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1. Zoltzics 2.5 Mg Orodispersible Tablets
2. Zoltzics 2.5 Mg Orodispersible Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Zoltzics 2.5 mg orodispersible tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 2.5 mg orodispersible tablet contains 2.5 mg zolmitriptan For a full list of excipients, see 6.1

3 PHARMACEUTICAL FORM

Orodispersible tablet

White, round, bevel-edged tablets of 6.4 mm, debossed with “2.5” on one side and nothing on the other side

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Zoltzics 2.5 mg orodispersible tablets are indicated for the acute treatment of migraine headache with or without aura.

Zoltzics 2.5 mg orodispersible tablets are not indicated for prophylaxis of migraine.

4.2    Posology and method of administration

Treatment of migraine

Adults

The recommended dose of Zoltzics 2.5 mg orodispersible tablets to treat a migraine attack is 2.5 mg. It is advisable that Zoltzics 2.5 mg orodispersible tablets are taken as early as possible after the onset of migraine headache but they are 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 5mg dose over the 2.5mg dose . Nevertheless, a 5mg dose may be beneficial for some patients.

The total daily intake should not exceed 10 mg. Not more than 2 doses of Zoltzics 2.5 mg orodispersible tablets should be taken in any 24 hour period.

Use in patients aged over 65 years

The safety and efficacy of Zoltzics 2.5 mg orodispersible tablets in individuals aged over 65 years have not been established. Use of Zoltzics 2.5 mg orodispersible tablets in the elderly is therefore not recommended.

Patients with hepatic impairment

Patients with mild or moderate hepatic impairment require no dose adjustment, however for patients with 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 4.3 and Section 5.2)

Interactions requiring dose adjustment (see Section 4.5)

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 also recommended in patients taking Cimetidine, and 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 Zoltzics 2.5 mg orodispersible tablets in paediatric patients have not been evaluated. Use of Zoltzics 2.5 mg orodispersible tablets in children is therefore not recommended.

Adolescents (12 - 17 years of age)

The efficacy of Zoltzics 2.5 mg orodispersible tablets was not demonstrated in a placebo controlled clinical trial for patients aged 12 to 17 years. Use of Zoltzics 2.5 mg orodispersible tablets in adolescents is therefore not recommended.

Method of administration

Oral use.

The Zoltzics 2.5 mg orodispersible tablets should be placed on the tongue. Prior to that, the mouth should be rinsed with some water if available. The tablet need not be taken with liquid; the tablet dissolves on the tongue and is swallowed with saliva.

4.3 Contraindications

Zoltzics 2.5 mg orodispersible tablets is contraindicated in patients with hypersensitivity to zolmitriptan or to any of the excipients.

Zolmitriptan is also contraindicated in moderate or severe hypertension, and mild uncontrolled hypertension

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

This class of compounds (5HT1B/1D receptor agonists), has been associated with coronary vasospasm, as a result, patients with ischaemic heart disease were excluded from clinical trials. Therefore, Zoltzics 2.5 mg orodispersible tablets must not be given to patients who have had myocardial infarction or have ischaemic heart disease, coronary vasospasm (Prinzmetal’s angina), peripheral vascular disease or patients who have symptoms or signs consistent with ischaemic heart disease.

Concurrent administration of ergotamine, derivatives of ergotamine (including methysergide), sumatriptan, naratriptan and other 5HT1B/1D receptor agonists with zolmitriptan is contraindicated (see Section 4.5).

Zolmitriptan must not be administered to patients with a history of cerebrovascular accident (CVA) or transient ischaemic attack (TIA).

Zolmitriptan is contraindicated in patients with a creatinine clearance of less than 15 ml/min

4.4 Special warnings and precautions for use

Zolmitriptan should only be used after 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 ophthalmophlegic migraine.

Stroke and other cerebrovascular events, such as haemorrhagic stroke and subarachnoid haemorrhage, have been reported in patients treated with 5HT1B/1D agonists including zolmitriptan. It should be noted that migraineurs may be at risk of certain cerebrovascular events.

Zolmitriptan, if taken during the aura, has not consistently been demonstrated to prevent the migraine headache and therefore Zoltzics 2.5 mg orodispersible tablets should only be taken during the headache phase of migraine. In very rare cases, as with other 5HT1B/1D agonists, coronary vasospasm, angina pectoris and myocardial infarction have been reported. Zoltzics 2.5 mg orodispersible tablets should not be given to patients with risk factors for ischaemic heart disease (e.g. smoking, hypertension, hyperlipidaemia, diabetes mellitus, heredity factors) 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 5HT1B/1D receptor agonists, sensations of 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 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.

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

Serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) has been reported following concomitant treatment with triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). These reactions can be severe. If concomitant treatment with zolmitriptan and an SSRI or SNRI is clinically warranted, appropriate observation of the patient is advised, particularly during treatment initiation, with dose increases, or with addition of another serotonergic medicinal product (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 medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

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).

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 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. Treatment with potent CYP1A2 inhibitors may increase the plasma concentrations of zolmitriptan and reduce the concentrations of the active metabolite. The clinical relevance of this is unknown. Dosage reduction is recommended with compounds of this type, such as fluvoxamine and the quinolones (e.g. ciprofloxacin).

Selegiline (a MAO-B inhibitor) and fluoxetine (an SSRI) did not result in any pharmacokinetic interaction with zolmitriptan. However, there have been 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).

