Zolmitriptan 5 mg Tablet, Orally Disintegrating, 100-count — NDC 68382-717-01 (Billing 68382-0717-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Zolmitriptan binds with high affinity to human recombinant 5-HT 1D and 5-HT 1B receptors, and moderate affinity for 5-HT 1A receptors. The N-desmethyl metabolite also has high affinity for 5-HT 1B/1D and moderate affinity for 5-HT 1A 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 zolmitriptan 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 arteriovenous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

12.3Pharmacokinetics Absorption, Distribution, Metabolism, and Excretion Absorption Zolmitriptan is well absorbed after oral administration for both zolmitriptan tablet s and the zolmitriptan orally disintegrating tablets. Zolmitriptan displays linear kinetics over the dose range of 2.5 to 50 mg. The AUC and C max of zolmitriptan are similar following administration of zolmitriptan tablets and zolmitriptan orally disintegrating tablets, but the T max is somewhat later with zolmitriptan orally disintegrating tablets, with a median T max of 3 hours for zolmitriptan orally disintegrating tablet compared with 1.5 hours for the zolmitriptan tablet.

The AUC, C max , and T max for the active N-desmethyl metabolite are similar for the two formulations. During a moderate to severe migraine attack, mean AUC 0-4 and C max for zolmitriptan, dosed as a zolmitriptan tablet, were decreased by 40% and 25%, respectively, and mean T max was delayed by one-half hour compared to the same patients during a migraine free period. Food has no significant effect on the bioavailability of zolmitriptan.

No accumulation occurred on multiple dosing. Distribution Mean absolute bioavailability is approximately 40%. The mean apparent volume of distribution is 7 L/kg.

Plasma protein binding of zolmitriptan is 25% over the concentration range of 10 to 1000 ng/mL. Metabolism Zolmitriptan is converted to an active N-desmethyl metabolite; the metabolite concentrations are about two-thirds that of zolmitriptan. Because the 5-HT 1B/1D potency of the metabolite is 2 to 6 times that of the parent compound, the metabolite may contribute a substantial portion of the overall effect after zolmitriptan administration.

Excretion Total radioactivity recovered in urine and feces was 65% and 30% of the administered dose, respectively. About 8% of the dose was recovered in the urine as unchanged zolmitriptan. Indole acetic acid metabolite accounted for 31% of the dose, followed by N-oxide (7%) and N-desmethyl (4%) metabolites.

The indole acetic acid and N-oxide metabolites are inactive. Mean total plasma clearance is 31.5 mL/min/kg, of which one-sixth is renal clearance.The renal clearance is greater than the glomerular filtration rate suggesting renal tubular secretion. Specific Populations Hepatic Impairment In patients with severe hepatic impairment, the mean C max , T max , and AUC 0-∞ of zolmitriptan were increased 1.5-fold, 2-fold (2 vs.

4 hours), and 3-fold, respectively, compared to subjects with normal hepatic function. Seven out of 27 patients experienced 20 to 80 mmHg elevations in systolic and/or diastolic blood pressure after a 10 mg zolmitriptan dose. Adjust the zolmitriptan dose in patients with moderate or severe hepatic impairment [see Dosage and Administration ( 2.3 ), Use in Specific Populations ( 8.6 ) ].

Renal Impairment Clearance of zolmitriptan was reduced by 25% in patients with severe renal impairment (Cl cr > 5 < 25 mL/min) compared to subjects with normal renal function (Cl cr > = 70 mL/min); no significant change in clearance was observed in patients with moderate rena… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Zolmitriptan binds with high affinity to human recombinant 5-HT 1D and 5-HT 1B receptors, and moderate affinity for 5-HT 1A receptors. The N-desmethyl metabolite also has high affinity for 5-HT 1B/1D and moderate affinity for 5-HT 1A 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 zolmitriptan 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 arteriovenous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

12.3Pharmacokinetics Absorption, Distribution, Metabolism, and Excretion Absorption Zolmitriptan is well absorbed after oral administration for both zolmitriptan tablet s and the zolmitriptan orally disintegrating tablets. Zolmitriptan displays linear kinetics over the dose range of 2.5 to 50 mg. The AUC and C max of zolmitriptan are similar following administration of zolmitriptan tablets and zolmitriptan orally disintegrating tablets, but the T max is somewhat later with zolmitriptan orally disintegrating tablets, with a median T max of 3 hours for zolmitriptan orally disintegrating tablet compared with 1.5 hours for the zolmitriptan tablet.

