RELPAX 20mg and 40mg Film-Coated Tablets.

Each film-coated tablet contains 20mg, and 40mg eletriptan (as hydrobromide).

For full list of excipients, see section 6.1.

Film-coated tablet.

Round, convex orange tablets debossed with 'REP 20' and 'REP 40' on one side and 'Pfizer' on the other.

Acute treatment of the headache phase of migraine attacks, with or without aura.

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.

The tablets should be swallowed whole with water.

Adults (18-65 years of age):

The recommended initial dose is 40mg.

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 40mg, (e.g. good tolerability and failure to respond in 2 out of 3 attacks), may be effectively treated with 80mg (2 x 40mg) in subsequent migraine attacks (see section 5.1 Pharmacodynamic Properties – Further information on Clinical Trials). A second dose of 80mg should not be taken within 24 hours.

The maximum daily dose should not exceed 80mg (see section 4.8 Undesirable effects).

Elderly (over 65 years of age)

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.

Adolescents (12-17 years of age)

The efficacy of RELPAX has not been established in this population and its use is therefore not recommended in this age group.

Children (6-11 years of age)

The safety and efficacy of RELPAX in children have not been evaluated. Therefore the use of RELPAX is not recommended in this age group (see 5.2 Pharmacokinetic Properties).

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 contra-indicated in these patients.

Renal Impairment

As the blood pressure effects of RELPAX are amplified in renal impairment (see 4.4 Special Warnings and Precautions for Use), a 20mg initial dose, is recommended in patients with mild or moderate renal impairment. The maximum daily dose should not exceed 40mg. RELPAX is contra-indicated, in patients with severe renal impairment.

Hypersensitivity to eletriptan hydrobromide or to any of the excipients.

Patients with severe hepatic or severe renal impairment.

Moderately severe or severe hypertension, or untreated mild hypertension.

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

Patients with significant arrhythmias or heart failure.

Patients with peripheral vascular disease.

Patients with 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 4.5 Interactions with other medicinal products and other forms of interaction). Concomitant administration of other 5-HT₁ receptor agonists with eletriptan.

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 eg. 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 4.8 Undesirable effects). Where such symptoms are thought to indicate ischaemic heart disease, no further dose should be taken and appropriate evaluation should be carried out.

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 4.3 Contra-indications).

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 60mg 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.

Excessive use of any anti-migraine medicinal product can lead to daily chronic headaches requiring a therapeutic window. Overuse of all triptans has been reported primarily in patients with chronic daily headache. Overuse of all triptans has been reported primarily in patients with chronic daily headache.

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).

Effect of other medicinal products on eletriptan

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 (160mg), verapamil (480mg) and fluconazole (100mg) the C_max 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 (1000mg) and ketoconazole (400mg), specific and potent inhibitors of CYP3A4, significant increases in eletriptan C_max (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 t_1/2 from 4.6 to 7.1 hours for erythromycin and from 4.8 to 8.3 hours for ketoconazole (see 5.2 Pharmacokinetic Properties). Therefore, RELPAX should not be used together with potent CYP3A4 inhibitors eg. 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 ergotamine-containing 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).

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.

Lactation: Eletriptan is excreted in human breast milk. In one study of 8 women given a single dose of 80mg, 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.

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.

RELPAX has been administered in clinical trials to over 5000 subjects, taking one or two doses of RELPAX 20 or 40 or 80mg. The most common adverse reactions noted were asthenia, somnolence, nausea and dizziness. In randomised clinical studies using doses of 20, 40 and 80mg, a trend for a dose-dependency of the incidence of adverse events has been shown. 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).

