Rizatriptan 10 mg Tablet, Film Coated — NDC 33342-088-41 (Billing 33342-0088-41)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Rizatriptan binds with high affinity to human cloned 5-HT 1B/1D receptors. Rizatriptan presumably exerts its therapeutic effects in the treatment of migraine headache by binding to 5-HT 1B/1D receptors located on intracranial blood vessels and sensory nerves of the trigeminal system.

12.3Pharmacokinetics Absorption Rizatriptan is completely absorbed following oral administration. The mean oral absolute bioavailability of the rizatriptan benzoate tablet is about 45%, and mean peak plasma concentrations (C max ) are reached in approximately 1 to 1.5 hours (T max ). The presence of a migraine headache did not appear to affect the absorption or pharmacokinetics of rizatriptan.

Food has no significant effect on the bioavailability of rizatriptan but delays the time to reach peak concentration by an hour. In clinical trials, rizatriptan benzoate was administered without regard to food. The bioavailability and C max of rizatriptan were similar following administration of rizatriptan benzoate tablets and rizatriptan benzoate orally disintegrating tablets, but the rate of absorption is somewhat slower with rizatriptan benzoate orally disintegrating tablets, with T max delayed by up to 0.7 hour.

AUC of rizatriptan is approximately 30% higher in females than in males. No accumulation occurred on multiple dosing. Distribution The mean volume of distribution is approximately 140 liters in male subjects and 110 liters in female subjects.

Rizatriptan is minimally bound (14%) to plasma proteins. Metabolism The primary route of rizatriptan metabolism is via oxidative deamination by monoamine oxidase-A (MAO-A) to the indole acetic acid metabolite, which is not active at the 5-HT 1B/1D receptor. N-monodesmethyl-rizatriptan, a metabolite with activity similar to that of parent compound at the 5-HT 1B/1D receptor, is formed to a minor degree.

Plasma concentrations of N-monodesmethyl-rizatriptan are approximately 14% of those of parent compound, and it is eliminated at a similar rate. Other minor metabolites, the N-oxide, the 6-hydroxy compound, and the sulfate conjugate of the 6-hydroxy metabolite are not active at the 5-HT 1B/1D receptor. Elimination The total radioactivity of the administered dose recovered over 120 hours in urine and feces was 82% and 12%, respectively, following a single 10-mg oral administration of 14 C-rizatriptan.

Following oral administration of 14 C-rizatriptan, rizatriptan accounted for about 17% of circulating plasma radioactivity. Approximately 14% of an oral dose is excreted in urine as unchanged rizatriptan while 51% is excreted as indole acetic acid metabolite, indicating substantial first pass metabolism. The plasma half-life of rizatriptan in males and females averages 2 to 3 hours.

Cytochrome P450 Isoforms Rizatriptan is not an inhibitor of the activities of human liver cytochrome P450 isoforms 3A4/5, 1A2, 2C9, 2C19, or 2E1; rizatriptan is a competitive inhibitor (K i = 1400 nM) of cytochrome P450 2D6, but only at high, clinically irrelevant concentrations. Special Populations Geriatric: Rizatriptan pharmacokinetics in healthy elderly non-migraineur volunteers (age 65 to 77 years) were similar to those in younger non-migraineur volunteers (age 18 to 45 years). Pediatric: The pharmacokinetics of rizatriptan was determined in pediatric migraineurs 6 to 17 years of age.

Exposures following single dose administration of 5 mg rizatriptan orally disintegrating tablets to pediatric patients weighing 20 to 39 kg (44-87 lb) or 10 mg rizatriptan orally disintegrating tablets to pediatric patients weighing ≥40 kg (88 lb) were similar to those observed following single dose administration of 10 mg rizatriptan orally disintegrating tablets to adults. Gender: The mean AUC 0-∞ and C max of rizatriptan (10 mg orally) were about 30% and 11% higher in females as compared to males, respectively, while T max occurred at approximately the same time.

Hepatic impairment: Following oral… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Rizatriptan binds with high affinity to human cloned 5-HT 1B/1D receptors. Rizatriptan presumably exerts its therapeutic effects in the treatment of migraine headache by binding to 5-HT 1B/1D receptors located on intracranial blood vessels and sensory nerves of the trigeminal system.

