4.1. Therapeutic indications

Zolmitriptan Grünenthal Nasal Spray is indicated for the acute treatment of migraine with or without aura in adults and adolescents aged 12 years and older.

4.2. Posology and method of administration

Posology

The recommended dose of Zolmitriptan Grünenthal Nasal Spray to treat a migraine attack is 5 mg.

Zolmitriptan Grünenthal Nasal Spray is administered as a single dose into one nostril. Zolmitriptan Grünenthal Nasal Spray provides particularly rapid onset of relief of migraine with the first signs of efficacy apparent within 15 minutes of dosing.

Zolmitriptan Grünenthal Nasal Spray provides an alternative non–oral formulation of zolmitriptan to that of Zomig oral tablets and orodispersible tablets. This formulation may also be beneficial where a non–oral route of treatment is either needed or preferred.

If symptoms persist or return within 24 hours a second dose has been shown to be effective. If a second dose is required, it should not be taken within 2 hours of the initial dose.

Zolmitriptan Grünenthal Nasal Spray is effective whenever the nasal spray is administered during a migraine attack; although it is advisable that Zolmitriptan Grünenthal Nasal Spray is taken as early as possible after the onset of migraine headache.

In the event of recurrent attacks, it is recommended that the total intake of Zolmitriptan Grünenthal Nasal Spray in a 24 hour period should not exceed 10 mg.

Zolmitriptan Grünenthal Nasal Spray is not indicated for prophylaxis of migraine.

Paediatric population (under 12 years of age)

The efficacy of Zolmitriptan Grünenthal Nasal Spray in children aged 11 years or under has not yet been established. Currently available data are described in sections 4.8 and 5.1 but no recommendation on a posology can be made. No data are available in children below 6 years. Use of Zolmitriptan Grünenthal Nasal Spray in children is therefore not recommended.

Use in adolescents (from the age of 12 years)

The recommended dose of Zolmitriptan Grünenthal Nasal to treat a migraine attack is 5 mg. It is advisable that Zolmitriptan Grünenthal Nasal is taken as early as possible after the onset of migraine headache but it is also effective if taken at a later stage.

Elderly

The safety and efficacy of Zolmitriptan Grünenthal Nasal Spray in individuals aged over 65 years have not been systematically evaluated.

Hepatic Impairment

The effect of hepatic disease on the pharmacokinetics of zolmitriptan nasal spray has not been evaluated. However, for patients with moderate or severe hepatic impairment metabolism after oral dosing is reduced and a maximum dose of 5 mg oral zolmitriptan in 24 hours is recommended (see Section 5.2).

Renal Impairment

No dosage adjustment required (see Section 5.2).

Method of administration

For nasal inhalation.

4.3. Contraindications

Zolmitriptan Grünenthal Nasal Spray is contraindicated in patients with:

• Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1

• Uncontrolled hypertension

• Ischaemic heart disease

• Coronary vasospasm/Prinzmetal's angina

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

• Concomitant administration of Zolmitriptan Grünenthal Nasal Spray with ergotamine or ergotamine derivatives or other 5-HT1 receptor agonists.

4.4. Special warnings and precautions for use

Zolmitriptan Grünenthal Nasal Spray should only be used where a clear diagnosis of migraine has been established. Care should be taken to exclude other potentially serious neurological conditions. There are no data on the use of Zolmitriptan Grünenthal Nasal Spray in hemiplegic or basilar migraine. Migraineurs may be at risk of certain cerebrovascular events. Cerebral haemorrhage, subarachnoid haemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with 5HT1B/1D agonists.

Zolmitriptan Grünenthal Nasal Spray 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 5HT1B/1D agonists, coronary vasospasm, angina pectoris and myocardial infarction have been reported. In patients with risk factors for ischaemic heart disease, cardiovascular evaluation prior to commencement of treatment with this class of compounds, including Zolmitriptan Grünenthal Nasal Spray, is recommended (see Section 4.3). 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 5HT1B/1D agonists, atypical sensations over the precordium (see Section 4.8) have been reported after the administration of Zolmitriptan Grünenthal Nasal Spray.

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 5HT 1B/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.

As with other 5HT 1B/1D agonists, there have been rare reports of anaphylaxis/anaphylactoid reactions in patients receiving Zolmitriptan Grünenthal Nasal Spray.

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 has been reported with combined use of triptans and serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Serotonin Syndrome is a potentially life-threatening condition and diagnosis is likely when (in presence of a serotonergic agent) one of the following is observed:

• Spontaneous clonus

• Inducible or ocular clonus with agitation or diaphoresis,

• Tremor and hyperreflexia

• Hypertonia and body temperature >38°C and inducible or ocular clonus.

Careful observation of the patient is advised if concomitant treatment with Zolmitriptan and an SSRI or SNRI is necessary, particularly during treatment initiation and dosage increases (see Section 4.5).

Withdrawal of the serotonergic drugs usually brings about a rapid improvement. Treatment depends on the type and severity of the symptoms.

