SUMATRIPTAN (Page 5 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In carcinogenicity studies in mouse and rat in which sumatriptan was administered orally for 78 and 104 weeks, respectively, there was no evidence in either species of an increase in tumors related to sumatriptan administration.

Carcinogenicity studies of sumatriptan using the nasal route have not been conducted.

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, or 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. 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.

Fertility studies of sumatriptan using the intranasal route have not been conducted.

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.

14 CLINICAL STUDIES

The efficacy of Sumatriptan Nasal Spray in the acute treatment of migraine headaches was demonstrated in 8 randomized, double-blind, placebo-controlled trials, of which 5 used the recommended dosing regimen and used the marketed formulation. Patients enrolled in these 5 trials were predominately female (86%) and Caucasian (95%), with a mean age of 41 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 2 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 Nasal Spray or other medication was allowed 2 to 24 hours after the initial treatment for recurrent headache. The frequency and time to use of these additional treatments were also determined. In all trials, doses of 10 and 20 mg were compared with placebo in the treatment of 1 to 3 migraine attacks. Patients received doses as a single spray into 1 nostril. In 2 trials, a 5-mg dose was also evaluated.

In all 5 trials utilizing the market formulation and recommended dosage regimen, the percentage of patients achieving headache response 2 hours after treatment was significantly greater among patients receiving Sumatriptan Nasal Spray at all doses (with one exception) compared with those who received placebo. In 4 of the 5 trials, there was a statistically significant greater percentage of patients with headache response at 2 hours in the 20-mg group when compared with the lower dose groups (5 and 10 mg). There were no statistically significant differences between the 5- and 10-mg dose groups in any trial. The results from the 5 controlled clinical trials are summarized in Table 2. Note that, in general, comparisons of results obtained in trials conducted under different conditions by different investigators with different samples of patients are ordinarily unreliable for purposes of quantitative comparison.

Table 2. Percentage of Patients with Headache Response (No or Mild Pain) 2 Hours following Treatment
a P <0.05 in comparison with placebo.
b P <0.05 in comparison with 10 mg.
c P <0.05 in comparison with 5 mg.
d Data are for attack 1 only of multi-attack trial for comparison.

Sumatriptan

Nasal Spray

5 mg

Sumatriptan

Nasal Spray

10 mg

Sumatriptan

Nasal Spray

20 mg

Placebo

Trial 1

49%a

46%a

64%a,b,c

25%

(n = 121)

(n = 112)

(n = 118)

(n = 63)

Trial 2

Not applicable

44%a

55%a,b

25%

(n = 273)

(n = 277)

(n = 138)

Trial 3

Not applicable

54%a

63%a

35%

(n = 106)

(n = 202)

(n = 100)

Trial 4

Not applicable

43%

62%a,b

29%

(n = 106)

(n = 215)

(n = 112)

Trial 5d

45%a

53%a

60%a,c

36%

(n = 296)

(n = 291)

(n = 286)

(n = 198)

The estimated probability of achieving an initial headache response over the 2 hours following treatment is depicted in Figure 1.

Figure 1. Estimated Probability of Achieving Initial Headache Response within 120 Minutesa

Figure 1
(click image for full-size original)

a The figure shows the probability over time of obtaining headache response (no or mild pain) following treatment with intranasal sumatriptan. The averages displayed are based on pooled data from the 5 clinical controlled trials providing evidence of efficacy. Kaplan-Meier plot with patients not achieving response within 120 minutes censored to 120 minutes.

For patients with migraine-associated nausea, photophobia, and phonophobia at baseline, there was a lower incidence of these symptoms at 2 hours following administration of Sumatriptan Nasal Spray 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 Migraine over the 24 Hours following the Initial Dose of Study Treatmenta

Figure 2
(click image for full-size original)

a Kaplan-Meier plot based on data obtained in the 3 clinical controlled trials providing evidence of efficacy with patients not using additional treatments censored to 24 hours. Plot also includes patients who had no response to the initial dose. No remedication was allowed within 2 hours postdose.

There is evidence that doses above 20 mg do not provide a greater effect than 20 mg. There was no evidence to suggest that treatment with sumatriptan was associated with an increase in the severity of recurrent headaches. The efficacy of Sumatriptan Nasal Spray was unaffected by presence of aura; duration of headache prior to treatment; gender, age, or weight of the subject; 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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