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ZOMIG RAPIMELT MIGRAINE CONTROL 2.5MG TABLETS

Active substance(s): ZOLMITRIPTAN

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Zomig Rapimelt Migraine Control 2.5 mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each orodispersible tablet contains 2.5 mg of zolmitriptan.
Excipient with known effect:
Each orodispersible table contains 5 mg of aspartame (E951).
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Oro-dispersible tablet

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Zomig Rapimelt Migraine Control is indicated for the acute treatment of
migraine with or without aura.
Zomig Rapimelt Migraine Control should only be used where there is a clear
diagnosis of migraine.

4.2

Posology and method of administration
Posology
Adults (18-65 years of age)
The recommended dose of Zomig Rapimelt Migraine Control to treat a
migraine attack is 2.5 mg.
If symptoms persist or return within 24 hours, a second dose of zolmitriptan
has been shown to be effective. If a second dose is required, it should not be
taken within 2 hours of the initial dose.
Zolmitriptan is equally effective whenever the tablets are taken during a
migraine attack; although it is advisable that Zomig Rapimelt Migraine
Control 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
Zomig Rapimelt Migraine Control in a 24 hour period should not exceed
5 mg.
If no relief is obtained after taking 5 mg then the patient should be referred to
a doctor.
Zomig Rapimelt Migraine Control is not indicated for prophylaxis of
migraine.
Special populations
Paediatric population
Children below the age of 12 years
The safety and efficacy of Zomig Rapimelt Migraine Control in children aged
0-12 years has not yet been established. No data are available. Use of Zomig
Rapimelt Migraine Control in children is therefore not recommended.
Adolescents (12 - 17 years of age)
The efficacy of Zomig Rapimelt Migraine Control tablets was not
demonstrated in a placebo controlled clinical trial for patients aged 12 to
17 years. Use of Zomig Rapimelt Migraine Control in adolescents is therefore
not recommended.
Older people
The safety and efficacy of Zomig Rapimelt Migraine Control in individuals
aged over 65 years have not been established. Zomig Rapimelt Migraine
Control tablets should not be used in patients aged over 65 years of age.
Patients with hepatic impairment
Metabolism is reduced in patients with hepatic impairment (see section 5.2.
The use of Zomig Rapimelt Migraine Control is contraindicated in patients
with severe hepatic impairment (see section 4.3 and section 5.2). No dosage
adjustment is required for patients with moderate hepatic impairment.
Patients with renal impairment
No dosage adjustment required (see section 5.2). The use of Zomig Rapimelt
Migraine Control is contraindicated in patients with severe renal impairment
(see section 4.3 and section 5.2).
Method of administration
Zomig Rapimelt Migraine Control is for oral use only.
Zomig Rapimelt Migraine Control rapidly dissolves when placed on the
tongue and is swallowed with the patient’s saliva. A drink of water is not
required when taking Zomig Rapimelt Migraine Control. Zomig Rapimelt
Migraine Control 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
Zomig Rapimelt Migraine Control is contraindicated in patients with:












4.4

Hypersensitivity to the active substance or to any of the excipients
listed in section 6.1.
Known hypertension.
Ischaemic heart disease (including previous myocardial infarction or
angina).
Severe hepatic or severe renal impairment.
Epilepsy or a history of seizures.
Atypical migraine (including hemiplegic or basilar migraine).
Peripheral vascular disease.
Coronary vasospasm/Prinzmetal’s angina.
A history of cerebrovascular accident (CVA) or transient ischaemic
attack (TIA).
Cardiac arrhythmias (including Wolff-Parkinson-White syndrome).
Concomitant administration of Zomig Rapimelt Migraine Control
tablets with ergotamine or ergotamine derivatives or other 5-HT1
receptor agonists.

Special warnings and precautions for use
Zomig Rapimelt Migraine Control should only be used where a clear diagnosis
of migraine has been established. Pharmacy supply of Zomig Rapimelt
Migraine Control is therefore not appropriate if the patients’ first migraine
attack occurred within the last 12 months; pharmacy supply is restricted to
patients with an established pattern of at least five migraine attacks.
Patients having 4 or more migraines a month should be referred to a doctor.
Care should be taken to exclude other potentially serious neurological
conditions.
Patients should be referred to a doctor for further assessment if any of the
following apply: their migraine symptoms do not disappear between attacks
(migraine is episodic); they are over the age of 50 and experiencing migraine
for the first time; their migraine headache lasts for longer than 24 hours; they
have a change in their usual migraine symptoms, or their migraines increase in
frequency.
There are no data on the use of Zomig Rapimelt Migraine Control in
hemiplegic or basilar migraine (see section 4.3). Migraneurs may be at risk of
certain cerebrovascular events. Cerebral haemorrhage, subarachnoid
haemorrhage, stroke, and other cerebrovascular events have been reported in
patients treated with 5HT1B/1D agonists.
Zomig Rapimelt Migraine Control should not be given to patients with
symptomatic Wolff-Parkinson-White syndrome or arrhythmias associated with
other cardiac accessory conduction pathways (see section 4.3).
In very rare cases, as with other 5HT1B/1D agonists, coronary vasospasm,
angina pectoris and myocardial infarction have been reported. Patients should

