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RELPAX 20MG FILM-COATED TABLETS

Active substance(s): ELETRIPTAN HYDROBROMIDE / ELETRIPTAN HYDROBROMIDE / ELETRIPTAN HYDROBROMIDE

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1. NAME OF THE MEDICINAL PRODUCT
RELPAX 20 mg film coated tablets.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

RELPAX 20 mg film-coated tablets
Each film-coated tablet contains 20 mg eletriptan (as hydrobromide).
Excipients with known effect:
Each film-coated tablet contains 23 mg lactose and 0.036 mg Sunset yellow
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Film-coated tablet.
RELPAX 20 mg film-coated tablets
Round, convex orange tablets debossed with ‘REP 20’ on one side and ‘Pfizer’ on the other.

4.1

Therapeutic indications
RELPAX is indicated in adults for the acute treatment of the headache phase of migraine
attacks, with or without aura.

4.2

Posology and method of administration
Posology
RELPAX tablets should be taken as early as possible after the onset of migraine headache but
they are also effective if taken at a later stage during a migraine attack.
RELPAX, if taken during the aura phase, has not been demonstrated to prevent migraine
headache and therefore RELPAX should only be taken during the headache phase of
migraine.
RELPAX tablets should not be used prophylactically.
Adults (18-65 years of age):
The recommended initial dose is 40 mg.

If headache returns within 24 hours: If the migraine headache recurs within 24 hours of an
initial response, a second dose of the same strength of RELPAX has been shown to be
effective in treating the recurrence. If a second dose is required, it should not be taken within
2 hours of the initial dose.
If no response is obtained: If a patient does not achieve a headache response to the first dose
of RELPAX within 2 hours, a second dose should not be taken for the same attack as clinical
trials have not adequately established efficacy with the second dose. Clinical trials show that
patients who do not respond to the treatment of an attack are still likely to respond to the
treatment of a subsequent attack.
Patients who do not obtain satisfactory efficacy after an appropriate trial of 40 mg, (e.g. good
tolerability and failure to respond in 2 out of 3 attacks), may be effectively treated with 80 mg
(2 x 40 mg) in subsequent migraine attacks (see section 5.1). A second dose of 80 mg should
not be taken within 24 hours.
The maximum daily dose should not exceed 80 mg (see section 4.8).
Elderly patients
The safety and effectiveness of eletriptan in patients over 65 years of age have not been
systematically evaluated due to the small number of such patients in clinical trials. Use of
RELPAX in the elderly is therefore not recommended.
Paediatric population
Adolescents (12-17 years of age)
The efficacy of RELPAX in adolescents aged 12 to 17 years has not been established. Current
available data are described in section 5.2 but no recommendation on a posology can be
made.
Children (6-11 years of age)
The safety and efficacy of RELPAX in children aged 6 to 11 years has not been established.
Current available data are described in section 5.2 but no recommendation on a posology can
be made.
Patients with hepatic impairment
No dose adjustment is required in patients with mild or moderate hepatic impairment. As
RELPAX has not been studied in patients with severe hepatic impairment, it is
contraindicated in these patients.
Patients with renal impairment
As the blood pressure effects of RELPAX are amplified in renal impairment (see section 4.4),
a 20 mg initial dose, is recommended in patients with mild or moderate renal impairment. The
maximum daily dose should not exceed 40 mg. RELPAX is contra-indicated, in patients with
severe renal impairment.
Method of administration
The tablets should be swallowed whole with water.

4.3

Contraindications

RELPAX is contraindicated in patients with

4.4



hypersensitivity to eletriptan hydrobromide or to any of the excipients listed in 6.1.



severe hepatic or severe renal impairment.



moderately severe or severe hypertension, or untreated mild hypertension.



confirmed coronary heart disease, including ischaemic heart disease (angina pectoris,
previous myocardial infarction or confirmed silent ischaemia), coronary artery vasospasm,
objective or subjective symptoms of ischaemic heart disease or Prinzmetal’s angina.



significant arrhythmias or heart failure.



peripheral vascular disease.



a history of cerebrovascular accident (CVA) or transient ischaemic attack (TIA).



Administration of ergotamine, or derivatives of ergotamine (including methysergide), within
24hr before or after treatment with eletriptan (see section 4.5).



Concomitant administration of other 5-HT1 receptor agonists with eletriptan.

