This information is intended for use by health professionals

1. Name of the medicinal product

Zolmitriptan 5 mg Orodispersible Tablets

2. Qualitative and quantitative composition

5 mg

One orodispersible tablet contains 5 mg zolmitriptan

Excipient: Each orodispersible tablet contains 4.0 mg aspartame.

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Orodispersible tablet

5 mg

White to off-white, round tablets debossed 'F11' on one side and plain on other side (diameter approximately: 8 mm).

4. Clinical particulars
4.1 Therapeutic indications

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

Zolmitriptan Orodispersible Tablets is not indicated for prophylaxis of migraine.

4.2 Posology and method of administration

The recommended dose of zolmitriptan to treat a migraine attack is 2.5 mg. It is advisable that Zolmitriptan Orodispersible Tablets 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 of migraine should recur within 24 hours following an initial response, a second dose 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 side effects. A controlled clinical study failed to demonstrate superiority of the 5 mg dose over the 2.5 mg dose.

Nevertheless, a 5 mg dose may be beneficial for some patients. In the event of recurrent attacks, it is recommended that the total daily intake of zolmitriptan in a 24-hour period should not exceed 10 mg.

Special populations

Patients with hepatic impairment

Metabolism is reduced in patients with hepatic impairment (See Section 5.2 Pharmacokinetic properties). Patients with mild hepatic impairment require no dose adjustment, however 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 in patients with a creatinine clearance of more than 15 ml/min. (5.2).

Interactions requiring dose adjustment (see Section 4.5 Interactions with other medicinal products and other forms of interactions).

For patients taking MAO-A inhibitors, a maximum dose of 5 mg in 24 hours is recommended.

A maximum dose of 5 mg zolmitriptan in 24 hours is recommended in patients taking cimetidine.

A maximum dose of 5 mg zolmitriptan in 24 hours is recommended in patients taking specific inhibitors of CYP 1A2 such as fluvoxamine and the quinolones (eg ciprofloxacin).

Use in Children (under 12 years of age)

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

Use in Adolescents (12 - 17 years of age)

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

Older people

The efficacy of zolmitriptan in individuals aged over 65 years have not been evaluated. Use of Zolmitriptan Orodispersible Tablets in the elderly is therefore not recommended.

Method of administration

The tablet need not be taken with liquid; the tablet dissolves on the tongue and is swallowed with saliva. This formulation can be used in situations in which liquids are not available, or to avoid the nausea and vomiting that may accompany the ingestion of tablets with liquids. The blister pack should be peeled open as shown on the foil (tablets should not be pushed through the foil). Zolmitriptan Orodispersible Tablets should be placed on the tongue, where it will dissolve and be swallowed with the saliva.

4.3 Contraindications

Zolmitriptan tablets 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.

• Ischaemic heart disease

• Coronary vasospasm/Prinzmetal's angina

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

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

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. There is no data on the use of zolmitriptan in hemiplegic or basilar migraine. Stroke and other cerebrovascular events have been reported in patients treated with 5HT1B/1D agonists. It should be noted that migraneurs 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 5HT1B/1D agonists, coronary vasospasm, angina pectoris and myocardial infarction have been reported. In patients with risk factors for ischaemic heart disease (e.g. smoking, hypertension, hyperlipidaemia, diabetes mellitus, heredity) cardiovascular evaluation prior to commencement of treatment with this class of compounds, including Zolmitriptan Orodispersible Tablets, is recommended (see Section 4.3 Contraindications). 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 5HT1B/1D receptor agonists, atypical sensations over the precordium such as heaviness, pressure or tightness over the precordium (See Section 4.8 Undesirable effects) 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 5HT1B/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.

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

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

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, in-coordination), and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). Careful observation of the patient is advised, if concomitant treatment with Zolmitriptan and an SSRI or SNRI is clinically warranted, particularly during treatment initiation and dosage increases (see section 4.5).

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.

Zolmitriptan Orodispersible Tablets contains aspartame (E951). Aspartame contains a source of phenylalanine and may be harmful for people with phenylketonuria.

