360 mg/kg/day during Week 21). There was no evidence in either species of an increasein tumors related to sumatriptan administration.
Mutagenesis
Sumatriptan was negative in in vitro (bacterial reverse mutation [Ames], gene cell mutation inChinese hamster V79/HGPRT, chromosomal aberration in human lymphocytes) and in vivo (ratmicronucleus) assays.
Impairment of Fertility
When sumatriptan (0, 5, 50, 500 mg/kg/day) was administered orally to male and female ratsprior to and throughout the mating period, there was a treatment-related decrease in fertilitysecondary to a decrease in mating in animals treated with doses greater than 5 mg/kg/day. It isnot 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 toand throughout the mating period, there was no evidence of impaired fertility at doses up to 60mg/kg/day.
13.2 Animal Toxicology and/or Pharmacology
Corneal Opacities
Dogs receiving oral sumatriptan developed corneal opacities and defects in the cornealepithelium. Corneal opacities were seen at the lowest dose tested, 2 mg/kg/day, and were presentafter 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 notestablished.
14 CLINICAL STUDIES
The efficacy of TOSYMRA is based on the relative bioavailability of TOSYMRA nasal spraycompared to sumatriptan subcutaneous injection (4 mg) in healthy adults [see Clinical
Pharmacology (12.3)].
In controlled clinical trials enrolling more than 1000 patients during migraine attacks who wereexperiencing moderate or severe pain and 1 or more of the symptoms enumerated in Table 3,onset of relief began as early as 10 minutes following a 6-mg sumatriptan injection. Lowerdoses of sumatriptan injection may also prove effective, although the proportion of patientsobtaining adequate relief was decreased and the latency to that relief is greater with lower
doses.
In Study 1, 6 different doses of sumatriptan injection (n = 30 each group) were compared withplacebo (n = 62) in a single-attack, parallel-group design; the dose-response relationship wasfound to be as shown in Table 2.
Table 2: Proportion of Patients with Migraine Relief and Incidence of Adverse
Reactions by Time and by Sumatriptan Dose in Study 1
Dose of
sumatriptan Percent Patients with Relief
a Adverse
Reactions
Incidence
(%)
Injection at 10
Minutes
at 30
Minutes
at 1 Hour at 2 Hours
Placebo
1 mg
2 mg
3 mg
4 mgb
6 mg
8 mg
5
10
7
17
13
10
23
15
40
23
47
37
63
57
24
43
57
57
50
73
80
21
40
43
60
57
70
83
55
63
63
77
80
83
93
a Relief is defined as the reduction of moderate or severe pain to no or mild pain after dosing without use of rescuemedication.
b Efficacy of Tosymra nasal spray was demonstrated based on bioavailability to 4 mg sumatriptan SC injection.
In 2 randomized, placebo-controlled clinical trials of sumatriptan injection 6 mg in 1,104 patientswith moderate or severe migraine pain (Studies 2 and 3), the onset of relief was less than 10minutes. Headache relief, as defined by a reduction in pain from severe or moderately severe tomild or no headache, was achieved in 70% of the patients within 1 hour of a single 6-mgsubcutaneous do |
