1
`®
`2 TREXIMET
`(sumatriptan and naproxen sodium)
`3
`4 Tablets
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`PRESCRIBING INFORMATION
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`5 WARNINGS
`6 Cardiovascular Risk: TREXIMET may cause an increased risk of serious cardiovascular
`thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may
`7
`increase with duration of use. Patients with cardiovascular disease or risk factors for
`8
`cardiovascular disease may be at greater risk (see WARNINGS: Cardiovascular Effects).
`9
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`10
`11 Gastrointestinal Risk: TREXIMET contains a nonsteroidal anti-inflammatory drug
`(NSAID). NSAID-containing products cause an increased risk of serious gastrointestinal
`12
`adverse events including bleeding, ulceration, and perforation of the stomach or intestines,
`13
`14 which can be fatal. These events can occur at any time during use and without warning
`symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see
`15
`16 WARNINGS: Risk of Gastrointestinal Ulceration, Bleeding, and Perforation With
`17 Nonsteroidal Anti-inflammatory Drug Therapy).
`
`18 DESCRIPTION
` TREXIMET contains sumatriptan (as the succinate), a selective 5-hydroxytryptamine1
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`20
`(5-HT1) receptor subtype agonist, and naproxen sodium, a member of the arylacetic acid group
`21
`of nonsteroidal anti-inflammatory drugs (NSAIDs).
`22
` Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl­
`23
`indole-5-methanesulfonamide succinate (1:1), and it has the following structure:
`24
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`The empirical formula is C14H21N3O2S•C4H6O4, representing a molecular weight of 413.5.
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`Sumatriptan succinate is a white to off-white powder that is readily soluble in water and in
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`saline.
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`Naproxen sodium is chemically designated as (S)-6-methoxy-α-methyl-2-naphthaleneacetic
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`acid, sodium salt, and it has the following structure:
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` The empirical formula is C14H13NaO3, representing a molecular weight of 252.23. Naproxen
` 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
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` phosphate, FD&C Blue No. 2, lecithin, magnesium stearate, maltodextrin, microcrystalline
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` cellulose, povidone, sodium bicarbonate, sodium carboxymethylcellulose, talc, and titanium
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` dioxide.
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` 42 CLINICAL PHARMACOLOGY
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` 43 Mechanism of Action: TREXIMET contains sumatriptan, a 5-HT1 receptor agonist that
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`44 mediates vasoconstriction of the human basilar artery and vasculature of human dura mater,
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`45 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
`46
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`47
`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-HT1B and 5-HT1D
`48
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`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-HT3, or 5-HT4 receptor subtypes or at alpha1-, alpha2-, or beta-adrenergic;
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`dopamine1; dopamine2; muscarinic; or benzodiazepine receptors. In addition to causing
`52
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`vasoconstriction, experimental data from animal studies show that sumatriptan also activates 5­
`53
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`54 HT1 receptors on peripheral terminals of the trigeminal nerve innervating cranial blood vessels.
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`Such an action may contribute to the antimigrainous effect of sumatriptan in humans. In the
`55
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`anesthetized dog, sumatriptan selectively reduces carotid arterial blood flow with little or no
`56
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`effect on arterial blood pressure or total peripheral resistance.
`57
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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
`60
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`61
`completely understood but may be related to prostaglandin synthetase inhibition.
