Relpax

Relpax

eletriptan

Manufacturer:

Pfizer

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Eletriptan HBr.
Description
Each film-coated tablet contains 40 mg eletriptan as eletriptan hydrobromide.
Excipients/Inactive Ingredients: Microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, titanium dioxide (E171), hypromellose, glycerol triacetate & sunset yellow aluminium lake (E110).
Action
Pharmacotherapeutic Group: Selective serotonin (5-HT1) agonist. ATC Code: N02CC.
Pharmacology: Pharmacodynamics: Mechanism of Action: Eletriptan is a potent and 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 anti-migraine mechanism of action. Eletriptan has modest affinity for the human recombinant 5-HT1A, 5-HT2B, 5-HT1E and 5-HT7 receptors.
Further Information on Clinical Trials: The efficacy and safety of eletriptan in the acute treatment of migraine has been evaluated in more than 5000 patients who received eletriptan 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.
Eletriptan was also effective in the treatment of associated symptoms of migraine such as vomiting, nausea, photophobia and phonophobia.
Eletriptan is consistently effective in migraine with or without aura and in menstrually associated migraine. Eletriptan does not help prevent migraine headache and therefore eletriptan 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 eletriptan than with normal volunteers (see Precautions). This cannot be explained by any pharmacokinetic changes and so may represent a specific pharmacodynamic response to eletriptan in patients with renal impairment.
Pharmacokinetics: Absorption: Eletriptan is rapidly and well absorbed across the gastrointestinal tract (at least 81%) after oral administration. 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.
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 twice daily), the drug accumulation over 7 days was greater than predicted (approximately 40%).
Distribution: The volume of distribution of eletriptan following intravenous 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 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 drug and so would not be expected to significantly contribute to the therapeutic action of eletriptan.
Elimination: Mean total plasma clearance of eletriptan following intravenous 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 (7-11 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 Insufficiency: 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.
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.
Toxicology: 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.
Indications/Uses
Acute treatment of migraine with or without aura.
Dosage/Direction 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.
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 as clinical trials have not adequately established efficacy with the second dose. Clinical trials show that the majority of patients who do not respond to the treatment of an attack will respond to the treatment of a subsequent attack.
Patients who do not obtain satisfactory efficacy with 40 mg may be effectively treated with 80 mg in a subsequent migraine attack.
The maximum daily dose should not exceed 160 mg.
Elderly (over 65 years of age): Safety and efficacy in patients over 65 years of age have not been systematically evaluated due to a small number of such patients in clinical trials. Blood pressure effects may be more marked in this population than in younger adults (see Precautions).
Adolescents (12-17 years of age): In a clinical trial in adolescents, a high placebo response rate was observed. 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 Pharmacology: Pharmacokinetics under Actions).
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 Precautions), doses higher than 40 mg should be used with caution.
Administration:
The tablets should be swallowed whole with water.
Overdosage
Subjects have received single doses of 120 mg without significant adverse effects. However, 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 haemodialysls or peritoneal dialysis has on the serum concentrations of eletriptan.
Contraindications
Hypersensitivity to eletriptan hydrobromide or to any of the excipients.
Patients with severe hepatic impairment.
As with other 5-hydroxytryptamine type 1 (5-HT1) receptor agonists, the following contraindications are based on the pharmacodynamic properties of eletriptan: Patients with uncontrolled hypertension.
Patients with confirmed coronary heart disease, including ischaemic heart disease (angina pectoris, previous myocardial infarction or confirmed silent ischaemia).
Patients with coronary artery vasospasm, objective or subjective symptoms of ischaemic heart disease or Prinzmetal’s angina.
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 24 hours before or after treatment with eletriptan (see Interactions).
Concomitant administration of other 5-HT1 receptor agonists.
Special Precautions
Serotonin Syndrome: Co-administration of eletriptan with other drugs having serotonergic activity, such as SNRIs and SSRIs, should be undertaken with caution due to reports of the development of serotonin syndrome in isolated cases of concomitant use of a triptan with other serotonergic drugs (see Interactions).
Eletriptan use with potent CYP3A4 inhibitors, e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, josamycin and protease inhibitors (ritonavir, indinavir and nelfinavir), is not recommended (see Interactions).
As with other 5-HT1 receptor agonists, 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.
As with other 5-HT1 receptor agonists, 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.
