SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

‘Zomig Rapimelt’5 mg Orodispersible Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each orodispersible tablets contains 5 mg of zolmitriptan.

For the full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Orodispersible tablets.

4.    CLINICAL PARTICULARS

4.1. Therapeutic indications

‘Zomig Rapimelt’ is indicated for the acute treatment of migraine with or without aura.

4.2 Posology and method of administration

Posology

The recommended dose of Zomig Rapimelt to treat a migraine attack is

2.5 mg.

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

If a patient does not achieve satisfactory relief with 2.5 mg doses, subsequent attacks can be treated with 5 mg doses of Zomig Rapimelt.

Zolmitriptan is equally effective whenever the tablets are taken during a migraine attack; although it is advisable that Zomig Rapimelt 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 Zomig Rapimelt in a 24 hour period should not exceed 10 mg.

Zomig Rapimelt is not indicated for prophylaxis of migraine.

Special populations

Paediatric population Children below the age of 12 years

The safety and efficacy of Zomig Rapimelt in children aged 0-12 years has not yet been established. No data are available. Use of Zomig Rapimelt in children is therefore not recommended.

Adolescents (12 - 17 years of age)

The efficacy of Zomig Rapimelt was not demonstrated in a placebo controlled clinical trial for patients aged 12 to 17 years. Use of Zomig Rapimelt in adolescents is therefore not recommended.

Older people

The safety and efficacy of Zomig Rapimelt in individuals aged over 65 years have not been established.

Patients with hepatic impairment

Metabolism is reduced in patients with hepatic impairment (see section 5.2). Therefore for patients with moderate or severe hepatic impairment a maximum dose of 5 mg in 24 hours is recommended.

Patients with renal impairment

No dosage adjustment required (see section 5.2).

Method of administration

To be taken by oral administration. Zomig Rapimelt rapidly dissolves when placed on the tongue and is swallowed with the patient’s saliva. A drink of water is not required when taking Zomig Rapimelt. Zomig Rapimelt can be taken when water is not available thus allowing early administration of treatment for a migraine attack. 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.

•    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 Zomig with ergotamine or ergotamine derivatives or other 5-HT₁ receptor agonists.

Zomig Rapimelt 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 Zomig Rapimelt in hemiplegic or basilar migraine. Migraneurs may be at risk of certain cerebrovascular events. Cerebral haemorrhage, subarachnoid haemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with 5HT_1B/1D agonists.

Zomig Rapimelt 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 5HT_1B/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 Zomig Rapimelt, 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 5HT_1B/1D agonists, atypical sensations 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 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 Zomig.

Patients with phenylketonuria should be informed that Zomig Rapimelt contains phenylalanine (a component of aspartame). Each 5 mg orally dispersible tablet contains 5.62 mg of phenylalanine.

Excessive use of an acute anti-migraine medicinal product may lead to an increased frequency of headache, potentially requiring withdrawal of treatment.

Serotonin Syndrome has been reported with combined use of triptans, and Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin Norepinephrine Reuptake Inhibitors (SNRIs). Serotonin Syndrome is a potentially life-threatening condition, and it may include signs and symptoms such as: mental status changes (e.g. agitation, hallucinations, coma), autonomic instability, (e.g. tachycardia, labile blood-pressure, hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). Careful observation of the patient is advised, if concomitant treatment with Zomig Rapimelt and an SSRI or SNRI is clinically warranted, particularly during treatment initiation and dosage increases (see section 4.5).

There is no evidence that concomitant use of migraine prophylactic medications has any effect on the efficacy or unwanted effects of Zomig Rapimelt (for example beta blockers, oral dihydroergotamine, pizotifen).

The pharmacokinetics and tolerability of Zomig Rapimelt, when administered as the conventional tablet, were unaffected by acute symptomatic treatments such as paracetamol, metoclopramide and ergotamine. Concomitant administration of other 5HT_1B/1D agonists within 24 hours of Zomig Rapimelt treatment should be avoided.