Special warnings and precautions for use
This medicinal product contains lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take
this medicine.
This medicinal product also contains sunset yellow which may cause allergic reactions.
RELPAX should not be used together with potent CYP3A4 inhibitors e.g., ketoconazole,
itraconazole, erythromycin, clarithromycin, josamycin and protease inhibitors (ritonavir,
indinavir and nelfinavir).
RELPAX should only be used where a clear diagnosis of migraine has been established.
RELPAX is not indicated for the management of hemiplegic, ophthalmoplegic, or basilar
migraine.
RELPAX should not be given for the treatment of ‘atypical’ headaches, i.e. headaches, which
may be related to a possibly serious condition (stroke, aneurysm rupture) where
cerebrovascular vasoconstriction may be harmful.
Eletriptan can be associated with transient symptoms including chest pain and tightness,
which may be intense and involve the throat (see section 4.8). Where such symptoms are
thought to indicate ischaemic heart disease, no further dose should be taken and appropriate
evaluation should be carried out.
Patients with cardiac failure

RELPAX should not be given without prior evaluation, to patients in whom unrecognised
cardiac disease is likely, or to patients at risk of coronary artery disease (CAD) [e.g., patients
with hypertension, diabetes, smokers or users of nicotine substitution therapy, men over 40
years of age, post-menopausal women and those with a strong family history of CAD].
Cardiac evaluations 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 when 5-HT1 agonists have been administered. Patients in whom CAD is established,
should not be given RELPAX (see section 4.3). 5-HT1 receptor agonists have been associated
with coronary vasospasm. In rare cases, myocardial ischaemia or infarction, have been
reported with 5-HT1 receptor agonists.
Undesirable effects may be more common during concomitant use of triptans and herbal
preparations containing St. John’s wort (Hypericum perforatum).
Within the clinical dose range, slight and transient increases in blood pressure have been seen
with eletriptan doses of 60 mg or greater. However, these increases have not been associated
with clinical sequelae in the clinical trial programme. The effect was much more pronounced
in renally impaired and elderly subjects. In renally impaired subjects, the range of mean
maximum increases in systolic blood pressure was 14 -17mmHg (normal 3mmHg) and for
diastolic blood pressure was 14 -21mmHg (normal 4mmHg). In elderly subjects, the mean
maximum increase in systolic blood pressure was 23mmHg compared with 13mmHg in
young adults (placebo 8mmHg). Post-marketing reports of increases in blood pressure have
also been received for patients taking 20 and 40 mg doses of eletriptan, and in non-renally
impaired and non-elderly patients.
Medication overuse headache (MOH)
Prolonged use of any 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 MOH should be suspected in patients who have frequent or
daily headaches despite (or because of) the regular use of headache medications.
Serotonin syndrome
Serotonin syndrome (including altered mental status, autonomic instability and neuromuscular
abnormalities) has been reported following concomitant treatment with triptans and selective
serotonin reuptake inhibitors (SSRIs) or serotonin noradrenaline reuptake inhibitors (SNRIs).
These reactions can be severe. If concomitant treatment with eletriptan and an SSRI or SNRI
is clinically warranted, appropriate observation of the patient is advised, particularly during
treatment initiation, with dose increases, or with addition of another serotonergic medication
(see section 4.5).

4.5

Interaction with other medicinal products and other forms of interaction
Effect of other medicinal products on eletriptan
In the pivotal clinical trials of eletriptan no evidence of interaction with beta-blockers,
tricyclic antidepressants, selective serotonin reuptake inhibitors and flunarizine was reported