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`62 Pharmacokinetics: TREXIMET is a formulation of 85 mg of sumatriptan (as sumatriptan
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`succinate) and 500 mg of naproxen sodium with a distinct pharmacokinetic profile. Cmax
`63
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`(median, range) for sumatriptan following administration of TREXIMET occurs at
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`approximately 1 hour (0.3 to 4.0 hours). Cmax (median, range) for naproxen following
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`administration of TREXIMET occurs at approximately 5 hours (0.3 to 12 hours). The
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`sumatriptan half-life is approximately 2 hours (15% to 43% CV) and the naproxen half-life is
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`approximately 19 hours (13% to 15% CV). The mean Cmax for sumatriptan when given as
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` TREXIMET is similar to that of sumatriptan when given as IMITREX® (sumatriptan succinate)
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` Tablets 100 mg alone. The median sumatriptan Tmax is only slightly different (1 hour for
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` TREXIMET and 1.5 hours for IMITREX). The Cmax for naproxen is approximately 36% lower,
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`and the Tmax occurs approximately 4 hours later from TREXIMET than from ANAPROX® DS
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`(naproxen sodium tablets) 550 mg. AUC values for sumatriptan and for naproxen are similar for
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`74
`TREXIMET compared to IMITREX or ANAPROX DS, respectively. In a crossover study in 16
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`75
`patients, the pharmacokinetics of both components administered as TREXIMET were similar
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`76
`during a migraine attack and during a migraine-free 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
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`0.6 hour. These data indicate that TREXIMET may be administered without regard to food.
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`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
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`proportional increase in plasma levels due to an increase in clearance caused by saturation of
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`plasma protein binding at higher doses (average trough Css = 36.5, 49.2, and 56.4 mg/L with 500,
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`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.
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`Metabolism: Most of a radiolabeled dose of sumatriptan excreted in the urine is the major
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`94 metabolite indole acetic acid (IAA) 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
`95
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`96 microsomes suggest that sumatriptan is metabolized by monoamine oxidase (MAO),
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`predominantly the A isoenzyme, and inhibitors of that enzyme may alter sumatriptan
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`pharmacokinetics to increase systemic exposure (see CONTRAINDICATIONS and
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`PRECAUTIONS: Drug Interactions: Monoamine Oxidase-A Inhibitors). No significant effect
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`100 was seen with an MAO-B inhibitor.
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`Naproxen is extensively metabolized to 6-0-desmethyl naproxen, and both parent and
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`102 metabolites do not induce metabolizing enzymes.
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`Elimination: Radiolabeled 14C-sumatriptan administered orally is largely renally excreted
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`(about 60%), with about 40% found in the feces. The elimination half-life of sumatriptan is
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`approximately 2 hours.
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`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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`than 1%), or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in
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`humans is approximately 19 hour s. The corresponding half-lives of both metabolites and
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`conjugates of naproxen are shorter than 12 hour s, and their rates of excretion have been found to
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`coincide closely with the rate of naproxen disappearance from the plasma. In patients with renal
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`failure, metabolites may accumulate (see PRECAUTIONS: Renal Effects).
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`113 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
`117 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.
` Hepatic Impairment: Because TREXIMET is a fixed-dose combination that cannot be
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`122
`adjusted for this patient population, it is contraindicated in patients with hepatic impairment (see
`123 CONTRAINDICATIONS and PRECAUTIONS: Hepatic Effects). The effect of hepatic
`124
`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.
` 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).
`ales and 4
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` The pharmacokinetics of oral sumatriptan in the elderly (mean age: 72 years, 2 m
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`females) and in patients with migraine (mean age: 38 years, 25 males and 155 females) were
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`similar to that in healthy male subjects (mean age: 30 years).
` Gender: In a pooled analysis of 5 pharmacokinetic studies, there was no effect of gender on
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`the systemic exposure of TREXIMET. In a study comparing the pharmacokinetics of
`sumatriptan in females and males, no differences were observed between genders for AUC, Cmax,
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`Tmax, and T½.
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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)
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`healthy male subjects.
`140 Drug Interactions: No formal drug interaction studies have been conducted with TREXIMET.
` Monoamine Oxidase Inhibitors: TREXIMET is contraindicated in patients taking MAO­
`141
`142 A inhibitors (see CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions). Treatment
`143 with MAO-A inhibitors generally leads to an increase of sumatriptan plasma levels. This
`144
`interaction has not been seen with an MAO-B inhibitor.