Data from healthy subjects suggest there are no pharmacokinetic or clinically significant interactions between Zomig Rapimelt 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 Zomig Rapimelt. Conversely it is advised to wait at least 6 hours following use of Zomig Rapimelt 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 Zomig Rapimelt in 24 hours is recommended in patients taking an MAO-A inhibitor.

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 Zomig

Rapimelt 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 does not affect the pharmacokinetic parameters of zolmitriptan. 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 5HTi_b/i_d 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

Zomig Rapimelt 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 Zomig Rapimelt 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 zolmitriptan. Zomig 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 safety profile

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

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

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

Symptoms

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

Management

The elimination half-life of zolmitriptan is 2.5 to 3 hours, (see section 5.2) and therefore monitoring of patients after overdose with Zomig Rapimelt 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Selective serotonin (5HTi) agonists. ATC code: N02CC03

Mechanism of action

In pre-clinical studies, zolmitriptan has been demonstrated to be a selective agonist for the vascular human recombinant 5HT_1B and 5HT_1D receptor subtypes. Zolmitriptan is a high affinity 5HT_1B/1D receptor agonist with modest affinity for 5HTi_A receptors. Zolmitriptan has no significant affinity (as measured by radioligand binding assays) or pharmacological activity at 5HT₂-, 5HT₃-, 5HT₄-, alphai-, alpha₂-, or betai-, adrenergic; Hi-, H₂-, histaminic; muscarinic; dopaminergic^ or dopaminergic₂ receptors. The 5HT_1d receptor is predominately located presynaptically at both the peripheral and central synapses of the trigeminal nerve and preclinical studies have shown that zolmitriptan is able to act at both these sites.

Clinical efficacy and safety

One controlled clinical trial in 696 adolescents with migraine failed to demonstrate superiority of zolmitriptan tablets at doses of 2.5 mg, 5 mg and 10 mg over placebo. Efficacy was not demonstrated.

Following oral administration of Zomig conventional tablets zolmitriptan is rapidly and well absorbed (at least 64%) in man. The mean absolute bioavailability of the parent compound is approximately 40%. There is an active metabolite (183C91, the N-desmethyl metabolite) which is also a 5HT _IB/iD agonist and is 2 to 6 times as potent, in animal models, as zolmitriptan.

In healthy subjects, when given as a single dose, zolmitriptan and its active metabolite 183C91, display dose-proportional AUC and C_max over the dose range 2.5 to 50 mg. Absorption is rapid with 75% of C_max achieved within 1 hour and plasma concentrations are sustained subsequently for 4 to 6 hours. Zolmitriptan absorption is unaffected by the presence of food. There is no evidence of accumulation on multiple dosing of zolmitriptan.

Zolmitriptan is eliminated largely by hepatic biotransformation followed by urinary excretion of the metabolites. There are three major metabolites: the indole acetic acid, (the major metabolite in plasma and urine), the N-oxide and N-desmethyl analogues. The N-desmethylated metabolite (183C91) is active whilst the others are not. Plasma concentrations of 183C91 are approximately half those of the parent drug, hence it would therefore be expected to contribute to the therapeutic action of Zomig Rapimelt. Over 60% of a single oral dose is excreted in the urine (mainly as the indole acetic acid metabolite) and about 30% in faeces, mainly as unchanged parent compound.

A study to evaluate the effect of liver disease on the pharmacokinetics of zolmitriptan showed that the AUC and C_max were increased by 94% and 50% respectively in patients with moderate liver disease and by 226% and 47% in patients with severe liver disease compared with healthy volunteers. Exposure to the metabolites, including the active metabolite, was decreased. For the 183C91 metabolite, AUC and C_max were reduced by 33% and 44% in patients with moderate liver disease and by 82% and 90% in patients with severe liver disease.

The plasma half-life (0/2) of zolmitriptan was 4.7 hours in healthy volunteers, 7.3 hours in patients with moderate liver disease and 12 hours in those with severe liver disease. The corresponding t/ values for the 183C91 metabolite were 5.7 hours, 7.5 hours and 7.8 hours respectively.

