Sumatriptan and Naproxen Sodium 85 mg; 500 mg Tablet, Film Coated, 9-count — NDC 65862-928-36 (Billing 65862-0928-36)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Sumatriptan and naproxen sodium tablets contain sumatriptan and naproxen. Sumatriptan binds with high affinity to cloned 5-HT 1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine headache through agonist effects at the 5-HT 1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of neuropeptide release.

Sumatriptan and naproxen sodium has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of sumatriptan and naproxen sodium, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Naproxen is a potent inhibitor of prostaglandin synthesis in vitro .

Naproxen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation.

Because naproxen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

12.2Pharmacodynamics 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 B 2 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-HT 1 agonists and NSAIDs in patients with and without a history of hypertension.

12.3Pharmacokinetics Absorption and Bioavailability Sumatriptan, when given as sumatriptan and naproxen sodium 85/500 mg, has a mean C max similar to that of sumatriptan succinate 100 mg tablets alone. The median T max 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 T max of 1.5 hours). Naproxen, when given as sumatriptan and naproxen sodium 85/500 mg, has a C max which is approximately 36% lower than naproxen sodium 550 mg tablets and a median T max 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 presys… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Sumatriptan and naproxen sodium tablets contain sumatriptan and naproxen. Sumatriptan binds with high affinity to cloned 5-HT 1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine headache through agonist effects at the 5-HT 1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of neuropeptide release.

Sumatriptan and naproxen sodium has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of sumatriptan and naproxen sodium, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Naproxen is a potent inhibitor of prostaglandin synthesis in vitro .

Naproxen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation.

Because naproxen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

12.3Pharmacokinetics Absorption and Bioavailability Sumatriptan, when given as sumatriptan and naproxen sodium 85/500 mg, has a mean C max similar to that of sumatriptan succinate 100 mg tablets alone. The median T max 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 T max of 1.5 hours). Naproxen, when given as sumatriptan and naproxen sodium 85/500 mg, has a C max which is approximately 36% lower than naproxen sodium 550 mg tablets and a median T max 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 T max 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

2.7L/kg. The volume of distribution of naproxen is

0.16L/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 C ss = 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… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics 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 B 2 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-HT 1 agonists and NSAIDs in patients with and without a history of hypertension.

14 CLINICAL STUDIES

14.1Adults The efficacy of sumatriptan and naproxen sodium in the acute treatment of migraine with or without aura in adults was demonstrated in 2 randomized, double-blind, multicenter, parallel-group trials utilizing placebo and each individual active component of sumatriptan and naproxen sodium 85/500 mg as comparison treatments (Study 1 and Study 2). Patients enrolled in these 2 trials were predominately female (87%) and white (88%), with a mean age of 40 years (range: 18 to 65 years). Patients were instructed to treat a migraine of moderate to severe pain with 1 tablet.

No rescue medication was allowed within 2 hours postdose. Patients evaluated their headache pain 2 hours after taking 1 dose of study medication; headache relief was defined as a reduction in headache severity from moderate or severe pain to mild or no pain. Associated symptoms of nausea, photophobia, and phonophobia were also evaluated.

Sustained pain free was defined as a reduction in headache severity from moderate or severe pain to no pain at 2 hours postdose without a return of mild, moderate, or severe pain and no use of rescue medication for 24 hours postdose. The results from Study 1 and 2 are summarized in Table 4. In both trials, the percentage of patients achieving headache pain relief 2 hours after treatment was significantly greater among patients receiving sumatriptan and naproxen sodium 85/500 mg (65% and 57%) compared with those who received placebo (28% and 29%).

Further, the percentage of patients who remained pain free without use of other medications through 24 hours postdose was significantly greater among patients receiving a single dose of sumatriptan and naproxen sodium 85/500 mg (25% and 23%) compared with those who received placebo (8% and 7%) or either sumatriptan (16% and 14%) or naproxen sodium (10%) alone. Table 4. Percentage of Adult Patients with 2-Hour Pain Relief and Sustained Pain Free Following Treatment a a P values provided only for prespecified comparisons. b P <0.05 versus placebo and sumatriptan. c P <0.01 versus placebo, sumatriptan, and naproxen sodium.

Sumatriptan and Naproxen Sodium Tablets 85/500 mg Sumatriptan 85 mg Naproxen Sodium 500 mg Placebo 2-Hour Pain Relief Study 1 65% b n = 364 55% n = 361 44% n = 356 28% n = 360 Study 2 57% b n = 362 50% n = 362 43% n = 364 29% n = 382 Sustained Pain Free (2 to 24 Hours) Study 1 25% c n = 364 16% n = 361 10% n = 356 8% n = 360 Study 2 23% c n = 362 14% n = 362 10% n = 364 7% n = 382 The percentage of patients achieving initial headache pain relief within 2 hours following treatment with sumatriptan and naproxen sodium 85/500 mg is shown in Figure 1.

Compared with placebo, there was a decreased incidence of photophobia, phonophobia, and nausea 2 hours after the administration of sumatriptan and naproxen sodium 85/500 mg. The estimated probability of taking a rescue medication over the first 24 hours is shown in Figure 2. Sumatriptan and naproxen sodium 85/500 mg was more effective than placebo regardless of the presence of aura; duration of headache prior to treatment; gender, age, or weight of the subject; or concomitant use of oral contraceptives or common migraine prophylactic drugs (e.g., beta-blockers, anti-epileptic drugs, tricyclic antidepressants).

Figure 1 Figure 2

14.2Pediatric Patients 12 to 17 Years of Age The efficacy of sumatriptan and naproxen sodium in the acute treatment of migraine with or without aura in pediatric patients 12 to 17 years of age was demonstrated in a randomized, double-blind, multicenter, parallel-group, placebo-controlled, multicenter trial comparing 3 doses of sumatriptan and naproxen sodium and placebo (Study 3). Patients enrolled in this trial were mostly female (59%) and white (81%), with a mean age of 15 years. Patients were required to have at least a 6-month history of migraine attacks with or without aura usually lasting 3 hours or more when untreated.

Following a single-blind, placebo run-in phase, plac… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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/m 2 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/m 2 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/m 2 basis). It is not clear whether this finding was due to an effect on males or females or both.

13.2Animal 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 dosage 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. The lowest dose tested is less than the MHDD (170 mg) of sumatriptan on a mg/m 2 basis.