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

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

As with other 5HT 1B/1D receptor antagonists zolmitriptan could delay the absorption of other medical products. There is no evidence that concomitant use of migraine prophylactic medications has any effect on the efficacy or unwanted effects of Zoltzics 2.5 mg orodispersible tablets (for example beta blockers, oral dihydroergotamine, and pizotifen).

The pharmacokinetics and tolerability of Zoltzics 2.5 mg orodispersible 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 treatment should be avoided. Similarly, admistration of zolmitriptan within 24 hours of the use of other 5HT1B/1D agonists should be avoided.

4.6 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.

Lactation

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.

4.7 Effects on ability to drive and use machines

In a small group of healthy individuals there was no significant impairment of performance of psychomotor tests with doses up to 20 mg zolmitriptan. Caution is recommended in patients performing skilled tasks (eg driving or operating machinery) as drowsiness and other symptoms may occur during a migraine attack. Also, dizziness and somnolence were observed after therapeutic doses of zolmitriptan.

4.8 Undesirable effects

Possible undesirable effects are typically transient, tend to occur within four 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 , < 1/10); uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000), very rare (<1/10,000), not known (frequency cannot be estimated from the available data).

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	Hypersensitivity reactions including urticaria, angioedema and anaphylactic reactions
Nervous system	Common	Abnormalities or disturbances of

Certain symptoms may be part of the migraine attack itself.

Overdose

Symptoms of intoxication

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

Treatment of intoxication

The mean elimination half-life of zolmitriptan orodispersible tablets is approximately 2.5 to 3 hours (see Section 5.2). Therefore monitoring of patients after overdose with Zoltzics 2.5 mg 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 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: Analgesics; Antimigraine preparations; Selective serotonin (5HT1) agonists.

ATC Code: N02CC03

Zolmitriptan has been demonstrated to be a selective agonist for 5-HT1B/1D receptors mediating vascular contraction. Zolmitriptan has high affinity for human recombinant 5-HT1B and 5-HT1D receptors, and modest affinity for 5-HT1A receptors. Zolmitriptan has no significant affinity or pharmacological activity at other 5-HT receptor subtypes (5-HT2, 5-HT3, 5-HT4) or adrenergic, histaminic, muscarinic or dopaminergic receptors.

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 by inhibition of neuropeptide release (calcitonin gene related peptide (CGRP), vasoactive intestinal peptide (VIP) and Substance P).

In clinical studies 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 is consistently effective in migraine with or without aura and in menstrually associated migraine.

For the original orodispersable tablet formulation of zolmitriptan 2.5 mg, this was proven in two placebo-controlled trials.

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.

5.2 Pharmacokinetic properties

Zolmitriptan orodispersable were previously demonstrated to be bioequivalent with the original filmcoated tablet formulation of zolmitriptan. AUC, Cmax and tmax for the active N-desmethyl metabolite of zolmitriptan were comparable with either formulation indicating that they are likely to demonstrate similar efficacy profiles. Also, Zolmitriptan 2.5 mg orodispersible tablets were bioequivalent to the original orodispersable 2.5 mg tablet formulation.

Therefore, throughout this document and particularly in the following pharmacokinetic paragraphs, crossreference is made to all data that were obtained with the original film-coated formulation of zolmitriptan, if not otherwise specified.

Zolmitriptan is rapidly and well absorbed after oral administration to man, (at least 64%). 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 4-5 hours after dosing. Zolmitriptan absorption is unaffected by the presence of food. There was no evidence of accumulation on multiple dosing of zolmitriptan.

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.

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. Following intravenous administration, the mean total plasma clearance is approximately 10 ml/min/kg, of which one quarter is renal clearance. Renal clearance is greater than glomerular filtration rate suggesting renal tubular secretion. The volume of distribution following iv 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 orodispersible tablet is approximately 2.5-3 hours. The half-lives of it’s 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 the halflife to 3 - 3.5 hours, an elimination half-life within the ranges seen in healthy volunteers.

The metabolism of zolmitriptan is reduced in hepatic impairment in proportion to the extent of the impairment. Zolmitriptan AUC and Cmax were increased by 226% and 50%, respectively and the half life was prolonged to 12 h in subjects with severe liver disease compared to healthy subjects. Exposure to the metabolites, including the active metabolite was reduced.

The pharmacokinetics of zolmitriptan in healthy elderly subjects were similar to those in healthy young volunteers. However the safety and efficacy of zolmitriptan in individuals aged over 65 years have not been established.

5.3 Preclinical safety data

Preclinical effects in single and repeat dose toxicity studies were observed only at exposures well in excess of the maximum human exposure.

The findings from in vitro and in vivo genetic toxicity studies show that genotoxic effects of zolmitriptan are not to be expected under the conditions of clinical use. No tumours relevant to the clinical use were found in mouse and rat carcinogenicity studies. As with other 5HT1B/1D receptor agonists, zolmitriptan binds to melanin.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Microcrystalline Cellulose

Crospovidone (Type B)

Citric acid anhydrous Mannitol

Sucralose micronized

Orange flavour (containing dextrin, modified food starch, natural flavours, maltodextrin, artificial flavours, butylated hydroxyanisole)

Macrogol 8000

Silica colloidal anhydrous

Magnesium Stearate

6.2    Incompatibilities

Not applicable

6.3    Shelf life

2 years

6.4    Special precautions for storage

Do not store above 30°C.

6.5    Nature and contents of container

Aluminium/Aluminium blister:

Pack sizes: 2, 6, 10, 12, 18 orodispersable tablets Not all pack sizes may be marketed.

6.6    Special precautions for disposal

The blister pack should be peeled open and tablets should not be pushed through the foil.