INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
RELPAX

SCHEDULING STATUS
Schedule 4

PRESCRIPTION REQUIRED

PROPRIETARY NAME
(and dosage form):

RELPAX
Eletriptan

RELPAX 20 mg Tablets
RELPAX 40 mg Tablets
RELPAX 80 mg Tablets

COMPOSITION
RELPAX 20 mg Tablets: Each tablet contains 20 mg eletriptan as eletriptan hydrobromide.
RELPAX 40 mg Tablets: Each tablet contains 40 mg eletriptan as eletriptan hydrobromide.
RELPAX 80 mg Tablets: Each tablet contains 80 mg eletriptan as eletriptan hydrobromide.
RELPAX film-coated tablets contain the following inactive ingredients:
Microcrystalline cellulose, lactose, croscarmellose sodium, magnesium stearate, hypromellose, glycerol triacetate and titanium dioxide and sunset yellow aluminium lake as colourants.

PHARMACOLOGICAL CLASSIFICATION
A 7.3 - Migraine preparations

PHARMACOLOGICAL ACTION
Eletriptan is a selective agonist at the vascular 5-HT1B and neuronal 5-HT1D receptors. Eletriptan also exhibits affinity for the 5-HT1F receptor which may contribute to its anti-migraine mechanism of action. Eletriptan has modest affinity for the human recombinant 5-HT1A, 5-HT2B, 5-HT1E and 5-HT7 receptors.
Eletriptan inhibits neurogenic inflammation in the dura mater of animals.
Absorption:
Eletriptan is absorbed (at least 81%) across the gastro-intestinal tract after oral administration to man. Absolute oral bioavailability across males and females is approximately 50%. The mean Tmax occurs at approximately 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.
On multiple dosing at clinical doses (40 mg tid and 80 mg bid), the drug accumulation over 7 days was greater than predicted (approximately 40%).
Distribution:
The volume of distribution of eletriptan following IV administration is 138 L 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 concentration of eletriptan following co-administration with erythromycin, a known selective and potent CYP3A4 inhibitor. 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 drug 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
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
Hepatic Insufficiency
Subjects with hepatic impairment (Child-Pugh A and B) demonstrated a 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.
Renal Insufficiency
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.

INDICATIONS
Acute treatment of migraine with or without aura

CONTRA-INDICATIONS

•	Hypersensitivity to any component of the preparation.
•	Severe hepatic impairment.
•	Uncontrolled hypertension.
•	Confirmed or suspected 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.
•	Peripheral arterial insufficiency.
•	A history of cerebrovascular accident (CVA) or transient ischaemic attack (TIA).
•	Concomitant administration of ergotamine, derivatives of ergotamine (including methysergide), or other 5-HT1 receptor agonists with eletriptan.
•	Pregnancy and lactation as safety has not been demonstrated.
•	Children (under 12 years) and adolescents (12-17 years), as safety and efficacy have not been demonstrated

WARNINGS
RELPAX should only be used where a clear diagnosis of migraine has been established. RELPAX is not indicated for the management of hemiplegic 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.
In patients in whom unrecognised cardiac disease is likely, cardiovascular evaluation prior to commencement of treatment with RELPAX is recommended.
RELPAX may cause increases in blood pressure that are usually mild and transient, but may be more pronounced in elderly and renally impaired subjects.
Effects on Ability to Drive and Use Machines
Caution is recommended in patients performing skilled tasks (e.g. driving or operating machinery) as drowsiness and dizziness may occur