12.3Pharmacokinetics Absorption Rizatriptan is completely absorbed following oral administration. The mean oral absolute bioavailability of the rizatriptan benzoate tablet is about 45%, and mean peak plasma concentrations (C max ) are reached in approximately 1 to 1.5 hours (T max ). The presence of a migraine headache did not appear to affect the absorption or pharmacokinetics of rizatriptan.

Food has no significant effect on the bioavailability of rizatriptan but delays the time to reach peak concentration by an hour. In clinical trials, rizatriptan benzoate was administered without regard to food. The bioavailability and C max of rizatriptan were similar following administration of rizatriptan benzoate tablets and rizatriptan benzoate orally disintegrating tablets, but the rate of absorption is somewhat slower with rizatriptan benzoate orally disintegrating tablets, with T max delayed by up to 0.7 hour.

AUC of rizatriptan is approximately 30% higher in females than in males. No accumulation occurred on multiple dosing. Distribution The mean volume of distribution is approximately 140 liters in male subjects and 110 liters in female subjects.

Rizatriptan is minimally bound (14%) to plasma proteins. Metabolism The primary route of rizatriptan metabolism is via oxidative deamination by monoamine oxidase-A (MAO-A) to the indole acetic acid metabolite, which is not active at the 5-HT 1B/1D receptor. N-monodesmethyl-rizatriptan, a metabolite with activity similar to that of parent compound at the 5-HT 1B/1D receptor, is formed to a minor degree.

Plasma concentrations of N-monodesmethyl-rizatriptan are approximately 14% of those of parent compound, and it is eliminated at a similar rate. Other minor metabolites, the N-oxide, the 6-hydroxy compound, and the sulfate conjugate of the 6-hydroxy metabolite are not active at the 5-HT 1B/1D receptor. Elimination The total radioactivity of the administered dose recovered over 120 hours in urine and feces was 82% and 12%, respectively, following a single 10-mg oral administration of 14 C-rizatriptan.

Following oral administration of 14 C-rizatriptan, rizatriptan accounted for about 17% of circulating plasma radioactivity. Approximately 14% of an oral dose is excreted in urine as unchanged rizatriptan while 51% is excreted as indole acetic acid metabolite, indicating substantial first pass metabolism. The plasma half-life of rizatriptan in males and females averages 2 to 3 hours.

Cytochrome P450 Isoforms Rizatriptan is not an inhibitor of the activities of human liver cytochrome P450 isoforms 3A4/5, 1A2, 2C9, 2C19, or 2E1; rizatriptan is a competitive inhibitor (K i = 1400 nM) of cytochrome P450 2D6, but only at high, clinically irrelevant concentrations. Special Populations Geriatric: Rizatriptan pharmacokinetics in healthy elderly non-migraineur volunteers (age 65 to 77 years) were similar to those in younger non-migraineur volunteers (age 18 to 45 years). Pediatric: The pharmacokinetics of rizatriptan was determined in pediatric migraineurs 6 to 17 years of age.

Exposures following single dose administration of 5 mg rizatriptan orally disintegrating tablets to pediatric patients weighing 20 to 39 kg (44-87 lb) or 10 mg rizatriptan orally disintegrating tablets to pediatric patients weighing ≥40 kg (88 lb) were similar to those observed following single dose administration of 10 mg rizatriptan orally disintegrating tablets to adults. Gender: The mean AUC 0-∞ and C max of rizatriptan (10 mg orally) were about 30% and 11% higher in females as compared to males, respectively, while T max occurred at approximately the same time.

Hepatic impairment: Following oral administration in patients with hepatic impairment caused by mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of rizatriptan were similar in patients with mild hepatic insufficiency compared to a control group of subjects with normal hepatic function; plasma concentrations of rizatriptan were approximately 30… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1Adults The efficacy of rizatriptan benzoate tablets was established in four multicenter, randomized, placebo-controlled trials. Patients enrolled in these studies were primarily female (84%) and Caucasian (88%), with a mean age of 40 years (range of 18 to 71). Patients were instructed to treat a moderate to severe headache.