but data from formal clinical interaction studies with these medicinal products are not
available (other than propranolol, see below).
Population pharmacokinetic analysis of clinical studies has suggested that the following
medicinal products (beta-blockers, tricyclic antidepressants, selective serotonin re-uptake
inhibitors, oestrogen based hormone replacement therapy, oestrogen containing oral
contraceptives and calcium channel blockers) are unlikely to have an effect on the
pharmacokinetic properties of eletriptan.
Eletriptan is not a substrate for MAO. Therefore there is no expectation of an interaction
between eletriptan and MAO inhibitors. Therefore no formal interaction study has been
undertaken.
In clinical studies with propranolol (160 mg), verapamil (480 mg) and fluconazole (100 mg)
the Cmax of eletriptan was increased 1.1 fold, 2.2 fold and 1.4 fold respectively. The increase
in eletriptan’s AUC being 1.3 fold, 2.7 fold and 2.0 fold respectively. These effects are not
considered clinically significant as there were no associated increases in blood pressure or
adverse events compared to administering eletriptan alone.
In clinical studies with erythromycin (1000 mg) and ketoconazole (400 mg), specific and
potent inhibitors of CYP3A4, significant increases in eletriptan Cmax (2 and 2.7- fold) and
AUC (3.6 and 5.9- fold) respectively, were observed. This increased exposure was associated
with an increase in eletriptan t1/2 from 4.6 to 7.1 hours for erythromycin and from 4.8 to 8.3
hours for ketoconazole (see section 5.2). Therefore, RELPAX should not be used together
with potent CYP3A4 inhibitors e.g.,
ketoconazole, itraconazole, erythromycin,
clarithromycin, josamycin and protease inhibitors (ritonavir, indinavir and nelfinavir).
In clinical studies with oral (caffeine/ergotamine) administered 1 and 2 hours after eletriptan,
minor though additive increases in blood pressure were observed which are predictable based
on the pharmacology of the two drugs. Therefore it is recommended that either ergotaminecontaining or ergot-type medications (e.g., dihydroergotamine) should not be taken within 24
hours of eletriptan dosing. Conversely, at least 24 hours should elapse after the
administration of an ergotamine-containing preparation before eletriptan is given.
Effect of eletriptan on other medicinal products
There is no in vitro or in vivo evidence that clinical doses (and associated concentrations) of
eletriptan will inhibit or induce cytochrome P450 enzymes including CYP3A4 drug
metabolising enzymes and therefore it is considered that eletriptan is unlikely to cause
clinically important drug interactions mediated by these enzymes.
Selective Serotonin Reuptake Inhibitors (SSRIs) /Serotonin Norepinephrine Reuptake
Inhibitors (SNRIs) and Serotonin Syndrome:
There have been reports describing patients with symptoms compatible with serotonin
syndrome (including altered mental status, autonomic instability and neuromuscular
abnormalities) following the use of selective serotonin reuptake inhibitors (SSRIs) or
serotonin noradrenaline reuptake inhibitors (SNRIs) and triptans (see section 4.4).

4.6

Fertility, pregnancy and lactation

Pregnancy: For RELPAX no clinical data on exposed pregnancies are available. Animal
studies do not indicate direct or indirect harmful effects with respect to pregnancy,
embryonal/fetal development, parturition or postnatal development. RELPAX should be used
during pregnancy only if clearly needed.
Breast-feeding: Eletriptan is excreted in human breast milk. In one study of 8 women given a
single dose of 80 mg, the mean total amount of eletriptan in breast milk over 24 hours in this
group was 0.02% of the dose. Nevertheless, caution should be exercised when considering
the administration of RELPAX to women who are breast-feeding. Infant exposure can be
minimised by avoiding breast-feeding for 24 hours after treatment.

4.7

Effects on ability to drive and use machines
RELPAX has moderate influence on the ability to drive and use machines. Migraine or
treatment with RELPAX may cause drowsiness or dizziness in some patients. Patients should
be advised to evaluate their ability to perform complex tasks such as driving during migraine
attacks and following administration of RELPAX.

4.8

Undesirable effects
Summary of the safety profile
RELPAX has been administered in clinical trials to over 5000 subjects, taking one or two
doses of RELPAX 20 or 40 or 80 mg. The most common adverse reactions noted were
asthenia, somnolence, nausea and dizziness. In randomised clinical studies using doses of 20,
40 and 80 mg, a trend for a dose-dependency of the incidence of adverse events has been
shown.
Tabulated list of adverse reactions
The following adverse reactions (with an incidence ≥1% and higher than placebo) were
reported in patients treated with therapeutic doses in clinical trials. Events are categorized by
frequency as common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), or rare (≥1/10,000
to <1/1,000).
System Organ Class
Infections and
infestations:

Common
pharyngitis,
and rhinitis

Uncommon

Blood and the
lymphatic system
disorders:
Metabolism and
nutrition disorders:

Rare
respiratory tract
infection
lymphadenopathy

anorexia

Psychiatric disorders:

Nervous system
disorders:

thinking abnormal,
agitation, confusion,
depersonalisation,
euphoria, depression,
and insomnia
somnolence,
headache,
dizziness,
tingling or
abnormal
sensation,
hypertonia,
hypoaesthesia,
and
myasthenia

Eye disorders:

Ear and labyrinth
disorders:

vertigo

Cardiac disorders:

palpitation,
and
tachycardia
flushing

Vascular disorders:

tremor,
hyperaesthesia, ataxia,
hypokinesia, speech
disorder, stupor, and
taste perversion

abnormal vision, eye
pain, photophobia, and
lacrimation disorder
ear pain, tinnitus

peripheral vascular
disorder
dyspnea, respiratory
disorder and yawning

shock

constipation,
oesophagitis, tongue
oedema and
eructation
hyperbilirubinaemia,
and increased AST
skin disorder and
urticaria

throat
tightness

Gastrointestinal
disorders:

abdominal
pain, nausea,
dry mouth, and
dyspepsia

diarrhoea, and glossitis

sweating

rash and pruritis

back pain,
myalgia

arthralgia, arthrosis
and bone pain

Musculoskeletal,
connective tissue and
bone disorders:

asthma and voice
alteration

arthritis, myopathy
and twitching

increased urinary
frequency, urinary
tract disorder and
polyuria

Renal and urinary
disorders:

