Consumer medicine information

APO-Zolmitriptan

Zolmitriptan

BRAND INFORMATION

Brand name

APO-Zolmitriptan Tablets

Active ingredient

Zolmitriptan

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Zolmitriptan.

What is in this leaflet

This leaflet answers some common questions about zolmitriptan. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may want to read it again.

What this medicine is used for

Zolmitriptan is used to relieve migraine headaches. It belongs to a group of medicines called serotonin agonists.

How it works

Migraine is thought to be caused by the widening of certain blood vessels in the brain. Zolmitriptan narrows the blood vessels to help ease the migraine.

Some people have a warning stage called 'aura' before the migraine headache starts. Aura can include numbness in the face or down one arm, mood changes, or problems with eyesight such as seeing blank spots or flashing lights.

Zolmitriptan can be used in migraine with or without aura. It should not be used to treat types of migraine called 'hemiplegic' or 'basilar' migraine.

Zolmitriptan does not work in headaches that are not migraine.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

This medicine is available only with a doctor's prescription.

This medicine is not addictive.

There is no experience of zolmitriptan use in children under 12 years of age. One study in children aged 12 to 17 years indicated no benefit with zolmitriptan treatment.

Before you take this medicine

When you must not take it

Do not take this medicine if you have an allergy to:

  • zolmitriptan
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin

Do not use this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • high blood pressure
  • a feeling of tightness, pressure of heaviness in the chest
  • a heart attack, other heart problems or a family history of heart problems
  • a stroke or dizzy spells caused by lack of blood flow to the brain
  • blood vessel problems causing poor circulation in the arms or legs
  • kidney or liver disease
  • high cholesterol levels in the blood
  • diabetes

Tell your doctor if you are pregnant, plan to become pregnant or are breastfeeding. Do not take this medicine until you and your doctor have discussed the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you start taking this medicine.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interact with zolmitriptan. These include:

  • other medicines for migraine, (e.g. sumatriptan, naratriptan, ergotamine, dihydroergotamine or methysergide)
  • medicines for depression
  • cimetidine, used for indigestion or stomach ulcers
  • quinolone antibiotics (e.g. norfloxacin)
  • St John's Wort (Hypericum perforatum)

These medicines may be affected by this medicine or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take this medicine

Follow all directions given to you by your doctor and pharmacist carefully. They may differ to the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

The usual dose is one tablet (2.5 mg) taken as soon as you feel the migraine headache starting.

If your migraine is still present after two hours, or if it returns within 24 hours, you can take another tablet.

Do not take more than 10 mg (four 2.5 mg tablets) in 24 hours.

How to take it

Swallow your tablets whole with a glass of water.

When to take it

You can take zolmitriptan when you feel the headache start or after it has already begun.

Zolmitriptan should not be used to prevent the migraine attacks from occurring.

It does not matter if you take it with or without food.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much of this medicine. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking this medicine.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

If you become pregnant whilst taking this medicine, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects.

Things you must not do

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not take your medicine to treat any other complaint unless your doctor tells you to.

Things to be careful of

Be careful driving or operating machinery until you know how this medicine affects you. Zolmitriptan can make some people feel dizzy or sleepy. Make sure you know how you react to zolmitriptan before you do anything that could be dangerous if you are dizzy or sleepy.

Side effects

Tell your doctor and pharmacist as soon as possible if you do not feel well while you are taking zolmitriptan.

This medicine helps most people with migraines, but may have unwanted side effects in some people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • increased feeling or sensitivity, especially in the skin
  • feeling warm
  • aching muscles not caused by exercise
  • dizziness
  • stomach upset, including nausea, pain, vomiting
  • headache
  • sleepiness, unusual tiredness or weakness
  • dry mouth

The above list includes the more common side effects of zolmitriptan.

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin (signs of an allergic reaction)
  • a feeling of tightness, pressure or heaviness in the chest, throat, neck, arms or legs
  • palpitations, irregular heartbeats, increased heart rate
  • numbness or loss of strength of the arms or legs, headache, dizziness, confusion, visual disturbance, difficulty swallowing, slurred speech or loss of speech (signs of a stroke)
  • bloody diarrhoea or prolonged stomach pain

These are very serious side effects and you may need urgent medical attention or hospitalisation:

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may occur in some patients.

