Relpax

The AUC and C_max of eletriptan are increased by approximately 20 to 30% following oral administration with a high fat meal.

The C_max and AUC of eletriptan were increased by 10% and 33%, respectively, following an 80 mg BID dose of propranolol administered for 7 days. No interactive increases in blood pressure were observed. No dose adjustment is necessary for patients also taking propranolol.

The effect of eletriptan on enzymes other than cytochrome P-450 has not been investigated. In vitro human liver microsome studies suggest that eletriptan has little potential to inhibit CYP1A2, 2C9, 2E1 and 3A4 at concentrations up to 100 μM. While eletriptan has an effect on CYP2D6 at high concentration (IC₅₀ of about 41 μM), this effect should not interfere with metabolism of other drugs when eletriptan is used at recommended doses. There is no in vitro or in vivo evidence that clinical doses of eletriptan will induce drug metabolizing enzymes. Therefore, eletriptan is unlikely to cause clinically important drug interactions mediated by these enzymes.

Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans (see Warnings and Precautions).

Interactions with laboratory tests have not been established.

It has also been shown that co-administration of verapamil and eletriptan yields about a 2-fold increase in C_max and about a 3-fold increase in AUC of eletriptan.

Interactions with herbal products have not been established.

In vitro studies have shown that eletriptan is metabolized by the CYP3A4 enzyme. A clinical study demonstrated about a 3-fold increase in C_max and about a 6-fold increase in the AUC of eletriptan when combined with ketoconazole. The half-life increased from 5 hours to 8 hours and the T_max increased from 2.8 hours to 5.4 hours. Another clinical study demonstrated about a 2-fold increase in C_max and about a 4-fold increase in AUC when erythromycin was co-administered with eletriptan. It has also been shown that co-administration of verapamil and eletriptan yields about a 2-fold increase in C_max and about a 3-fold increase in AUC of eletriptan, and that co-administration of fluconazole and eletriptan yields about a 1.4-fold increase in C_max and about a 2-fold increase in AUC of eletriptan.

RELPAX is contraindicated within 72 hours of treatment with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir and nelfinavir. RELPAX is contraindicated within 72 hours with drugs that have demonstrated potent CYP3A4 inhibition and have this potent effect described in the Contraindications or Warnings and Precautions sections of their Product Monograph (see Contraindications, Warnings and Precautions and Dosage and Administration).

A clinical study demonstrated about a 3-fold increase in C_max and about a 6-fold increase in the AUC of eletriptan when co-administered with ketoconazole. The half-life of eletriptan increased from 5 hours to 8 hours and the T_max increased from 2.8 hours to 5.4 hours (see Action and Clinical Pharmacology, Pharmacokinetics).

Co-administration of fluconazole and eletriptan yields about a 1.4-fold increase in C_max and about a 2-fold increase in AUC of eletriptan.

A clinical study demonstrated about a 2-fold increase in eletriptan C_max and about a 4-fold increase in AUC when erythromycin was co-administered with eletriptan. This increased exposure was associated with an increase in eletriptan t_½ from 4.6 hours to 7.1 hours (see Action and Clinical Pharmacology, Pharmacokinetics).

Eletriptan is not a substrate for monoamine oxidase (MAO) enzymes. Therefore there is no expectation of an interaction between RELPAX and MAO inhibitors.

Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine [DHE] or methysergide) and RELPAX tablets within 24 hours is not recommended (see Action and Clinical Pharmacology, Pharmacokinetics and Contraindications).

Concomitant use of other 5-HT₁ agonists within 24 hours of RELPAX treatment is not recommended (see Contraindications).

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 (see Action and Clinical Pharmacology and Contraindications).

Eletriptan is metabolized by the CYP3A4 enzyme. Concomitant use of RELPAX and potent CYP3A4 inhibitors may lead to significant increases in AUC and C_max, therefore RELPAX tablets are contraindicated within 72 hours of treatment with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, clarithromycin, troleandomycin, ritonavir, nelfinavir and nefazodone. RELPAX is contraindicated within 72 hours with drugs that have demonstrated potent CYP3A4 inhibition and have this potent effect described in the Contraindications or Warnings and Precautions sections of their labeling (see Warnings and Precautions, Drug Interactions and Contraindications).

