Zomig full prescribing information

1. NAME OF THE MEDICINAL PRODUCT

ZOMIG

ZOMIG RAPIMELT

ZOMIG NASAL SPRAY

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

ZOMIG tablets for oral administration contain 2.5 mg or 5 mg of zolmitriptan.

ZOMIG RAPIMELT orodispersible tablets contain 2.5 mg or 5 mg of zolmitriptan.

ZOMIG NASAL SPRAY is an aqueous solution containing 25 mg/ml zolmitriptan for 2.5 mg and 50 mg/ml zolmitriptan for 5 mg, buffered to pH 5.0. The device delivers a unit dose of 2.5 mg or 5 mg and is intended for a single use only.

3. PHARMACEUTICAL FORM

ZOMIG: Tablets.

ZOMIG RAPIMELT: Orodispersible tablets

ZOMIG NASAL SPRAY: Nasal Spray

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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

4.2 Posology and method of administration

Oral formulations:

The recommended dose of ZOMIG tablets and ZOMIG RAPIMELT to treat a migraine attack is 2.5 mg.

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

ZOMIG is equally effective whenever the tablets are taken during a migraine attack; although it is advisable that ZOMIG tablets are taken as early as possible after the onset of migraine headache.

The ZOMIG conventional tablet should be swallowed whole with water.

The ZOMIG RAPIMELT orodispersible tablet rapidly dissolves when placed on the tongue and is swallowed with the patient’s saliva. A drink of water is not required when taking the ZOMIG RAPIMELT orodispersible tablet. ZOMIG RAPIMELT orodispersible tablets 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. ZOMIG and ZOMIG RAPIMELT provide significant efficacy within 1 hour of dosing.

Nasal Spray:

The recommended dose of ZOMIG NASAL SPRAY to treat a migraine attack is 5 mg.

ZOMIG NASAL SPRAY is administered as a single dose into one nostril. The nasal spray provides an alternative non-oral formulation of zolmitriptan to that of ZOMIG oral tablets and orodispersible tablets. ZOMIG NASAL SPRAY provides a particularly rapid onset of relief of migraine with significant efficacy apparent within 15 minutes of dosing.
This formulation may also be beneficial where a non-oral route of treatment is either needed or preferred.

All formulations

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.

In the event of recurrent attacks, it is recommended that the total intake of ZOMIG, in a 24 hour period, should not exceed 10 mg

ZOMIG is not indicated for prophylaxis of migraine.

Use in patient subgroups

ZOMIG is consistently effective in migraine, with or without aura, and in menstrually associated migraine. The efficacy of ZOMIG is also unaffected by gender, duration of the attack, pre-treatment nausea and concomitant use of common prophylactic migraine drugs. The effect of ZOMIG NASAL SPRAY is unaffected by co-administered nasal sympathomimetic decongestants.

Use in children

The efficacy of ZOMIG tablets 2.5, 5 and 10 mg was not established in a placebo controlled clinical trial for patients aged 12 to 17 years. The profile and frequency of adverse events are consistent with ZOMIG tablets use in adults. The efficacy and safety of ZOMIG in paediatric patients below 12 years have not been evaluated.

Use in the elderly

The safety and efficacy of ZOMIG in individuals aged over 65 years have not been systematically evaluated.

Patients with hepatic impairment

Although metabolism is reduced in patients with mild or moderate hepatic impairment (seeSection 5.2), no dosage adjustment is required. 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 (see Section 5.2).

4.3 Contraindications

ZOMIG is contraindicated in patients with:

Known hypersensitivity to any component of the product.

Uncontrolled hypertension.

Ischaemic heart disease.

Coronary vasospasm/Prinzmetal’s angina.

4.4 Special warnings and special precautions for use

ZOMIG 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 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 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, 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. Where such symptoms are thought to indicate ischemic heart disease, no further doses of zolmitriptan should be given and appropriate evaluation 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.

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 ZOMIG and an SSRI or SNRI, particularly during treatment initiation and dosage increases (See 4.5).

ZOMIG RAPIMELT:

Patients with phenylketonuria should be informed that ZOMIG RAPIMELT orodispersible tablets contain phenylalanine (a component of aspartame). Each 2.5 mg orodispersible tablet contains 2.81 mg of phenylalanine, and each 5 mg tablet contains 5.62 mg of phenylalanine.

