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Relpax (Tablet, Film Coated)

Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2052

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Relpax (Tablet, Film Coated)
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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. The choice of dose should therefore be made on an individual basis. An 80 mg dose, although also effective, was associated with an increased incidence of adverse events. Therefore, the maximum recommended single dose is 40 mg. If after the initial dose, headache improves but then returns, a repeat dose may be beneficial. If a second dose is required, it should be taken at least 2 hours after the initial dose. 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 80 mg. The safety of treating an average of more than 3 headaches in a 30-day period has not been established.<br/>CYP3A4 Inhibitors: Eletriptan is metabolized by the CYP3A4 enzyme. Eletriptan should not be used within at least 72 hours of treatment with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir and nelfinavir. Eletriptan should not be used within 72 hours with drugs that have demonstrated potent CYP3A4 inhibition and have this potent effect described in the CONTRAINDICATIONS, WARNINGS or PRECAUTIONS sections of their labeling .<br/>Hepatic Impairment: The drug should not be given to patients with severe hepatic impairment since the effect of severe hepatic impairment on eletriptan metabolism was not evaluated. No dose adjustment is necessary in mild to moderate impairment .
dailymed-instance:descripti...
RELPAX (eletriptan) Tablets contain eletriptan hydrobromide, which is a selective 5-hydroxytryptamine 1B/1D (5-HT1B/1D) receptor agonist. Eletriptan is chemically designated as (R)-3-[(1-Methyl-2-pyrrolidinyl)methyl]-5-[2-(phenylsulfonyl)ethyl]-1H-indole monohydrobromide, and it has the following chemical structure: The empirical formula is CHNOS . HBr, representing a molecular weight of 463.40. Eletriptan hydrobromide is a white to light pale colored powder that is readily soluble in water. Each RELPAX Tablet for oral administration contains 24.2 or 48.5 mg of eletriptan hydrobromide equivalent to 20 mg or 40 mg of eletriptan, respectively. Each tablet also contains the inactive ingredients microcrystalline cellulose NF, lactose NF, croscarmellose sodium NF, magnesium stearate NF, titanium dioxide USP, hypromellose, triacetin USP and FD&C Yellow No. 6 aluminum lake.
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Mechanism of Action: Eletriptan binds with high affinity to 5-HT, 5-HTand 5-HTreceptors, has modest affinity for 5-HT, 5-HT, 5-HTand 5-HTreceptors, and little or no affinity for 5-HT, 5-HT, 5-HT, 5-HT, 5-HTand 5-HTreceptors. Eletriptan has no significant affinity or pharmacological activity at adrenergic alpha, alpha, or beta; dopaminergic Dor D; 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-HTreceptors 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-HTreceptors 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.<br/>Pharmacokinetics:<br/>Absorption: Eletriptan is 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 Tis 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 Cof eletriptan are increased by approximately 20 to 30% following oral administration with a high fat meal.<br/>Distribution: The volume of distribution of eletriptan following IV administration is 138L. Plasma protein binding is moderate and approximately 85%.<br/>Metabolism: 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 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 .<br/>Elimination: The terminal elimination half-life of eletriptan is approximately 4 hours. Mean renal clearance (CL) following oral administration is approximately 3.9 L/h. Non-renal clearance accounts for about 90% of the total clearance.<br/>Special Populations:<br/>Age: The pharmacokinetics of eletriptan are generally unaffected by age. Eletriptan 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 increased 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) .<br/>Gender: The pharmacokinetics of eletriptan are unaffected by gender.<br/>Race: A comparison of pharmacokinetic studies run in western countries with those run in Japan has indicated an approximate 35% reduction in the exposure of eletriptan in Japanese male volunteers compared to western males. Population pharmacokinetic analysis of two clinical studies indicates no evidence of pharmacokinetic differences between Caucasians and non-Caucasian patients.<br/>Menstrual Cycle: In a study of 16 healthy females, the pharmacokinetics of eletriptan remained consistent throughout the phases of the menstrual cycle.<br/>Renal Impairment: 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 .<br/>Hepatic Impairment: The effects of severe hepatic impairment on eletriptan metabolism have not been evaluated. Subjects with mild or moderate hepatic impairment demonstrated an increase in both AUC (34%) and half-life. The Cwas increased by 18% .<br/>Drug Interactions:<br/>CYP3A4 inhibitors: In vitro studies have shown that eletriptan is metabolized by the CYP3A4 enzyme. A clinical study demonstrated about a 3-fold increase in Cand 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 Tincreased from 2.8 hours to 5.4 hours. Another clinical study demonstrated about a 2-fold increase in Cand 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 Cand 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 Cand about a 2-fold increase in AUC of eletriptan. Eletriptan should not be used within at least 72 hours of treatment with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir and nelfinavir. Eletriptan should not be used within 72 hours with drugs that have demonstrated potent CYP3A4 inhibition and have this potent effect described in the CONTRAINDICATIONS, WARNINGS or PRECAUTIONS sections of their labeling .<br/>Propranolol: The Cand AUC of eletriptan were increased by 10 and 33%, respectively, in the presence of propranolol. No interactive increases in blood pressure were observed. No dosage adjustment appears to be needed for patients taking propranolol .<br/>The effect of eletriptan on other drugs: 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��M. While eletriptan has an effect on CYP2D6 at high concentration, 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.
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RELPAX Tablets of 20 mg and 40 mg eletriptan (base) as the hydrobromide. RELPAX Tablets are orange, round, convex shaped, film-coated tablets with appropriate debossing. They are supplied in the following strengths and package configurations: Store at 25��C (77��F); excursions permitted to 15���30��C (59���86��F) [see USP Controlled Room Temperature].