In controlled clinical trials, single doses of 20 mg and 40 mg were effective for the acute treatment of migraine in adults. A greater proportion of patients had a response following a 40 mg dose than following a 20 mg dose. Individuals may vary in response to doses of RELPAX tablets.

When initiating treatment with RELPAX, a starting dose of 20 mg or 40 mg may be considered. Patients who do not obtain satisfactory efficacy after an initial trial of 20 mg may be effectively treated with 40 mg in subsequent migraine attacks. The choice of dose should therefore be made on an individual basis, according to the clinical status of the patient and weighing the possible risk/benefit of the 40 mg dose. A minimal effective dose should be used.

If after an initial dose of 20 mg, headache improves but then returns a repeat dose of 20 mg may be beneficial and should be taken at least 2 hours after the initial dose. If an initial dose of 40 mg is taken, a second dose is not recommended.

If the initial dose is ineffective, controlled clinical trials have not shown a benefit of a second dose to treat the same attack.

The maximum daily dose should not exceed 40 mg.

The safety of treating an average of more than 3 headaches in a 30-day period has not been established.

RELPAX (eletriptan hydrobromide) tablets should be taken as early as possible after the onset of a migraine attack, but are also effective if taken at a later stage. RELPAX tablets should not be used prophylactically.

In some patients with renal impairment, an elevation in blood pressure was observed. A total daily dose of greater than 20 mg should be administered with caution (see Action and Clinical Pharmacology and Warnings and Precautions).

RELPAX tablets should be swallowed whole with water.

Infrequent: anorexia, constipation, diarrhea, eructation, esophagitis, flatulence, gastritis, gastrointestinal disorder, glossitis, increased salivation and liver function tests abnormal. Rare: gingivitis, hematemesis, increased appetite, rectal disorder, stomatitis, tongue disorder, tongue edema and tooth disorder.

Infrequent: abnormal vision, conjunctivitis, ear pain, eye pain, lacrimation disorder, photophobia, taste perversion and tinnitus. Rare: abnormality of accommodation, dry eyes, ear disorder, eye hemorrhage, otitis media, parosmia and ptosis.

syncope.

Frequent: sweating. Infrequent: pruritus, rash and skin disorder. Rare: alopecia, dry skin, eczema, exfoliative dermatitis, maculopapular rash, psoriasis, skin discolouration, skin hypertrophy and urticaria.

Rare: goiter, thyroid adenoma and thyroiditis.

pruritus, rash, urticaria.

Frequent: pharyngitis. Infrequent: asthma, dyspnea, respiratory disorder, respiratory tract infection, rhinitis, voice alteration and yawn. Rare: bronchitis, choking sensation, cough increased, epistaxis, hiccup, hyperventilation, laryngitis, sinusitis and sputum increased.

Significant elevations in systemic blood pressure, including hypertensive crisis, have been reported on rare occasions in patients with and without a history of hypertension treated with other 5-HT₁ agonists. RELPAX is contraindicated in patients with uncontrolled hypertension (see Contraindications).

Frequent: hypertonia, hypesthesia and vertigo. Infrequent: abnormal dreams, agitation, anxiety, apathy, ataxia, confusion, depersonalization, depression, emotional lability, euphoria, hyperesthesia, hyperkinesia, incoordination, insomnia, nervousness, speech disorder, stupor, thinking abnormal and tremor. Rare: abnormal gait, amnesia, aphasia, catatonic reaction, dementia, diplopia, dystonia, hallucinations, hemiplegia, hyperalgesia, hypokinesia, hysteria, manic reaction, neuropathy, neurosis, oculogyric crisis, paralysis, psychotic depression, sleep disorder and twitching.

Infrequent: creatine phosphokinase increased, edema, peripheral edema and thirst. Rare: alkaline phosphatase increased, bilirubinemia, hyperglycemia, weight gain and weight loss.

