Imigran Injection

Imigran Subject

Each pre-filled syringe contains 6mg of sumatriptan base, as the succinate salt, in an isotonic solution of 0.5ml.

Pre-filled syringes for use in conjunction with an auto injector for subcutaneous injection.

Subcutaneous Injection is indicated for the acute relief of migraine attacks, with or without aura, and for the acute treatment of cluster headache. Imigran should only be used where there is a clear diagnosis of migraine or cluster headache.

Imigran should not be used prophylactically.

It is recommended to start the treatment at the first sign of a migraine headache or associated symptoms such as nausea, vomiting or photophobia. It is equally effective at whatever stage of the attack it is administered. Imigran Injection should be injected subcutaneously using an auto-injector. Patients should be advised to observe strictly the instruction leaflet for the Imigran auto-injector especially regarding the safe disposal of syringes and needles.

Migraine:

Adult: The recommended adult dose of Imigran is a single 6mg subcutaneous injection. Patients who do not respond to this dose should not take a second dose of Imigran for the same attack. Imigran may be taken for subsequent attacks. Patients who respond initially but whose migraine returns may take a further dose at any time in the next 24 hours provided that one hour has elapsed since the first dose.

The maximum dose in 24 hours is two 6mg injections (12mg).

Imigran is recommended as monotherapy for the acute treatment of migraine and should not be given concomitantly with other acute migraine therapies. If a patient fails to respond to a single dose of Imigran there are no reasons, either on theoretical grounds or from limited clinical experience, to withhold products containing aspirin or non-steroidal anti-inflammatory drugs or paracetamol for further treatment of the attack.

Cluster headache:

Adult:

The recommended adult dose is a single 6mg subcutaneous injection for each cluster attack. The maximum dose in 24 hours is two 6mg injections (12mg) with a minimum interval of one hour between the two doses.

Children and Adolescents (under 18 years of age):

Sumatriptan Injection is not recommended for use in children and adolescents as sumatriptan injection has not been studied in these age categories.

Elderly (over 65):

Experience of the use of Imigran 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.

Hypersensitivity to any component of the preparation.

Sumatriptan should not be given to patients who have had myocardial infarction or have ischaemic heart disease, coronary vasospasm (Prinzmetal's angina), peripheral vascular disease or patients who have symptoms or signs consistent with ischaemic heart disease.

Sumatriptan should not be administered to patients with a history of cerebovascular accident (CVA) or transient ischaemic attack (TIA).

Sumatriptan should not be administered to patients with severe hepatic impairment.

The use of sumatriptan in patients with moderate and severe hypertension and mild uncontrolled hypertension is contraindicated.

The concomitant administration of ergotamine or derivatives of ergotamine (including methysergide) or any triptan/5-hydroxytryptamine₁ (5-HT₁) receptor agonist with sumatriptan is contraindicated. (see section 4.5)

Concurrent administration of monoamine oxidase inhibitors and sumatriptan is contraindicated.

Imigran Injection must not be used within two weeks of discontinuation of therapy with monoamine oxidase inhibitors.

Warnings: Imigran should only be used where there is a clear diagnosis of migraine or cluster headache.

Sumatriptan is not indicated for use in the management of hemiplegic, basilar or opthalmoplegic migraine.

The recommended doses of Sumatriptan should not be exceeded.

Imigran Injection should not be given intravenously because of its potential to cause vasospasm. The vasospasm may result in arrhythmias, ischaemic ECG changes or myocardial infarction.

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 risk of certain cerebrovascular events (e.g. 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. Where such symptoms are thought to indicate ischaemic heart disease, no further doses of sumatriptan should be given and appropriate evaluation should be carried out.

Sumatriptan should not be given to patients with risk factors for ischaemic heart disease without prior cardiovascular evaluation (See section 4.3 ). Special consideration should be given to postmenopausal women and males over 40 with these risk factors. These evaluations however, 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.

If the patient experiences symptoms which are severe or persistent or are consistent with angina, further doses should not be taken until appropriate investigations have been carried out to check for the possibility of ischaemic changes.

Precautions: 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 post-marketing reports describing patients with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan. 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.

Sumatriptan should be administered with caution to patients with conditions which may affect significantly the absorption, metabolism or excretion of the drug e.g. impaired hepatic or renal function.

Sumatriptan should be used with caution in patients with a history of seizures or other risk factors which lower the seizure threshold, as seizures have been reported in association with sumatriptan (see section 4.8).

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.

Undesirable effects may be more common during concomitant use of triptans and herbal preparations containing St John's Wort (Hypericum perforatum).

Prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained and treatment should be discontinued. The diagnosis of medication overuse headache (MOH) should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications.

Studies in healthy subjects show that Imigran does not interact with propranolol, flunarizine, pizotifen or alcohol.

Sumatriptan has the potential to interact with monoamine oxidase inhibitors (MAOIs), ergotamine and derivatives of ergotamine (see also section 4.3).

There are limited data on an interaction with preparations containing ergotamine or another triptan/5-HT1 receptor agonist. The increased risk of coronary vasospasm is a theoretical possibility and concomitant administration is contraindicated (see section 4.3).

The period of time that should elapse between the use of sumatriptan and ergotamine-containing preparations or another triptan/5-HT1 receptor agonist is not known. This will also depend on the doses and types of products used. The effects may be additive. It is advised to wait at least 24 hours following the use of ergotamine-containing preparations or another triptan/5-HT1 receptor agonist before administering sumatriptan. Conversely, it is advised to wait at least 6 hours following use of sumatriptan before administering an ergotamine-containing product and at least 24 hours before administering another triptan/5-HT1 receptor agonist.