Reproductive system
and breast disorders:
General disorders and
administration site
conditions:

conjunctivitis

bradycardia

Respiratory, thoracic
and mediastinal
disorders:

Hepato-biliary
disorders:
Skin and subcutaneous
tissue disorders:

emotional lability

breast pain and
menorrhagia
feeling hot,
asthenia, chest
symptoms
(pain,
tightness,
pressure),
chills and pain

malaise, face oedema,
thirst, oedema and
peripheral oedema

The common adverse events seen with eletriptan are typical of adverse events reported with
5-HT1 agonists as a class.
In post-marketing experience, the following undesirable effects have been reported:
Immune system disorders: allergic reactions, some of which may be serious, including
angioedema
Nervous system disorders: serotonin syndrome, rare cases of syncope, cerebrovascular
accident
Vascular disorders: hypertension
Cardiac disorders: myocardial ischaemia or infarction, arteriospasm coronary
Gastrointestinal disorders: as with some other 5HT 1B/1D agonists, rare reports of ischaemic
colitis have been received, vomiting.
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 at www.mhra.gov.uk/yellowcard.
4.9 Overdose
Subjects have received single doses of 120 mg without significant adverse effects. However based on
the pharmacology of this class, hypertension or other more serious cardiovascular symptoms could
occur on overdose.
In cases of overdose, standard supportive measures should be adopted as required. The elimination
half-life of eletriptan is about 4 hours, and therefore monitoring of patients and provision of general
supportive therapy after overdose with eletriptan should continue for at least 20 hours or while signs
and symptoms persist.
It is unknown what effect haemodialysis or peritoneal dialysis has on the serum concentrations of
eletriptan.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Selective Serotonin (5HT1) receptor agonists ATC code: NO2C
C06
Mechanism of action
Eletriptan is a selective agonist at the vascular 5-HT1B and neuronal 5-HT1D receptors.
Eletriptan also exhibits high affinity for the 5-HT1F receptor which may contribute to its antimigraine mechanism of action. Eletriptan has modest affinity for the human recombinant 5HT1A, 5-HT2B, 5-HT1E and 5-HT7 receptors.

Clinical efficacy and safety
The efficacy and safety of RELPAX in the acute treatment of migraine has been evaluated in
10 placebo-controlled trials involving more than 6000 patients (all treatment groups) at doses
of 20 to 80 mg. Headache relief occurred as early as 30 minutes following oral dosing.
Response rates (i.e. reduction of moderate or severe headache pain to no or mild pain) 2 hours
after dosing were 59-77% for the 80 mg dose, 54-65% for the 40 mg dose, 47-54% for the 20
mg dose, and 19-40% following placebo. RELPAX was also effective in the treatment of
associated symptoms of migraine such as vomiting, nausea, photophobia and phonophobia.
The recommendation for dose titration to 80 mg, is derived from open label long term studies
and from a short term double blind study, where only a trend towards statistical significance
was observed.
RELPAX remains effective in menstrually associated migraine. RELPAX, if taken during the
aura phase, has not been demonstrated to prevent migraine headache and therefore RELPAX
should only be taken during the headache phase of migraine.
In a non placebo controlled pharmacokinetic study of patients with renal impairment, larger
elevations in blood pressure were recorded after an 80 mg dose of RELPAX than with normal
volunteers (see Section 4.4). This cannot be explained by any pharmacokinetic changes and
so may represent a specific pharmacodynamic response to eletriptan in patients with renal
impairment.