Treatment-Emergent Adverse Events by Initial Oral Dose of RELPAX and Placebo Reported by at Least 1% Patients with Migraine from Controlled Clinical Trials

Infrequent: arthralgia, arthritis, arthrosis, bone pain, myalgia and myasthenia. Rare: bone neoplasm, joint disorder, myopathy and tenosynovitis.

Frequent: back pain, chills and pain. Infrequent: face edema and malaise. Rare: abdomen enlarged, abscess, accidental injury, allergic reaction, fever, flu syndrome, halitosis, hernia, hypothermia, lab test abnormal, moniliasis, rheumatoid arthritis and shock.

Infrequent: impotence, polyuria, urinary frequency and urinary tract disorder. Rare: breast pain, kidney pain, leukorrhea, menorrhagia, menstrual disorder and vaginitis.

In postmarketing experience, the following additional undesirable effects have been reported:

As with other 5-HT₁ agonists, RELPAX has been associated with sensations of heaviness, pressure, tightness or pain which may be intense. These may occur in any part of the body including the chest, throat, neck, jaw and upper limbs.

Serious cardiac events, including some that have been fatal, have occurred following the use of other 5-HT₁ agonists. These events are extremely rare and most have been reported in patients with risk factors of CAD. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation (see Contraindications and Warnings and Precautions).

allergic reaction, some of which may be serious.

The frequencies of less commonly reported adverse clinical events are listed below by body system in order of decreasing frequency. Because the reports include events observed in open studies, the role of RELPAX tablets in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, etc., limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of patients reporting an event divided by the total number of patients (N=4719) exposed to RELPAX. All reported events are included except those already listed in Table 1, those too general to be informative, and those not reasonably associated with the use of the drug. Frequent adverse events are those occurring in at least 1/100 patients, infrequent adverse events are those occurring in 1/100 to 1/1000 patients, and rare adverse events are those occurring in fewer than 1/1000 patients.

ischaemic colitis.

Rare: anemia, cyanosis, leukopenia, lymphadenopathy, monocytosis and purpura.

Frequent: palpitation. Infrequent: hypertension, migraine, peripheral vascular disorder and tachycardia. Rare: angina pectoris, arrhythmia, atrial fibrillation, AV block, bradycardia, hypotension, syncope, thrombophlebitis, cerebrovascular disorder, vasospasm and ventricular arrhythmia.

Experience of the use of RELPAX in patients aged over 65 years is limited. Therefore the use of RELPAX in patients over 65 years is not recommended (see Warnings and Precautions).

The safety and efficacy of RELPAX in children has not been established and its use in this age group is not recommended (see Warnings and Precautions).

RELPAX (eletriptan hydrobromide) is indicated for the acute treatment of migraine with or without aura in adults.

RELPAX tablets are not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic, ophthalmoplegic or basilar migraine (see Contraindications). Safety and effectiveness of RELPAX tablets have not been established for cluster headache, which is present in an older, predominantly male population.

No significant overdoses in clinical trials have been reported. Twenty-one (21) subjects have received single doses of 120 mg in Phase 1 trials and 427 in Phase 2/3 trials without significant adverse effects. Based on the pharmacology of 5-HT₁ agonists, hypertension or other more serious cardiovascular symptoms could occur on overdose.

In case of overdose, standard supportive measures should be adopted. The elimination half-life of eletriptan is about 4 hours (see Action and Clinical Pharmacology), and therefore monitoring of patients after overdose with eletriptan should continue for at least 20 hours, or longer should symptoms or signs persist.

There is no specific antidote to eletriptan. In cases of severe intoxication, intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system.

It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentration of eletriptan.

Each orange, round, film-coated tablet, printed “REP40” on one side and PFIZER on the reverse, contains: eletriptan HBr 48.5 mg equivalent to eletriptan (base) 40 mg. Nonmedicinal ingredients: croscarmellose sodium, FD&C Yellow No. 6 aluminum lake, hypromellose, lactose monohydrate, microcrystalline cellulose, magnesium stearate, titanium dioxide and triacetin. Blister packs of 3.

