Zolmitriptan OD (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, 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.

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 12-65). 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

Placebo Zolmitriptantablets1 mg Zolmitriptantablets2.5 mg Zolmitriptantablets 5 mg
Study 1a 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 4b 44% (n=55) NA NA 59%* (n=491)
Study 5 36% (n=92) NA 62%* (n=178) NA

n=number of patients randomized
* p<0.05 in comparison with placebo.
# p<0.05 in comparison with 1 mg.
a Study 1 was the only study in which patients treated the headache in a clinic setting.
b Study 4 was the only study where patients were excluded who had previously used sumatriptan.
NA — not applicable

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*

fig 1
(click image for full-size original)

* 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 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 The Estimated Probability Of Patients Taking A Second Dose Or Other Medication For Migraines Over The 24 Hours Following The Initial Dose Of Study Treatment in Pooled Studies 2, 3, and 5*

fig 2
(click image for full-size original)

*In this Kaplan-Meier plot, 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. The studies did not allow taking additional doses of study medication within 2 hours post-dose.

The efficacy of zolmitriptan was unaffected by presence of aura; duration of headache prior to treatment; relationship to menses; gender, age or weight of the patient; pre-treatment nausea or concomitant use of common migraine prophylactic drugs.

Zolmitriptan Orally Disintegrating Tablets
The efficacy of zolmitriptan orally disintegrating tablets 2.5 mg was demonstrated in a randomized, placebo-controlled trial (Study 6) that was similar in design to the trials of zolmitriptan tablets. Patients were instructed to treat a moderate to severe headache. Of the 471 patients treated in Study 6, 87% were female and 97% were Caucasian, with a mean age of 41 years (range 18-62).
At 2 hours post-dosing, there was a statistically significant greater percentage of patients treated with zolmitriptan orally disintegrating tablets 2.5 mg with a headache response (reduction in headache severity from moderate or severe pain to mild or no headache) compared to patients treated with placebo (63% vs. 22%). The estimated probability of achieving an initial headache response by 2 hours following treatment with zolmitriptan orally disintegrating tablets is depicted in Figure 3. Figure 3 Estimated Probability of Achieving Initial Headache Response (Reduction in Headache Severity from Moderate or Severe Pain to Mild or No Headache) Within 2 Hours in Study 6*

fig 3
(click image for full-size original)

*In this Kaplan-Meier plot 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 zolmitriptan orally disintegrating tablets as compared to placebo.
Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment 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 in Study 6 is summarized in Figure 4.

Figure 4 The Estimated Probability of Patients Taking a Second Dose or Other Medication for Migraines Over the 24 Hours Following The Initial Dose of Study Treatment in Study 6*

fig 4
(click image for full-size original)

* In this Kaplan-Meier plot, patients not taking 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. Taking another dose of study medication was allowed 2 hours post-dose in Study 6. In contrast to studies of zolmitriptan tablets (Studies 1, 2, 3, 4, and 5), Study 6 allowed re-dosing of zolmitriptan orally disintegrating tablets prior to 4 hours.

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