` Alcohol: The effect of alcohol consumption on the pharmacokinetics of TREXIMET has not
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`been studied. Alcohol consumed 30 m
`inutes prior to sumatriptan ingestion had no effect on the
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`pharmacokinetics of sumatriptan.
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` 148 CLINICAL TRIALS
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`The efficacy of TREXIMET in providing relief from migraine was demonstrated in 2
` 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.
` Patients enrolled in these 2 trials were predominately female (87%) and Caucasian (88%), with a
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` 153 mean age of 40 years (range 18 to 65 years). Patients were instructed to treat a migraine of
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` 154 moderate to severe pain with 1 tablet. No rescue medication was allowed within 2 hours
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` postdose. Patients evaluated their headache pain 2 hours after taking 1 dose of study medication;
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` headache relief was defined as a reduction in headache severity from moderate or severe pain to
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` 157 mild or no pain. Associated symptoms of nausea, photophobia, and phonophobia were also
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` evaluated. Sustained pain free was defined as a reduction in headache severity from moderate or
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` 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 the 2 controlled clinical
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` trials are summarized in Table 1. In both trials, the percentage of patients achieving headache
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` pain relief 2 hours after treatment was significantly greater among patients receiving
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` TREXIMET (65% and 57%) compared with those who received placebo (28% and 29%).
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` 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 with those who received placebo (8% and 7%) or either
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` sumatriptan (16% and 14%) or naproxen sodium (10%) alone.
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` 169 Table 1. Percentage of Patients With 2-Hour Pain Relief and Sustained Pain Free
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` Following Treatmenta
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`TREXIMET
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` Sumatriptan
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` 85 mg
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` Naproxen Sodium
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` 500 mg
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` Placebo
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` 2-Hour Pain Relief
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` Study 1 (all patients)
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` 55%
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` n = 361
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` 50%
` n = 362
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` 44%
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` n = 356
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` 43%
` n = 364
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` 10%
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` n = 356
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` 10%
` n = 364
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` 28%
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` n = 360
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` 29%
` n = 382
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` 8%
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` n = 360
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` 7%
` n = 382
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` 65%b
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` n = 364
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` 57%b
` n = 362
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` Sustained Pain Free (2-24 Hours)
` 25%c
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` 16%
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` Study 1
` n = 361
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` n = 364
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` 23%c
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` 14%
` n = 362
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` n = 362
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` aP values provided only for prespecified comparisons.
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`bP<0.05 versus placebo and sumatriptan.
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` cP<0.01 versus placebo, sumatriptan, and naproxen sodium.
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` Study 2 (all patients)
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` Study 2
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` Note that comparisons of the performance of different drugs based upon results
`obtained in different clinical trials are never reliable. Because studies are generally
`conducted at different times, with different samples of patients, by different investigators,
`employing different criteria and/or different interpretations of the same criteria, under
`different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment
`response and the timing of response may be expected to vary considerably from study to
`study.
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`treatment with TREXIMET is shown in Figure 1.
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`Figure 1. Percentage of Patients With Initial Headache Pain Relief Within 2 Hours
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` The percentage of patients achieving initial headache pain relief within 2 hour s following
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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
`rescue medication over the first 24 hours is shown in Figure 2.
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`Figure 2. Estimated Probability of Taking a Rescue Medication Over the 24 Hours
`Following the First Dosea
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`a Kaplan-Meier plot based on data obtained in the 2 clinical controlled trials providing
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`evidence of efficacy with patients not using additional treatments censored to 24 hour s.
`Plot also includes patients who had no response to the initial dose. No rescue
`medication was allowed within 2 hours postdose.
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` TREXIMET was more effective than placebo regardless of the presence of aura; duration of
`headache prior to treatment; gender, age, or weight of the patient; or concomitant use of oral
`contraceptives or common migraine prophylactic drugs (e.g., beta-blockers, anti-epileptic drugs,
`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
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`options when deciding to use TREXIMET.