Storage and disposal

Storage

Keep your medicine in the pack until it is time to take it. If you take your medicine out of the pack it may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any leftover medicine.

Product description

What it looks like

Light pink, round, film-coated tablets, debossed with '2.5' on one side and plain on the other. Blister pack of 2 or 6 tablets. AUST R 200878.

Ingredients

Each tablet contains 2.5 mg zolmitriptan as the active ingredient.

It also contains the following:

  • microcrystalline cellulose
  • lactose
  • sodium starch glycollate type A
  • magnesium stearate
  • Opadry complete film coating system 02G84574 Pink

This medicine does not contain gluten, sucrose, tartrazine or any other azo dyes.

Contains sugars as lactose.

Sponsor

Arrotex Pharmaceuticals Pty Ltd
15 – 17 Chapel Street
Cremorne VIC 3121

This leaflet was prepared In March 2023.

Published by MIMS April 2023

BRAND INFORMATION

Brand name

APO-Zolmitriptan Tablets

Active ingredient

Zolmitriptan

Schedule

S4

 

1 Name of Medicine

Zolmitriptan.

2 Qualitative and Quantitative Composition

Each tablet contains 2.5 mg zolmitriptan, as the active ingredient.

Excipients with known effect.

Lactose.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

2.5 mg film coated tablet.

Light pink, round, film coated tablets, debossed with '2.5' on one side and plain on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of Administration

APO-Zolmitriptan tablets are intended for oral administration.
The tablet should be swallowed whole with water.

Dosage.

The recommended initial dose of zolmitriptan to treat a migraine attack is 2.5 mg.
If symptoms of migraine persist or recur within 24 hours of 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 achieve satisfactory relief with 2.5 mg doses, subsequent attacks can be treated with 5 mg doses of zolmitriptan.
The onset of action in responders is apparent within 1 hour of dosing.
Zolmitriptan is equally effective whenever the tablets are taken during a migraine attack, although it is advisable that 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, in a 24 our period, should not exceed 10 mg.
Zolmitriptan is not indicated for prophylaxis of migraine.

Patient sub-groups.

Zolmitriptan is consistently effective in migraine, with or without aura, and in menstrually associated migraine. The efficacy of zolmitriptan is also unaffected by gender, duration of the attack, pre-treatment nausea and concomitant use of common prophylactic migraine drugs.

Paediatric use.

The efficacy of zolmitriptan tablets was not established in a placebo-controlled clinical trial for patients aged 12 to 17 years. The efficacy and safety of zolmitriptan in paediatric patients below 12 years have not been evaluated.

Use in the elderly.

The safety and efficacy of zolmitriptan in individuals aged over 65 years have not been systematically evaluated. Use of zolmitriptan in the elderly is therefore not recommended.

Use in adults with hepatic impairment.

Although metabolism is reduced in patients with mild or moderate hepatic impairment (see Section 5.2 Pharmacokinetic Properties), no dosage adjustment is required. However, for patients with severe hepatic impairment a maximum dose of 5 mg in 24 hours is recommended.

Use in adults with renal impairment.

A study was carried out in patients with creatinine clearances from 5 to 39 mL/min. No dosage adjustment required (see Section 5.2 Pharmacokinetic Properties).

Instructions for use/handling.

APO-Zolmitriptan tablets: No specific instructions.

4.3 Contraindications

Zolmitriptan is contraindicated in the following cases:
Hypersensitivity to any component of the product.
A history of myocardial infarction.
Ischaemic heart disease; Prinzmetal angina/coronary vasospasm; peripheral vascular disease; symptoms or signs consistent with ischaemic heart disease.
Moderate or severe hypertension and mild uncontrolled hypertension.
Ergotamine or ergotamine derivatives should not be used concomitantly with zolmitriptan.
Other 5HT1D receptor agonists should not be used concomitantly with zolmitriptan.
Creatinine clearance of less than 15 mL/min.
On theoretical grounds (see Section 5 Pharmacological Properties), zolmitriptan should not be administered to patients with a history of cerebrovascular accident (CVA) or transient ischaemic attack (TIA).

