4.1. Therapeutic indications

Zolmitriptan is indicated for the acute treatment of migraine headache with or without aura.

4.2. Posology and method of administration

Posology:

The recommended dose of Zolmitriptan to treat a migraine attack is 2.5 mg. It is advisable that Zolmitriptan is taken as early as possible after the onset of migraine headache but it is also effective if taken at a later stage.

If symptoms should recur within 24 hours following an initial response, a second dose of zolmitriptan may be taken. If a second dose is required, it should not be taken within 2 hours of the initial dose. If a patient does not respond to the first dose, it is unlikely that a second dose will be of benefit in the same attack.

If a patient does not achieve satisfactory relief with 2.5 mg doses, for subsequent attacks 5 mg doses of Zolmitriptan could be considered. Caution is advised due to an increased incidence of undesirable effects. A controlled clinical study failed to demonstrate superiority of the 5mg dose over the 2.5 mg dose. Nevertheless a 5mg dose may be of benefit in some patients.

The total daily intake should not exceed 10 mg. Not more than 2 doses of Zolmitriptan should be taken in any 24 hour period.

Zolmitriptan is not indicated for prophylaxis of migraine.

Special populations:

Patients aged over 65 years

Safety and efficacy of Zolmitriptan in individuals aged over 65 years have not been established.

Hepatic impairment

Patients with mild or moderate hepatic impairment require no dose adjustment, however for patients with severe hepatic impairment, a maximum dose of 5mg in 24 hours is recommended.

Renal impairment

No dosage adjustment required in patients with a creatinine clearance of more than 15ml/min (see sections 4.3 and 5.2).

Paediatric population

Children (under 12 years of age)

Safety and efficacy of zolmitriptan tablets in paediatric patients have not been evaluated. Use of Zolmitriptan in children is therefore not recommended.

Adolescents (12 - 17 years of age)

The efficacy of zolmitriptan tablets was not demonstrated in a placebo controlled clinical trial for patients aged 12 -17 years. Use of Zolmitriptan tablets in adolescents is therefore not recommended.

Method of administration:

The tablet need not be taken with liquid; Zolmitriptan orodispersible tablets rapidly dissolve when placed on the tongue and are swallowed with the patient's saliva. Zolmitriptan orodispersible tablets can be used in situations in which liquids are not available. This formulation may also be beneficial for patients who suffer from nausea and are unable to drink during a migraine attack, or for patients who do not like swallowing conventional tablets. However, a delay in the absorption of zolmitriptan from orodispersible tablets can occur which may delay the onset of action.

4.3. Contraindications

Zolmitriptan is contraindicated in patients with:

• Hypersensitivity to zolmitriptan or to any of the excipients listed in section 6.1,

• Moderate or severe hypertension, and mild uncontrolled hypertension.

• A history of myocardial infarction or ischaemic heart disease.

• Patients with symptoms or signs consistent with ischaemic heart disease.

• Coronary vasospasm/Prinzmetal's angina.

• Peripheral vascular disease

• A history of cerebrovascular accident (CVA) or transient ischaemic attack (TIA).

• Concomitant administration of zolmitriptan with ergotamine or ergotamine derivatives (including methysergide) or other 5-HT1 receptor agonists (e.g. sumatriptan, naratriptan).

• Creatinine clearance lower than 15 ml/min.

4.4. Special warnings and precautions for use

Zolmitriptan should only be used where a clear diagnosis of migraine has been established. 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. Zolmitriptan is not indicated for use in hemiplegic, basilar or ophthalmoplegic migraine. Cerebral haemorrhage, subarachnoid haemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with 5-HT1B/1D agonists. It should be noted that migraineurs may be at risk of certain cerebrovascular events.

Zolmitriptan should not be given to patients with symptomatic Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathways.

In very rare cases, as with other 5-HT1B/1D agonists, coronary vasospasm, angina pectoris and myocardial infarction have been reported. Zolmitriptan should not be given to patients with risk factors for ischaemic heart disease (e.g. smoking, hypertension, hyperlipidaemia, diabetes mellitus, heredity) 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.

As with other 5-HT1B/1D agonists, heaviness, pressure or tightness over the precordium (see section 4.8) have been reported after the administration of zolmitriptan. If chest pain or symptoms consistent with ischaemic heart disease occur, no further doses of zolmitriptan should be taken until after appropriate medical evaluation has been carried out.As with other 5-HT1B/1D agonists transient increases in systemic blood pressure have been reported in patients with and without a history of hypertension; very rarely these increases in blood pressure have been associated with significant clinical events. The dose recommendation for zolmitriptan should not be exceeded.

As with other 5-HT1B/1D agonists, there have been rare reports of anaphylaxis/anaphylactoid reactions in patients receiving zolmitriptan.

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 should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications.

Serotonin syndrome

Concomitant administration of Zolmitriptan and buprenorphine/opioids may result in serotonin syndrome, a potentially life-threatening condition (see section 4.5).

If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.

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

Zolmitriptan, when administered as conventional oral tablets, if taken during the aura, has not been demonstrated to prevent the migraine headache and therefore Zolmitriptan should be taken during the headache phase of migraine.

Zolmitriptan contains aspartame, and sodium

Aspartame is hydrolysed in the gastrointestinal tract when orally ingested. One of the major hydrolysis products is phenylalanine.

