Sumatriptan and Naproxen Sodium (Page 8 of 11)

12.2 Pharmacodynamics

In a healthy volunteer study, 10 days of concomitant administration of naproxen 220 mg once-daily with low-dose immediate-release aspirin (81 mg) showed an interaction with the antiplatelet activity of aspirin as measured by % serum thromboxane B2 inhibition at 24 hours following the day 10 dose [98.7% (aspirin alone) vs 93.1% (naproxen and aspirin)]. The interaction was observed even following discontinuation of naproxen on day 11 (while aspirin dose was continued) but normalized by day 13. In the same study, the interaction was greater when naproxen was administered 30 minutes prior to aspirin [98.7% vs 87.7%] and minimal when aspirin was administered 30 minutes prior to naproxen [98.7% vs 95.4%].
Following administration of naproxen 220 mg twice-daily with low-dose immediate–release aspirin (first naproxen dose given 30 minutes prior to aspirin), the interaction was minimal at 24 h following day 10 dose [98.7% vs 95.7%]. However, the interaction was more prominent after discontinuation of naproxen (washout) on day 11 [98.7% vs 84.3%] and did not normalize completely by day 13 [98.5% vs 90.7%] [see Drug Interactions (7.1)].

Blood Pressure

In a randomized, double-blind, parallel group, active control trial, sumatriptan and naproxen sodium 85/500 mg administered intermittently over 6 months did not increase blood pressure in a normotensive adult population (n = 122). However, significant elevation in blood pressure has been reported with 5-HT1 agonists and NSAIDs in patients with and without a history of hypertension.

12.3 Pharmacokinetics

Absorption and Bioavailability

Sumatriptan, when given as sumatriptan and naproxen sodium 85/500 mg, has a mean Cmax similar to that of sumatriptan succinate 100 mg tablets alone. The median Tmax of sumatriptan, when given as sumatriptan and naproxen sodium 85/500 mg, was 1 hour (range: 0.3 to 4.0 hours), which is slightly different compared with sumatriptan succinate 100 mg tablets (median Tmax of 1.5 hours). Naproxen, when given as sumatriptan and naproxen sodium 85/500 mg, has a Cmax which is approximately 36% lower than naproxen sodium 550 mg tablets and a median Tmax of 5 hours (range: 0.3 to 12 hours), which is approximately 4 hours later than from naproxen sodium tablets 550 mg. AUC values for sumatriptan and for naproxen are similar for sumatriptan and naproxen sodium 85/500 mg compared with sumatriptan succinate 100 mg tablets or naproxen sodium 550 mg tablets, respectively. In a crossover trial in 16 subjects, the pharmacokinetics of both components administered as sumatriptan and naproxen sodium 85/500 mg were similar during a migraine attack and during a migraine-free period.

Bioavailability of sumatriptan is approximately 15%, primarily due to presystemic (first-pass) metabolism and partly due to incomplete absorption.

Naproxen is absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%.

Food had no significant effect on the bioavailability of sumatriptan or naproxen administered as sumatriptan and naproxen sodium, but slightly delayed the Tmax of sumatriptan by about 0.6 hour [see Dosage and Administration (2.3)].

Distribution

Plasma protein binding is 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated. The volume of distribution of sumatriptan is 2.7 L/kg.

The volume of distribution of naproxen is 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin bound. At doses of naproxen greater than 500 mg/day, there is a less-than-proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css = 36.5, 49.2, and 56.4 mg/L with 500-; 1,000-; and 1,500 mg daily doses of naproxen, respectively). However, the concentration of unbound naproxen continues to increase proportionally to dose.

Metabolism

In vitro studies with human microsomes suggest that sumatriptan is metabolized by monoamine oxidase (MAO), predominantly the A isoenzyme. No significant effect was seen with an MAO-B inhibitor.

Naproxen is extensively metabolized to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes.

Elimination

The elimination half-life of sumatriptan is approximately 2 hours. Radiolabeled 14 C-sumatriptan administered orally is largely renally excreted (about 60%), with about 40% found in the feces. 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. Three percent of the dose can be recovered as unchanged sumatriptan.

The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (less than 1%), 6-0-desmethyl naproxen (less than 1%), or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in humans is approximately 19 hours. The corresponding half-lives of both metabolites and conjugates of naproxen are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen disappearance from the plasma. In patients with renal failure, metabolites may accumulate.