4.4 Special Warnings and Precautions for Use

Cerebrovascular events have been reported in patients treated with 5HT1 agonists, some resulting in fatalities. In a number of cases, it appears that the cerebrovascular events were primary, the agonist having been administered in the incorrect belief that the symptoms were a consequence of the migraine. Zolmitriptan should only be used when 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 5HT1 agonists.
There have been rare reports of anaphylaxis/anaphylactoid reactions in patients receiving zolmitriptan.
Zolmitriptan should not be given to patients with symptomatic Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathways.
This class of compounds (5HT1B/1D agonists) has been associated with coronary vasospasm, angina pectoris and myocardial infarction. In very rare cases this has occurred with zolmitriptan. 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 Contraindications). 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 5HT1D agonists, atypical sensations over the precordium (see Section 4.8 Adverse Effects (Undesirable Effects)) have been reported after the administration of zolmitriptan. Where such symptoms are thought to indicate ischaemic heart disease, no further doses of zolmitriptan should be given and appropriate evaluation carried out.
Serotonin syndrome has been reported with combined use of triptans, and selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline 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, weakness), and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea).
In accordance with the Hunter Criteria, 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 when zolmitriptan is administered with an SSRI or SNRI, particularly during treatment initiation and dosage increases (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Withdrawal of the serotonergic medicines usually brings about an improvement. Treatment depends on the type and severity of the symptoms.
Overuse of acute migraine medications may lead to exacerbations of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused medications, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.
Transient increases in systemic blood pressure (which may be more pronounced in the elderly) 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.

Use in adults with hepatic impairment.

Although metabolism is reduced in patients with mild or moderate hepatic impairment (see Section 5.2 Pharmacokinetic Properties), no dosage adjustment is required. However, for patients with severe hepatic impairment a maximum dose of 5 mg in 24 hours is recommended.

Use in adults with renal impairment.

A study was carried out in patients with creatinine clearances from 5 to 39 mL/min. No dosage adjustment required (see Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

The safety and efficacy of Zolmitriptan in individuals aged over 65 years have not been systematically evaluated.
Use of Zolmitriptan in the elderly is therefore not recommended.

Paediatric use.

The efficacy of zolmitriptan tablets was not established in a placebo-controlled clinical trial for patients aged 12 to 17 years. The efficacy and safety of zolmitriptan in paediatric patients below 12 years have not been evaluated.

Effects on laboratory tests.

Zolmitriptan is not known to interfere with commonly employed clinical laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 were unaffected by acute symptomatic treatments such as paracetamol, metoclopramide and ergotamine. Concomitant administration of other 5HT1D agonists within 24 hours of zolmitriptan treatment should be avoided.
Data from healthy subjects suggest 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.
The major metabolite of zolmitriptan, the indole acetic acid (2161W92), is derived from the active metabolite, N-desmethyl zolmitriptan (183C91), by the action of monoamine oxidase A. This is evidenced by the effects of co-administration of the selective MAO-A inhibitor, moclobemide, which resulted in a 3-fold increase in the exposure to N-desmethylzolmitriptan but had minimal effects (increase of 26% in AUC) on zolmitriptan levels. (The metabolite N-desmethylzolmitriptan is also a 5HT1D agonist with higher receptor affinity than the parent drug and therefore contributes to the overall effect after zolmitriptan administration). Hence, in patients taking a MAO-A inhibitor (selective or non-selective), a maximum intake of 5 mg zolmitriptan in 24 hours is recommended.
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 CYP1A2 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). Following the administration of rifampicin, no clinically relevant differences in the pharmacokinetics of zolmitriptan or its active metabolite were observed.
Cases of life-threatening syndrome have been reported during combined use of triptans and SSRIs (e.g. fluoxetine, fluvoxamine, paroxetine, sertraline) and SNRIs (e.g. venlafaxine) (see Section 4.4 Special Warnings and Precautions for Use).
As with other 5HT1B/1D agonists, there is a potential pharmacodynamic interaction 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

Effects on fertility.