5.2

Pharmacokinetic properties
Absorption
Eletriptan is rapidly and well absorbed across the gastro-intestinal tract (at least 81%) after
oral administration. Absolute oral bioavailability across males and females is approximately
50%. The median Tmax is 1.5 hours after oral dosing. Linear pharmacokinetics were
demonstrated over the clinical dose range (20-80 mg).
The AUC and Cmax of eletriptan were increased by approximately 20-30% following oral
administration with a high fat meal. Following oral administration during a migraine attack,
there was a reduction of approximately 30% in AUC and Tmax was increased to 2.8 hours.
Following repeated doses (20 mg three times daily ) for 5-7 days, the pharmacokinetics of
eletriptan remained linear and accumulation was predictable. On multiple dosing of larger
doses (40 mg three times daily and 80 mg two times daily), the accumulation of eletriptan
over 7 days was greater than predicted (approximately 40%).
Distribution
The volume of distribution of eletriptan following IV administration is 138L indicating
distribution into the tissues. Eletriptan is only moderately protein bound (approximately
85%).
Biotransformation

In vitro studies indicate that eletriptan is primarily metabolised by hepatic cytochrome P-450
enzyme CYP3A4. This finding is substantiated by increased plasma concentrations of
eletriptan following co-administration with erythromycin and ketoconazole, known selective
and potent CYP3A4 inhibitors. In vitro studies also indicate a small involvement of CYP2D6
although clinical studies do not indicate any evidence of polymorphism with this enzyme.
There are two major circulating metabolites identified that significantly contribute to plasma
radioactivity following administration of C14-labelled eletriptan. The metabolite formed by
N-oxidation, has demonstrated no activity in animal in vitro models. The metabolite formed
by N-demethylation, has been demonstrated to have similar activity to eletriptan in animal in
vitro models. A third area of radioactivity in plasma has not been formally identified, but is
most likely to be a mixture of hydroxylated metabolites which have also been observed
excreted in urine and faeces.
The plasma concentrations of the N-demethylated active metabolite are only 10-20% of those
of parent and so would not be expected to significantly contribute to the therapeutic action of
eletriptan.
Elimination
Mean total plasma clearance of eletriptan following IV administration is 36 L/h with a
resultant plasma half-life of approximately 4 hours. The mean renal clearance following oral
administration is approximately 3.9 L/h. Non-renal clearance accounts for approximately
90% of the total clearance indicating that eletriptan is eliminated primarily by metabolism.
Pharmacokinetics in Special Patient Groups
Gender
A meta analysis across clinical pharmacology studies and a population pharmacokinetic
analysis of clinical trial data indicate that gender does not have any clinically significant
influence on plasma concentrations of eletriptan.
Elderly (over 65 years of age)
Though not statistically significant, there is a small reduction (16%) in clearance associated
with a statistically significant increased half-life (from approximately 4.4 hours to 5.7 hours)
between elderly (65-93 years) and younger adult subjects.
Adolescents (12-17 years of age)
The pharmacokinetics of eletriptan (40 mg and 80 mg) in adolescent migraine patients dosed
between attacks, were similar to those seen in healthy adults.
Children (6-11 years of age)
The clearance of eletriptan is unchanged in children relative to adolescents. However the
volume of distribution is lower in children resulting in higher plasma levels than would be
predicted following the same dose in adults.
Patients with hepatic impairment
Subjects with hepatic impairment (Child-Pugh A and B) demonstrated a statistically
significant increase in both AUC (34%) and half-life. There was a small increase in Cmax
(18%). This small change in exposure is not considered clinically relevant.

Patients with renal impairment
Subjects with mild (creatinine clearance 61-89 ml/min), moderate (creatinine clearance 31-60
ml/min) or severe (creatinine clearance <30 ml/min) renal impairment did not have any
statistically significant alterations in their eletriptan pharmacokinetics or plasma protein
binding. Blood pressure elevations were observed in this group.

5.3

Preclinical safety data
Preclinical data, revealed no special hazard for humans based on conventional studies of
safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity and toxicity to
reproduction.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Core Tablet: Microcrystalline cellulose, lactose monohydrate, croscarmellose sodium and
magnesium stearate.
Film Coat: titanium dioxide (E171), hypromellose, lactose monohydrate, glycerol triacetate
and Sunset Yellow FCF Aluminium Lake (E110).

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years

6.4

Special precautions for storage
Opaque PVC/Aclar/Aluminium blister: this medicinal product does not require any

special storage conditions HDPE bottles: keep the container tightly closed, in order to
protect from moisture

6.5

Nature and Content of Container
Opaque PVC/Aclar/Aluminium blister packs containing 2, 3, 4, 6, 10, 18, 30 and 100
tablets.
HDPE bottles with child-resistant HDPE/PP closures containing 30 and 100 tablets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements

7.

MARKETING AUTHORISATION HOLDER
Pfizer Limited
Sandwich
Kent, CT13 9NJ
United Kingdom

8.

MARKETING AUTHORISATION NUMBER(S)
PL 00057/0452

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
12/02/2011

10

DATE OF REVISION OF THE TEXT
08/05/2014

Expand Transcript

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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