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 ZOMIG (for example beta blockers, oral dihydroergotamine, pizotifen).

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

Ergot-containing drugs have been reported to cause prolonged vasopastic reactions. Because there is a theoretical basis that these effects may be additive, 24 hours should elapse between the use of ergotamine containing or ergot-type medications (like dihydroergotamine or methysergide) and zolmitriptan. Conversely it is advised to wait at least 6 hours following use of ZOMIG before administering an ergotamine containing preparation.

Concomitant administration of other 5HT1B/1D agonists within 12 hours of ZOMIG treatment, should be avoided.

Cases of life threatening syndrome have been reported during combined use of triptans, and Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g. fluoxetine, paroxetine, sertraline) and Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) (e.g. venlafaxine, duloxetine) (See 4.4).

The absorption and pharmacokinetics of ZOMIG NASAL SPRAY are unaltered by prior administration of the sympathomimetic vasoconstrictor, xylometazoline.

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 of ZOMIG 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 (183C91) were doubled. A maximum dose of 5 mg ZOMIG 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 (eg, ciprofloxacin). Following the administration of rifampicin, no clinically relevant differences in the pharmacokinetics of zolmitriptan or its active metabolite were observed.

4.6 Pregnancy and lactation

Pregnancy

ZOMIG 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.

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 ZOMIG 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 ZOMIG. Use is unlikely to result in an impairment of the ability of patients to drive or operate machinery. However it should be taken into account that somnolence may occur.

4.8 Undesirable effects

ZOMIG 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 four hours of dosing and are no more frequent following repeated dosing.

The incidences of ADRs associated with ZOMIG therapy are tabulated below according to the format recommended by the Council for International Organizations of Medical Sciences (CIOMS III Working Group; 1995).

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4.9 Overdose

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

The elimination half-life of zolmitriptan administration is approximately 3 hours, (see Section 5.2) and therefore monitoring of patients after overdose with ZOMIG 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

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 5HT_1A 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.

It has been demonstrated that the pain sensitive structures of the cranial cavity in humans are the blood vessels and the vasculature of the dura mater.

These tissues are innervated by trigeminal afferent fibres. In animal models the administration of zolmitriptan, with its agonist activity on the vascular 5HT1 receptors causes vasoconstriction associated with an inhibition of the release of calcitonin gene related peptide (CGRP), Vasoactive Intestinal Peptide (VIP) and substance P. These two events, vasoconstriction and inhibition of neuropeptide release are thought to cause relief from the migraine attack and associated nausea and vomiting, photophobia and phonophobia within 1 hour of administration of ZOMIG and ZOMIG RAPIMELT and 15 minutes of administration of ZOMIG NASAL SPRAY.

In addition to these peripheral actions, zolmitriptan has action on the central nervous system allowing access to both the peripheral and migraine centres in the brain stem which may explain the consistent effect over a series of attacks in a single patient. Vasodilatation is achieved with the activation of a reflex pathway mediated by trigeminal orthodromic fibres and parasympathetic innervation of the cerebral circulation via the release of VIP as a main effector transmitter. Zolmitriptan blocks this reflex pathway and the release of VIP.

ZOMIG NASAL SPRAY:

In a clinical trial with ZOMIG NASAL SPRAY including just over 1300 migraine patients treating up to 3 migraine attacks the onset of efficacy is apparent from 15 minutes for both the 2.5 mg and 5 mg doses. At 2 hours post dose ZOMIG NASAL SPRAY 5 mg demonstrated headache response (from severe/moderate to mild/none) in 70% and pain free response in 36% of attacks compared to 59% and 26% for the 2.5 mg dose and 31% and 8% respectively for placebo. The proportion of patients with undesirable effects increased with increasing dose.

5.2 Pharmacokinetic properties

ZOMIG:

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 (183C91, the N-desmethyl metabolite) which is also a 5HT_1B/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 183C91, 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.