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

From studies using oral zolmitriptan tablets, there is no evidence that concomitant use of migraine prophylactic medications has any effect on the efficacy or unwanted effects of Zolmitriptan Grünenthal Nasal Spray (for example beta-blockers, oral dihydroergotamine, pizotifen).

The pharmacokinetics and tolerability of Zomig oral tablets were unaffected by acute symptomatic treatments such as paracetamol, metoclopramide and ergotamine.

Concomitant administration of other 5HT1B/1D agonists within 24 hours of Zolmitriptan Grünenthal Nasal Spray treatment should be avoided.

Data from healthy subjects suggest that there are no pharmacokinetic or clinically significant interactions between Zolmitriptan Grünenthal Nasal Spray and ergotamine, however, the increased risk of coronary vasospasm is a theoretical possibility. Therefore, it is advised to wait at least 24 hours following the use of ergotamine containing preparations before administering Zolmitriptan Grünenthal Nasal Spray. Conversely, it is advised to wait at least six hours following use of Zolmitriptan Grünenthal Nasal Spray before administering any ergotamine preparation (see Section 4.3).

Following co-administration of moclobemide, a specific MAO-A inhibitor, and Zomig oral tablets, 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 Grünenthal Nasal Spray in 24 hours is recommended in patients taking an MAO-A inhibitor.

Following the co-administration of cimetidine, a general P450 inhibitor, and Zomig oral tablets, 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 metabolite (N-desmethylzolmitriptan) were doubled. A maximum dose of 5 mg Zolmitriptan Grünenthal Nasal Spray 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).

Fluoxetine did not affect the pharmacokinetic parameters of zolmitriptan in a study using oral zolmitriptan tablets. Therapeutic doses of the specific serotonin reuptake inhibitors, fluoxetine, sertraline, paroxetine and citalopram do not inhibit CYP1A2. However, Serotonin Syndrome has been reported during combined use of triptans, and SSRIs (e.g. fluoxetine, paroxetine, sertraline) and SNRIs (e.g. venlafaxine, duloxetine) (see section 4.4).

As with other 5HT1b/1d agonists, there is the potential for dynamic interactions with the herbal remedy St John's wort (Hypericum perforatum) which may result in an increase in undesirable effects.

The absorption and pharmacokinetics of Zolmitriptan is unaltered by prior administration of the sympathomimetic vasoconstrictor, xylometazoline.

4.6. Fertility, pregnancy and lactation

Pregnancy

Zolmitriptan Grünenthal Nasal Spray should be used in pregnancy only if the benefits to the mother justify potential risk to the foetus. There are no studies in pregnant women, but there is no evidence of teratogenicity in animal studies (see Section 5.3).

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 Grünenthal Nasal Spray to women who are breast-feeding.

4.7. Effects on ability to drive and use machines

There was no significant impairment of performance of psychomotor tests with doses up to 20 mg oral Zomig. Zolmitriptan Grünenthal Nasal Spray has no or negligible influence on the ability to drive and use machines. However, it should be taken into account that somnolence may occur.

4.8. Undesirable effects

Summary of the safety profile

Zolmitriptan is well tolerated. Adverse reactions are typically mild/moderate, transient, not serious and resolve spontaneously without additional treatment.

Possible adverse reactions tend to occur within 4 hours of dosing and are no more frequent following repeated dosing.

Tabulated list of adverse reactions

Adverse reactions are classified according to frequency and system organ class. Frequency categories are defined according to the following convention: Very common (≥1/10); Common (≥1/100 to < 1/10); Uncommon (≥1/1,000 to < 1/100); Rare (≥1/10,000 to < 1/1,000); Very rare (<1/10,000). The following undesirable effects have been reported following administration with zolmitriptan:

System Organ Class

Frequency

Undesirable Effect

Immune system disorders

Rare

Anaphylaxis/Anaphylactoid Reactions;

Hypersensitivity reactions.

Nervous system disorder

Very common

Taste disturbance.

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.

Respiratory , thoracic and mediastinal disorders

Common

Epistaxis;

Discomfort of nasal cavity.

Gastrointestinal disorders

Common

Abdominal pain;

Dry mouth;

Nausea;

Vomiting;

Dysphagia.

Very rare

Bloody diarrhoea;

Gastrointestinal infarction or necrosis;

Gastrointestinal ischaemic events;

Ischaemic colitis;

Splenic infarction.

Skin and subcutaneous tissue disorders

Rare

Angioedema;

Urticaria.

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.

Paediatric population

Data from multicentre, double-blind, randomised placebo-controlled, cross-over clinical trial involving 168 paediatric subjects (6 to 11 years) with migraine headache as well as post-marketing data support the adverse event profile. The type and severity of adverse reactions were similar to those in adults. However, no statements can be made regarding the frequencies. No new safety issues have been identified from the completed paediatric trial for the age group investigated.

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

4.9. Overdose

Symptoms

There has been no experience of overdose with zolmitriptan nasal spray. Volunteers receiving single oral doses of 50 mg commonly experienced sedation.

Management

The elimination half-life of zolmitriptan following intranasal administration is 3 hours, (see Section 5.2) and therefore monitoring of patients after overdose with Zolmitriptan Grünenthal Nasal Spray 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.