be assessed for risk of undiagnosed cardiovascular disease prior to receiving
Zomig Rapimelt Migraine Control. The following risk factors for
cardiovascular disease should be taken into account:
• Diabetes mellitus
• Regular smoker (10 or more daily)
• Family history of Ischaemic Heart Disease
• Hypercholesterolaemia
• Post-menopausal female
• Male aged over 40 years
• Body Mass Index > 30 kg/m2
Patients with three or more of the above risk factors should not receive Zomig
Rapimelt Migraine Control until they have been further assessed by a doctor.
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.
A new diagnosis of migraine or change in severity of symptoms may imply
contraindication to the combined oral contraceptive pill, especially in the
presence of one or more cardiovascular risk factors or migraine with aura.
Women taking a combined oral contraceptive should consult a doctor if the
onset of migraine is recent or if their symptoms become more severe.
As with other 5HT1B/1D agonists, atypical sensations such as heaviness,
tightness, pain or pressure over the precordium (see section 4.8) have been
reported after the administration of zolmitriptan. If chest pain or symptoms
consistent with ischaemic heart disease occur, no further doses of zolmitriptan
should be taken until after appropriate medical evaluation has been carried out.
As with other 5HT1B/1D agonists transient increases in systemic blood pressure
have been reported in patients with and without a history of hypertension; very
rarely these increases in blood pressure have been associated with significant
clinical events.
As with other 5HT1B/1D agonists, there have been rare reports of
anaphylaxis/anaphylactoid reactions in patients receiving Zomig Rapimelt
Migraine Control tablets.
Patients with phenylketonuria should be informed that Zomig Rapimelt
Migraine Control contains phenylalanine (a component of aspartame). Each
2.5 mg orally dispersible tablet contains 2.81 mg of phenylalanine.
Excessive use of an acute anti-migraine medicinal product may lead to an
increased frequency of headache, potentially requiring withdrawal of
treatment. Patients should be referred to a doctor if this occurs.
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 is clinically warranted, particularly during treatment
initiation and dosage increases (see section 4.5).
Patients taking St John’s wort should not take Zomig Rapimelt Migraine
Control without first consulting a doctor (see section 4.5).
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 Zomig, 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 Zomig Rapimelt Migraine Control
treatment should be avoided.
Data from healthy subjects suggest there are no pharmacokinetic or clinically
significant interactions between Zomig 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 Zomig. Conversely it is advised to wait at
least six hours following use of Zomig 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 ‘Zomig
Rapimelt Migraine Control’ in 24 hours is recommended in patients taking an
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 Rapimelt Migraine
Control' 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).
Fluoxetine does not affect the pharmacokinetic parameters of zolmitriptan.
Therapeutic doses of the specific serotonin reuptake inhibitors, fluoxetine,
sertraline, paroxetine and citalopram do not inhibit CYP1A2. However,
Serotonin Syndrome has been reported during combined use of triptans, and
SSRIs (e.g. fluoxetine, paroxetine, sertraline) and SNRIs (e.g. venlafaxine,
duloxetine) (see section 4.4).
As with other 5HT1b/1d agonists, there is the potential for dynamic interactions
with the herbal remedy St John’s wort (Hypericum perforatum) which may
result in an increase in undesirable effects.