Cardiovascular evaluation prior to commencement of treatment with eletriptan is recommended for patients in whom cardiovascular disease is likely or in patients at risk of cardiovascular disease or patients at risk of coronary artery disease (CAD) (e.g. patients with hypertension, diabetes, smokers, men over 40 years of age, post-menopausal women and those with a strong family history of CAD). Patients in whom CAD is established should not be treated with eletriptan (see Contraindications).
Eletriptan has not been systematically evaluated for use in patients with heart failure. As with other 5-HT1 receptor agonists, use in these patients is not recommended.
Within the clinical dose range, slight and transient increases in blood pressure have been seen with eletriptan doses of 60 mg or greater. The effect was more pronounced in renally impaired and elderly subjects. In a clinical pharmacology study, a single oral 80 mg dose was administered to normal (n=6) subjects and to subjects with severe (n=5), moderate (n=5) and mild (n=6) degrees of renal impairment. The maximum increase from baseline in subjects with renal impairment ranged from 14 to 17 mmHg for systolic blood pressure or 14 to 21 mmHg for diastolic blood pressure and was greater than that observed in the normal subjects (3-4 mmHg).
Excessive use of any anti-migraine medicinal product can lead to daily chronic headaches. Overuse of all triptans has been reported primarily in patients with chronic daily headache.
Effects on Ability to Drive and Operate Machinery: Migraine or treatment with some 5-HT1 receptor agonists, including eletriptan, may cause drowsiness or dizziness in some patients. Therefore, caution is recommended in patients performing skilled tasks (e.g. driving or operating machinery) during the migraine attack and following administration of eletriptan.
Use In Pregnancy & Lactation
Use in Pregnancy: The safety of eletriptan in pregnant women has not been established. There is no evidence of teratogenicity in animal studies. Administration of RELPAX should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.
Use in Lactation: 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.
Adverse Reactions
RELPAX has been administered in clinical trials to more than 5,000 patients.
Eletriptan is generally well tolerated. Adverse reactions were usually transient and mild to moderate in nature and resolved spontaneously without additional treatment. 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 only took one dose.
The following adverse reactions (with an incidence ≥1% and higher than placebo) were reported in patients treated with therapeutic doses in clinical trials: Nervous System Disorders: Common: Dizziness, headache, hypertonia, hypoesthesia, myasthenia, paraesthesia, somnolence.
Ear and Labyrinth Disorders: Common: Vertigo.
Cardiac Disorders: Common: Palpitation, tachycardia.
Vascular Disorders: Common: Sensation of warmth or flushing.
Respiratory, Thoracic and Mediastinal Disorders: Common: Pharyngitis, throat tightness.
Gastrointestinal Disorders: Common: Abdominal pain, dry mouth, dyspepsia, nausea.
Skin and Subcutaneous Tissue Disorders: Common: Sweating.
Musculoskeletal, Connective Tissue and Bone Disorders: Common: Back pain, myalgia.
General Disorders and Administration Site Conditions: Common: Asthenia, chest symptoms (pain, tightness, pressure), chills, pain.
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 additional undesirable effects have been reported: Immune System Disorders: Allergic reaction, some of which may be serious, including angioedema.
Nervous System Disorders: Rare cases of syncope.
Vascular: Hypertension.
Gastrointestinal Disorders: Vomiting, rare cases of ischaemic colitis.
Cardiac Disorders: Myocardial ischemia or infarction, arteriospasm coronary.
Skin and Subcutaneous Tissue Disorders: Pruritus, rash, urticaria.
Drug Interactions
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 Interaction with serotonergic active drugs as follows).
Population pharmacokinetic analysis of clinical studies has suggested that the following medicinal products (beta-blockers, tricyclic antidepressants, selective serotonin re-uptake inhibitors, estrogen based hormone replacement therapy, estrogen containing oral contraceptives and calcium channel blockers) are unlikely to have an effect on the pharmacokinetic properties of eletriptan (see Interaction with Serotonergic Active Drugs as follows).
Eletriptan is not a substrate for monoamine oxidase (MAO). There is no expectation of a pharmacokinetic 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 (1,000 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 with erythromycin and from 4.8 to 8.3 hours with ketoconazole (see Pharmacology: Pharmacokinetics under Actions). Therefore, eletriptan 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 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 of eletriptan will inhibit or induce cytochrome P450 enzymes, including CYP3A4 drug metabolizing enzymes. Therefore, it is considered that eletriptan is unlikely to cause clinically important drug interactions mediated by these enzymes.
Interaction with Serotonergic Active Drugs: Co-administration of 5-HT agonists, including eletriptan, with drugs having serotonergic activity, such as SSRIs and SNRIs, may increase the risk of serotonin syndrome. If concomitant treatment with eletriptan and a serotonergic active drug is clinically warranted, caution is advised. Careful observation of the patient is warranted particularly during treatment initiation or dose increase of either drug (see Precautions).
Caution For Usage
Incompatibilities: None.
Storage
Do not store above 30°C.
ATC Classification
N02CC06 - eletriptan ; Belongs to the class of selective serotonin (5HT1) agonists preparations. Used to relieve migraine.
Presentation/Packing
FC tab 40 mg (round, convex, orange, debossed with 'REP 40' on one side and 'Pfizer' on the other) x 2's.
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