Eletriptan Hydrobromide 20 mg Tablet, Film Coated, 6-count — NDC 59651-104-69 (Billing 59651-0104-69)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action 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-HT 7 receptors. 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 eletriptan hydrobromide for the treatment of migraine headache is thought to be due to the agonist effects at the 5-HT 1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

12.3Pharmacokinetics 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 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 hydrobromide can be taken with or without food.

Distribution: The volume of distribution of eletriptan following IV administration is 138L. Plasma protein binding is moderate and approximately 85%. 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 to 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 [see Contraindications (4) and Drug Interactions (7.2) ] .

Elimination: The terminal elimination half-life of eletriptan is approximately 4 hours. Mean renal clearance (CL R ) following oral administration is approximately

3.9L/h. Non-renal clearance accounts for about 90% of the total clearance. Specific Populations 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) ] . 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) [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.

Menstrual Cycle: In a study of 16 healthy females, the pharmacokinetics of eletriptan remained consistent throughout the phases of the menstrual cycle. 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 was increased by 18%. No dose adjustment is necessary in subj… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action 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-HT 7 receptors. 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 eletriptan hydrobromide for the treatment of migraine headache is thought to be due to the agonist effects at the 5-HT 1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

12.3Pharmacokinetics 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 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 hydrobromide can be taken with or without food.

Distribution: The volume of distribution of eletriptan following IV administration is 138L. Plasma protein binding is moderate and approximately 85%. 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 to 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 [see Contraindications (4) and Drug Interactions (7.2) ] .

Elimination: The terminal elimination half-life of eletriptan is approximately 4 hours. Mean renal clearance (CL R ) following oral administration is approximately

3.9L/h. Non-renal clearance accounts for about 90% of the total clearance. Specific Populations 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) ] . 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) [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.

Menstrual Cycle: In a study of 16 healthy females, the pharmacokinetics of eletriptan remained consistent throughout the phases of the menstrual cycle. 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 was increased by 18%. No dose adjustment is necessary in subjects with mild or moderate hepatic impairment. The effects of severe hepatic impairment on eletriptan metabolism have not been evaluated [see Use in Specific Populations (8.6) ] .

Drug Interaction Studies 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 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… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES The efficacy of eletriptan hydrobromide 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 (age 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 eletriptan hydrobromide 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 eletriptan hydrobromide at all doses compared to those who received placebo. The two-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 Eletriptan Hydrobromide 20 mg Eletriptan Hydrobromide 40 mg Eletriptan Hydrobromide 80 mg Study 1 23.8% 54.3%* 65.0%* 77.1%* (n=126) (n=129) (n=117) (n=118) Study 2 19.0% NA 61.6%* 64.6%* (n=232) (n=430) (n=446) Study 3 21.7% 47.3%* 61.9%* 58.6%* (n=276) (n=273) (n=281) (n=290) Study 4 39.5% NA 62.3%* 70.0%* (n=86) (n=175) (n=170) Study 5 20.6% NA 53.9%* 67.9%* (n=102) (n=206) (n=209) Study 6 31.3% NA 63.9%* 66.9%* (n=80) (n=169) (n=160) Study 7 29.5% NA 57.5%* NA (n=122) (n=492) * p value < 0.05 vs placebo NA - Not Applicable 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: Estimated Probability of Initial Headache Response Within 2 Hours* *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 eletriptan hydrobromide 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.

Figure 2: Estimated Probability of Taking a Second Dose/Other Medication Over th… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis 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.

Mutagenesis Eletriptan was negative in in vitro (bacteria reverse mutation (Ames), mammalian cell gene mutation (CHO/ HGPRT), chromosomal aberration assay in human lymphocytes) and in vivo (mouse micronucleus) assays. Impairment of Fertility 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.