Each orange, round, film-coated tablet, printed “REP20” on one side and PFIZER on the reverse, contains: eletriptan HBr 24.2 mg equivalent to eletriptan (base) 20 mg. Nonmedicinal ingredients: croscarmellose sodium, FD&C Yellow No. 6 aluminum lake, hypromellose, lactose monohydrate, microcrystalline cellulose, magnesium stearate, titanium dioxide and triacetin. Blister packs of 3.

There was no significant change in clearance observed in subjects with mild, moderate or severe renal impairment. In some of these patients, an elevation in blood pressure was observed (see Action and Clinical Pharmacology, Pharmacokinetics and Dosage and Administration).

Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with 5-HT₁ agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack).

Eletriptan is metabolized by the CYP3A4 enzyme. RELPAX is contraindicated within 72 hours of treatment with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir. RELPAX is contraindicated within 72 hours with drugs that have demonstrated potent CYP3A4 inhibition and have this potent effect described in the Contraindications or Warnings and Precautions sections of their labeling (see Drug Interactions and Dosage and Administration).

In a clinical pharmacology study, in subjects undergoing diagnostic coronary angiography, a subject with a history of angina, hypertension and hypercholesterolemia, receiving intravenous eletriptan (C_max of 127 ng/mL equivalent to 60 mg oral eletriptan), reported chest tightness and experienced angiographically documented coronary vasospasm with no ECG changes indicative of ischemia. There was also 1 report of atrial fibrillation in a patient with a past history of atrial fibrillation.

Because 5-HT₁ agonists may cause coronary artery vasospasm, patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of CAD or a predisposition to Prinzmetal's variant angina before receiving additional doses of medication, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud's syndrome, following the use of any 5-HT₁ agonist are candidates for further evaluation (see Contraindications).

In another coronary angiography study, supratherapeutic doses of eletriptan (comparable to 2×80 mg in the presence of a potent CYP3A4 inhibitor), administered as a rapid intravenous infusion, were compared with a standard formulation and dose of sumatriptan (6 mg sc) and placebo. There were 8 subjective reports of vasoconstriction in the eletriptan group (compared with no cases in the sumatriptan or placebo groups); however, mean change in coronary artery diameter, as determined by quantitative coronary angiography, did not differ in the 3 treatment groups.

The safety of eletriptan in pregnant women has not been established. Administration of RELPAX tablets should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus.

In reproductive toxicity studies in rats and rabbits, oral administration of eletriptan was associated with developmental toxicity (decreased fetal and pup weights) and an increased incidence of fetal structural abnormalities). Effects on fetal and pup weights were observed at doses that were, on a mg/m² basis, 6 to 12 times greater than the clinical MRDD of 80 mg. The increase in structural alterations occurred in the rat and rabbit at doses that, on a mg/m² basis, were 12 times greater than (rat) and approximately equal to (rabbit) the MRDD.

When pregnant rats were administered eletriptan during the period of organogenesis at doses of 10, 30 or 100 mg/kg/day, fetal weights were decreased and the incidences of vertebral and sternebral variations were increased at 100 mg/kg/day (approximately 12 times the MRDD on a mg/m² basis). The 100 mg/kg dose was also maternally toxic, as evidenced by decreased maternal body weight gain during gestation. The no-effect dose for developmental toxicity in rats exposed during organogenesis was 30 mg/kg, which is approximately 4 times the MRDD on a mg/m² basis.

When doses of 5, 10 or 50 mg/kg/day were given to New Zealand White rabbits throughout organogenesis, fetal weights were decreased at 50 mg/kg, which is approximately 12 times the MRDD on a mg/m² basis. The incidences of fused sternebrae and vena cava deviations were increased in all treated groups. Maternal toxicity was not produced at any dose. A no-effect dose for developmental toxicity in rabbits exposed during organogenesis was not established, and the 5 mg/kg dose is approximately equal to the MRDD on a mg/m² basis.

When female rats were treated with 5, 15 or 50 mg/kg/day during late gestation and lactation, in utero deaths were increased and pup weights were decreased postnatally at 50 mg/kg/day. The effect on pup weights persisted to adulthood. Exposure to parent drug (AUC) at that dose was approximately 4 times that achieved in humans receiving the MRDD. The 50 mg/kg/day dose was mildly maternally toxic, as evidenced by minimally decreased maternal body weight gain during gestation. The no-effect dose for developmental effects was 15 mg/kg, a dose that produced an AUC for parent drug approximately equal to that achieved in humans receiving the MRDD.

Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasions in patients receiving other 5-HT₁ agonists with and without a history of hypertension. In clinical pharmacology studies, oral eletriptan (at doses of 60 mg or more) was shown to cause small transient dose-related increases in blood pressure, predominantly diastolic, consistent with its mechanism of action and with other 5-HT_1B/1D agonists. The effect was more pronounced in renally impaired and elderly subjects. A single patient with hepatic cirrhosis received eletriptan 80 mg and experienced a blood pressure of 220/96 mmHg 5 hours after dosing. The treatment-related event persisted for 7 hours.

RELPAX tablets are contraindicated in patients with uncontrolled or severe hypertension (see Contraindications).

The effects of severe hepatic impairment on eletriptan metabolism were not evaluated. RELPAX tablets should not be given to patients with severe hepatic impairment.

Subjects with mild or moderate hepatic impairments demonstrated an increase in AUC (34%), C_max (18%) and in half-life. No dose adjustment is necessary in mild to moderate impairment (see Action and Clinical Pharmacology, Pharmacokinetics, and Dosage and Administration).

RELPAX has been given to only 50 patients over the age of 65. Blood pressure was increased to a greater extent in elderly subjects than in young subjects. The pharmacokinetic disposition of eletriptan in the elderly is similar to that seen in younger adults. There is a statistically significant increase in half-life (from about 4.4 hours to 5.7 hours) between elderly (65 to 93 years of age) and younger adult subjects (18 to 45 years of age) (see Action and Clinical Pharmacology, Special Populations and Conditions). Experience of the use of RELPAX in patients aged over 65 years is limited. Therefore the use of RELPAX in patients over 65 years is not recommended.

Although the abuse potential of RELPAX tablets has not been assessed, no abuse of, tolerance to, or withdrawal from, or drug-seeking behavior was observed in patients who received RELPAX in clinical trials or their extensions. The 5-HT_1B/1D agonists, as a class, have not been associated with drug abuse.

RELPAX (eletriptan hydrobromide) tablets should only be used where a clear diagnosis of migraine has been established.

Care should be taken to exclude other potentially serious neurologic conditions before treating headache in patients not previously diagnosed with migraine headache or who experience a headache that is atypical for them. There have been rare reports where patients received 5-HT₁ agonists for severe headaches that were subsequently shown to have been secondary to an evolving neurologic lesion. For newly diagnosed patients or patients presenting with atypical symptoms, the diagnosis of migraine should be reconsidered if no response is seen after the first dose of eletriptan.

Eletriptan was not mutagenic in bacterial or mammalian cell assays in vitro, testing negative in the Ames reverse mutation test and the hypoxanthineguanine phosphoribosyl transferase (HGPRT) mutation test in Chinese hamster ovary cells. It was not clastogenic in 2 in vivo mouse micronucleus assays. Results were equivocal in in vitro human lymphocyte clastogenicity tests, in which the incidence of polyploidy was increased in the absence of metabolic activation (-S9 conditions), but not in the presence of metabolic activation.

Lifetime carcinogenicity studies, 104 weeks in duration, were carried out in mice and rats by administering eletriptan in the diet at doses of up to 400 mg/kg/day. In rats, the incidence of testicular interstitial cell adenomas was increased at the high dose of 75 mg/kg/day. The estimated exposure (AUC) to parent drug at that dose was approximately 6 times that achieved in humans receiving the maximum recommended daily dose (MRDD) of 80 mg, and at the no-effect dose of 15 mg/kg/day it was approximately 2 times the human exposure at the MRDD. In mice, the incidence of hepatocellular adenomas was increased at the high dose of 400 mg/kg/day. The exposure to parent drug (AUC) at that dose was approximately 18 times that achieved in humans receiving the MRDD, and the AUC at the no-effect dose of 90 mg/kg/day was approximately 7 times the human exposure at the MRDD.

