Onzetra Xsail (Page 4 of 6)

12.3 Pharmacokinetics

Absorption and Bioavailability

The mean maximum concentration (Cmax ) following a 22 mg nasal dose of ONZETRA Xsail was 21 ng/mL (range: 9 to 61 ng/mL), and the AUC0-∞ was 65 ng∙hr/ml (range: 40 to 107 ng/mL). Peak plasma concentration (Tmax ) was achieved on average 45 minutes (range: 10 minutes to 2 hours) following ONZETRA Xsail administration. The bioavailability of ONZETRA relative to subcutaneous injection was approximately 19%, primarily due to pre-systemic metabolism and partly due to incomplete absorption. Sumatriptan bioavailability following liquid nasal spray administration is 14%, similar to that after oral administration (15%).

Distribution

Protein binding of sumatriptan, determined by equilibrium dialysis over the concentration range of 10 to 1000 ng/mL, is approximately 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated. The apparent volume of distribution is 2.7 L/kg.

Metabolism

In vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO (predominately A isoenzyme). Most of a radiolabeled dose of sumatriptan excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive.

Elimination

The elimination half-life of sumatriptan administered as a nasal powder by the Xsail device is approximately 3 hours, similar to the half-life seen with sumatriptan nasal spray. Only 3% of a nasal spray dose is excreted in the urine as unchanged sumatriptan; 42% of a nasal spray dose is excreted as the major metabolite, the indole acetic acid analogue of sumatriptan. The total plasma clearance of the nasal spray is approximately 1200 mL/min.

Specific Populations

Age

The pharmacokinetics of oral sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females) and in patients with migraine (mean age: 38 years, 25 males and 155 females) were similar to that in healthy male subjects (mean age: 30 years). Intranasal sumatriptan has not been evaluated for age differences.

Race

The systemic clearance and Cmax of subcutaneous sumatriptan were similar in black (n=34) and Caucasian (n=38) healthy male subjects. Intranasal sumatriptan has not been evaluated for race differences.

Renal Impairment

The effect of renal impairment on the pharmacokinetics of sumatriptan has not been examined.

Hepatic Impairment

The effect of mild hepatic disease on the pharmacokinetics of sumatriptan has not been evaluated. Following oral administration, an approximately 70% increase in Cmax and AUC was observed in one small trial of patients with moderate liver impairment (n=8) matched for sex, age, and weight with healthy subjects (n=8). Similar changes can be expected following intranasal administration.

The pharmacokinetics of sumatriptan in patients with severe hepatic impairment has not been studied [see Contraindications (4)].

Drug Interaction Studies

Monoamine Oxidase-A Inhibitors

Treatment with MAO-A inhibitors generally leads to an increase of sumatriptan plasma levels [see Contraindications (4) and Drug Interactions (7.2)]. MAO inhibitors interaction studies have not been performed with intranasal sumatriptan.

Due to gut and hepatic metabolic first-pass effects, the increase of systemic exposure after co-administration of an MAO-A inhibitor with oral sumatriptan is greater than after co-administration of the MAO inhibitors with subcutaneous sumatriptan. The effects of an MAO inhibitor on systemic exposure after intranasal sumatriptan would be expected to be greater than the effect after subcutaneous sumatriptan but smaller than the effect after oral sumatriptan because only swallowed drug would be subject to first-pass effects.

In a trial of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of subcutaneous sumatriptan, resulting in a 2-fold increase in the area under the sumatriptan plasma concentration-time curve (AUC), corresponding to a 40% increase in elimination half-life.

A small study evaluating the effect of pretreatment with an MAO-A inhibitor on the bioavailability from a 25 mg oral sumatriptan tablet resulted in an approximately 7-fold increase in systemic exposure.

Xylometazoline

An in vivo drug interaction trial indicated that 3 drops of xylometazoline (0.1% w/v), a decongestant, administered 15 minutes prior to a 20 mg nasal spray dose of sumatriptan did not alter the pharmacokinetics of sumatriptan.

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 weeks 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 of 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 ONZETRA Xsail for the acute treatment of migraine with or without aura was established in a multicenter, randomized, double-blind, placebo-controlled study (Study 1).

Migraineurs enrolled in Study 1 were primarily female (84%) and Caucasian (86%), with a mean age of 42 years (range of 19 to 64). Patients were instructed to treat a moderate to severe migraine headache. Additional medications were allowed as rescue therapy beginning 2 hours after the initial treatment.

In Study 1, the proportion of patients who had headache relief defined as a reduction from moderate or severe pain to mild or no pain was assessed at 15, 30, 60, 90 minutes and 2, 24 and 48 hours after treatment with study drug. Associated symptoms of nausea, photophobia, and phonophobia were assessed as secondary endpoints. The proportion of patients who had no headache at 2 hours (120 minutes) was also assessed.

The percentage of patients achieving headache relief 2 hours after treatment was significantly greater in the ONZETRA Xsail 22 mg group compared to those who received placebo (see Table 2 and Figure 1). 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 ONZETRA Xsail compared with placebo.

Table 2: Percentage of Patients With Headache Relief (Primary Efficacy Endpoint), with No Headache, No Nausea, No Photophobia, and No Phonophobia 2 hours Post Treatment with ONZETRA Xsail (Study 1)
2 hours post treatmentONZETRA 22 mg (n=108)Placebo (n=104)
*
p <0.05 versus placebo
Headache Relief68%*45%
No Headache34% *17%
No Nausea82%79%
No Photophobia52%40%
No Phonophobia68%56%

Figure 1: Percentage of Patients with Headache Relief within 2 Hours with ONZETRA Xsail

Figure 1
(click image for full-size original)

The efficacy of ONZETRA Xsail 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 was insufficient data to assess the impact of race on efficacy.

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