RELPAX- eletriptan hydrobromide_tablet

Animal Data
When pregnant rats were administered eletriptan (0, 10, 30, or 100 mg/kg/day) during the period of organogenesis, fetal weights were decreased and the incidences of vertebral and sternebral variations were increased at 100 mg/kg/day (approximately 12 times the maximum recommended human dose [MRHD] of 80 mg/day on a mg/m 2 2 When eletriptan (0, 5, 10, or 50 mg/kg/day) was orally administered to pregnant rabbits throughout organogenesis, fetal weights were decreased at 50 mg/kg/day. The incidences of fused sternebrae and vena cava deviations were increased at all doses. Maternal toxicity was not evident at any dose. A no-effect dose for adverse effects on embryofetal development in rabbits was not established; the lowest dose tested (5 mg/kg/day) is similar to the MRHD on a mg/m 2 Oral administration of eletriptan (0, 5, 15, or 50 mg/kg/day) to female rats throughout pregnancy and lactation resulted in a decrease in offspring viability and body weight at the highest dose tested. The no-effect dose for adverse effects on pre- and postnatal development in rats (15 mg/kg/day) is approximately 2 times the MRHD on a mg/m 2
CLINICAL PHARMACOLOGY
Eletriptan binds with high affinity to 5-HT 1B 1D 1F 1A 1E 2B 7 Migraines are likely due to local cranial vasodilatation and/or to the release of sensory neuropeptides (vasoactive intestinal peptide, substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system. The therapeutic activity of RELPAX for the treatment of migraine headache is thought to be due to the agonist effects at the 5-HT 1B/1D 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 T max max The volume of distribution of eletriptan following IV administration is 138L. Plasma protein binding is moderate and approximately 85%. 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 [see Contraindications (4) Drug Interactions (7. 2) The terminal elimination half-life of eletriptan is approximately 4 hours. Mean renal clearance (CL R The pharmacokinetics of eletriptan are generally unaffected by age. Blood pressure was increased to a greater extent in elderly subjects than in young subjects [see Use in Specific Populations (8. 5) 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) [see Use in Specific Populations (8. 5) The pharmacokinetics of eletriptan are unaffected by gender. 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. In a study of 16 healthy females, the pharmacokinetics of eletriptan remained consistent throughout the phases of the menstrual cycle. 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 (5. 8) Subjects with mild or moderate hepatic impairment demonstrated an increase in both AUC (34%) and half-life. The C max [see Use in Specific Populations (8. 6) In vitro max max max max max RELPAX is contraindicated within at least 72 hours of treatment with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir and nelfinavir. RELPAX should not be used within 72 hours with drugs that have demonstrated potent CYP3A4 inhibition [see Contraindications (4) The C max The effect of eletriptan on enzymes other than cytochrome P450 has not been investigated. In vitro in vitro in vivo.

RELPAX is indicated for the acute treatment of migraine with or without aura in adults. Limitations of Use: RELPAX is a serotonin (5-HT 1B/1D 1 Limitations of Use: 1 1 1.

The maximum recommended single dose is 40 mg. 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 [see Clinical Studies (14) If the migraine has not resolved by 2 hours after taking RELPAX, or returns after transient improvement, a second dose may be administered at least 2 hours after the first dose. The maximum daily dose should not exceed 80 mg. The safety of treating an average of more than 3 migraine attacks in a 30-day period has not been established. 2 2 2.