A fertility study by the oral route of administration, during which male and female rats were dosed daily with zolmitriptan prior to and throughout the mating period, showed no evidence of impaired fertility at doses producing plasma concentrations greater than 100 times those attained in humans after the maximum recommended daily dose of 10 mg (based on AUC).
(Category B3)
There are no adequate and well-controlled studies in pregnant women. Studies in rats and rabbits treated with oral zolmitriptan during organogenesis, showed no direct teratogenic effects. Plasma concentrations in rats and rabbits receiving the highest doses were greater than 100 times and 40 times, respectively, the exposure (based on AUC) attained in humans after the maximum recommended daily dose of 10 mg. Administration of zolmitriptan should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.
 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.

4.7 Effects on Ability to Drive and Use Machines

Even though there was no significant impairment of psychomotor test performances in healthy volunteers following doses of up to 20 mg, somnolence was reported in pharmacological and clinical trials. Caution is recommended in patients performing skilled tasks (e.g. driving or operating machinery) as drowsiness and other symptoms may occur during a migraine attack and following treatment.

4.8 Adverse Effects (Undesirable Effects)

Zolmitriptan is well tolerated. Adverse reactions are typically mild/moderate, transient, not serious and resolve spontaneously without additional treatment. The adverse event profile has been demonstrated to be similar for the administration of either 2.5 mg or 5 mg of zolmitriptan.
Possible adverse reactions tend to occur within four hours of dosing and are no more frequent following repeated dosing; certain symptoms may be considered to be part of the migraine attack itself.

Clinical trial data.

The incidence of adverse drug reactions associated with zolmitriptan therapy is tabulated in Table 1 according to the format recommended by the Council for International Organisations of Medical Sciences (CIOMS III working group; 1995).

Zolmitriptan tablet (2.5 mg and 5 mg) controlled clinical studies.

Table 2 lists the adverse events that occurred in ≥ 2% of the patients in any one of the zolmitriptan (2.5 mg and 5 mg) or sumatriptan 100 mg dose groups of the controlled clinical trials. Only events that were more frequent in a treatment group compared to the placebo groups are included.
Other adverse events reported less frequently are listed below; these are classified by body system categories and given in order of decreasing frequency, using the definitions: uncommon - occurring in 1/100-1/1,000 patients; rare - occurring in fewer than 1/1,000 patients. All reported events are included except those already listed in Table 2, those too general to be informative and those not reasonably associated with the use of the drug.

Atypical sensation.

Uncommon: hyperaesthesia of the mouth and skin.

General.

Uncommon: allergy reaction, chills, facial oedema, fever, malaise and photosensitivity.

Cardiovascular.

Uncommon: arrhythmias, hypertension and syncope.
Rare: bradycardia, extrasystoles, postural hypotension, QT prolongation, tachycardia and thrombophlebitis.

Digestive.

Uncommon: increased appetite, tongue oedema, oesophagitis, gastroenteritis, liver function abnormality and thirst.
Rare: anorexia, constipation, gastritis, haematemesis, pancreatitis, melena and ulcer.

Haemic.

Uncommon: ecchymosis.
Rare: cyanosis, thrombocytopenia, eosinophilia and leucopoenia.

Metabolic.

Uncommon: oedema.
Rare: hyperglycaemia and alkaline phosphatase increased.

Musculoskeletal.

Uncommon: back pain, leg cramps and tenosynovitis.
Rare: arthritis, tetany and twitching.

Neurological.

Uncommon: agitation, anxiety, depression, emotional lability and insomnia.
Rare: akathisia, amnesia, apathy, ataxia, dystonia, euphoria, hallucinations, cerebral ischaemia, hyperkinesia, hypotonia, hypertonia and irritability.

Respiratory.

Uncommon: bronchitis, bronchospasm, epistaxis, hiccup, laryngitis and yawn.
Rare: apnoea and voice alteration.

Skin.

Uncommon: pruritus, rash and urticaria.

Special senses.

Uncommon: dry eye, eye pain, hyperacusis, ear pain, parosmia and tinnitus.
Rare: diplopia and lacrimation.