The AUC, C max , and T max for the active N-desmethyl metabolite are similar for the two formulations. During a moderate to severe migraine attack, mean AUC 0-4 and C max for zolmitriptan, dosed as a zolmitriptan tablet, were decreased by 40% and 25%, respectively, and mean T max was delayed by one-half hour compared to the same patients during a migraine free period. Food has no significant effect on the bioavailability of zolmitriptan.

No accumulation occurred on multiple dosing. Distribution Mean absolute bioavailability is approximately 40%. The mean apparent volume of distribution is 7 L/kg.

Plasma protein binding of zolmitriptan is 25% over the concentration range of 10 to 1000 ng/mL. Metabolism Zolmitriptan is converted to an active N-desmethyl metabolite; the metabolite concentrations are about two-thirds that of zolmitriptan. Because the 5-HT 1B/1D potency of the metabolite is 2 to 6 times that of the parent compound, the metabolite may contribute a substantial portion of the overall effect after zolmitriptan administration.

Excretion Total radioactivity recovered in urine and feces was 65% and 30% of the administered dose, respectively. About 8% of the dose was recovered in the urine as unchanged zolmitriptan. Indole acetic acid metabolite accounted for 31% of the dose, followed by N-oxide (7%) and N-desmethyl (4%) metabolites.

The indole acetic acid and N-oxide metabolites are inactive. Mean total plasma clearance is 31.5 mL/min/kg, of which one-sixth is renal clearance.The renal clearance is greater than the glomerular filtration rate suggesting renal tubular secretion. Specific Populations Hepatic Impairment In patients with severe hepatic impairment, the mean C max , T max , and AUC 0-∞ of zolmitriptan were increased 1.5-fold, 2-fold (2 vs.

4 hours), and 3-fold, respectively, compared to subjects with normal hepatic function. Seven out of 27 patients experienced 20 to 80 mmHg elevations in systolic and/or diastolic blood pressure after a 10 mg zolmitriptan dose. Adjust the zolmitriptan dose in patients with moderate or severe hepatic impairment [see Dosage and Administration ( 2.3 ), Use in Specific Populations ( 8.6 ) ].

Renal Impairment Clearance of zolmitriptan was reduced by 25% in patients with severe renal impairment (Cl cr > 5 < 25 mL/min) compared to subjects with normal renal function (Cl cr > = 70 mL/min); no significant change in clearance was observed in patients with moderate renal impairment (Cl cr > 26 < 50 mL/min). Age Zolmitriptan pharmacokinetics in healthy elderly non -migraineur volunteers (age 65 to 76 years) was similar to those in younger non-migraineur volunteers (age 18 to 39 years). Sex Mean plasma concentrations of zolmitriptan were up to 1.5-fold higher in females than males.

Race Retrospective analysis of pharmacokinetic data between Japanese and Caucasians revealed no significant differences. Hypertensive Patients No differences in the pharmacokinetics of zolmitriptan or its effects on blood pressure were seen in mild to moderate hypertensive volunteers compared with normotensive controls. Drug Interaction Studies All drug interaction studies were performed in healthy volunteers using a single 10 mg dose of zolmitriptan and a single dose of the other drug except where otherwise noted.

MAO Inhibitors Following one week of administration of mocl… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES Zolmitriptan Tablets The efficacy of zolmitriptan tablets in the acute treatment of migraine headaches was demonstrated in five randomized, double-blind, placebo-controlled studies (Studies 1, 2, 3, 4, and 5), of which two utilized the 1 mg dose, two utilized the 2.5 mg dose and four utilized the 5 mg dose. In Study 1, patients treated their headaches in a clinic setting. In the other studies, patients treated their headaches as outpatients.