In a rat fertility and early embryonic development study, doses tested were 50, 100 and 200 mg/kg/day, resulting in systemic exposures to parent drug in rats, based on AUC, that were 4, 8, and 16 times MRDD, respectively, in males and 7, 14, and 28 times MRDD, respectively, in females. There was a prolongation of the estrous cycle at the 200 mg/kg/day dose due to an increase in duration of estrus, based on vaginal smears. There were also dose-related, statistically significant decreases in mean numbers of corpora lutea per dam at all 3 doses, resulting in decreases in mean numbers of implants and viable fetuses per dam. This suggests a partial inhibition of ovulation by eletriptan. There was no-effect on fertility of males and no other effect on fertility of females.

Patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that RELPAX does not affect them adversely.

Safety and effectiveness of RELPAX tablets in pediatric patients have not been established; therefore, RELPAX is not recommended for use in patients under 18 years of age.

The efficacy of RELPAX tablets (40 mg) in patients 11-17 was not established in a randomized, placebo-controlled trial of 274 adolescent migraineurs, there were no statistically significant differences between treatment groups. The headache response rate at 2 hours was 57% for both RELPAX 40 mg tablets and placebo. Adverse events observed were similar in nature to those reported in clinical trials in adults. RELPAX is not recommended for use in patients under 18 years of age.

Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans. If concomitant treatment with RELPAX and SSRIs (e.g., fluoxetine, paroxetine, sertraline) or SNRIs (e.g., venlafaxine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) (see Drug Interactions).

5-HT₁ agonists may cause vasospastic reactions other than coronary artery spasm. Both peripheral vascular ischemia and colonic ischemia with abdominal pain, and bloody diarrhea have been reported with 5-HT₁ agonists.

As with other triptans, eletriptan has been associated with transient pain or pressure sensation in the chest or throat. Because of the potential of 5-HT₁ agonists to cause coronary vasospasm, eletriptan should not be given to patients with documented ischemic or vasospastic coronary artery disease (CAD) (see Contraindications). It is strongly recommended that eletriptan not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease, or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient's medical history, electrocardiographic, or other investigations reveal findings indicative of, or consistent with coronary artery vasospasm or myocardial ischemia, eletriptan should not be administered (see Contraindications).

These evaluations, however, may not identify every patient who has cardiac disease, and in very rare cases, serious cardiac events, such as myocardial infarction or coronary ischemia have occurred in patients without evidence of underlying cardiovascular disease.

For patients with risk factors predictive of CAD who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of eletriptan take place in the setting of a physician's office or similar medically staffed and equipped facility unless the patient has previously received eletriptan. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining, on the first occasion of use, an electrocardiogram (ECG) during the interval immediately following administration of eletriptan, in patients with risk factors. However, an absence of drug-induced cardiovascular effects on the occasion of the initial dose does not preclude the possibility of such effects occurring with subsequent administrations.

It is recommended that patients who are intermittent long-term users of 5-HT₁ agonists including eletriptan, and who have or acquire risk factors predictive of CAD, as described above, undergo periodic cardiovascular evaluation as they continue to use eletriptan.

If symptoms consistent with angina occur after the use of eletriptan, ECG evaluation should be carried out to look for ischemic changes.

The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to therapy with eletriptan.

Discomfort in the chest, neck, throat and jaw (including pain, pressure, heaviness, and tightness) has been reported after administration of eletriptan. Because 5-HT₁ agonists may cause coronary vasospasm, patients who experience signs or symptoms suggestive of angina following eletriptan should be evaluated for the presence of CAD or a predisposition to variant angina before receiving additional doses, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud's syndrome following eletriptan should be evaluated for atherosclerosis or predisposition to vasospasm (see Contraindications and Warnings and Precautions and Adverse Reactions, Clinical Trial Adverse Drug Reactions).

In subjects (n=10) with suspected coronary artery disease undergoing angiography, a 5-HT₁ agonist at a subcutaneous dose of 1.5 mg produced an 8% increase in aortic blood pressure, an 18% increase in pulmonary artery blood pressure, and an 8% increase in systemic vascular resistance. In addition, mild chest pain or tightness was reported by 4 subjects. Clinically significant increases in blood pressure were experienced by 3 of the subjects (2 of whom also had chest pain/discomfort). Diagnostic angiogram results revealed that 9 subjects had normal coronary arteries and 1 had insignificant coronary artery disease.