`209
` TREXIMET is not intended for the prophylactic therapy of migraine or for use in the
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`211 management of hemiplegic or basilar migraine (see CONTRAINDICATIONS). Safety and
`212
`effectiveness of TREXIMET have not been established for cluster headache.
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`213 CONTRAINDICATIONS
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`214 Cardiac, Cerebrovascular, or Peripheral Vascular Disease: TREXIMET should not
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`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
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`cardiovascular diseases should not receive TREXIMET, nor should patients who have had
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`coronary artery bypass graft (CABG) surgery. Ischemic cardiac syndromes include, but
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`are not limited to, angina pectoris of any type (e.g., stable angina of effort and vasospastic
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`219
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`forms of angina, such as the Prinzmetal variant), all forms of myocardial infarction, and
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`silent myocardial ischemia. Cerebrovascular syndromes include, but are not limited to,
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`strokes of any type as well as transient ischemic attacks. Peripheral vascular disease
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`includes, but is not limited to, ischemic bowel disease (see WARNINGS: Cardiovascular
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`223
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`224 Effects).
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`225 Uncontrolled Hypertension: TREXIMET should not be given to patients with
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`uncontrolled hypertension because the components have been shown to increase blood
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`226
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`pressure.
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`227
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`228 Monoamine Oxidase-A Inhibitors: Concurrent administration of MAO-A inhibitors or
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`use of TREXIMET within 2 weeks of discontinuation of MAO-A inhibitor therapy is
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`229
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`contraindicated (see CLINICAL PHARMACOLOGY: Drug Interactions and
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`230
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`PRECAUTIONS: Drug Interactions).
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`231
`232 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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`233
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`should not be used within 24 hours of each other (see PRECAUTIONS: Drug Interactions).
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`234
`235 Other 5-HT1 Agonists: Since TREXIMET contains sumatriptan, it should not be
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`administered within 24 hours of another 5-HT1 agonist.
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`236
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`237 Hemiplegic or Basilar Migraine: TREXIMET should not be administered to patients
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`238 with hemiplegic or basilar migraine.
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`239 Hepatic Impairment: TREXIMET is contraindicated in patients with hepatic impairment
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`(see CLINICAL PHARMACOLOGY: Special Populations, PRECAUTIONS: Hepatic
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`240
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`241 Effects, and PRECAUTIONS: Geriatric Use).
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`242 Allergy to Naproxen/Asthma, Nasal Polyps, Urticaria, and Hypotension
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`243 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
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`244
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`over-the-counter products containing naproxen. It is also contraindicated in patients in
`245
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`246 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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`247
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`naproxen, whether of the true allergic type or the pharmacologic idiosyncratic type (e.g.,
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`248
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`aspirin hypersensitivity syndrome), usually but not always occur in patients with a known
`249
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`history of such reactions. Both types of reactions have the potential of being fatal.
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`250
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`251 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
`253
`discontinued (see WARNINGS: Anaphylactic/Anaphylactoid Reactions and
`254
`PRECAUTIONS: Preexisting Asthma).
`255
`256 Hypersensitivity to Sumatriptan or Naproxen: TREXIMET is contraindicated in
`patients with hypersensitivity to sumatriptan, naproxen, or any other component of the
`257
`product.
`258
`
`259 WARNINGS
` TREXIMET should only be used where a clear diagnosis of migraine headache has been
`260
`established.
`261
`262 Cardiovascular Effects: Risk of Myocardial Ischemia and/or Infarction and Other
`263 Adverse Cardiac Events: TREXIMET should not be given to patients with documented
`ischemic or vasospastic coronary artery disease (CAD) or to patients with a history of
`264
`265 CABG surgery (see CONTRAINDICATIONS). It is strongly recommended that
`sumatriptan-containing products not be given to patients in whom unrecognized CAD is
`266
`predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker,
`267
`obesity, diabetes, strong family history of CAD, female with surgical or physiological
`268
`269 menopause, male over 40 years of age) unless a cardiovascular evaluation provides
`satisfactory clinical evidence that the patient is reasonably free of CAD and ischemic
`270
`271 myocardial disease or other significant underlying cardiovascular disease. The sensitivity
`of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to
`272
`coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the
`273
`patient’s medical history or electrocardiographic investigations reveal findings indicative
`274
`of, or consistent with, coronary artery vasospasm or myocardial ischemia, TREXIMET
`275
`should not be administered (see CONTRAINDICATIONS).
