ZOMIG (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 seen in male rats receiving 400 mg/kg/day. The no-effect dose for tumors in rats (100 mg/kg/day) was associated with a plasma AUC ≈700 times that in humans at the MRHD.

13.2 Animal Toxicology and/or Pharmacology

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 micronucleus assays in mouse and rat.

13.3 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 maximum recommended human dose of 10 mg/day.

14 CLINICAL STUDIES

The efficacy of ZOMIG Nasal Spray 5 mg in the acute treatment of migraine headache with or without aura was demonstrated in a randomized, outpatient, double-blind, placebo-controlled trial.

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 15, 30, 45 minutes and 1, 2, and 4 hours after dosing. Pain free response rates and associated symptoms such as nausea, photophobia, and phonophobia were also assessed. A dose of escape medication was allowed 4 to 24 hours after the initial treatment for persistent and recurrent headache.

Of the 1372 patients treated in the study, 83% were female and 99% were Caucasian, with a mean age of 40.6 years (range 18 to 65 years).

The two hour headache response rates in patients treated with ZOMIG Nasal Spray were statistically significant among patients receiving ZOMIG Nasal Spray compared with placebo. There was a greater percentage of patients with a headache response at 2 hours in the higher dose groups. The headache response efficacy endpoints of the controlled clinical study, analyzed from the first attack data, are shown in Table 2.

Table 2: First Attack Data: Percentage of Patients with Headache Response to ZOMIG Nasal Spray (Mild or No Headache) 2 Hours Following Treatment

(N = number of randomized patients treating a migraine attack). The 2 hour headache response wNas the primary end-point.

NPLACEBO
(226)
ZOMIG
5 mg
(235)
*
p <0.0001 in comparison with placebo

2 hours

31%

69%*

The estimated probability of achieving an initial headache response by 4 hours following treatment with ZOMIG Nasal Spray is depicted in Figure 1.

figure one graph
(click image for full-size original)

Note:

Figure 1 shows the Kaplan-Meier plot of the probability over time of obtaining headache response (moderate or severe headache improving to mild or no pain) following treatment with zolmitriptan nasal spray. The averages displayed are based on a placebo controlled, outpatient trial providing evidence of efficacy. Patients not achieving headache response or taking additional treatment prior to 4 hours were censored to 4 hours.

For patients with migraine associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of ZOMIG Nasal Spray as compared with placebo.

Four 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 two graph
(click image for full-size original)

*This Kaplan-Meier plot is based on data obtained from the placebo controlled clinical trial. 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. It should be noted that the protocol did not allow remedication within 4 hours post dose.

The efficacy of ZOMIG was unaffected by presence of aura; presence of headache upon awakening, relationship to menses; gender, age or weight of the patient; or presence of pre-treatment nausea.

The efficacy of ZOMIG Nasal Spray 5 mg was further supported by an interim analysis of another similarly designed trial. The 2 hour headache response rates for the first 210 subjects in that study for ZOMIG 5 mg and placebo were 70% and 47%, respectively (N=108 and 102, respectively, p=0.0006).

16 HOW SUPPLIED/STORAGE AND HANDLING

The ZOMIG Nasal Spray device is a blue colored plastic device with a gray protection cap, labeled to indicate the nominal dose. Each ZOMIG Nasal Spray device administers a single dose of ZOMIG.

ZOMIG Nasal Spray is supplied as a clear to pale yellow solution of zolmitriptan, buffered to a pH 5.0. Each ZOMIG Nasal Spray device contains 5 mg of zolmitriptan in a 100-μL unit dose aqueous buffered solution containing citric acid, anhydrous, USP, disodium phosphate dodecahydrate USP and purified water USP.

5 mg ZOMIG® Nasal Spray is supplied in boxes of 6 single use nasal spray units. (NDC 21695-955-06).

Each ZOMIG® Nasal Spray single dose unit spray supplies 5 mg of zolmitriptan. The ZOMIG® Nasal Spray unit must be discarded after use.

Store at controlled room temperature, 20-25°C (68-77°F) [see USP].

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling (17.5)

17.1 Risk of Myocardial Ischemia and/or Infarction, Other Adverse Cardiac Events, Other Vasospasm-related Event, and Cerebrovascular Events

Patients should be informed that ZOMIG may cause serious cardiovascular side effects such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up [see Warnings and Precautions (5.1, 5.3, 5.4)].

17.2 Serotonin Syndrome

Patients should be cautioned about the risk of serotonin syndrome with the use of ZOMIG or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.5)].

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