In an additional study with this same drug, migraine patients (n=35) free of cardiovascular disease were subjected to assessments of myocardial perfusion by positron emission tomography while receiving a subcutaneous 1.5 mg dose in the absence of a migraine attack. Reduced coronary vasodilatory reserve (~10%), increased coronary resistance (~20%), and decreased hyperaemic myocardial blood flow (~10%) were noted. The relevance of these findings to the use of the recommended oral dose of this 5-HT₁ agonist is not known.

Transient corneal opacities were seen in dogs receiving oral eletriptan at 5 mg/kg and above. They were observed during the first week of treatment, but were not present thereafter despite continued treatment. Exposure at the no-effect dose level of 2.5 mg/kg exceeded that achieved in humans at the maximum recommended daily dose.

Cases of myocardial infarction and cardiac death have been reported in patients with cardiovascular risk factors (e.g. hypertension, hyperlipidemia, strong family history of CAD) or with inappropriate concomitant use of therapeutic doses of eletriptan and other triptans.

The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively if the cases were actually caused by eletriptan or to reliably assess causation in individual cases.

As with other triptans, eletriptan may cause coronary artery vasospasm. Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of other 5-HT₁ agonists. Considering the extent of use of 5-HT₁ agonists in patients with migraine, the incidence of these events is extremely low.

Patients with symptomatic Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders should not receive RELPAX.

As with other 5-HT₁ agonists, sensations of tightness, pain, pressure, and heaviness have been reported after treatment with RELPAX (eletriptan hydrobromide) tablets in the precordium, throat and jaw. Events that are localized to the chest, throat, neck and jaw have not been associated with arrhythmias or ischemic ECG changes in clinical trials.

Rare hypersensitivity (anaphylaxis/anaphylactoid) reactions have occurred in patients receiving other 5-HT₁ agonists. Such reactions can be life-threatening or fatal. In general, hypersensitivity reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. Owing to the possibility of cross-reactive hypersensitivity reactions, RELPAX should not be used in patients having a history of hypersensitivity to chemically-related 5-HT₁ receptor agonists (see Adverse Reactions).

Caution should be observed if eletriptan is to be used in patients with a history of seizures or other risk factors, such as structural brain lesions, which lower the convulsion threshold.

In rats treated with a single intravenous (3 mg/kg) dose of radiolabelled eletriptan, elimination of radioactivity from the retina was prolonged, suggesting that eletriptan and/or its metabolites may bind to the melanin of the eye. Because there could be accumulation in melanin-rich tissues over time, this raises the possibility that eletriptan could cause toxicity in these tissues after extended use. There were, however, no adverse ophthalmologic changes related to treatment with eletriptan in the 1-year dog toxicity study. Although no systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic monitoring are offered, prescribers should be aware of the possibility of long-term ophthalmologic effects.

Caution should be exercised when RELPAX tablets are administered to nursing women.

Eletriptan is excreted in human breast milk. In 1 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 approximately 0.02% of the administered dose. The ratio of eletriptan mean concentration in breast milk to plasma was 1:4, but there was great variability. The resulting eletriptan concentration-time profile was similar to that seen in the plasma over 24 hours, with very low concentrations of drug (mean 1.7 ng/mL) still present in the milk 18-24 hours post-dose. The N-desmethyl active metabolite was not measured in the breast milk.

The effects of severe hepatic impairment on eletriptan metabolism have not been evaluated. Subjects with mild or moderate hepatic impairment demonstrated an increase of eletriptan in AUC (34%), C_max (18%) and half-life (see Contraindications, Warnings and Precautions and Dosage and Administration for severe hepatic impairment).

RELPAX (eletriptan hydrobromide) has been given to only 50 patients over the age of 65. There is a statistically significant increase in half-life (from about 4.4 hours to 5.7 hours) in the elderly compared to younger adult subjects based on population pharmacokinetic analysis (see Warnings and Precautions, Special Populations).