Urogenital.

Uncommon: haematuria, cystitis, polyuria, urinary frequency, urinary urgency.
Rare: miscarriage and dysmenorrhoea.

Post-marketing data.

See Section 4.8 Adverse Effects (Undesirable Effects).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

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 Pharmacokinetic Properties) and therefore monitoring of patients after overdose with zolmitriptan 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.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

In preclinical 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, α1, α2, or β1 adrenergic; H1, H2, histaminic; muscarinic; dopaminergic1, or dopaminergic2 receptors. The N-desmethyl metabolite, N-desmethylzolmitriptan, is also a 5HT1B/1D agonist and is 2 to 6 times more potent, in animal models, than zolmitriptan. This metabolite shows higher in vitro affinity for 5HT1B/1D receptors than zolmitriptan and also has modest affinity for 5HT1A 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 proposed to cause relief from the migraine attack, as reflected by an onset of pain relief within 1 hour of administration and relief of nausea and vomiting, photophobia and phonophobia associated with migraine.
In addition to these peripheral actions, experimental studies in animals suggest 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. It is suggested that zolmitriptan blocks this reflex pathway and the release of VIP.

Clinical trials.

Treatment of acute migraine, with or without aura, with zolmitriptan tablets.

Overall there were 4,003 unique individuals who participated in the zolmitriptan clinical development. A total of 3,096 unique individuals were exposed to zolmitriptan. Of this total, 316 unique individuals were accounted for in clinical pharmacology studies; 2,633 in placebo controlled treatment of migraine studies, 79 in the long-term multiple attack study (study 015; 2,058 subjects in total, 79 of whom were unique subjects not previously exposed to zolmitriptan), 38 in two uncontrolled patient treatment studies; and 30 in an acute prevention of migraine study. In addition 524 unique individuals were exposed to placebo (119 in clinical pharmacology studies, 401 in treatment of migraine studies).
These subjects received almost 50,000 oral doses of zolmitriptan. Across all patient studies, a total of 34,296 attacks were treated with zolmitriptan. The majority of these (31,579) were treated in a long-term study.
In patient studies, the protocol inclusion criteria required patients to have an established diagnosis of migraine, with or without aura (as defined by the International Headache Society criteria). Patients had a migraine history of at least 1 year with an age of onset less than 50 years and had one to six migraines per month over the preceding 6 months. In addition, patients had to have screening laboratory values within acceptable ranges and be without evidence of ischaemic heart disease, arrhythmia, or accessory pathways, based on a 12-lead ECG. The age range of patients was 18-65 years in most studies.
The first of the pivotal studies was a phase II study of almost 1,200 patients comparing zolmitriptan (n = 900) to placebo. The response rates at 2 hours in patients receiving placebo, zolmitriptan 5 mg, 10 mg, 15 mg and 20 mg were 21%, 61%, 67%, 67% and 74%, respectively. The response rate had been slightly lower at 1 hour post-dosing, being 16% in the group receiving placebo and 44-50% in the groups treated with zolmitriptan. The percentage of patients with no pain at 2 hours was 1% in the placebo group, and 39%, 39%, 43% and 47% in the zolmitriptan 5 mg, 10 mg, 15 mg and 20 mg groups, respectively. The placebo group also showed a far greater recurrence rate over 24 hours than the zolmitriptan groups, with median time to recurrence being 4.5 hours with placebo and 15.3 hours with zolmitriptan.
The incidence of adverse events was proportional to dose, and consisted predominantly of asthenia, heaviness (in the chest, limbs, head), nausea, paraesthesia, a feeling of warmth, dizziness, somnolence, vertigo and dry mouth. Of the cardiovascular events, 34 were noted with zolmitriptan versus 1 with placebo, but there was only 1 serious adverse event (tachycardia in a patient with a pre-existing condition of Wolff-Parkinson-White syndrome (see Section 4.4 Special Warnings and Precautions for Use).
The phase III study also investigated approximately 1,200 patients, but included lower doses of zolmitriptan (1 mg, 2.5 mg, 5 mg and 10 mg). The findings indicated that the response to zolmitriptan 1 mg was greater than the response to placebo, however no difference between placebo and zolmitriptan 1 mg was found in another study. The 2.5 mg dose was associated with a response rate of 63% versus 65% with the 5 mg dose, suggesting that these two dose levels were equi-effective. This study also showed the incidence of nausea to be reduced significantly with zolmitriptan treatment when compared with placebo. The safety profile of zolmitriptan was similar to that observed in the previous trials. There were no serious adverse events reported in this selected trial population.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration of zolmitriptan tablets, it is rapidly and well absorbed (at least 64%). The mean absolute bioavailability of the parent compound is approximately 40% but there is some degree of intersubject variability.
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.
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.