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No significant overdoses in premarketing clinical trials have been reported. Volunteers (N=21) have received single doses of 120 mg without significant adverse effects. Daily doses of 160 mg were commonly employed in Phase III trials. Based on the pharmacology of the 5-HTagonists, hypertension or other more serious cardiovascular symptoms could occur on overdose. The elimination half-life of eletriptan is about 4 hours 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.
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eletriptan hydrobromide
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Relpax (Tablet, Film Coated)
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Serious cardiac events, including some that have been fatal, have occurred following the use of 5-HTagonists including RELPAX. These events are extremely rare and most have been reported in patients with risk factors predictive of CAD. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation .<br/>Incidence in Controlled Clinical Trials: Among 4,597 patients who treated the first migraine headache with RELPAX in short-term placebo-controlled trials, the most common adverse events reported with treatment with RELPAX were asthenia, nausea, dizziness, and somnolence. These events appear to be dose-related. In long-term open-label studies where patients were allowed to treat multiple migraine attacks for up to 1 year, 128 (8.3%) out of 1,544 patients discontinued treatment due to adverse events. Table 2 lists adverse events that occurred in the subset of 5,125 migraineurs who received eletriptan doses of 20 mg, 40 mg and 80 mg or placebo in worldwide placebo-controlled clinical trials. The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, those frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Only adverse events that were more frequent in a RELPAX treatment group compared to the placebo group with an incidence greater than or equal to 2% are included in Table 2. RELPAX is generally well tolerated. Across all doses, most adverse reactions were mild and transient. The frequency of adverse events in clinical trials did not increase when up to 2 doses of RELPAX were taken within 24 hours. The incidence of adverse events in controlled clinical trials was not affected by gender, age, or race of the patients. Adverse event frequencies were also unchanged by concomitant use of drugs commonly taken for migraine prophylaxis (e.g., SSRIs, beta blockers, calcium channel blockers, tricyclic antidepressants), estrogen replacement therapy and oral contraceptives.<br/>Other Events Observed in Association With the Administration of RELPAX Tablets: In the paragraphs that follow, the frequencies of less commonly reported adverse clinical events are presented. 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=4,719) exposed to RELPAX. All reported events are included except those already listed in Table 2, those too general to be informative, and those not reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: 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. General: Frequent were back pain, chills and pain. Infrequent were face edema and malaise. Rare were abdomen enlarged, abscess, accidental injury, allergic reaction, fever, flu syndrome, halitosis, hernia, hypothermia, lab test abnormal, moniliasis, rheumatoid arthritis and shock. Cardiovascular: Frequent was palpitation. Infrequent were hypertension, migraine, peripheral vascular disorder and tachycardia. Rare were angina pectoris, arrhythmia, atrial fibrillation, AV block, bradycardia, hypotension, syncope, thrombophlebitis, cerebrovascular disorder, vasospasm and ventricular arrhythmia. Digestive: Infrequent were anorexia, constipation, diarrhea, eructation, esophagitis, flatulence, gastritis, gastrointestinal disorder, glossitis, increased salivation and liver function tests abnormal. Rare were gingivitis, hematemesis, increased appetite, rectal disorder, stomatitis, tongue disorder, tongue edema and tooth disorder. Endocrine: Rare were goiter, thyroid adenoma and thyroiditis. Hemic and Lymphatic: Rare were anemia, cyanosis, leukopenia, lymphadenopathy, monocytosis and purpura. Metabolic: Infrequent were creatine phosphokinase increased, edema, peripheral edema and thirst. Rare were alkaline phosphatase increased, bilirubinemia, hyperglycemia, weight gain and weight loss. Musculoskeletal: Infrequent were arthralgia, arthritis, arthrosis, bone pain, myalgia and myasthenia. Rare were bone neoplasm, joint disorder, myopathy and tenosynovitis. Neurological: Frequent were hypertonia, hypesthesia and vertigo. Infrequent were 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 were 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. Respiratory: Frequent was pharyngitis. Infrequent were asthma, dyspnea, respiratory disorder, respiratory tract infection, rhinitis, voice alteration and yawn. Rare were bronchitis, choking sensation, cough increased, epistaxis, hiccup, hyperventilation, laryngitis, sinusitis and sputum increased. Skin and Appendages: Frequent was sweating. Infrequent were pruritus, rash and skin disorder. Rare were alopecia, dry skin, eczema, exfoliative dermatitis, maculopapular rash, psoriasis, skin discoloration, skin hypertrophy and urticaria. Special Senses: Infrequent was abnormal vision, conjunctivitis, ear pain, eye pain, lacrimation disorder, photophobia, taste perversion and tinnitus. Rare were abnormality of accommodation, dry eyes, ear disorder, eye hemorrhage, otitis media, parosmia and ptosis. Urogenital: Infrequent were impotence, polyuria, urinary frequency and urinary tract disorder. Rare were breast pain, kidney pain, leukorrhea, menorrhagia, menstrual disorder and vaginitis.<br/>Other Events Observed During Post-Marketing Use: The following adverse reaction(s) have been identified during postapproval use of RELPAX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Neurological: seizure Digestive: vomiting
dailymed-instance:indicatio...
RELPAX is indicated for the acute treatment of migraine with or without aura in adults. RELPAX is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine . Safety and effectiveness of RELPAX Tablets have not been established for cluster headache, which is present in an older, predominantly male population.
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Relpax