Blood pressure was increased to a greater extent in elderly subjects than in young subjects.

The volume of distribution following IV administration is 138L. Plasma protein binding is moderate and approximately 85%.

Eletriptan is rapidly and well absorbed after oral administration with peak plasma levels occurring approximately 1.5 hours after dosing to healthy subjects. In patients with moderate to severe migraine, the median T_max is 2.0 hours. The mean absolute bioavailability of eletriptan is approximately 50%. The oral pharmacokinetics are slightly more than dose proportional over the clinical dose range. The AUC and C_max of eletriptan are increased by approximately 20 to 30% following oral administration with a high fat meal.

Eletriptan binds with high affinity to 5-HT_1B, 5-HT_1D and 5-HT_1F receptors, has modest affinity for 5-HT_1A, 5-HT_1E, 5-HT_2B and 5-HT₇ receptors, and little or no affinity for 5-HT_2A, 5-HT_2C, 5-HT₃, 5-HT₄, 5-HT_5A and 5-HT₆ receptors.

Eletriptan has no significant affinity or pharmacological activity at adrenergic alpha₁, alpha₂, or beta; dopaminergic D₁ or D₂; muscarinic; or opioid receptors.

Two theories have been proposed to explain the efficacy of 5-HT receptor agonists in migraine. One theory suggests that activation of 5-HT₁ receptors located on intracranial blood vessels, including those on the arteriovenous anastomoses, leads to vasoconstriction, which is correlated with the relief of migraine headache. The other hypothesis suggests that activation of 5-HT₁ receptors on sensory nerve endings in the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release.

In the anesthetized dog, eletriptan has been shown to reduce carotid arterial blood flow, with only a small increase in arterial blood pressure at high doses. While the effect on blood flow was selective for the carotid arterial bed, decreases in coronary artery diameter were observed. Eletriptan has also been shown to inhibit trigeminal nerve activity in the rat.

A comparison of the pharmacokinetic studies conducted in western countries and those conducted in Japan have indicated an approximate 35% reduction in the exposure of eletriptan in Japanese male volunteers compared to western males.

Population pharmacokinetic analysis of 2 clinical studies indicates no evidence of pharmacokinetic differences between Caucasians and non-Caucasian patients.

There was no significant change in clearance observed in subjects with mild, moderate or severe renal impairment, though blood pressure elevations were observed in this population (see Warnings and Precautions and Dosage and Administration).

The pharmacokinetics of eletriptan are unaffected by gender.

The N-demethylated metabolite of eletriptan is the only known active metabolite. This metabolite causes vasoconstriction similar to eletriptan in animal models. Though the half-life of the metabolite is estimated to be about 13 hours, the plasma concentration of the N-demethylated metabolite is 10-20% of that of parent drug and is unlikely to contribute significantly to the overall effect of the parent compound. In vitro studies indicate that eletriptan is primarily metabolized by cytochrome P-450 enzyme CYP3A4 (see Contraindications, Warnings and Precautions and Drug Interactions).

In a study of 16 healthy females, the pharmacokinetic profile of eletriptan remained consistent throughout the phases of the menstrual cycle.

The volume of distribution following oral administration is lower in children <12 years of age resulting in higher plasma concentrations than would be predicted following the same dose in adults. RELPAX is not recommended for use in patients under 18 years of age (see Warnings and Precautions, Special Populations).

RELPAX is contraindicated within 72 hours of treatment with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir. RELPAX is contraindicated within 72 hours with drugs that have demonstrated potent CYP3A4 inhibition and have this potent effect described in the Contraindications, or Warnings and Precautions sections of their labeling (see Warnings and Precautions, Drug Interactions and Dosage and Administration).

RELPAX is contraindicated within 24 hours of treatment with another 5-HT₁ agonist, an ergotamine containing or ergot type medication such as dihydroergotamine (DHE) or methysergide.

RELPAX is contraindicated in patients with hemiplegic ophthalmoplegic or basilar migraine.

RELPAX tablets are contraindicated in patients with severe hepatic impairment.

RELPAX tablets are contraindicated in patients with known hypersensitivity to eletriptan or to any of its inactive ingredients.