Infections and infestations:

Common: pharyngitis, and rhinitis

Rare: respiratory tract infection

Blood and the lymphatic system disorders:

Rare: lymphadenopathy

Metabolism and nutrition disorders:

Uncommon: anorexia

Psychiatric disorders:

Uncommon: thinking abnormal, agitation, confusion, depersonalisation, euphoria, depression, and insomnia

Rare: emotional lability

Nervous system disorders:

Common: somnolence, headache, dizziness, tingling or abnormal sensation, hypertonia, hypoaesthesia, and myasthenia

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

Eye disorders:

Uncommon: abnormal vision, eye pain, photophobia, and lacrimation disorder

Rare: conjuntivitis

Ear and labyrinth disorders:

Common: vertigo

Uncommon: ear pain, tinnitus

Cardiac disorders:

Common: palpitation, and tachycardia

Rare: bradycardia

Vascular disorders:

Common: flushing

Uncommon: peripheral vascular disorder

Rare: shock

Respiratory, thoracic and mediastinal disorders:

Common: throat tightness

Uncommon: dyspnea, respiratory disorder and yawning

Rare: asthma and voice alteration

Gastrointestinal disorders:

Common: abdominal pain, nausea, dry mouth, and dyspepsia

Uncommon: diarrhoea, and glossitis

Rare: constipation, oesophagitis, tongue oedema and eructation

Hepato-biliary disorders:

Rare: bilirubinaemia, and increased AST

Skin and subcutaneous tissue disorders:

Common: sweating

Uncommon: rash and pruritis

Rare: skin disorder and urticaria

Musculoskeletal, connective tissue and bone disorders:

Common: back pain, myalgia

Uncommon: arthralgia, arthrosis and bone pain

Rare: arthritis, myopathy and twitching

Renal and urinary disorders:

Uncommon: increased urinary frequency, urinary tract disorder and polyuria

Reproductive system and breast disorders:

Rare: breast pain and menorrhagia

General disorders and administration site conditions:

Common: feeling hot, asthenia, chest symptoms (pain, tightness, pressure), and chills

Uncommon: 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

Nervous system disorders: Serotonin syndrome, Rare cases of syncope

Vascular Disorders: hypertension

Gastrointestinal disorders: As with some other 5HT 1B/1D agonists, rare reports of ischaemic colitis have been received., vomiting

Subjects have received single doses of 120mg 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.

Pharmacotherapeutic group: Selective Serotonin (5HT₁) receptor agonists ATC code: NO2CC06

Mode of action/pharmacology: Eletriptan is a selective agonist at the vascular 5-HT_1B and neuronal 5-HT_1D receptors. Eletriptan also exhibits high affinity for the 5-HT_1F receptor which may contribute to its anti-migraine mechanism of action. Eletriptan has modest affinity for the human recombinant 5-HT_1A, 5-HT_2B, 5-HT_1E and 5-HT₇ receptors.

Further Information on Clinical Trials

The efficacy of RELPAX in the acute treatment of migraine has been evaluated in 10 placebo-controlled trials that included about 4000 patients who received RELPAX at doses of 20 to 80mg. 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 80mg dose, 54-65% for the 40mg dose, 47-54% for the 20mg 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 80mg, 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 80mg 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.

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 T_max is 1.5 hours after oral dosing. Linear pharmacokinetics were demonstrated over the clinical dose range (20-80mg).

The AUC and C_max 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 T_max was increased to 2.8 hours.

Following repeated doses (20mg tid) for 5-7 days, the pharmacokinetics of eletriptan remained linear and accumulation was predictable. On multiple dosing of larger doses (40mg tid and 80mg bid), 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%).

Metabolism:

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 (40mg and 80mg) 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.

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 C_max (18%). This small change in exposure is not considered clinically relevant.

Renal Impairment

Subjects with mild (creatinine clearance 61-89ml/min), moderate (creatinine clearance 31-60ml/min) or severe (creatinine clearance <30ml/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.

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

Core Tablet: Microcrystalline cellulose, lactose monohydrate, croscarmellose sodium and magnesium stearate.

Film Coat: titanium dioxide (E171), hypromellose, lactose monohydrate, triacetin and Sunset Yellow Aluminium Lake (E110).

Not Applicable.

3 years

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

Opaque PVC/Aclar/Aluminium blister packs containing 2, 3, 4, 6, 10, 18, 30 and 100 tablets (20, 40mg).

HDPE bottles with child-resistant HDPE/PP closures containing 30 and 100 tablets (20, 40mg).

Not all pack sizes may be marketed.

No special requirements.

Pfizer Limited

Sandwich

Kent, CT13 9NJ

United Kingdom

PL 00057/0452

PL 00057/0453

May 2011

POM

Company reference: RP 6_0