The following adverse reactions are described elsewhere in other sections of the prescribing information: [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 4) [see Warnings and Precautions (5. 5) [see Warnings and Precautions (5. 6) [see Warnings and Precautions (5. 7) [see Warnings and Precautions (5. 8) [see Contraindications (4) Warnings and Precautions (5. 9) Most common adverse reactions (>= 5% and > placebo) were asthenia, nausea, dizziness, and somnolence. These reactions appear to be dose-related. 1 To report SUSPECTED ADVERSE REACTIONS, contact Viatris at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Among 4,597 patients who treated the first migraine headache with RELPAX in short-term placebo-controlled trials, the most common adverse reactions reported with treatment with RELPAX were asthenia, nausea, dizziness, and somnolence. 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 reactions. Table 1 lists adverse reactions 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. Only adverse reactions 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 1. Table 1: Adverse Reactions Incidence in Placebo-Controlled Migraine Clinical Trials: Reactions Reported by >= 2% Patients Treated with RELPAX and More Than Placebo Adverse Reaction Type Placebo (n=988) RELPAX 20 mg (n=431) RELPAX 40 mg (n=1774) RELPAX 80 mg (n=1932) ATYPICAL SENSATIONS Paresthesia 2% 3% 3% 4% Flushing/feeling of warmth 2% 2% 2% 2% PAIN AND PRESSURE SENSATIONS Chest en dash tightness/pain/pressure 1% 1% 2% 4% Abdominal en dash 1% 1% 2% 2% DIGESTIVE Dry mouth 2% 2% 3% 4% Dyspepsia 1% 1% 2% 2% Dysphagia en dash throat tightness/difficulty swallowing 0. 2% 1% 2% 2% Nausea 5% 4% 5% 8% NEUROLOGICAL Dizziness 3% 3% 6% 7% Somnolence 4% 3% 6% 7% Headache 3% 4% 3% 4% OTHER Asthenia 3% 4% 5% 10% The frequency of adverse reactions in clinical trials did not increase when up to 2 doses of RELPAX were taken within 24 hours. The incidence of adverse reactions in controlled clinical trials was not affected by gender, age, or race of the patients. Adverse reaction frequencies were also unchanged by concomitant use of drugs commonly taken for migraine prophylaxis (e. , SSRIs, beta blockers, calcium channel blockers, tricyclic antidepressants), estrogen replacement therapy or oral contraceptives. The following adverse reaction(s) have been identified during post approval 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: Digestive:.

RELPAX is contraindicated in patients with: [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 4) [see Warnings and Precautions (5. 5) [see Warnings and Precautions (5. 8) 1 1 [see Drug Interactions (7. 9) [see Drug Interactions (7. 2) Clinical Pharmacology (12. 3) 4 4 4 4 4 4 1 4 4 4.

USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, may cause fetal harm ( 8. 1 Available human data on the use of RELPAX in pregnant women are not sufficient to draw conclusions about drug-associated risk for major birth defects and miscarriage. In animal studies, oral administration of eletriptan during pregnancy or throughout pregnancy and lactation was associated with developmental toxicity (decreased fetal and pup weights, increased incidences of fetal structural abnormalities, decreased pup viability) at clinically-relevant doses [see Data In the U. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2. 9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. Several studies have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy. A study using linked data from the Medical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for triptans before pregnancy only. Of the 189 women who redeemed prescriptions for eletriptan during the first trimester, 4 (2. 1%) had infants with major congenital malformations, while for the 174 women who redeemed prescriptions for eletriptan before, but not during, pregnancy, 11 (6. 3%) had infants with major congenital malformations. Methodological limitations of this study, including small size of the eletriptan population and infrequent events, do not allow for thorough characterization of risk. When pregnant rats were administered eletriptan (0, 10, 30, or 100 mg/kg/day) during the period of organogenesis, fetal weights were decreased and the incidences of vertebral and sternebral variations were increased at 100 mg/kg/day (approximately 12 times the maximum recommended human dose [MRHD] of 80 mg/day on a mg/m 2 2 When eletriptan (0, 5, 10, or 50 mg/kg/day) was orally administered to pregnant rabbits throughout organogenesis, fetal weights were decreased at 50 mg/kg/day. The incidences of fused sternebrae and vena cava deviations were increased at all doses. Maternal toxicity was not evident at any dose. A no-effect dose for adverse effects on embryofetal development in rabbits was not established; the lowest dose tested (5 mg/kg/day) is similar to the MRHD on a mg/m 2 Oral administration of eletriptan (0, 5, 15, or 50 mg/kg/day) to female rats throughout pregnancy and lactation resulted in a decrease in offspring viability and body weight at the highest dose tested. The no-effect dose for adverse effects on pre- and postnatal development in rats (15 mg/kg/day) is approximately 2 times the MRHD on a mg/m 2 Eletriptan is excreted in human milk. There are no data on the effects of eletriptan on the breastfed infant or the effects of eletriptan on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RELPAX and any potential adverse effects on the breastfed child from RELPAX or from the underlying maternal condition. Infant exposure can be minimized by avoiding breastfeeding for 24 hours after treatment. Safety and effectiveness in pediatric patients have not been established. The efficacy of RELPAX Tablets (40 mg) in patients 11-17 was not established in a randomized, placebo-controlled trial of 274 adolescent migraineurs [see Clinical Studies (14) 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 [see Clinical Pharmacology (12. 3) The effect of severe hepatic impairment on RELPAX metabolism has not been evaluated. RELPAX is not recommended for use in patients with severe hepatic impairment [see Clinical Pharmacology (12.
Age
The pharmacokinetics of eletriptan are generally unaffected by age. Blood pressure was increased to a greater extent in elderly subjects than in young subjects [see Use in Specific Populations (8.5) 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) [see Use in Specific Populations (8.5)
Gender
The pharmacokinetics of eletriptan are unaffected by gender.
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.
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 [see Warnings and Precautions (5.8)
Hepatic Impairment
Subjects with mild or moderate hepatic impairment demonstrated an increase in both AUC (34%) and half-life. The C max [see Use in Specific Populations (8.6)