`276
` For patients with risk factors predictive of CAD who are determined to have a
`277
`satisfactory cardiovascular evaluation, it is strongly recommended that administration of
`278
`the first dose of TREXIMET take place in the setting of a physician’s office or similar
`279
`280 medically staffed and equipped facility unless the patient has previously received
`sumatriptan. Because cardiac ischemia can occur in the absence of clinical symptoms,
`281
`consideration should be given to obtaining an electrocardiogram (ECG) immediately
`282
`following first-time use of TREXIMET in patients with risk factors.
`283
`
`It is recommended that patients who are intermittent long-term users of TREXIMET
`284
`and who have or acquire risk factors predictive of CAD as described above undergo
`285
`periodic cardiovascular evaluation as they continue to use TREXIMET.
`286
` The systematic approach described above is intended to reduce the likelihood that
`287
`patients with unrecognized cardiovascular disease will be inadvertently exposed to
`288
`sumatriptan-containing products.
`289
` Cardiac Events and Fatalities Associated With 5-HT1 Agonists: Serious adverse
`290
`291
`cardiac events, including a cute 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
`292
`sumatriptan. Considering the extent of use of 5-HT1 agonists in patients with migraine, the
`293
`incidence of these events is extremely low.
`294
` The fact that sumatriptan can cause coronary vasospasm, that some of these events have
`295
`occurred in patients with no prior cardiac disease history and with documented absence of CAD,
`296
`and the close proximity of the events to sumatriptan use support the conclusion that some of
`297
`these cases were caused by the drug. In cases, however, where there has been known underlying
`298
`coronary artery disease, the relationship is uncertain.
`299
` Cardiovascular Thrombotic Events and Fatalities Associated With Nonsteroidal
`300
`301 Anti-inflammatory Drugs: Clinical trials of several COX-2 selective and nonselective
`302 NSAIDs of up to 3 years’ duration have shown an increased risk of serious cardiovascular
`303
`thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both
`304 COX-2 selective and nonselective, may have a similar risk. Patients with known cardiovascular
`305
`disease or risk factors for cardiovascular disease may be at greater risk. To minimize the
`306
`potential risk for an adverse cardiovascular event in patients treated with an NSAID, the lowest
`307
`effective dose should be used for the shortest duration possible. Physicians and patients should
`308
`remain alert for the development of such events, even in the absence of previous cardiovascular
`309
`symptoms. Patients should be informed about the signs and/or symptoms of serious
`310
`cardiovascular events and the steps to take if they occur.
`311
` There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of
`312
`serious cardiovascular thrombotic events associated with NSAID use. The concurrent use of
`313
`aspirin and an NSAID does increase the risk of serious gastrointestinal events (see WARNINGS:
`314 Risk of Gastrointestinal Ulceration, Bleeding, and Perforation With Nonsteroidal
`315 Anti-inflammatory Drug Therapy).
` Premarketing Experience With TREXIMET: Among 3,302 patients with migraine who
`316
`317
`received TREXIMET in premarketing c ontrolled and uncontrolled clinical trials, a 47-year-old
`318
`female with cardiac risk factors in an open-label 12-month safety study experienced signs and
`319
`symptoms of acute coronary syndrome approximately 2 hours after receiving TREXIMET.