ZOMIG RAPIMELT:

Following oral administration of ZOMIG conventional tablets, zolmitriptan is rapidly and well absorbed (at least 64%). 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_1B/1D agonist and is 2 to 6 times as potent, in animal models, as zolmitriptan. The ZOMIG RAPIMELT orodispersible formulation was found to be bioequivalent with the conventional tablet in terms of AUC and Cmax for zolmitriptan and its active metabolite (183C91). The time to maximum plasma concentration following administration of ZOMIG RAPIMELT orodispersible is similar for the active metabolite (183C91) but can be prolonged for zolmitriptan with this formulation relative to the conventional tablet. In a clinical pharmacology study to compare the two formulations, for the active metabolite 183C91, the tmax ranged from 0.75 to 5 hours (median 3.0 hours) for the conventional tablet, and 1 to 6 hours (median 3.0 hours) for the orodispersible tablet, whereas for zolmitriptan the ranges were 0.5 to 3 hours (median 1.5 hours) and 0.6 to 5 hours (median 3.0 hours), respectively. However, plasma concentrations of zolmitriptan for the orodispersible and conventional tablet formulations are similar up to 45 minutes post dose, the period of most importance for initial absorption following administration.

ZOMIG NASAL SPRAY:

Zolmitriptan, following intranasal administration, is rapidly absorbed with detectable levels in the plasma within 5 minutes of dosing. A proportion of the dose is directly absorbed in the naso-pharynx. 40% of Cmax is achieved within 15 minutes. Plasma concentrations are sustained for 4 to 6 hours. Elimination of zolmitriptan and the active metabolite 183C91 after oral and intranasal delivery were similar; the mean elimination half-life (t ½) for both zolmitriptan and 183C91 are approximately 3 hours. The bioavailability of intranasal zolmitriptan relative to oral administration is 102%.

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 Ndesmethylated 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. Over 60% of a single oral dose is excreted in the urine (mainly as the indoleacetic acid metabolite) and about 30% in faeces mainly as unchanged parent compound.

The plasma concentrations and pharmacokinetics of zolmitriptan and the three major metabolites for the nasal spray and conventional tablet formulations are similar.

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.

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 iv 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.
Renal clearance of zolmitriptan and 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.

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

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

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 ZOMIG has been conducted. At the maximum tolerated doses of ZOMIG, 1200 mg/kg/day and 30 mg/kg/day in rats and rabbits, respectively, no signs of teratogenicity were apparent.

A number of genotoxicity tests have been performed. It was concluded that ZOMIG 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

The following should be checked against that which is marketed locally.

6.1 List of excipients

The following excipients are contained in each ZOMIG compressed tablet as indicated:

Iron oxide (Yellow - 2.5 mg tablet, Red - 5.0 mg tablet)
Hypromellose
Lactose
Magnesium Stearate
Microcrystalline Cellulose
Polyethylene glycol (400 and 8000)
Sodium Starch Glycollate
Titanium dioxide

Each ZOMIG RAPIMELT orodispersible tablet contains the following excipients:

Aspartame
Citric Acid
Colloidal Silicon dioxide
Crospovidone
Magnesium Stearate
Mannitol
Microcrystalline Cellulose
Orange Flavour SN027512
Sodium Bicarbonate

Each ZOMIG NASAL SPRAY contains the following excipients:

Citric Acid
Disodium Phosphate
Purified Water

6.2 Incompatibilities

None known.

6.3 Shelf-life

ZOMIG tablets: 3 years. Do not store above 30°C.

ZOMIG RAPIMELT orodispersible tablets: 2 years. Do not store above 30°C.

ZOMIG NASAL SPRAY: 2 years. Do not store above 25°C.

6.4 Special precautions for storage

None.

6.5 Nature and contents of container

ZOMIG tablets: Foil/foil blister pack.

ZOMIG RAPIMELT orodispersible tablets: PVC aluminium/aluminium blister pack.

ZOMIG NASAL SPRAY: USP/Ph Eur Type I glass vials which are closed with chlorobutyl rubber stoppers. The vials are assembled into a unit dose nasal spray device, comprising a vial holder, an actuation device and a protection cover.

6.6 Instructions for use, handling and disposal

ZOMIG tablets: No specific instructions.

ZOMIG RAPIMELT orodispersible tablets: 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.

ZOMIG NASAL SPRAY: The protective cover must not be removed until immediately before use. Please consult separate instruction leaflet.