4.5 Interaction with other medicinal products and other forms of interaction

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

The pharmacokinetics and tolerability of zolmitriptan, when administered as the conventional tablet, were unaffected by acute symptomatic treatments such as paracetamol, metoclopramide and ergotamine.

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

Data from healthy subjects suggests 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 an ergotamine containing product (see section 4.3 Contraindications).

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 a MAO-A inhibitor. The drugs 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 specific inhibitors of CYP 1A2 cannot be excluded. Therefore, the same dosage reduction is recommended with compounds of this type, such as fluvoxamine and the quinolones (eg ciprofloxacin).

Selegiline (a MAO-B inhibitor) and fluoxetine (an SSRI) did not result in any pharmacokinetic interaction with zolmitriptan. Therapeutic doses of the specific serotonin reuptake inhibitors, fluoxetine, sertraline, paroxetine and citalopram do not inhibit CYP1A2. However, there have been reports describing patients with symptoms compatible with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following combined use of selective serotonin reuptake inhibitors (SSRIs) (e.g. fluoxetine, paroxetine, sertraline) or serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g. venlafaxine, duloxetine) with triptans (see section 4.4 Special warnings and precautions for use).

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

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.

4.6 Fertility, pregnancy and lactation

Pregnancy: The safety of this medicinal 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 during pregnancy should only be considered if the expected benefit to the mother justifies potential risk to the foetus (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 to women who are breast-feeding.

4.7 Effects on ability to drive and use machines

Zolmitriptan Orodispersible Tablets 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. However, it should be taken into account that somnolence may occur.

4.8 Undesirable effects

Zolmitriptan Orodispersible Tablets is well tolerated. Possible undesirable effects are typically mild/ moderate, transient and not serious. Symptoms tend to occur within four hours of dosing, and 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 ( ≥ 1/1,000 to < 1/100), rare ( ≥ 1/10,000 to < 1/1,000), very rare ( < 1/10,000).

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

The following undesirable effects have been reported following administration of zolmitriptan:

System Organ Class

Frequency

Undesirable Effect

Immune system disorders

Rare

Anaphylaxis/ Anaphylactoid reactions; Hypersensitivity reactions;

Nervous system disorders

Common

Abnormalities or disturbances or sensation;

Dizziness;

Headache;

Hyperaesthesia;

Paraesthesia;

Somnolence;

Warm sensation

Cardiac disorders

Common

Palpitations

Uncommon

Tachycardia

Very rare

Myocardial infarction;

Angina pectoris;

Coronary vasospasm

Vascular disorders

Uncommon

Transient increases in systemic blood pressure

Gastrointestinal disorders

Common

Abdominal pain;

Nausea;

Vomiting;

Dry mouth

Dysphagia

Very rare

Bloody diarrhoea;

Gastrointestinal infarction or necrosis;

Gastrointestinal ischaemic events;

Ischaemic colitis;

Splenic infarction

Skin and subcutaneous tissue disorders

Rare

Angiodema;

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 disorders

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

4.9 Overdose

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

The elimination half-life of zolmitriptan tablets is 2.5 to 3 hours, (see Section 5.2) and therefore monitoring of patients after overdose with Zolmitriptan Orodispersible Tablets 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 (5HT1) agonists. ATC Classification: N02CC03

In preclinical studies, zolmitriptan has been demonstrated to be a selective agonist for the vascular human recombinant 5-HTIB/1D receptor subtypes. Zolmitriptan is a high affinity human recombinant 5-HTIB receptor agonist, with modest affinity for 5-HTIA receptors. Zolmitriptan has no significant affinity (as measured by radioligand binding assays) or pharmacological activity at other 5-HT receptor subtypes (5-HT2, 5-HT3, 5-HT4) or adrenergic, histaminic, muscarinic or dopaminergic receptors. The 5HT1D 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 of these sites.

In animal models, the administration of zolmitriptan causes vasoconstriction in the carotid arterial circulation. In addition, experimental studies in animals suggest that zolmitriptan inhibits central and peripheral trigeminal nerve activity with inhibition of neuropeptide release (calcitonin gene related peptide (CGRP), vasoactive intestinal peptide (VIP) and Substance P).