` Drug-Associated Cerebrovascular Events and Fatalities: Cerebral hemorrhage,
`320
`321
`subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in
`322
`patients treated with oral or subcutaneous sumatriptan, and some have resulted in fatalities. The
`323
`relationship of sumatriptan to these events is uncertain. In a number of cases, it appears possible
`324
`that the cerebrovascular events were primary, sumatriptan having been administered in the
`325
`incorrect belief that the symptoms experienced were a consequence of migraine when they were
`326
`not. As with other acute migraine therapies, before treating headaches in patients not previously
`327
`diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should
`328
`be taken to exclude other potentially serious neurological conditions. It should also be noted that
`329
`patients with migraine may be at increased risk of certain cerebrovascular events (e.g.,
`330
`cerebrovascular accident, transient ischemic attack).
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` Other Vasospasm-Related Events: Sumatriptan may cause vasospastic reactions other
`331
`than coronary artery vasospasm. Both peripheral vascular ischemia and colonic ischemia with
`332
`abdominal pain and bloody diarrhea have been reported. Transient and permanent blindness and
`333
`significant partial vision loss have been reported with the use of sumatriptan. Visual disorders
`334
`335 may also be part of a migraine attack.
`Increase in Blood Pressure: TREXIMET is contraindicated in patients with uncontrolled
`336
`
`337
`hypertension (see CONTRAINDICATIONS). TREXIMET should be used with caution in
`338
`patients with controlled hypertension.
`339
` Significant elevation in blood pressure, including h ypertensive crisis, has been reported in
`340
`patients with and without a history of hypertension receiving sumatriptan. Sumatriptan­
`341
`containing products should be administered with caution to patients with controlled hypertension
`342
`as transient increases in blood pressure and peripheral vascular resistance have been observed.
`343
` NSAID-containing products can lead to onset of new hypertension or worsening of
`344
`preexisting hypertension, either of which may contribute to the increased incidence of
`345
`cardiovascular events. Patients taking thiazides or loop diuretics may have impaired response to
`346
`these therapies when taking NSAIDs. The potential effect on blood pressure associated with
`347
`long-term use of TREXIMET has not been studied. Blood pressure should be monitored closely
`348
`during the initiation of NSAID treatment and throughout the course of therapy.
` Congestive Heart Failure and Edema: TREXIMET should be used with caution in
`349
`350
`patients with fluid retention or heart failure. Fluid retention and edema have been observed in
`351
`some patients taking NSAIDs. Since each TREXIMET tablet contains 61.2 mg of sodium (about
`352
`2.7 m Eq/500 m g of naproxen sodium), this should be considered in patients whose overall intake
`353
`of sodium must be severely restricted.
`354 Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome
`355 may occur with triptans, including treatment with TREXIMET, particularly during combined use
`356 with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake
`357
`inhibitors (SNRIs). If concomitant treatment with TREXIMET and an SSRI (e.g., fluoxetine,
`358
`paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine,
`359
`duloxetine) is clinically warranted, careful observation of the patient is advised, particularly
`360
`during treatment initiation and dose increases. Serotonin syndrome symptoms may include
`361 mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g.,
`362
`tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia,
`363
`incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) (see
`364
`PRECAUTIONS: Drug Interactions).
`365 Risk of Gastrointestinal Ulceration, Bleeding, and Perforation With Nonsteroidal
`366 Anti-inflammatory Drug Therapy: TREXIMET contains an NSAID. NSAID-containing
`367
`products can cause serious gastrointestinal adverse events including inflammation, bleeding,
`368
`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
`369
`370
`patients treated with NSAIDs. Only 1 in 5 patients who develop a serious upper gastrointestinal
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`adverse event on NSAID therapy is symptomatic. Upper gastrointestinal ulcers, gross bleeding,
`371
`or perforation caused by NSAIDs appear to occur in approximately 1% of patients treated daily
`372
`for 3 to 6 m onths and in about 2% to 4% of patients treated for 1 year. These trends continue
`373
`374 with longer duration of use, increasing the likelihood of developing a serious gastrointestinal
`375
`event at some time during the course of therapy.