 18 years of age have been identified.
Cardiovascular.
Myocardial infarction.
Cerebrovascular.
Cerebellar infarction.
Neurology.
Seizures, tremor and dystonia.
Non-site specific.
Anaphylaxis.
Skin.
Urticaria, rash.
General disorders.
"Pain trauma activated" and "Pain inflammation activated" - frequency not known.
See Table 1.
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.4.9 Overdose
Single doses up to 400 mg with Imigran Migraine tablets orally were not associated with side effects other than those mentioned. There is no experience of doses greater than these.
If overdosage with Imigran Migraine 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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action.
Sumatriptan has been demonstrated to be a specific vascular 5-hydroxytryptamine-1 (5HT1) receptor agonist with no effect at other 5HT receptor (5HT2-5HT7) subtypes. The vascular 5HT1 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 trials.
Clinical studies conducted in the adult population.
Table 2 demonstrates 2 and 4 hour efficacy results in two placebo-controlled studies of sumatriptan tablets in 332 adult migraineurs experiencing moderate or severe pain.
Specific studies involving asthmatic patients have not been conducted, however a few asthmatic patients were included in the clinical trials.
5.2 Pharmacokinetic Properties
After oral administration, sumatriptan is rapidly absorbed, 70% of maximum concentration occurring at 45 minutes. After a 100 mg dose the mean maximum plasma concentration is 54 nanogram/mL. Mean absolute oral bioavailability is 14% partly due to pre-systemic metabolism and partly due to incomplete absorption. Oral absorption of sumatriptan is not significantly affected by food.
Imigran Migraine Lactose Free tablets and Imigran Migraine tablets have been established to be bioequivalent in the fasted state. In the fasted state, sumatriptan tmax was, on average, 10-15 minutes earlier for Imigran Migraine Lactose Free relative to Imigran Migraine tablets. Imigran Migraine Lactose Free after a high fat meal resulted in an average 12% increase in AUC(0-∞) and 15% increase in Cmax relative to Imigran Migraine Lactose Free in the fasted state. AUC(0-2) was estimated to be an average of only 5% lower and tmax delayed by only 6.5 minutes for Imigran Migraine Lactose Free in the fed, relative to the fasted state. These variations are not considered to be of clinical significance.
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 the 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 or intranasal sumatriptan do not appear to be significantly affected by migraine attacks.
In a pilot study no significant differences were found in the pharmacokinetic parameters between elderly and young healthy volunteers.
5.3 Preclinical Safety Data
Genotoxicity.
No data available.
Carcinogenicity.
No data available.6 Pharmaceutical Particulars
6.1 List of Excipients
Imigran Migraine tablets 50 mg.
Each tablet contains 50 mg sumatriptan base as the succinate salt.
The tablets also contain: lactose, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, Opadry YS-1-1441-G.
6.2 Incompatibilities
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Tablets.
Store below 30°C.
6.5 Nature and Contents of Container
Imigran Migraine tablets 50 mg are available in packs containing 2 tablets in aluminium foil blisters.
Not all strengths, dose forms, pack sizes, container types are being distributed in Australia.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.
6.7 Physicochemical Properties
The chemical name of sumatriptan is 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methane sulphonamide. The molecular formula of sumatriptan is C14H21N3O2S, the relative molecular mass is 295.4. It takes the form of a white to pale yellow powder.
Chemically, sumatriptan succinate is: 3-[2-(dimethylamino) ethyl]-N-methyl-1H-indole-5-methane sulphonamide, butane-1,4-dioate (1:1). The molecular formula of sumatriptan succinate is C14H21N3O2SC4H6O4, the relative molecular mass is 413.5. It takes the form of a white to off-white powder.
Chemical structure.
CAS number.
103628-48-4.7 Medicine Schedule (Poisons Standard)
Schedule 3: pharmacist only medicine.
Summary Table of Changes