There have been rare post-marketing reports describing patients with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the use of SSRIs and sumatriptan. Serotonin syndrome has also been reported following concomitant treatment with triptans and SNRIs (see section 4.4).

Post-marketing data from the use of sumatriptan during the first trimester in over 1,000 women are available. Although these data contain insufficient information to draw definitive conclusions, they do not point to an increased risk of congenital defects. Experience with the use of sumatriptan in the second and third trimester is limited.

Evaluation of experimental animal studies does not indicate direct teratogenic effects or harmful effects on peri- and postnatal development. However, embryofoetal viability might be affected in the rabbit (see section 5.3). Administration of sumatriptan should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.

It has been demonstrated that following subcutaneous administration sumatriptan is excreted into breast milk. Infant exposure can be minimised by avoiding breast feeding for 12 hours after treatment, during which time any breast milk expressed should be discarded.

Drowsiness may occur as a result of migraine or its treatment with Sumatriptan. Caution is recommended in patients performing skilled tasks, e.g., driving or operating machinery.

Adverse events are listed below by system organ class and frequency [4]. Frequencies are defined as: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000) and very rare (<1/10,000) including isolated reports.

Clinical Trial Data

Nervous System Disorders

Common: Dizziness, drowsiness, sensory disturbance including paraesthesia and hypoaesthesia.

Vascular Disorders

Common: Transient increases in blood pressure arising soon after treatment. Flushing.

Respiratory, Thoracic and Mediastinal Disorders

Common Dyspnoea.

Gastrointestinal Disorders

Common: Nausea and vomiting occurred in some patients but it is unclear if this is related to sumatriptan or the underlying condition.

Musculoskeletal and Connective Tissue Disorders

Common: Sensations of heaviness (usually transient and may be intense and can affect any part of the body including the chest and throat).

General Disorders and Administration Site Conditions

Very common: Transient injection site pain. Injection site stinging/burning, swelling, erythema, bruising and bleeding have also been reported.

Common: Pain, sensations of heat or cold, pressure or tightness (these events are usually transient and may be intense and can affect any part of the body including the chest and throat).

Feelings of weakness, fatigue (both events are mostly mild to moderate in intensity and transient).

Investigations

Very rare: Minor disturbances in liver function tests have occasionally been observed

Post-Marketing Data

Immune System Disorders

Very rare: Hypersensitivity reactions ranging from cutaneous hypersensitivity to anaphylaxis.

Nervous System Disorders

Very rare: Seizures, 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.

Tremor, dystonia, nystagmus, scotoma.

Eye Disorders

Very rare: Flickering, diplopia, reduced vision. Loss of vision including reports of permanent defects. However, visual disorders may also occur during a migraine attack itself.

Cardiac Disorders

Very rare: Bradycardia, tachycardia, palpitations, cardiac arrhythmias, transient ischaemic ECG changes, coronary artery vasospasm, angina, myocardial infarction (see Contraindications, Warnings and Precautions).

Vascular Disorders

Very rare: Hypotension, Raynaud's phenomenon.

Gastrointestinal Disorders

Very rare: Ischaemic colitis

Musculoskeletal, Connective Tissue and Bone Disorders

Very rare: Neck stiffness.

There have been some reports of overdosage with Imigran Injection. Patients have received single injections of up to 12mg subcutaneously without significant adverse effects. Doses in excess of 16mg subcutaneously were not associated with side effects other than those mentioned.

If overdosage with Imigran 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 Imigran.

Pharmacotherapeutic group: Analgesics: Selective 5-HT₁ receptor agonists.

ATC Code: N02CC01

Sumatriptan has been demonstrated to be a specific and selective 5-hydroxytryptamine (5-HT_1D) receptor agonist with no effect on other 5-HT receptor (5-HT₂-5-HT₇) subtypes. The vascular 5-HT_1D 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 from animal studies suggests that sumatriptan inhibits trigeminal nerve activity. Both these actions (cranial vasoconstriction and inhibition of trigeminal nerve activity) may contribute to the anti-migraine action of sumatriptan in humans.

Sumatriptan remains effective in treating menstrual migraine i.e. migraine without aura that occurs between 3 days prior and up to 5 days post onset of menstruation. Sumatriptan should be taken as soon as possible in an attack.

Clinical response begins 10 to 15 minutes following a 6mg subcutaneous injection.

Because of its route of administration Imigran Injection may be particularly suitable for patients who suffer with nausea and vomiting during an attack.

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 phase half life is approximately two hours.

Plasma protein binding is low (14 to 21%), mean 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 the urine where it is present as a free acid and the glucuronide conjugate. It has no known 5-HT₁ or 5-HT₂ activity. Minor metabolites have not been identified.

In a pilot study no significant differences were found in the pharmacokinetic parameters between the elderly and young healthy volunteers.

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 150 times those seen in man after a 6 mg subcutaneous 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 100 times those in man by the subcutaneous route.

In rabbits embryolethality, without marked teratogenic defects, was seen. The relevance for humans of these findings is unknown.

Sodium Chloride

Water for Injection

None Reported

Two years when stored below 30^oC and protected from light

Imigran Injection should be stored below 30^oC and protected from light.

Treatment pack : 2 pre-filled syringes (in cases) plus an auto-injector, in a plastic tray within a carton.

Refill pack : 2 pre-filled syringes (in cases) in a carton or 6 pre-filled syringes(ie three cases each containing 2 pre-filled syringes).

None stated.

Glaxo Wellcome UK Limited Trading as GlaxoSmithKline UK

Stockley Park West

Uxbridge

Middlesex, UB11 1BT

PL 10949/0113

11/07/1997

30 December 2008

POM