Sumatriptan Succinate (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
In carcinogenicity studies in mouse and rat, sumatriptan was administered orally for 78 and 104 weeks, respectively, at doses up to 160 mg/kg/day (the high dose in rat was reduced from 360 mg/kg/day during Week 21). There was no evidence in either species of an increase in tumors related to sumatriptan administration. Plasma exposures (AUC) at the highest doses tested were 20 and 8 times that in humans at the maximum recommended human dose (MRHD) of 200 mg/day.

Mutagenesis
Sumatriptan was negative in in vitro (bacterial reverse mutation [Ames], gene cell mutation in Chinese hamster V79/HGPRT, chromosomal aberration in human lymphocytes) and in vivo (rat micronucleus) assays.

Impairment of Fertility
When sumatriptan (5, 50, 500 mg/kg/day) was administered orally to male and female rats prior to and throughout the mating period, there was a treatment-related decrease in fertility secondary to a decrease in mating in animals treated with doses greater than 5 mg/kg/day (less than the MRHD on a mg/m2 basis). It is not clear whether this finding was due to an effect on males or females or both.
When sumatriptan was administered by subcutaneous injection to male and female rats prior to and throughout the mating period, there was no evidence of impaired fertility at doses up to 60 mg/kg/day.

13.2 Animal Toxicology and/or Pharmacology

Corneal Opacities
Dogs receiving oral sumatriptan developed corneal opacities and defects in the corneal epithelium. Corneal opacities were seen at the lowest dose tested, 2 mg/kg/day, and were present after 1 month of treatment. Defects in the corneal epithelium were noted in a 60-week study. Earlier examinations for these toxicities were not conducted and no-effect doses were not established. Plasma exposure at the lowest dose tested was approximately 2 times that in humans at the MRHD.

14 CLINICAL STUDIES

The efficacy of sumatriptan succinate tablets in the acute treatment of migraine headaches was demonstrated in 3 randomized, double-blind, placebo-controlled trials. Patients enrolled in these 3 trials were predominately female (87%) and Caucasian (97%), with a mean age of 40 years (range: 18 to 65 years). 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 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 postdose. A second dose of sumatriptan succinate tablets or other medication was allowed 4 to 24 hours after the initial treatment for recurrent headache. Acetaminophen was offered to patients in Trials 2 and 3 beginning at 2 hours after initial treatment if the migraine pain had not improved or had worsened. Additional medications were allowed 4 to 24 hours after the initial treatment for recurrent headache or as rescue in all 3 trials. The frequency and time to use of these additional treatments were also determined. In all trials, doses of 25, 50, and 100 mg were compared with placebo in the treatment of migraine attacks. In 1 trial, doses of 25, 50, and 100 mg were also compared with each other.
In all 3 trials, the percentage of patients achieving headache response 2 and 4 hours after treatment was significantly greater among patients receiving sumatriptan succinate tablets at all doses compared with those who received placebo. In 1 of the 3 trials, there was a statistically significant greater percentage of patients with headache response at 2 and 4 hours in the 50 mg or 100 mg group when compared with the 25 mg dose groups. There were no statistically significant differences between the 50 mg and 100 mg dose groups in any trial. The results from the 3 controlled clinical trials are summarized in Table 2.
Table 2. Percentage of Patients with Headache Response (Mild or No Headache) 2 and 4 Hours following Treatment

Sumatriptan Succinate Tablets 25 mg 2 h 4 h

Sumatriptan Succinate Tablets 50 mg 2 h 4 h

Sumatriptan Succinate Tablets 100 mg 2 h 4 h

Placebo 2 h 4 h

Trial 1

52%a 67% a (n = 298)

61% a ,b 78% a ,b (n = 296)

62% a ,b 79% a ,b (n = 296)

27% 38%(n = 94)

Trial 2

52% a 70% a (n = 66)

50% a 68% a (n = 62)

56%a 71%a (n = 66)

26% 38%(n = 65)

Trial 3

52% a 65% a (n = 48)

54% a 72% a (n = 46)

57%a 78% a (n = 46)

17% 19%(n = 47)

a P<0.05 in comparison with placebo.
b P<0.05 in comparison with 25 mg. The estimated probability of achieving an initial headache response over the 4 hours following treatment in pooled Trials 1, 2, and 3 is depicted in Figure 1.

Sumatriptan-figure-1
(click image for full-size original)

For patients with migraine-associated nausea, photophobia, and/or phonophobia at baseline, there was a lower incidence of these symptoms at 2 hours (Trial 1) and at 4 hours (Trials 1, 2, and 3) following administration of sumatriptan succinate tablets compared with placebo. As early as 2 hours in Trials 2 and 3, or as early as 4 hours in Trial 1, through 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.

Sumatriptan-figure-2
(click image for full-size original)

There is evidence that doses above 50 mg do not provide a greater effect than 50 mg. There was no evidence to suggest that treatment with sumatriptan succinate tablets was associated with an increase in the severity of recurrent headaches. The efficacy of sumatriptan succinate tablets was unaffected by presence of aura; duration of headache prior to treatment; gender, age, or weight of the subject; relationship to menses; or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants). There were insufficient data to assess the impact of race on efficacy.

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