In Study 4, patients who had previously used sumatriptan were excluded, whereas in the other studies no such exclusion was applied. Patients enrolled in these 5 studies were predominantly female (82%) and Caucasian (97%) with a mean age of 40 years (range 12 to 65). 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 at 1, 2, and, in most studies, 4 hours after dosing. Associated symptoms such as nausea, photophobia, and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours post-dose.

A second dose of zolmitriptan tablets or other medication was allowed 2 to 24 hours after the initial treatment for persistent and recurrent headache. The frequency and time to use of these additional treatments were also recorded. In all studies, the effect of zolmitriptan was compared to placebo in the treatment of a single migraine attack.

In all five studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater among patients who received zolmitriptan tablets at all doses (except for the 1 mg dose in the smallest study) compared to those who received placebo. In Studies 1 and 3, there was a statistically significant greater percentage of patients with headache response at 2 hours in the higher dose groups (2.5 and/or 5 mg) compared to the 1 mg dose group. There were no statistically significant differences between the 2.5 and 5 mg dose groups (or of doses up to 20 mg) for the primary end point of headache response at 2 hours in any study.

The results of these controlled clinical studies are summarized in Table 2. Table 2 Percentage of Patients with Headache Response (Reduction in Headache Severity from Moderate or Severe Pain to Mild or No Headache) 2 Hours Following Treatment in Studies 1 through 5 * Study 1 was the only study in which patients treated the headache in a clinic setting. † n = number of patients randomized ‡ NA = not applicable § P<0.05 in comparison with placebo. ¶ P<0.05 in comparison with 1 mg. # Study 4 was the only study where patients were excluded who had previously used sumatriptan.

Placebo Zolmitriptan tablets 1 mg Zolmitriptan tablets 2.5 mg Zolmitriptan tablets 5 mg Study 1 * 16% (n † =19) 27% (n=22) NA ‡ 60% §¶ (n=20) Study 2 19% (n=88) NA NA 66% § (n=179) Study 3 34% (n=121) 50% § (n=140) 65% §¶ (n=260) 67% §¶ (n=245) Study 4 # 44% (n=55) NA NA 59% § (n=491) Study 5 36% (n=92) NA NA 62% § (n=178) NA The estimated probability of achieving an initial headache response by 4 hours following treatment in pooled Studies 2, 3, and 5 is depicted in Figure 1. Figure 1 Estimated Probability of Achieving Initial Headache Response (Reduction in Headache Severity from Moderate or Severe Pain to Mild or No Headache) Within 4 Hours of Treatment in Pooled Studies 2, 3, and 5* * In this Kaplan-Meier plot, the averages displayed are based on pooled data from 3 placebo controlled, outpatient trials.

Patients not achieving headache response or taking additional treatment prior to 4 hours were censored at 4 hours. For patients with migraine associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of zolmitriptan tablets as compared with placebo. Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the f… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.3Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Zolmitriptan was administered to mice and rats at doses up to 400 mg/kg/day. Mice were dosed for 85 weeks (males) and 92 weeks (females); rats were dosed for 101 weeks (males) and 86 weeks (females). There was no evidence of drug-induced tumors in mice at plasma exposures (AUC) up to approximately 700 times that in humans at the maximum recommended human dose (MRHD) of 10 mg/day.

In rats, there was an increase in the incidence of thyroid follicular cell hyperplasia and thyroid follicular cell adenomas in male rats receiving 400 mg/kg/day. No increase in tumors was observed in rats at 100 mg/kg/day, a dose associated with a plasma AUC approximately 700 times that in humans at the MRHD. Mutagenesis Zolmitriptan was positive in an in vitro bacterial reverse mutation (Ames) assay and in an in vitro chromosomal aberration assay in human lymphocytes.

Zolmitriptan was negative in an in vitro mammalian gene cell mutation (CHO/HGPRT) assay and in oral in vivo mouse micronucleus assays in mouse and rat. Impairment of Fertility Studies of male and female rats administered zolmitriptan prior to and during mating and up to implantation showed no impairment of fertility at oral doses up to 400 mg/kg/day. The plasma exposure (AUC) at this dose was approximately 3000 times that in humans at the MRHD.