This medicine contains less than 1 mmol sodium (23 mg) per orodispersible tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Interaction studies were performed with caffeine, ergotamine, dihydroergotamine, paracetamol, metoclopramide, pizotifen, fluoxetine, rifampicin and propranolol and no clinically relevant differences in the pharmacokinetics of zolmitriptan or its active metabolite were observed.

Data from healthy subjects suggest there are no pharmacokinetic or clinically significant interactions between zolmitriptan and ergotamine, however, the increased risk of coronary vasospasm is a theoretical possibility, and concomitant administration is contraindicated. It is advised to wait at least 24 hours following the use of ergotamine containing preparations before administering zolmitriptan. Conversely it is advised to wait at least six hours following use of zolmitriptan before administering any ergotamine preparation (see section 4.3).

Following administration of moclobemide, a specific MAO-A inhibitor, there was a small increase (26%) in AUC for zolmitriptan and a 3-fold increase in AUC of the active metabolite. Therefore, a maximum intake of 5 mg Zolmitriptan in 24 hours is recommended in patients taking an MAO-A inhibitor. The medicinal products should not be used together if doses of moclobemide higher than 150 mg b.i.d. are administered.

Following the administration of cimetidine, a general P450 inhibitor, the half life of zolmitriptan was increased by 44% and the AUC increased by 48%. In addition the half life and AUC of the active N-desmethylated metabolite (183C91) were doubled. A maximum dose of 5 mg Zolmitriptan in 24 hours is recommended in patients taking cimetidine. Based on the overall interaction profile, an interaction with inhibitors of the cytochrome P450 isoenzyme CYP1A2 cannot be excluded. Therefore, the same dosage reduction is recommended with compounds of this type, such as fluvoxamine and the quinolone antibiotics (e.g. ciprofloxacin).

Selegiline (a MAO-B inhibitor) and fluoxetine (a selective serotonin reuptake inhibitor, SSRI) did not result in any pharmacokinetic interaction with zolmitriptan. However, there have been isolated reports describing patients with symptoms compatible with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the use of selective serotonin reuptake inhibitors (SSRIs), or serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans (see section 4.4).

Zolmitriptan should be used cautiously when co-administered with:

• Buprenorphine/opioids as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (see section 4.4).

As with other 5-HT1B/1D receptor agonists, zolmitriptan could delay the absorption of other medicinal products.

Concomitant administration of other 5-HT1B/1D agonists within 24 hours of zolmitriptan treatment should be avoided. Similarly, administration of zolmitriptan within 24 hours of the use of other 5-HT1B/1D agonists should be avoided.

4.6. Fertility, pregnancy and lactation

Pregnancy

The safety of this medical product for use in human pregnancy has not been established. Evaluation of experimental animals studies does not indicate direct teratogenic effects. However, some findings in embryotoxicity studies suggested impaired embryo viability. Administration of zolmitriptan should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.

Breast-feeding

Studies have shown that zolmitriptan passes into the milk of lactating animals. No data exist for passage of zolmitriptan into human breast milk. Therefore, caution should be exercised when administering Zolmitriptan to women who are breastfeeding. Infant exposure should be minimised by avoiding breast feeding for 24 hours after treatment.

Fertility

There are no data indicating that zolmitriptan may affect fertility.

4.7. Effects on ability to drive and use machines

Zolmitriptan has no or negligible influence on the ability to drive and use machines.

There was no significant impairment of performance of psychomotor tests with doses up to 20 mg zolmitriptan in a small group of healthy individuals. Caution is recommended in patients performing skilled tasks (e.g. driving or operating machinery) as drowsiness and other symptoms may occur during a migraine attack.

4.8. Undesirable effects

Possible undesirable reactions are typically transient, tend to occur within 4 hours of dosing, are no more frequent following repeated dosing and resolve spontaneously without additional treatment.

The following definitions apply to the incidence of the undesirable effects: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System organ class

Frequency

Undesirable effect

Immune system disorders

Rare

Hypersensitivity reactions including urticaria, angioedema and anaphylactic reaction

Nervous system disorders

Common

Abnormalities or disturbances of sensation

Dizziness

Headache

Hyperaesthesia

Paraesthesia

Somnolence

Warm sensation

Cardiac disorders

Common

Palpitations

Uncommon

Tachycardia

Very rare

Angina pectoris

Coronary Vasospasm

Myocardial Infarction

Vascular disorders

Uncommon

Transient increases in systemic blood pressure

Slight increases in blood pressure

Gastrointestinal disorders

Common

Abdominal Pain

Dry mouth

Nausea

Vomiting

Dysphagia

Very rare

Gastrointestinal infarction or necrosis

Gastrointestinal ischaemic events which may present as bloody diarrhoea or abdominal pain

Ischaemic colitis

Splenic Infarction

Musculoskeletal and connective tissue disorders

Common

Muscle weakness

Myalgia

Renal and urinary

disorders

Uncommon

Polyuria

Increased Urinary frequency

Very rare

Urinary Urgency

General disorders and administration site conditions

Common

Asthenia

Heaviness, tightness, pain or pressure in throat, neck limbs or chest

Certain symptoms may be part of the migraine attack itself.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Volunteers receiving single oral doses of 50mg commonly experienced sedation.

The elimination half-life of zolmitriptan is 2.5- 3 hours, (see section 5.2) and therefore monitoring of patients after overdose with Zolmitriptan should continue for at least 15 hours or while symptoms or signs persist.

There is no specific antidote to zolmitriptan. In cases of severe intoxication, intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system.

It is unknown what effect haemodialysis or peritoneal dialysis has on the serum concentrations of zolmitriptan.