Following intravenous administration, the mean total plasma clearance is approximately 10 ml/min/kg, of which one third is renal clearance. Renal clearance is greater than glomerular filtration rate suggesting renal tubular secretion. The volume of distribution following intravenous administration is 2.4 L/kg. Plasma protein binding is low (approximately 25%). The mean elimination half-life of zolmitriptan is 2.5 to 3 hours. The half-lives of its metabolites are similar, suggesting their elimination is formation-rate limited.

In a small group of healthy individuals there was no pharmacokinetic interaction with ergotamine. Concomitant administration of zolmitriptan with ergotamine/caffeine was well tolerated and did not result in any increase in adverse events or blood pressure changes as compared with zolmitriptan alone (see section 4.5).

Following the administration of rifampicin, no clinically relevant differences in the pharmacokinetics of zolmitriptan or its active metabolite were observed.

Selegiline, an MAO-B inhibitor, and fluoxetine (a selective serotonin reuptake inhibitor; SSRI) had no effect on the pharmacokinetic parameters of zolmitriptan (see section 4.4).

Zomig Rapimelt was demonstrated to be bioequivalent with the conventional tablet in terms of AUC and C_max for zolmitriptan and its active metabolite 183C91. Clinical pharmacology data show that the t_max for zolmitriptan can be later for the orally dispersible tablet (range 0.6 to 5h, median 3h) compared to the conventional tablet (range 0.5 to 3h, median 1.5h). The t_max for the active metabolite was similar for both formulations (median 3h).

Special populations Renal impairment

Renal clearance of zolmitriptan and all its metabolites is reduced (7 to 8 fold) in patients with moderate to severe renal impairment compared to healthy subjects, although the AUC of the parent compound and the active metabolite were only slightly higher (16 and 35% respectively) with a 1 hour increase in half-life to 3 to 3.5 hours. These parameters are within the ranges seen in healthy volunteers.

Older people

The pharmacokinetics of zolmitriptan in healthy elderly subjects were similar to those in healthy young volunteers.

5.3 Preclinical safety data

An oral teratology study of zolmitriptan has been conducted. At the maximum tolerated doses, 1200 mg/kg/day (AUC 605 pg/ml.h : approx. 3700 x AUC of the human maximum recommended daily intake of 15 mg) and 30 mg/kg/day (AUC 4.9 pg/ml.h : approx. 30 x AUC of the human maximum recommended daily intake of 15 mg) in rats and rabbits, respectively, no signs of teratogenicity were apparent.

Five genotoxicity tests have been performed. It was concluded that ‘Zomig Rapimelt’ is not likely to pose any genetic risk in humans.

Carcinogenicity studies in rats and mice were conducted at the highest feasible doses and gave no suggestion of tumorogenicity.

Reproductive studies in male and female rats, at dose levels limited by toxicity, revealed no effect on fertility.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

The following excipients are contained in each Zomig Rapimelt as indicated:

Aspartame (E951)

Citric Acid Anhydrous Silica Colloidal Anhydrous Crospovidone Magnesium stearate Mannitol (E421)

Microcrystalline Cellulose Orange Flavour SN027512 Sodium Hydrogen Carbonate

6.2 Incompatibilities

Not applicable.

Shelf-life

2 years

6.4. Special precautions for storage

Do not store above 30^oC.

6.5. Nature and contents of container

PVC aluminium/aluminium blister pack of 6 tablets (1 strip of 6 tablets).

6.6 Special precautions for disposal and other handling

The blister pack should be peeled open as shown on the foil (tablets should not be pushed through the foil). The Zomig Rapimelt tablet should be placed on the tongue, where it will dissolve and be swallowed with the saliva.

7. MARKETING AUTHORISATION HOLDER

AstraZeneca UK Ltd 600 Capability Green Luton LU1 3LU United Kingdom

8. MARKETING AUTHORISATION NUMBER

PL 17901/0230

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21^st September 2004 Date of latest renewal: 18^th June 2008

DATE OF REVISION OF THE TEXT

10/06/2015