Headache response, defined as a reduction of moderate or severe headache pain to no or mild headache pain, was assessed for up to 2 hours (Study 1) or up to 4 hours after dosing (Studies 2, 3 and 4). Associated symptoms of nausea, photophobia, and phonophobia and maintenance of response up to 24 hours post-dose were evaluated. A second dose of rizatriptan benzoate tablets was allowed 2 to 24 hours after dosing for treatment of recurrent headache in Studies 1 and 2.

Additional analgesics and/or antiemetics were allowed 2 hours after initial treatment for rescue in all four studies. In all studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater in patients who received either rizatriptan benzoate 5 mg or 10 mg compared to those who received placebo. In a separate study, doses of 2.5 mg were not different from placebo.

Doses greater than 10 mg were associated with an increased incidence of adverse effects. The results from the four controlled studies are summarized in Table 2. Table 2: Response Rates 2 Hours Following Treatment of Initial Headache in Studies 1, 2, 3, and 4 Study Placebo Rizatriptan Benzoate Tablets 5 mg Rizatriptan Benzoate Tablets 10 mg 1 35% (n=304) 62% * (n=458) 71% *,† (n=456) 2 ‡ 37% (n=82) — 77% * (n=320) 3 23% (n=80) 63% * (n=352) — 4 40% (n=159) 60% * (n=164) 67% * (n=385) * p-value < 0.05 in comparison with placebo. † p-value < 0.05 in comparison with 5 mg. ‡ Results for initial headache only.

Comparisons of drug performance based upon results obtained in different clinical trials may not be reliable. Because studies are 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 in pooled Studies 1, 2, 3, and 4 is depicted in Figure 1.

Figure 1: Estimated Probability of Achieving an Initial Headache Response by 2 Hours in Pooled Studies 1, 2, 3, and 4 * * Figure 1 shows the Kaplan-Meier plot of the probability over time of obtaining headache response (no or mild pain) following treatment with rizatriptan benzoate or placebo. The averages displayed are based on pooled data from 4 placebo-controlled, outpatient trials providing evidence of efficacy (Studies 1, 2, 3, and 4). Patients taking additional treatment or not achieving headache response 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 rizatriptan benzoate compared to placebo. Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain response in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.

Figure 2: Estimated Probability of Patients Taking a Second Dose of Rizatriptan Benzoate Tablets or Other Medication for Migraines Over the 24 Hours Following the Initial Dose of Study Treatment in Pooled Studies 1, 2, 3, and 4* *This Kaplan-Meier plot is based on data obtained in 4 placebo-controlled outpatient clinical trials (Studies 1, 2,… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Oral carcinogenicity studies of rizatriptan were conducted in mice (100 weeks) and rats (106 weeks) at doses of up to 125 mg/kg/day. There was no evidence of an increase in tumor incidence related to rizatriptan in either species. Plasma exposures (AUC) at the highest dose tested were approximately 150 (mice) and 240 times (rats) that in humans at the maximum recommended human dose (MRHD) of 30 mg/day.

Mutagenesis Rizatriptan was neither mutagenic nor clastogenic in a battery of in vitro and in vivo genetic toxicity studies, including: the microbial mutagenesis (Ames) assay, in vitro mammalian cell mutagenesis and chromosomal aberration assays, and the in vivo chromosomal aberration assay in mouse. Impairment of Fertility Oral administration of rizatriptan (0, 2, 10, or 100 mg/kg/day) to female rats prior to and during mating and continuing throughout gestation and lactation resulted in no effect on fertility; however, altered estrous cyclicity and delays in time to mating were observed at the highest dose tested.

Plasma exposure at the no-effect dose (10 mg/kg/day) for reproductive toxicity was approximately 15 times that in humans at the MRHD. Oral administration of rizatriptan (0, 5, 35, or 250 mg/kg/day) to male rats prior to and during mating resulted in no impairment of fertility or reproductive performance. Plasma exposure (AUC) at the highest dose tested was approximately 550 times that in humans at the MRHD.