DRUG INTERACTIONS
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 within 24 hours of each other is contraindicated. 1 [see Contraindications (4) Potent CYP3A4 inhibitors significantly increase the exposure of RELPAX. RELPAX should not be used within at least 72 hours of treatment with potent CYP3A4 inhibitors [see Contraindications (4) Clinical Pharmacology (12. 3) Cases of serotonin syndrome have been reported during co-administration of triptans and SSRIs, SNRIs, TCAs and MAO inhibitors [see Warnings and Precautions (5.
CYP3A4 Inhibitors
In vitro max max max max max RELPAX is contraindicated within at least 72 hours of treatment with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir and nelfinavir. RELPAX should not be used within 72 hours with drugs that have demonstrated potent CYP3A4 inhibition [see Contraindications (4)
The Effect of Eletriptan on Other Drugs
The effect of eletriptan on enzymes other than cytochrome P450 has not been investigated. In vitro in vitro in vivo

Human Data
A study using linked data from the Medical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for triptans before pregnancy only. Of the 189 women who redeemed prescriptions for eletriptan during the first trimester, 4 (2.1%) had infants with major congenital malformations, while for the 174 women who redeemed prescriptions for eletriptan before, but not during, pregnancy, 11 (6.3%) had infants with major congenital malformations. Methodological limitations of this study, including small size of the eletriptan population and infrequent events, do not allow for thorough characterization of risk.
OVERDOSAGE
The elimination half-life of eletriptan is about 4 hours [see Clinical Pharmacology (12.3) There is no specific antidote to eletriptan. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentration of eletriptan.
Menstrual Cycle
In a study of 16 healthy females, the pharmacokinetics of eletriptan remained consistent throughout the phases of the menstrual cycle.
NONCLINICAL TOXICOLOGY
Eletriptan was administered to rats and mice in the diet for 104 weeks. In rats, the incidence of testicular interstitial cell adenomas was increased at the high dose of 75 mg/kg/day, but not at 15 mg/kg/day, a dose associated with plasma exposures (AUC) approximately 2 times that in humans at the MRHD of 80 mg/day. In mice, the incidence of hepatocellular adenomas was increased at the high dose of 400 mg/kg/day, but not a dose of 90 mg/kg/day, associated with plasma AUC approximately 7 times that in humans at the MRHD. Eletriptan was negative in in vitro in vivo In a fertility and early embryonic development study, eletriptan (50, 100, or 200 mg/kg/day) was orally administered to male and female rats prior to and throughout mating and continuing in females to implantation. Plasma exposures (AUC) were 4, 8 and 16 times in males and 7, 14 and 28 times in females, respectively, that in humans at the MRHD. Prolongation of the estrous cycle and decreases in the number of corpora lutea, implants, and viable fetuses per dam were observed at 200 mg/kg/day. Male fertility parameters were not affected.
CLINICAL STUDIES
The efficacy of RELPAX in the acute treatment of migraines was evaluated in eight randomized, double-blind placebo-controlled studies. All eight studies used 40 mg. Seven studies evaluated an 80 mg dose and two studies included a 20 mg dose. In all eight studies, randomized patients treated their headaches as outpatients. Seven studies enrolled adults and one study enrolled adolescents (ages 11 to 17). Patients treated in the seven adult studies were predominantly female (85%) and Caucasian (94%) with a mean age of 40 years (range 18 to 78). In all studies, patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 2 hours after dosing. Associated symptoms such as nausea, vomiting, photophobia and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours post dose. In the adult studies, a second dose of RELPAX or other medication was allowed 2 to 24 hours after the initial treatment for both persistent and recurrent headaches. The incidence and time to use of these additional treatments were also recorded. In the seven adult studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater among patients receiving RELPAX at all doses compared to those who received placebo. The 2-hour response rates from these controlled clinical studies are summarized in Table 2. Table 2: Percentage of Patients with Headache Response (Mild or No Headache) 2 Hours Following Treatment Placebo RELPAX 20 mg RELPAX 40 mg RELPAX 80 mg NA - Not Applicable Study 1 23. 3% p value < 0. 05 vs placebo 65. 1% Study 2 19. 6% Study 3 21. 6% Study 4 39. 0% Study 5 20. 9% Study 6 31. 9% Study 7 29. 5% NA Comparisons of the performance of different drugs based upon results obtained in different clinical trials are never reliable. Because studies are generally conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc. ), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study. The estimated probability of achieving an initial headache response within 2 hours following treatment is depicted in Figure 1. *Figure 1 shows the Kaplan-Meier plot of probability over time of obtaining headache response (no or mild pain) following treatment with eletriptan. The plot is based on 7 placebo-controlled, outpatient trials in adults providing evidence of efficacy (Studies 1 through 7). Patients not achieving headache response or taking additional treatment prior to 2 hours were censored at 2 hours. For patients with migraine-associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of RELPAX as compared to placebo. Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication. The estimated probability of taking a second dose or other medications for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2. *This Kaplan-Meier plot is based on data obtained in 7 placebo-controlled trials in adults (Studies 1 through 7). Patients were instructed to take a second dose of study medication as follows: a) in the event of no response at 2 hours (studies 2 and 4-7) or at 4 hours (study 3); b) in the event of headache recurrence within 24 hours (studies 2-7). Patients not using additional treatments were censored at 24 hours. The plot includes both patients who had headache response at 2 hours and those who had no response to the initial dose. It should be noted that the protocols did not allow re-medication within 2 hours post dose. The efficacy of RELPAX was unaffected by the duration of attack, gender or age of the patient, relationship to menses, or concomitant use of estrogen replacement therapy/oral contraceptives or frequently used migraine prophylactic drugs. In a single study in adolescents (n=274), 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. Figure 1 Figure 2.
Patient Information
RELPAX registered (eletriptan hydrobromide) Tablets Please read this information before you start taking RELPAX and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. What is the most important information I should know about RELPAX? RELPAX can cause serious side effects, including: Heart attack and other heart problems. Heart problems may lead to death. Stop taking RELPAX and get emergency medical help right away if you have any of the following symptoms of a heart attack: RELPAX is not for people with risk factors for heart disease unless a heart exam is done and shows no problem. You have a higher risk for heart disease if you: Serotonin syndrome Ask your doctor or pharmacist for a list of these medicines if you are not sure. Call your doctor right away if you have any of the following symptoms of serotonin syndrome: What is RELPAX? RELPAX is a prescription medicine used to treat acute migraine headaches with or without aura in adults. RELPAX is for people who have been diagnosed with migraine headaches. RELPAX is not used to prevent or decrease the number of migraine headaches you have. It is not known if RELPAX is safe and effective to treat cluster headaches. It is not known if RELPAX is safe and effective in children. Who should not take RELPAX? Do not registered registered registered registered registered registered registered registered registered registered registered registered registered registered registered registered registered registered registered registered registered What should I tell my doctor before taking RELPAX? Before you take RELPAX, tell your doctor if you: Tell your doctor about all the medicines you take Especially tell your doctor if you Ask your doctor or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them to show your doctor or pharmacist when you get a new medicine. How should I take RELPAX? What should I avoid while taking RELPAX? RELPAX can cause dizziness, weakness, or drowsiness. If you have these symptoms, do not drive a car, use machinery, or do anything where you need to be alert. What are the possible side effects of RELPAX? RELPAX may cause serious side effects. These serious side effects include: changes in color or sensation in your fingers and toes (Raynaud''s syndrome) stomach and intestinal problems (gastrointestinal and colonic ischemic events). problems with blood circulation to your legs and feet (peripheral vascular ischemia). medication overuse headaches. The most common side effects of RELPAX include: Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of RELPAX. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. How should I store RELPAX? Store RELPAX at room temperature between 68°F to 77°F (20°C to 25°C). General information about the safe and effective use of RELPAX Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use RELPAX for a condition for which it was not prescribed. Do not give RELPAX to other people, even if they have the same symptoms you have. It may harm them. This Patient Information summarizes the most important information about RELPAX. If you would like more information about RELPAX, talk with your doctor. You can ask your doctor or pharmacist for information on RELPAX that is written for health professionals. For more information, call Viatris at 1-877-446-3679 (1-877-4-INFO-RX). What are the ingredients in RELPAX? Active ingredient: eletriptan hydrobromide Inactive ingredients: croscarmellose sodium, FD&C Yellow No. 6 Aluminum Lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin. Distributed by: Viatris Specialty LLC copyright 2024 Viatris Inc. RELPAX is a registered trademark of Viatris Specialty LLC, a Viatris Company. The brands listed are trademarks of their respective owners. This Patient Information has been approved by the U.S. Food and Drug Administration. UPJ:PL:RLPX:R2 Revised: 1/2024

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