Distribution.

Plasma protein binding of zolmitriptan and the N-desmethyl metabolite is low (approximately 25%). The volume of distribution for the parent drug following i.v. administration is 2.4 L/kg.

Metabolism.

Metabolism of zolmitriptan is dependent on CYP1A2 and the metabolism of the active metabolite N-desmethylzolmitriptan is via the monoamine oxidase A (MAO-A) enzyme system. 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 (1N-desmethylzolmitriptan) is active whilst the others are not. Plasma concentrations of 1N-desmethylzolmitriptan are approximately half those of the parent drug, hence it would therefore be expected to contribute to the therapeutic action.

Excretion.

Zolmitriptan is eliminated largely by hepatic biotransformation followed by urinary excretion of the metabolites. 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 half-life (T½) of zolmitriptan was 4.7 hours in healthy volunteers. The corresponding T½ values for the N-desmethylzolmitriptan metabolite was 5.7 hours. Following intravenous administration, the mean total plasma clearance is approximately 10 mL/min/kg, for the parent drug, of which one-quarter is renal clearance. Renal clearance is greater than glomerular filtration rate suggesting renal tubular secretion. 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.

Special patient populations.

Hepatic impairment.

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 N-desmethylzolmitriptan 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 (T1/2) of zolmitriptan was 7.3 hours in patients with moderate liver disease and 12 hours in those with severe liver disease. The corresponding T1/2 values for the 1N-desmethylzolmitriptan metabolite were 7.5 hours and 7.8 hours respectively.

Renal impairment.

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.

Pharmacokinetic interaction with other medications.

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

Elderly.

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

5.3 Preclinical Safety Data

Genotoxicity.

Zolmitriptan showed no evidence of genotoxicity in a series of assays for gene mutations (bacteria and Chinese hamster ovary cells). Tests for chromosomal damage in human lymphocytes in vitro, showed that zolmitriptan was clastogenic, however, zolmitriptan was not clastogenic in vivo.

Carcinogenicity.

In carcinogenicity studies, rats and mice were given zolmitriptan by oral gavage for 104 and 92 weeks, respectively. Average plasma concentrations in rats and mice receiving the highest doses were greater than 100 times the exposure (based on AUC) attained in humans after the maximum recommended daily dose of 10 mg. The rat study revealed an increased incidence of thyroid follicular cell adenoma at the highest dose tested, thought to be due to enhanced hepatic thyroxine clearance. There was no evidence of an increased incidence of tumours in the mouse.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, lactose, sodium starch glycollate type A, magnesium stearate and Opadry complete film coating system 02G84574 (PI 108588): hypromellose, titanium dioxide, macrogol 400, macrogol 8000, iron oxide red.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Store in original container.

6.5 Nature and Contents of Container

Blister pack (aluminum foil/aluminum foil) of 2 or 6 tablets (AUST R 200878).
APO and APOTEX are registered trademarks of Apotex Inc.
Not all pack sizes may be available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Zolmitriptan is a white to almost white powder slightly soluble in water (1.3 mg/mL at 250°C) but shows greater solubility in 0.1 M hydrochloric acid. Zolmitriptan has a pKa of 9.6. Zolmitriptan is a chiral molecule, which is synthesized as the S enantiomer.

Chemical name.

(S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone.

Chemical structure.


Molecular formula.

C16H21N3O2.

Molecular weight.

287.36.

CAS number.

139264-17-8.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes