CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
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`21-926
`
`LABELING
`
`

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`NDA 21-926 FDA Approved Labeling Text dated April 15, 2008
`
`PRESCRIBING INFORMATION
`
`TREXIMET”
`(sumatriptan and naproxen sodium)
`Tablets
`
`WARNINGS
`
`Cardiovascular Risk: TREXIMET may cause an increased risk of serious cardiovascular
`
`thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may
`increase with duration of use. Patients with cardiovascular disease or risk factors for
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`cardiovascular disease may be at greater risk (see WARNINGS: Cardiovascular Effects).
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`
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`Gastrointestinal Risk: TREXIMET contains a nonsteroidal anti-inflammatory drug
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`(NSAID). NSAID-containing products cause an increased risk of serious gastrointestinal
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`adverse events including bleeding, ulceration, and perforation of the stomach or intestines,
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`which can be fatal. These events can occur at any time during use and without warning
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`symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see
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`WARNINGS: Risk of Gastrointestinal Ulceration, Bleeding, and Perforation With
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`NonsteroidalAnti-inflammatory Drug Therapy).
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`DESCRIPTION
`
`TREXIMET contains sumatriptan (as the succinate), a selective 5-hydroxytryptamine1
`(5-HT1) receptor subtype agonist, and naproxen sodium, a member of the arylacetic acid group
`of nonsteroidal anti-inflammatory drugs (NSAIDs).
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`Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl] -N—methyl-
`
`indole-S—methanesulfonamide succinate (1:1), and it has the following structure:
`
`.
`
`CH20H2NICHaiz
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`COOH
`
`The empirical formula is C14H21N30280C4H604, representing a molecular weight of 413.5.
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`Sumatn'ptan succinate is a white to off-white powder that is readily soluble in water and in
`saline.
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`Naproxen sodium is chemically designated as (S)-6-methoxy-0t-methyl-2-naphthaleneacetic
`
`acid, sodium salt, and it has the following structure:
`
`AmNr—A
`\OOO\IO\UI
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`NDA 21-926 FDA Approved Labeling Text dated April 15, 2008
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`m at ....
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`The empirical formula is C14H13Na03, representing a molecular weight of 252.23. Naproxen
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`sodium is a white-to-creamy white crystalline solid, freely soluble in water at neutral pH.
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`Each TREXIMET Tablet for oral administration contains 119 mg of sumatriptan succinate
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`equivalent to 85 mg of sumatriptan and 500 mg of naproxen sodium. Each tablet also contains
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`the inactive ingredients croscarmellose sodium, dextrose monohydrate, dibasic calcium
`
`phosphate, FD&C Blue No. 2, lecithin, magnesium stearate, maltodextrin, microcrystalline
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`cellulose, povidone, sodium bicarbonate, sodium carboxymethylcellulose, talc, and titanium
`dioxide.
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`CLINICAL PHARMACOLOGY
`
`Mechanism of Action: TREXIMET contains sumatriptan, a 5—HT1 receptor agonist that
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`mediates vasoconstriction of the human basilar artery and vasculature of human dura mater,
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`which correlates with the relief of migraine headache. It also contains naproxen, an NSAID that
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`inhibits the synthesis of inflammatory mediators. Therefore, sumatriptan and naproxen contribute
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`to the relief of migraine through pharmacologically different mechanisms of action.
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`Sumatriptan is a 5-HT1 receptor agonist that binds with high affinity to 5—HT“; and 5-HT1 D
`
`receptors. Sumatriptan has only a weak affinity for 5-HT1A, 5—HT5A, and 5-HT7 receptors and no
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`significant affinity (as measured using standard radioligand binding assays) or pharmacological
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`activity at 5—HT2, 5-HT; or 5-HT4 receptor subtypes or at alphal-, alpha2-, or beta-adrenergic;
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`dopaminel; dopaminez; muscarinic; or benzodiazepine receptors. In addition to causing
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`vasoconstriction, experimental data from animal studies show that sumatriptan also activates
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`5-HT1 receptors on peripheral terminals of the tn'geminal nerve innervating cranial blood vessels.
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`Such an action may contribute to the antimigrainous effect of sumatriptan in humans. In the
`anesthetized dog, sumatriptan selectively reduces carotid arterial blood flow with little or no
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`effect on arterial blood pressure or total peripheral resistance.
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`Naproxen sodium is an NSAID with analgesic and antipyretic properties. The sodium salt of
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`naproxen has been developed as a more rapidly absorbed formulation of naproxen for use as an
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`analgesic. The mechanism of action of the naproxen anion, like that of other NSAIDs, is not
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`completely understood but may be related to prostaglandin synthetase inhibition.
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`Pharmacokinetics: TREXIMET is a formulation of 85 mg of sumatriptan (as sumatriptan
`
`succinate) and 500 mg of naproxen sodium with a distinct pharmacokinetic profile. Cmax for
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`sumatriptan following administration of TREXIMET occurs at approximately 1 hour (median,
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`range 0.3-4.0 hours). Cmax for naproxen following administration of TREXIMET occurs at
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`approximately 5 hours (median, range 0.3 to 12 hours). The sumatriptan half-life is
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`approximately 2 hours (15% to- -43% CV) and the naproxen half-life is approximately 19 hours
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`(13% to— -15% CV). The mean Cmax for sumatriptan when given as TREXIMET is similar to that
`
`, of sumatriptan when given as IMITREX Tablets 100 mg alone. The median sumatriptan Tmax is
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`only slightly different (1 hour for TREXIMET and 1.5 hours for IMITREX). The Cmax for
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`naproxen is approximately 36% lower, and the Tmax occurs approximately 4 hours later from
`TREXIMET than from ANAPROX® DS (naproxen sodium tablets) 550 mg. AUC values for
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`sumatriptan and for naproxen are similar for TREXIMET compared to IMITREX or ANAPROX
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`DS, respectively. In a crossover study in 16 patients, the pharmacokinetics of both components
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`administered as TREXIMET were similar during a migraine attack and during a migraine-flee
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`period.
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`Absorption and Bioavailability: Bioavailability of sumatriptan is approximately 15%,
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`primarily due to presystemic (first—pass) metabolism and partly due to incomplete absorption.
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`Naproxen is rapidly and completely absorbed from the gastrointestinal tract with an in vivo
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`bioavailability of 95%.
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`Food Effects: Food had no significant effect on the bioavailability of sumatriptan or
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`naproxen administered as TREXIMET, but slightly delayed the Tmax of sumatriptan by about
`0.6 hour. These data indicate that TREXIMET may be administered without regard to food.
`Distribution: The volume of distribution of sumatriptan is 2.4 L/kg. Plasma protein binding
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`is 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been
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`evaluated, but would be expected to be minor, given the low protein binding.
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`The volume of distribution of naproxen is 0.16 L/kg. At therapeutic levels naproxen is greater
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`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
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`unbound naproxen continues to increase proportionally to dose.
`
`Metabolism: Most of a radiolabeled dose of sumatriptan excreted in the urine is the major
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`metabolite indole acetic acid (1AA) or the IAA glucuronide, both of which are inactive. Three
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`percent of the dose can be recovered as unchanged sumatriptan. In vitro studies with human
`
`microsomes suggest that sumatriptan is metabolized by monoamine oxidase (MAO),
`
`predominantly the A isoenzyme, and inhibitors of that enzyme may alter sumatriptan
`
`“pharmacokinetics to increase systemic exposure (see CONTRAINDICATIONS and
`
`PRECAUTIONS: Drug Interactions: Monoamine Oxidase-A Inhibitors). 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: Radiolabeled 14C-sumatriptan administered orally is largely renally excreted
`(about 60%), with about 40% found in the feces. The elimination half-life of sumatriptan is
`
`approximately 2 hours.
`
`The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any
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`dose is excreted in the urine, primarily as naproxen (less than 1%), 6-0-desmethyl naproxen (less
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`NDA 21-926 FDA Approved Labeling Text dated April 15, 2008
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`than 1%), or theirconjugates (66% to 92%). The plasma half—life of the naproxen anion in
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`humans is approximately 19 hours. The corresponding half—lives of both metabolites and
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`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 (see PRECAUTIONS: Renal Effects).
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`Special Populations: Renal Impairment: TREXIMET is not recommended for use in
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`patients with creatinine clearance less than 30 mL/min (see PRECAUTIONS: Renal Effects).
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`The effect of renal impairment on the pharmacokinetics of TREXIMET has not been studied.
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`Minimal change in clinical effect would be expected with regard to sumatriptan as it is largely
`metabolized to an inactive substance.
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`Since naproxen and its metabolites and conjugates are primarily excreted by the kidney, the
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`potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency.
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`Elimination of naproxen is decreased in patients with severe renal impairment.
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`Hepatic Impairment: Because TREXIMET is a fixed-dose combination that cannot be
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`adjusted for this patient population, it is contraindicated in patients with hepatic impairment (see
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`CONTRAINDICATIONS and PRECAUTIONS: Hepatic Effects). The effect of hepatic
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`impairment on the pharmacokinetics of TREXIMET has not been studied. Sumatriptan is
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`contraindicated in patients with severe hepatic impairment and the dose is limited to 50 mg in
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`patients with liver disease.
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`Age: The effect of age (elderly or pediatric patients) on the pharmacokinetics of TREXIMET
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`has not been studied. Elderly patients are more likely to have decreased hepatic function and
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`decreased renal function (see PRECAUTIONS: Geriatric Use).
`
`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 I
`similar to that in healthy male subjects (mean age, 30 years).
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`Gender: In a pooled analysis of 5 pharrnacokinetic studies, there was no effect of gender on
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`the systemic exposure of TREXIMET. In a study comparing the pharmacokinetics of
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`sumatriptan in females and males, no differences were observed between genders for AUC, Cmax,
`Tmax, and TI/z.
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`Race: The effect of race on the pharmacokinetics of TREXIMET has not been studied. The
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`systemic clearance and Cmax of sumatriptan were similar in black (n = 34) and Caucasian (n = 38)
`healthy male subjects.
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`Drug Interactions: No formal drug interaction studies have been conducted with TREXIIVEET.
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`Monoamine Oxidase Inhibitors: TREXIMET is contraindicated in patients taking MAO-
`
`A inhibitors (see CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions). Treatment
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`with MAO-A inhibitors generally leads to an increase of sumatriptan plasma levels. This
`interaction has not been seen with an MAO-B inhibitor.
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`' Alcohol: The effect of alcohol consumption on the pharmacokinetics of TREXIMET has not
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`been studied. Alcohol consumed 30 minutes prior to sumatriptan ingestion had no effect on the
`
`pharmacokinetics of sumatriptan.
`
`

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`NDA 21-926 FDA Approved Labeling Text dated April 15, 2008
`
`CLINICAL TRIALS
`
`The efficacy of TREXIMET in providing relief from migraine was demonstrated in 2
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`randomized, double—blind, multicenter, parallel-group trials utilizing placebo and each individual
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`active component of TREXIMET (sumatriptan and naproxen sodium) as comparison treatments.
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`Patients enrolled in these 2 trials were predominately female (87%) and Caucasian (88%), with a
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`mean age of 40 years (range 18 to 65 years). Patients were instructed to treat a migraine of
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`moderate to severe pain with 1 tablet. Patients evaluated their headache pain 2 hours after taking
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`1 dose of study medication; headache relief was defined as a reduction in headache severity from
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`moderate or severe pain to mild or no pain. Associated symptoms of nausea, photophobia, and
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`phonophobia were also evaluated. Sustained pain fiee was defined as a reduction in headache
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`severity from moderate or severe pain to no pain at 2 hours postdose without a return of mild,
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`moderate, or severe pain and no use of rescue medication for 24 hours postdose. The results from
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`the 2 controlled clinical trials are summarized in Table 1. In both trials, the percentage of patients
`achieving headache pain relief 2 hours after treatment was significantly greater among patients
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`receiving TREXIMET (65% and 57%) compared to those who received placebo (28% and 29%).
`
`Further, the percentage of patients who remained pain free without use of other medications
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`through 24 hours postdose was significantly greater among patients receiving a single dose of
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`TREXIMET (25% and 23%) compared to those who received placebo (8% and 7%) or either
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`sumatriptan (16% and 14%) or naproxen sodium (10%) alone.
`
`'
`
`Table 1. Percentage of Patients With 2-Hour Pain Relief and Sustained Pain Free
`Followin Treatment*
`
`
`
`
`
`Sumatriptan Naproxen Sodium
`
`TREXIMET
`
`85 mg
`
`500 mg
`
`Placebo
`
`2-Hour Pain Relief
`
`n=364
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`n=36l
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`n=356
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`n=360
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`n=362
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`n=362
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`n=364
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`n=382
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`Sustained Pain Free 2-24 Hours
`
`
`
`
`
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`n=364
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`n=361
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`n=356
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`n=360
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`.
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`n=362
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`n=362
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`- n=364
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`n=382
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`*p values provided only for prespecified comparisons.
`lp<0.05 versus placebo and sumatriptan.
`1p<0.01 versus placebo, sumatriptan, and naproxen sodium.
`
`Note that comparisons of the performance of different drugs based upon results
`
`obtained in different clinical trials are never reliable. Because studies are generally
`
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`

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`NDA 21-926 FDA Approved Labeling Text dated April 15, 2008
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`conducted at different times, with different samples of patients, by different investigators,
`
`employing different criteria and/or different interpretations of the same criteria, under
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`different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment
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`response and the timing of response may be expected to vary considerably from study to
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`study.
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`The percentage of patients achieving initial headache pain relief within 2 hours following
`
`treatment with TREXIMET is shown in Figure 1.
`
`Figure 1. Percentage of Patients With Initial Headache Pain Relief Within 2 Hours
`
`mammwmmr
`
`0 mm
`O mast-:9
`I Mammalian
`'I' Placebo
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`90
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`"mm
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`Compared with placebo, there was a decreased incidence of photophobia, phonophobia, and
`nausea 2 hours after the administration of TREXIMET. The estimated probability of taking a
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`rescue medication over the first 24 hours is shown in Figure 2.
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`1 9 1
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`

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`NDA 21-926 FDA Approved Labeling Text dated April 15, 2008
`
`Figure 2. Estimated Probability of Taking a Rescue Medication Over the 24 Hours
`Following the First Dosei‘
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`100
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`90
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`0 m
`O mailing
`I "mammalian“
`'I' Placebo
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`10 /
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`Hull: Poem
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`* Kaplan-Meier plot based on data obtained in the 2 clinical controlled trials providing evidence
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`of efficacy with patients not using additional treatments censored to 24 hours. Plot also
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`includes patients who had no response to the initial dose. No rescue medication was allowed
`within 2 hours postdose.
`
`I
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`TREXIMET was more effective than placebo regardless of the presence of aura; duration of
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`headache prior to treatment; gender, age, or weight of the patient; or concomitant use of oral
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`contraceptives or common migraine prophylactic drugs (e.g., beta-blockers, anti-epileptic drugs,
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`tricyclic antidepressants).
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`INDICATIONS AND USAGE ‘
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`TREXIMET is indicated for the acute treatment of migraine attacks with or without aura in
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`adults. Carefully consider the potential benefits and risks of TREXIMET and other treatment
`
`options when deciding to use TREXIMET.
`
`TREXIMET is not intended for the prophylactic therapy of migraine or for use in the
`
`management of hemiplegic or basilar migraine (see CONTRAINDICATIONS). Safety and
`effectiveness of TREXIMET have not been established for cluster headache.
`
`CONTRAINDICATIONS
`
`Cardiac, Cerebrovascular, or Peripheral Vascular Disease: TREXIMET should not
`
`be given to patients with history, symptoms, or signs of ischemic cardiac, cerebrovascular,
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`or peripheral vascular syndromes. In addition, patients with other significant underlying
`
`cardiovascular diseases should not receive TREXIMET, nor should patients who have had
`coronary artery bypass graft (CABG) surgery. Ischemic cardiac syndromes include, but
`
`are not limited to, angina pectoris of any type (e.g., stable angina of effort and vasospastic
`forms of angina, such as the Prinzmetal variant), all forms of myocardial infarction, and
`
`silent myocardial ischemia. Cerebrovascular syndromes include, but are not limited to,
`
`strokes of any type as well as transient ischemic attacks. Peripheral vascular disease
`includes, but is not limited to, ischemic bowel disease (see WARNINGS: Cardiovascular
`
`Effects).
`
`.
`
`Uncontrolled Hypertension: TREXIMET should not be given to patients with
`uncontrolled hypertension because the components have been shown to increase blood
`pressure.
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`Monoamine Oxidase-A Inhibitors: Concurrent administration of MAO-A inhibitors or
`
`use of TREXIMET within 2 weeks of discontinuation of MAO-A inhibitor therapy is
`
`contraindicated (see CLINICAL PHARMACOLOGY: Drug Interactions and
`
`PRECAUTIONS: Drug Interactions).
`
`'
`
`Ergotamine—Containing or Ergot-Type Medications: TREXIMET and any
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`ergotamine-containing or ergot-type medication (like dihydroergotamine or methysergide)
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`should not be used within 24 hours of each other (see PRECAUTIONS: Drug Interactions).
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`Other 5-HT1 Agonists: Since TREXIMET contains sumatriptan, it should not be
`
`administered within 24 hours of another 5-HT1 agonist.
`
`Hemiplegic or Basilar Migraine: TREXIMET should not be administered to patients
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`with hemiplegic or basilar migraine.
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`Hepatic Impairment: TREXIMET is contraindicated in patients with hepatic impairment
`
`(see CLINICAL PHARMACOLOGY: Special Populations, PRECAUTIONS: Hepatic
`
`Effects, and PRECAUTIONS: Geriatric Use).
`
`Allergy to Naproxen/Asthma, Nasal Polyps, Urticaria, and Hypotension
`
`Associated With Nonsteroidal Anti-inflammatory Drugs: TREXIMET is
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`contraindicated in patients who have had allergic reactions to prescription as well as to
`
`over-the—counter products containing naproxen. It is also contraindicated in patients in
`
`whom aspirin or other nonsteroidal anti-inflammatory/analgesic drugs induce the
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`syndrome of asthma, rhinitis, and nasal polyps. Anaphylactic/anaphylactoid reactions to
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`naproxen, whether of the true allergic type or the pharmacologic idiosyncratic type (e.g.,
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`aspirin hypersensitivity syndrome), usually but not always occur in patients with a known
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`history of such reactions. Both types of reactions have the potential of being fatal.
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`Therefore, careful questioning of patients for medical conditions such as asthma, nasal
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`polyps, urticaria, and hypotension associated with NSAIDs before starting therapy is
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`important. In addition, if such symptoms occur during therapy, treatment should be
`discontinued (see WARNINGS: Anaphylactic/Anaphylactoid Reactions and
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`PRECAUTIONS: Preexisting Asthma).
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`NDA 21-926 FDA Approved Labeling Text dated April 15, 2008
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`Hypersensitivity to Sumatriptan or Naproxen: TREXIMET is contraindicated in
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`patients with hypersensitivity to sumatriptan, naproxen, or any other component of the
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`product.
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`WARNINGS
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`.
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`TREXIMET should only be used where a clear diagnosis of migraine headache has been
`established.
`,
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`Cardiovascular Effects: Risk of Myocardial Ischemia and/or Infarction and Other
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`Adverse Cardiac Events: TREXIMET should not be given to patients with documented
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`ischemic or vasospastic coronary artery disease (CAD) or to patients with a history of
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`CABG surgery (see CONTRAINDICATIONS). It is strongly recommended that
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`sumatriptan-containing products not be given to patients in whom unrecognized CAD is
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`predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker,
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`obesity, diabetes, strong family history of CAD, female with surgical or physiological
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`menopause, male over 40 years of age) unless a cardiovascular evaluation provides
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`satisfactory clinical evidence that the patient is reasonably free of CAD and ischemic
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`myocardial disease or other significant underlying cardiovascular disease. The sensitivity
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`of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to
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`coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the
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`patient’s medical history or electrocardiographic investigations reveal findings indicative
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`of, or consistent with, coronary artery vasospasm or myocardial ischemia, TREXIMET
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`should not be administered (see CONTRAINDICATIONS).
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`For patients with risk factors predictive of CAD who are determined to have a
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`satisfactory cardiovascular evaluation, it is strongly recommended that administration of
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`the first dose of TREXIMET take place in the setting of a physician’s office or similar
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`medically staffed and equipped facility unless the patient has previously received
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`sumatriptan. Because cardiac ischemia can occur in the absence of clinical symptoms,
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`consideration should be given to obtaining an electrocardiogram (ECG) immediately
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`following first-time use of TREXIMET in patients with risk factors.
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`It is recommended that patients who are intermittent long-term users of TREXIMET
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`and who have or acquire risk factors predictive of CAD as described above undergo
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`periodic cardiovascular evaluation as they continue to use TREXIMET.
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`The systematic approach described above is intended to reduce the likelihood that
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`patients with unrecognized cardiovascular disease will be inadvertently exposed to
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`sumatriptan-containing products.
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`Cardiac Events and Fatalities Associated With 5-HT1 Agonists: Serious adverse
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`cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac
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`rhythm, and death have been reported within a few hours following the administration of
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`sumatriptan. Considering the extent of use of 5—HT] agonists in patients with migraine, the
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`incidence of these events is extremely low.
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`The fact that sumatriptan can cause coronary vasospasm, that some of these events have
`occurred in patients with no prior cardiac disease history and with documented absence of CAD,
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`and the close proximity of the events to sumatriptan use support the conclusion that some of
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`these cases were caused by the drug. In cases, however, where there has been known underlying
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`coronary artery disease, the relationship is uncertain.
`Cardiovascular Thrombotic Events and Fatalities Associated With Nonsteroidal
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`Anti-inflammatory Drugs: Clinical trials of several COX-2 selective and nonselective
`NSAIDs of up to 3 years of duration have shown an increased risk of serious cardiovascular
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`thrombotic events, myocardial infarction, and stroke, which can be fatal. A11 NSAIDs, both
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`COX-2 selective and nonselective, may have a similar risk. Patients with known cardiovascular
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`disease or risk factors for cardiovascular disease may be at greater risk. To minimize the
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`potential risk for an adverse cardiovascular event in patients treated with an NSAID, the lowest
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`effective dose should be used for the shortest duration possible. Physicians and patients should
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`remain alert for the development of such events, even in the absence of previous cardiovascular
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`symptoms. Patients should be informed about the signs and/or symptoms of serious
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`cardiovascular events and the steps to take if they occur.
`
`There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of
`
`serious cardiovascular thrombotic events associated with NSAID use. The concurrent use of
`aspirin and an NSAID does increase the risk of serious gastrointestinal events (see WARNINGS:
`
`Risk of Gastrointestinal Ulceration, Bleeding, and Perforation With Nonsteroidal
`
`Anti-inflammatory Drug Therapy).
`
`Premarketing Experience With TREXIMET: Among 3,302 patients with migraine who
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`received TREXIMET in premarketing controlled and uncontrolled clinical trials, a 47-year-old
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`female with cardiac risk factors in an open-label 12-month safety study experienced signs and
`symptoms of acute coronary syndrome approximately 2 hours after receiving TREXIMET.
`Drug-Associated Cerebrovascular Events and Fatalities: Cerebral hemorrhage,
`subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in
`patients treated with oral or subcutaneous sumatriptan, and some have resulted in fatalities. The
`relationship of sumatriptan to these events is uncertain. In a number of cases, it appears possible
`that the cerebrovascular events were primary, sumatriptan having been administered in the
`
`V
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`incorrect belief that the symptoms experienced were a consequence of migraine when they were
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`not. As with other acute migraine therapies, before treating headaches in patients not previously
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`diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should
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`be taken to exclude other potentially serious neurological conditions. It should also be noted that
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`patients with migraine may be at increased risk of certain cerebrovascular events (e.g.,
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`cerebrovascular accident, transient ischemic attack).