4.6

Fertility, pregnancy and lactation

Pregnancy
Zomig Rapimelt Migraine Control should only be used in pregnancy on the
advice of a doctor, and 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,
Zomig Rapimelt Migraine Control is not to be used in breast-feeding women
except on the advice of a doctor.
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. Zomig Rapimelt Mirgraine Control 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 safety profile
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 4 hours of dosing and are no
more frequent following repeated dosing.
Tabulated list of adverse reactions
Adverse reactions are classified according to frequency and system organ
class. Frequency categories are defined according to the following convention:
Very common (≥1/10); Common (≥1/100 to < 1/10); Uncommon (≥1/1,000 to
< 1/100); Rare (≥1/10,000 to < 1/1,000); Very rare (<1/10,000); Not known
(cannot be estimated from the available data). The following undesirable
effects have been reported following administration with zolmitriptan:
System Organ Class

Frequency

Undesirable Effect

Immune system disorders

Rare

Anaphylaxis/Anaphylactoid Reactions;
Hypersensitivity reactions

Nervous system disorder

Common

Abnormalities or disturbances of
sensation;
Dizziness;
Headache;
Hyperaesthesia;
Paraesthesia;
Somnolence;
Warm sensation

Cardiac disorders

Common

Palpitations

Uncommon

Tachycardia

Very rare

Angina pectoris;
Coronary vasospasm;
Myocardial infarction

Vascular disorders

Uncommon

Transient increases in systemic blood
pressure

Gastrointestinal disorders

Common

Abdominal pain;
Dry mouth;
Nausea;
Vomiting
Dysphagia

Very rare

Bloody diarrhoea;
Gastrointestinal infarction or necrosis;
Gastrointestinal ischaemic events;
Ischaemic colitis;
Splenic infarction

Skin and subcutaneous
tissue disorders

Rare

Angioedema;
Urticaria

Musculoskeletal and
connective tissue
disorders

Common

Muscle weakness;
Myalgia

Renal and urinary
disorders

Uncommon

Polyuria;
Increased urinary frequency

Very rare

Urinary urgency

Common

Asthenia;
Heaviness, tightness, pain or pressure in
throat, neck, limbs or chest

General disorders and
administration site
conditions

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

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 Zomig Rapimelt Migraine
Control 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 5HT1B and 5HT1D receptor
subtypes. Zolmitriptan is a high affinity 5HT1B/1D receptor agonist with modest
affinity for 5HT1A receptors. Zolmitriptan has no significant affinity (as
measured by radioligand binding assays) or pharmacological activity at 5HT2-,
5HT3-, 5HT4-, alpha1-, alpha2-, or beta1-, adrenergic; H1-, H2-, histaminic;
muscarinic; dopaminergic1, or dopaminergic2 receptors. The 5HT1D receptor is
predominately located presynaptically at both the peripheral and central
synapses of the trigeminal nerve and preclinical studies have shown that
zolmitriptan is able to act at both these sites.
Clinical efficacy and safety
One controlled clinical trial in 696 adolescents with migraine failed to
demonstrate superiority of zolmitriptan tablets at doses of 2.5 mg, 5 mg and
10 mg over placebo. Efficacy was not demonstrated.

5.2

Pharmacokinetic properties
Following oral administration of Zomig 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 (183C91, the N-desmethyl metabolite) 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 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.
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 (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 Rapimelt Migraine Control. 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
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 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.
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.
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.
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.
Zomig Rapimelt Migraine Control was demonstrated to be bioequivalent with
the conventional tablet in terms of AUC and Cmax for zolmitriptan and its
active metabolite 183C91. 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).
Special populations
Older people
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, 1200mg/kg/day (AUC 605μg/ml.h : approx. 3700 x AUC of
the human maximum recommended daily intake of 15mg) and 30mg/kg/day
(AUC 4.9μg/ml.h : approx. 30 x AUC of the human maximum recommended
daily intake of 15mg) in rats and rabbits, respectively, no signs of
teratogenicity were apparent.
Five genotoxicity tests have been performed. It was concluded that Zomig
Rapimelt Migraine Control 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
Each Zomig Rapimelt Migraine Control oro-dispersible tablet contains the
following excipients:
Aspartame
Citric Acid Anhydrous
Silica Colloidal Anhydrous
Crospovidone
Magnesium Stearate
Mannitol
Microcrystalline Cellulose
Orange Flavour SN027512
Sodium Hydrogen Carbonate

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years.

6.4

Special precautions for storage
Do not store above 30oC.

6.5

Nature and contents of container
PVC aluminium/aluminium blister pack of 2 tablets

6.6

Special precautions for disposal and other handling
The blister pack should be peeled open as shown on the foil (tablets should not
be pushed through the foil). The Zomig Rapimelt Migraine Control tablet
should be placed on the tongue, where it will dissolve and be swallowed with
the saliva.

7

MARKETING AUTHORISATION HOLDER
AstraZeneca UK Ltd
600 Capability Green
Luton
LU1 3LU
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 17901/0238

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
Date of first authorisation: 28 May 2014

10

DATE OF REVISION OF THE TEXT
10/06/2015

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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