Relpax

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.

Shelf life

3 years

Relpax price

Incompatibilities

Not applicable.

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).

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).

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.

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.

Pharmacotherapeutic group

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 anti-migraine mechanism of action. Eletriptan has modest affinity for the human recombinant 5-HT1A, 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. This cannot be explained by any pharmacokinetic changes and so may represent a specific pharmacodynamic response to eletriptan in patients with renal impairment.

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.

Date of revision of the text

02/2018

Marketing authorisation holder

Pfizer Limited

Sandwich

Kent, CT13 9NJ

United Kingdom

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.

Nature and contents of container

Opaque PVC/Aclar/Aluminium blister packs containing 2, 3, 4, 5, 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.

Marketing authorisation number(s)

PL 00057/0453

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.

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.

Special precautions for disposal and other handling

No special requirements.

Date of first authorisation/renewal of the authorisation

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. 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 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.