DOSAGE AND DIRECTIONS FOR USE
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.
RELPAX tablets should not be used prophylactically.
RELPAX should only be taken during the headache phase of migraine.
The tablets should be swallowed whole with water.
Adults (18-65 years of age):
The recommended initial dose is 40 mg.
If headache returns within 24 hours: If after an initial response migraine headache recurs within 24 hours, an additional 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. Clinical trials show that patients who do not respond to the treatment of an initial attack respond to the treatment of a subsequent attack.
Patients who do not obtain satisfactory efficacy with 40 mg may have the dose increased to 80 mg in a subsequent migraine attack.
The maximum daily dose should not exceed 160 mg.
A 20 mg dose of RELPAX is recommended in patients receiving erythromycin and other specific potent CYP3A4 inhibitors e.g. ketoconazole, itraconazole and clarithromycin. The total daily intake should not exceed 40 mg for these patients.
Elderly (over 65 years of age)
As effects on blood pressure may be more marked in elderly patients than in younger adults (see Warnings section), doses higher than 40 mg should be used with caution.
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.
Renal Impairment
As the blood pressure effects of RELPAX are amplified in renal impairment (see Warnings section), doses higher than 40 mg should be used with caution.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
The incidence and severity of adverse events seen in patients who took two doses of the same strength to treat a single attack were similar to these observed in patients who had taken only one dose.
The following adverse reactions (with incidence >1% and higher than placebo) were reported in patients treated with therapeutic doses in clinical trials:
General: asthenia, chest tightness, abdominal pain, pain, back pain, chills, sweating.
CNS: somnolence, dizziness, paraesthesia, sensation of stiffness, headache, hypaesthesia, vertigo.
Gastrointestinal: nausea, dry mouth, throat tightness, dyspepsia.
Cardiovascular: sensation of warmth or flushing.
Respiratory: pharyngitis.
Interactions with other medicines and other forms of Interaction
Effect of other medicines on eletriptan
There is no evidence that concomitant use of migraine prophylactic medications (e.g.beta-blockers, tricyclic antidepressants, selective serotonin reuptake inhibitors, methysergide and flunarizine)has any effect on the efficacy or undesired effects of eletriptan.
In clinical studies with propranolol, the exposure of eletriptan was increased by 33% (AUC). This effect is not considered clinically significant as there was no associated increase in blood pressure or adverse events compared to administering eletriptan alone.
In clinical studies with erythromycin, a specific and potent inhibitor of CYP3A4, significant increases in eletriptan Cmax (2 fold) and AUC (4 fold) were observed in the presence of erythromycin. This increased exposure was associated with an increase in eletriptan t½ from 4.6 to 7.1 hours (see Pharmacological Action).Therefore a 20 mg dose of RELPAX isrecommende in patients receiving erythromycin and other specific potent CYP3A4 inhibitors e.g.ketoconazole, itraconazole and clarithromycin. The total daily intake should not exceed 40 mg.
In clinical studies with oral Cafergot (caffeine/ergotamine) administered 1 and 2 hours after eletriptan, additive increases in blood pressure were observed. Therefore, it is recommended that either ergotamine-containing or ergot-type medications (e.g. dihydroergotamine or methysergide)shouldnot 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.
Population pharmacokinetic analysis of clinical studies has shown that the following medicines (beta- blockers, tricyclic antidepressants, selective serotonin re-uptake inhibitors, oestrogen based hormone replacement therapy, oestrogen containing oral contraceptives and calcium channel blockers) have no 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.
Effect of eletriptan on other medicines
In vitro human liver microsome studies suggest that eletriptan has little potential to inhibit CYP1A2, 2C9, 2E1 and 3A4 at concentrations up to 100 microM. Eletriptan does have a small effect on CYP2D6 with an IC50 of approximately 41 microM. The average Cmax of eletriptan following a single oral dose of 80 mg was 0.5 microM. There is no in vitro or in vivo evidence that clinical doses (and associated concentrations) of eletriptan will induce drug metabolising enzymes. Therefore eletriptan is unlikely to cause clinically important drug interactions mediated by these enzymes.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
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 have on the serum concentrations of eletriptan.

IDENTIFICATION
RELPAX 20 mg Tablets: Orange standard round convex film coated tablets debossed with “REP 20”on one side and “Pfizer”on the other.
RELPAX 40 mg Tablets: Orange standard round convex film coated tablets debossed with “REP 40”on one side and “Pfizer”on the other.
RELPAX 80 mg Tablets: Orange standard round convex film coated tablets debossed with “REP 80”on one side and “Pfizer”on the other.

PRESENTATION
RELPAX 20 mg, 40 mg and 80 mg Tablets:
Aclar blister packs containing 2 or 4 tablets

STORAGE INSTRUCTIONS
Store below 25°C. Keep out of the reach of children.

REGISTRATION NUMBERS

20 mg tablets:	34/7.3/0077
40 mg tablets:	34/7.3/0078
80 mg tablets:	34/7.3/0079

NAME AND BUSINESS ADDRESS OF APPLICANT
Pfizer Laboratories (Pty) Ltd
102 Rivonia Road
Sandton, 2196
SOUTH AFRICA

DATE OF PUBLICATION OF THIS PACKAGE INSERT
18 December 2001

Updated on this site: February 2005
Source: Pharmaceutical Industry

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