This information is intended for use by health professionals

1. Name of the medicinal product

Zolmitriptan 5mg Orodispersible Tablets

2. Qualitative and quantitative composition

Each 5mg orodispersible tablet contains 5mg zolmitriptan.

Excipient with known effect:

Each 5mg orodispersible tablet contains 8 mg aspartame.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Orodispersible tablet.

Zolmitriptan 5mg Orodispersible Tablets are white to off white, round, flat faced, bevel edged uncoated tablets, debossed with "Z2" on one side and plain on the other side.

4. Clinical particulars
4.1 Therapeutic indications

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 2.5mg.

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 2.5mg doses, subsequent attacks can be treated with 5mg doses of zolmitriptan.

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

Zolmitriptan is not indicated for prophylaxis of migraine.

Paediatric population (Children below the age of 12 years)

The safety and efficacy of zolmitriptan in children aged 0-12 years has not yet been established. No data are available. Use of Zolmitriptan Orodispersible Tablets 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 to 17 years. Use of zolmitriptan in adolescents is therefore not recommended.

Elderly The safety and efficacy of zolmitriptan in individuals aged over 65 years have not been established. Use of zolmitriptan in older people is therefore not recommended.

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 in patients with a creatinine clearance of more than 15 ml/min. (See section 5.2)

Interactions requiring dose adjustment (see section 4.5)

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

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

Method of administration

To be taken by oral 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 (tablets should not be pushed through the foil).

4.3 Contraindications

• 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.

• Concomitant administration of zolmitriptan with ergotamine, ergotamine derivatives or other 5HT1 receptor agonists

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

4.4 Special warnings and precautions for use

Zolmitriptan 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 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 5HT1B/1D agonists.

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, cardiovascular evaluation prior to commencement of treatment with this class of compounds, including zolmitriptan, 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. 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.

As with other 5HT1B/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 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.

Excipients with known effect

This medicine contains 8.00mg aspartame in each 5mg orodispersible tablet. Aspartame is a source of phenylalanine. It may be harmful in patients with phenylketonuria (PKU), the rare genetic disease in which phenylalanine builds up as the body cannot remove it properly. Neither non-clinical nor clinical data are available to assess aspartame use in infants below 12 weeks of age.

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

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.

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. Therefore, 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).

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 5mg zolmitriptan in 24 hours, is recommended in patients taking a 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 (N-desmethylzolmitriptan) were doubled. A maximum dose of 5mg 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 CYP 1A2 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 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:

Zolmitriptan 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).

Breastfeeding:

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 Orodispersible Tablets 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 20mg zolmitriptan. Zolmitriptan 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), not known (cannot be estimated from the available data).

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 disorder

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.

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.

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 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 tablets is 2.5 to 3 hours, (see section 5.2) and therefore monitoring of patients after overdose with Zolmitriptan 5mg 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 serotonine (5HT1) 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 5HT1B and 5HT1D receptor subtypes. Zolmitriptan is a high affinity 5HT1B/1D receptor agonist with modest affinity for 5HT1A receptors. Zolmitriptan has no significant affinity (as measured by radioligand binding assays) or pharmacological activity at 5HT2-, 5HT3-, 5HT4-, alpha1-, alpha2-, or beta1-, adrenergic; H1-, H2-, histaminic; muscarinic; dopaminergic1, or dopaminergic2 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 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.

5.2 Pharmacokinetic properties

Following oral administration of 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 (N-desmethylzolmitriptan) which is also a 5HT IB/1D 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 N-desmethylzolmitriptan, display dose-proportional AUC and Cmax over the dose range 2.5 to 50 mg. Absorption is rapid with 75% of Cmax 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 is pharmacologically active whilst the others are not. Zolmitriptan is metabolised by CYP1A2, forming N-desmethylzolmitriptan. The active metabolite is then further metabolised through MAO-A enzyme system. 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 orodispersible. 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 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 active metabolite (N-desmethylzomitriptan), 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 N-desmethylzolmitriptan 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).

Zolmitriptan orodispersible was demonstrated to be bioequivalent with the conventional tablet in terms of AUC and Cmax for zolmitriptan and its active metabolite desmethylzolmitriptan. 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).

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.

Elderly

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 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 zolmitriptan 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

Mannitol (E421)

Calcium silicate

Microcrystalline cellulose

Aspartame (E951)

Sodium starch glycolate Type A

Crospovidone Type B

Colloidal anhydrous silica

Magnesium stearate

Orange Cream Flavour (containing e.g. maltodextrin (maize), acacia (E414), ascorbic acid (E300), butylhydroxyanisole (E320))

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

Peelable aluminium/aluminium blisters.

Aluminium/aluminium blister pack.

Pack sizes:

2, 3, 6 or 12 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements

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

7. Marketing authorisation holder

Accord-UK Ltd

(Trading style: Accord)

Whiddon Valley

Barnstaple

Devon

EX32 8NS

8. Marketing authorisation number(s)

0142/1207

9. Date of first authorisation/renewal of the authorisation

28/07/2009

Renewal Approved: 03/07/2013

10. Date of revision of the text

29/10/2021