`
`Other Vasospasm-Related Events: Sumatriptan may cause vasospastic reactions other
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`than coronary artery vasospasm. Both peripheral vascular ischemia and colonic ischenria with
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`abdominal pain and bloody diarrhea have been reported. Transient and permanent blindness and
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`10
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`NDA 21-926 FDA Approved Labeling Text dated April 15, 2008
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`significant partial vision loss have been reported with the use of sumatriptan. Visual disorders
`
`may also be part of a migraine attack.
`
`Increase in Blood Pressure: TREXIMET is contraindicated in patients with uncontrolled '
`
`hypertension (see CONTRAINDICATIONS). TREXIMET should be used with caution in
`
`patients with controlled hypertension.
`
`Significant elevation in blood pressure, including hypertensive crisis, has been reported in
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`patients with and without a history of hypertension receiving sumatriptan. Sumatriptan—
`
`containing products should be administered with caution to patients with controlled hypertension
`
`as transient increases in blood pressure and peripheral vascular resistance have been observed.
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`NSAID-containing products can lead to onset of new hypertension or worsening of
`
`preexisting hypertension, either of which may contribute to the increased incidence of
`cardiovascular events. Patients taking thiazides or loop diuretics may have impaired response to
`
`these therapies when taking NSAIDs. The potential effect on blood pressure associated with
`
`long-term use of TREXIMET has not been studied. Blood pressure should be monitored closely
`during the initiation of NSAID treatment and throughout the course of therapy.
`Congestive Heart Failure and Edema: TREXIMET should be used with caution in
`
`patients with fluid retention or heart failure. Fluid retention and edema have been observed in
`
`some patients taking NSAIDs. Since each TREXIMET tablet contains 61.2 mg of sodium (about
`
`2.7 mEq/SOO mg of naproxen sodium), this should be considered in patients whose overall intake
`
`of sodium must be severely restricted.
`
`Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome
`
`may occur with triptans, including treatment with TREXIMET, particularly during combined use
`
`with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake
`inhibitors (SNRIs). If concomitant treatment with TREXIMET and an SSRI (e.g., fluoxetine,
`
`paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., verrlafaxine,
`
`duloxetine) is clinically warranted, careful observation of the patient is advised, particularly
`
`during treatment initiation and dose increases. Serotonin syndrome symptoms may include
`
`mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e. g.,
`
`tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia,
`
`incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) (see
`
`PRECAUTIONS: Drug Interactions).
`
`Risk of Gastrointestinal Ulceration, Bleeding, and Perforation With Nonsteroidal
`
`Anti-inflammatory Drug Therapy: TREXIMET contains an NSAID. NSAID-containing
`
`products can cause serious gastrointestinal adverse events including inflammation, bleeding,
`
`ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal.
`
`These serious adverse events can occur at any time, with or without warning symptoms, in
`patients treated with NSAIDs. Only 1 in 5 patients who develop a serious upper gastrointestinal
`adverse event on NSAID therapy is symptomatic. Upper gastrointestinal ulcers, gross bleeding,
`
`or perforation caused by NSAIDs appear to occur in approximately 1% of patients treated daily
`
`.372 .
`
`for 3 to 6 months and in about 2% to 4% of patients treated for 1 year. These trends continue
`
`11
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`NDA 21—926 FDA Approved Labeling Text dated April 15, 2008
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`with longer duration of use, increasing the likelihood of developing a serious gastrointestinal
`
`event at some time during the course of therapy. However, even short-term therapy is not
`
`without risk. Among 3,302 patients with migraine who received TREXIMET in premarketing
`
`controlled and uncontrolled clinical trials, 1 patient experienced a recurrence of gastric ulcer
`
`after taking 8 doses over 3 weeks, and 1 patient developed a gastric ulcer after treating an
`average of 8 attacks per month over 7 months.
`
`NSAID-containing products, including TREXIMET, should be prescribed with extreme
`
`caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a
`
`prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a
`
`greater than 10—fold increased risk for developing gastrointestinal bleeding compared to patients
`
`with neither of these risk factors. Other factors that increase the risk for gastrointestinal bleeding
`in patients treated with NSAIDs include concomitant use of oral corticosteroids or
`
`anticoagulants, lon