Sumatriptan

Sumatriptan 3 mg/0.5 ml solution for injection in pre-filled pen

Each pre-filled pen contains sumatriptan succinate equivalent to 3 mg of sumatriptan.

Excipient with known effect:

Each 0.5ml of solution for injection contains 1.63 mg of sodium.

For the full list of excipients, see section 6.1.

Solution for injection in pre-filled pen

Clear, colourless to pale yellow solution free from visible particles.

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

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

Sumatriptan should not be used prophylactically.

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.

Posology

Adults

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.

The recommended adult dose of Sumatriptan is a single 6 mg subcutaneous injection (which can be provided with Sumatriptan 6 mg/0.5 ml pre-filled pen). However, some patients might benefit from a lower dose of 3 mg, which can be administered with Sumatriptan 3 mg/0.5 ml.

Patients who do not respond to this dose should not take a second dose of Sumatriptan for the same attack. A second dose may be taken for a subsequent attack at any time in the next 24 hours provided that one hour has elapsed since the first dose.

If a patient fails to respond to a single dose of this medicinal product there are no reasons, either on theoretical grounds or from limited clinical experience, to withhold products containing acetylsalicylic acid or non-steroidal anti-inflammatory drugs or paracetamol for further treatment of the attack.

Patients who respond initially but whose migraine returns may take a second dose at any time in the next 24 hours provided that one hour has elapsed since the first dose.

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).

Paediatric population (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.

Method of administration

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 (for example on the upper arm or thigh), straight up at a right angle (90°). Sumatriptan should not be injected into areas where the skin is tender, bruised, red, or hard. By pressing and immediately releasing the blue button a first click sound is heard indicating that the dose is started. The pen must be kept pressed onto the skin until a second click is heard. This indicates that the dose is completed. Now the pen can be lifted off the skin. The safety needle cover of the pen will automatically extend to cover the needle. The inspection window will be blue confirming that the injection is complete. Patients should be advised to strictly observe the instruction leaflet for this medicinal product especially regarding the use of the pre-filled pen.

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).

Warnings:

Sumatriptan 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 opthalmoplegic migraine.

The recommended doses of this medicinal product should not be exceeded.

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).

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.

Sumatriptan should be administered with caution to patients with mild controlled hypertension, since transient increases in blood pressure and peripheral vascular resistance have been observed in a small proportion of patients (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 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 (see section 4.5).

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.

This medicinal product contains less than 1 mmol sodium (23mg) per dose (3mg) that is to say essentially 'sodium free'.

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.

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.

Fertility

There are no data on the effects of sumatriptan on fertility in humans.

Sumatriptan has minor to moderate influence on the ability to drive and use machines.

Drowsiness may occur as a result of migraine or its treatment with sumatriptan. This may influence the ability to drive and to operate machinery.

No studies on the effects on the ability to drive and use machines have been performed.

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), 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.

Not known: Dysphagia.

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

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).

Not known: Pain trauma activated.

Not known: Pain inflammation activated.

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.

Investigations

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

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.

There have been some reports of overdosage with sumatriptan.

Patients have received single injections of up to 12 mg 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.

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.

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

Absorption

Following subcutaneous injection, sumatriptan has a high mean bioavailability (96%) with peak serum concentrations occurring in 25 minutes. Following sumatriptan 3 mg subcutaneous injection, peak serum concentration reaches in 13 minutes and average peak serum concentration is 42 ng/ml. The elimination phase half-life is approximately 97.6 min.

Distribution

Plasma protein binding is low (14 to 21%), mean volume of distribution is 170 litres. Mean total plasma clearance is approximately 1160 ml/min and the mean renal plasma clearance is approximately 260 ml/min.

Non-renal clearance accounts for about 80% of the total clearance.

Sumatriptan shows a dose proportional increase in C_max and AUC in the dose range of 1 to 16 mg upon subcutaneous administration. Mean volume of distribution is 177.5 litres. Mean plasma clearance is approximately 1197 ml/min and renal clearance is approximately 264 ml/min.

Elimination

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.

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 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.

Sodium chloride

Water for injection

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

2 years

This medicinal product does not require any special temperature storage conditions. Store in the original package in order to protect from light.

Prefilled pen, composed of 1 ml type I (Ph.Eur) glass barrel with attached 27 gauge needle & ½ inch length, black chlorobutyl plunger stopper, packed in a PVC (polyvinyl chloride) blister with a PET (polyethylene terephthalate) peelable lidding film.

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

Not all package sizes may be marketed.

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

Sun Pharmaceutical Industries Europe B.V.

Polarisavenue 87

2132 JH Hoofddorp

The Netherlands

PL 31750/0161

06/03/2020

11/01/2021