SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Sumatriptan 6 mg/0.5 ml Solution for Injection

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-filled pen contains 6 mg of sumatriptan, as sumatriptan succinate.

Excipient with known effect:

Sodium 1.3 mg

For the full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Solution for Injection

Clear, colourless to pale yellow solution.

The pH is between 4.2 and 5.3. The osmolarity is between 260 to 340 mOsmols.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

4.2    Posology and method of administration

Sumatriptan Injection should not be used prophylactically.

Sumatriptan should be injected subcutaneously using a pre-filled pen. After removal of the needle shield, the open end of the pre-filled pen is to be placed on the injection site, straight up at a right angle (90°). By pressing the blue button a first click sound is heard. The button must be held down for a count to ten while holding the pen. The safety needle cover of the pen will automatically extend to cover the needle. The inspection window will be blue confirming the injection is complete. Patients should be advised to observe strictly the instruction leaflet for the Sumatriptan Injection especially regarding the use of the pre-filled pen.

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.

Adults

Migraine and cluster headache:

It is recommended to start the treatment at the first sign of a migraine headache, cluster headache or associated symptoms such as nausea, vomiting or photophobia. It is equally effective at whatever stage of the attack it is administered.

Migraine:

The recommended adult dose of Sumatriptan is a single 6 mg subcutaneous injection. Patients who do not respond to this dose should not take a second dose of Sumatriptan for the same attack. Sumatriptan 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 6 mg injections (12 mg).

Sumatriptan is recommended as monotherapy for the acute treatment of a migraine attack and should not be given concomitantly with other acute migraine therapies like ergotamine or derivatives or ergotamine (including methysergide) (see Section 4.3). If a patient fails to respond to a single dose of Sumatriptan there are no reasons, either on theoretical grounds or from limited clinical experience, to withhold products containing acetylsalicylic acid or nonsteroidal anti-inflammatory drugs or paracetamol for further treatment of the attack.

Cluster headache:

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

Children and Adolescents (under 18 years of age):

Sumatriptan 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 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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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 is contraindicated (See section 4.5).

Concurrent administration of monoamine oxidase inhibitors and sumatriptan is contraindicated.

Sumatriptan must not be used within two weeks of discontinuation of therapy with monoamine oxidase inhibitors (see section 4.5).

4.4 Special warnings and precautions for use

Warnings:

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

The recommended doses of Sumatriptan should not be exceeded.

This medicinal product contains less than 1 mmol sodium (23mg) per dose, i.e. ‘essential sodium free’.

Sumatriptan 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, including those patients who are heavy smokers or users of nicotine substitution therapies, 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 (see section 4.8).

• 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.

4.5 Interaction with other medicinal products and other forms of interaction

There is no evidence of interactions with propranolol, flunarizine, pizotifen or alcohol.

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.

An interaction may occur between sumatriptan and MAOIs and concomitant administration is contra-indicated (see Section 4.3).

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). There may also be a risk of serotonergic syndrome if sumatriptan is used concomitantly with lithium.

4.6 Fertility, pregnancy and lactation

Pregnancy

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.

Breastfeeding

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.

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    Undesirable effects

Adverse events are listed below by system organ class and frequency. 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, ), not known (cannot be estimated from the available data). Some of the symptoms reported as undesirable effects may be associated symptoms of migraine.

Immune System Disorders

Not known: Hypersensitivity reactions ranging from cutaneous hypersensitivity (such as urticaria) to anaphylaxis.

Psychiatric disorders

Not known: Anxiety.

Nervous System Disorders

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

Not known: 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

Not known: 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

Not known: Bradycardia, tachycardia, palpitations, cardiac arrhythmias, transient ischaemic ECG changes, coronary artery vasospasm, myocardial infarction, angina (see section 4.3 and 4.4).

Vascular disorders

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

Not known: Hypotension, Raynaud’s phenomenon.

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.

Not known: Ischaemic colitis.

Not known: Diarrhoea.

Skin and subcutaneous tissue disorders

Not known: Hyperhidrosis.

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). Myalgia.

Not known: Neck stiffness.

Not known: Arthralgia.

General Disorders and Administration Site Conditions

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.

The most common side effects associated with treatment with sumatriptan administered subcutaneously are:

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.

Although direct comparisons are not available, flushing, paraesthesia and sensations of heat, pressure, and heaviness may be more common after sumatriptan injection.

Conversely, nausea, vomiting and fatigue appear to be less frequent with subcutaneous administration of sumatriptan injection than with tablets.

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, website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

There have been some reports of overdosage with Sumatriptan.

Patients have received single injections of up to 12mg subcutaneously without significant adverse effects.

Doses in excess of 16 mg subcutaneously were not associated with side effects other than those mentioned.

If overdosage with Sumatriptan 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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: analgesics; antimigraine preparations; selective serotonin (5HT1) agonists, ATC Code: N02CC01.

Sumatriptan has been demonstrated to be a specific and selective 5-hydroxytryptamine (5-HT1D) receptor agonist with no effect on other 5-HT receptor (5-HT2-5-HT7) subtypes. The vascular 5-HT1D 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 6 mg subcutaneous injection.

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

5.2    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 phase halflife 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.

5.3    Preclinical safety data

Sumatriptan was devoid of genotoxic and carcinogenic activity in in-vitro systems and animal studies.

In a rat fertility study a reduction of insemination was seen at exposures sufficiently in excess of the maximum human exposure.

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

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sodium Chloride Water for Injection

6.2    Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3    Shelf life

3 years

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5    Nature and contents of container

Prefilled pen, composed of 1 ml type I (Ph.Eur) glass barrel with attached 27 gauge needle & 54 inch length, black chlorobutyl plunger stopper.

Package size: 1, 2 or 6 pre-filled pens.

Not all package sizes may be marketed.

6.6    Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Sun Pharmaceutical Industries Europe B.V.

Polarisavenue 87 2132 JH Hoofddorp The Netherlands

MARKETING AUTHORISATION NUMBER(S)

PL 31750/0012

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22/01/2010 / 01/04/2012

DATE OF REVISION OF THE TEXT

12/01/2015