Zolmitriptan 5 mg orodispersible tablets – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Zolmitriptan 5 mg orodispersible tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 mg orodispersible tablet contains 5 mg zolmitriptan.

Excipient with known effect:

Each 5 mg orodispersible tablet contains 0,500 mg aspartame.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Orodispersible tablet.

Zolmitriptan 5 mg orodispersible tablets are white to off-white round flat tablets of 7.0 mm diameter, debossed with “5” on one side, having a characteristic flavour.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Zolmitriptan is indicated in adults aged 18 years and older for 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 2.5 mg.

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

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

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

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

Zolmitriptan is not indicated for prophylaxis of migraine.

Paediatric population (Children below the age of 12 years) The safety and efficacy of zolmitriptan tablets in children aged 0-12 years has not yet been established. No data are available. Use of Zolmitriptan in children is therefore not recommended.

Adolescents (12 - 17 years of age)

The efficacy of Zolmitriptan was not demonstrated in a placebo controlled clinical trials for patient 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.

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.

Renal impairment

No dosage adjustment required (see section 5.2).

Method of administration

The blister pack should be peeled open (tablets should not be pushed through the foil). The ‘Zolmitriptan’ should be placed on the tongue, where it will dissolve and be swallowed with the saliva.

To be taken by oral administration. Zolmitriptan rapidly dissolves when placed on the tongue and is swallowed with the patient’s saliva. A drink of water is not required when taking Zolmitriptan. Zolmitriptan 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

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

• A history of cerebrovascular accident (CVA) or

  transient ischaemic attack (TIA).

• Concomitant administration of Zolmitriptan 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. 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. Migraineurs 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.

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 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 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 5HT_1B/1D agonists, atypical sensations over the precordium (see Section 4.8) have been reported after the administration of zolmitriptan. If chest pain or symptoms consistent with ischaemic heart disease occur, no further doses of zolmitriptan should be taken until after appropriate medical evaluation has been carried out.

As with other 5HT_1B/1D agonists transient increases in systemic blood pressure have been reported in patients with and without a history of hypertension; very rarely these increases in blood pressure have been associated with significant clinical events.

As with other 5HT_1B/1D agonists, there have been rare reports of anaphylaxis/anaphylactoid reactions in patients receiving Zolmitriptan.

Zolmitriptan contains aspartame. Aspartame is a source of phenylalanine. Patients with phenylketonuria should be informed that Zolmitriptan contains phenylalanine (a component of aspartame). Neither non-clinical nor clinical data are available to assess aspartame use in infants below 12 weeks of age.

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 sdosage 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.

This medicine contains less than 1 mmol sodium (23 mg) 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 6 hours following use of zolmitriptan before administering any ergotamine preparation (see section 4.3).

Following administration of moclobemide, a specific MAO-A inhibitor, there was a small increase (26%) in AUC for zolmitriptan and a 3 fold increase in AUC of the active metabolite. Therefore, a maximum intake of 5 mg 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 5 mg 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 quinolones 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 5HT_1B/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).

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

There was no significant impairment of performance of

psychomotor tests with doses up to 20 mg 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, <1/10); uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <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 with zolmitriptan:

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

Symptoms

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

Management

The elimination half-life of zolmitriptan is 2.5 to 3 hours, (see section 5.2) and therefore monitoring of patients after overdose with zolmitriptan 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 code: N02CC03

Mechanism of action

In pre-clinical studies, zolmitriptan has been demonstrated to be a selective agonist for the vascular human recombinant 5HT_1B and 5HT_1D receptor subtypes. Zolmitriptan is a high affinity 5HT_1B/1D receptor agonist with modest affinity for 5HT_IA receptors. Zolmitriptan has no significant affinity (as measured by radioligand binding assays) or pharmacological activity at 5HT_2-, 5HT_3-, 5HT_4-, 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 ‘Zolmitriptan’ 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 (Ndesmethylzolmitriptan) 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 C_max over the dose range 2.5 to 50 mg. Absorption is rapid with 75% of C_max achieved within 1 hour and plasma concentrations are sustained subsequently for 4 to 6 hours.

Zolmitriptan absorption is unaffected by the presence of food. There is no evidence of accumulation on multiple dosing of zolmitriptan.

Zolmitriptan is eliminated largely by hepatic biotransformation followed by urinary excretion of the metabolites. There are three major metabolites: the indole acetic acid, (the major metabolite in plasma and urine), the N-oxide and N-desmethyl analogues. The N-desmethylated metabolite 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.

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

(Ndesmethylzomitriptan), 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 was demonstrated to be bioequivalent with the conventional tablet in terms of AUC and Cmax for zolmitriptan and its active metabolite N-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)

Magnesium Aluminometasilicate

Hydroxy Propyl Cellulose

Aspartame (E951)

Sodium Lauril Sulfate

Basic Butylated Methacrylate Copolymer

Talc

Colloidal anhydrous silica

Magnesium stearate

Peppermint Flavour (containing maltodextrin, natural flavours and modified corn starch)

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

Peelable cold-formed aluminium blisters.

Pack sizes:

Zolmitriptan 5 mg orodispersible tablets: 2, 3, 6, 9, 12 or 18 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Jubilant Pharmaceuticals nv

Axxes Business Park

Guldensporenpark 22 – Block C

9820 Merelbeke

Belgium

8 MARKETING AUTHORISATION NUMBER(S)

PL 19156/0052

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

10/03/2016

10 DATE OF REVISION OF THE TEXT

29/05/2026