Specific Populations

Geriatrics

The pharmacokinetics of sumatriptan and naproxen sodium in geriatric patients have not been studied. Elderly patients are more likely to have decreased hepatic function and decreased renal function [see Specific Populations (8.5)].

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).

Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction, which represents <1% of the total concentration, increased in the elderly (range of unbound trough naproxen from 0.12% to 0.19% in elderly subjects versus 0.05% to 0.075% in younger subjects).

Pediatrics

A pharmacokinetic study compared 3 doses of sumatriptan and naproxen sodium in pediatric patients 12 to 17 years of age (n=24) with adults (n=26). The AUC and Cmax of sumatriptan were 50 to 60% higher following a single dose of sumatriptan and naproxen sodium 10/60 mg in pediatric patients 12 to 17 years of age (n=7) compared with adult subjects (n=8), and were 6 to 26% higher following a single dose of sumatriptan and naproxen sodium 30/180 mg or 85/500 mg in pediatrics than adults. Naproxen pharmacokinetic parameters were similar between pediatrics and adults.

Renal Impairment

The effect of renal impairment on the pharmacokinetics of sumatriptan and naproxen sodium has not been studied. Since naproxen and its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment. [see Warnings and Precautions (5.12), Use in Specific Populations (8.6)].

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of sumatriptan and naproxen sodium has not been studied. In a study in patients with moderate hepatic impairment (n = 8) matched for sex, age, and weight with healthy subjects (n = 8), patients with hepatic impairment had an approximately 70% increase in AUC and Cmax of sumatriptan and a Tmax 40 minutes earlier compared to healthy subjects. The pharmacokinetics of sumatriptan in patients with severe hepatic impairment has not been studied.

Gender

In a pooled analysis of 5 pharmacokinetic trials, there was no effect of gender on the systemic exposure of sumatriptan and naproxen sodium.

Race

The effect of race on the pharmacokinetics of sumatriptan and naproxen sodium has not been studied. The systemic clearance and Cmax of sumatriptan were similar in black (n = 34) and white (n = 38) healthy male subjects.

Drug Interaction Studies

Aspirin

When naproxen was administered with aspirin (>1 gram/day), the protein binding of naproxen was reduced, although the clearance of free naproxen was not altered. See Table 3 for clinically significant drug interactions of naproxen, an NSAID, with aspirin [see Drug Interactions (7)].

Propranolol

Propranolol 80 mg given twice daily had no significant effect on sumatriptan pharmacokinetics. See Table 3 for clinically significant drug interactions of propranolol, a beta-blocker, with sumatriptan and naproxen sodium [see Drug Interactions (7)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

The carcinogenic potential of sumatriptan and naproxen sodium has not been studied.

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 highest doses tested are approximately 5 (mouse) and 9 (rat) times the maximum human daily dose (MHDD) of 170 mg sumatriptan on a mg/m2 basis (two tablets of sumatriptan and naproxen sodium 85/500 mg in a 24-hour period).

The carcinogenic potential of naproxen was evaluated in a 2-year oral carcinogenicity study in rats at doses of 8, 16, and 24 mg/kg/day and in another 2-year oral carcinogenicity study in rats at a dose of 8 mg/kg/day. No evidence of tumorigenicity was found in either study. The highest dose tested is less than the MHDD (1000 mg) of naproxen, on a mg/m2 basis.

Mutagenesis

Sumatriptan and naproxen sodium tested alone and in combination were negative in an in vitro bacterial reverse mutation assay, and in an in vivo micronucleus assay in mice.

The combination of sumatriptan and naproxen sodium was negative in an in vitro mouse lymphoma tk assay in the presence and absence of metabolic activation. However, in separate in vitro mouse lymphoma tk assays, naproxen sodium alone was reproducibly positive in the presence of metabolic activation.

Naproxen sodium alone and in combination with sumatriptan was positive in an in vitro clastogenicity assay in mammalian cells in the presence and absence of metabolic activation. The clastogenic effect for the combination was reproducible within this assay and was greater than observed with naproxen sodium alone. Sumatriptan alone was negative in these assays.

Chromosomal aberrations were not induced in peripheral blood lymphocytes following 7 days of twice-daily dosing with sumatriptan and naproxen sodium in human volunteers.

In previous studies, sumatriptan alone 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

The effect of sumatriptan and naproxen sodium on fertility in animals has not been studied.

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 drug-related decrease in fertility secondary to a decrease in mating in animals treated with doses greater than 5 mg/kg/day (less than the MHDD of 170 mg on a mg/m2 basis). It is not clear whether this finding was due to an effect on males or females or both.

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