In clinical studies with zolmtriptan conventional tablets the onset of efficacy is apparent from one hour, with increasing efficacy being noted between 2 and 4 hours on headache and other symptoms of migraine such as nausea, photophobia and phonophobia.

Zolmitriptan, when administered as conventional oral tablets, is consistently effective in migraine with or without aura and in menstrually associated migraine. Zolmitriptan, when administered as conventional oral tablets, if taken during the aura, has not been demonstrated to prevent the migraine headache and therefore Zolmitriptan Orodispersible Tablets should be taken during the headache phase of migraine.

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.

5.2 Pharmacokinetic properties

Following oral administration of Zolmitriptan conventional tablets, zolmitriptan is rapidly and well absorbed (at least 64%) after oral administration to man. The mean absolute bioavailability of the parent compound is approximately 40%. There is an active metabolite (the N-desmethyl metabolite) which is also a 5HT1B/1D receptor 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, the N-desmethyl metabolite, display dose-proportional AUC and Cmax over the dose range 2.5 to 50 mg. Absorption of zolmitriptan is rapid. In healthy volunteers, 75% of Cmax is achieved within 1 hour, and after this the concentration of zolmitriptan in plasma is maintained at approximately this level until 4-6 hours after dosing.

Zolmitriptan absorption is unaffected by the presence of food. There was 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 is active whilst the others are not. Plasma concentrations of the N-desmethylated metabolite are approximately half those of the parent drug, hence it would therefore be expected to contribute to the therapeutic action of zolmitriptan'. 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.

Plasma concentration of zolmitriptan and its metabolites are lower in the first 4 hours after drug administration during a migraine compared with a migraine-free period, suggesting delayed absorption consistent with the reduced rate of gastric emptying observed during a migraine attack.

A study to evaluate the effect of liver disease on the pharmacokinetics of zolmitriptan showed that the AUC and Cmax 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 Cmax 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 (t½) 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 t½ values for the 183C91 metabolite were 5.7 hours, 7.5 hours and 7.8 hours respectively.

The metabolism of zolmitriptan is reduced in hepatic impairment in proportion to the extent of the impairment.

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 of zolmitriptan and the N-desmethyl metabolite 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.

Renal clearance of zolmitriptan and all its metabolites is reduced (7-8 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.

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 for precautions regarding ergotamine use).

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 for warnings and precautions regarding concomitant use with SSRIs).

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

Zolmitriptan orodispersible tablets were demonstrated to be bioequivalent with the conventional tablet in terms of AUC and Cmax for zolmitriptan and its active metabolite 183C91. Clinical pharmacology data show that the tmax 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 tmax for the active metabolite was similar for both formulations (median 3h).

5.3 Preclinical safety data

Effects in non-clinical studies for single and repeat dose toxicity studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

An oral teratology study of zolmitriptan has been conducted. At the maximum tolerated doses, 1200 mg/kg/day (AUC 605 μg/ml.h : approx. 3700 x AUC of the human maximum recommended daily intake of 15 mg) and 30 mg/kg/day (AUC 4.9 μg/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.

As with other 5HT1B/1D receptor agonists, zolmitriptan binds to melanin.

6. Pharmaceutical particulars
6.1 List of excipients

5mg

Mannitol (E421)

Cellulose microcrystalline

Crospovidone Type A

Aspartame E951

Silica colloidal anhydrous

Talc

Magnesium Stearate

Peppermint Flavour (containing natural flavouring substances and modified food starch E1450)

6.2 Incompatibilities

Not applicable

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

5 mg

Aluminium/Aluminium peelable blisters in cartons containing 2, 3, 4, 5, 6, 12 and 18 orodispersible tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

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

7. Marketing authorisation holder

Glenmark Pharmaceuticals Europe Limited

Laxmi House, 2-B Draycott Avenue,

Kenton, Harrow, Middlesex, HA3 0BU,

United Kingdom

8. Marketing authorisation number(s)

PL 25258/0095

9. Date of first authorisation/renewal of the authorisation

30/01/2012

10. Date of revision of the text

12/05/2016