1
`®
`2 TREXIMET
`(sumatriptan and naproxen sodium)
`3
`4 Tablets
`
`PRESCRIBING INFORMATION
`
`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
`
`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
`19
` TREXIMET contains sumatriptan (as the succinate), a selective 5-hydroxytryptamine1
`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
`
`
`25
`
`26
`
`27
`28
`29
`30
`31
`
`
`The empirical formula is C14H21N3O2SC4H6O4, representing a molecular weight of 413.5.
`
`
`Sumatriptan succinate is a white to off-white powder that is readily soluble in water and in
`
`saline.
`
`
`Naproxen sodium is chemically designated as (S)-6-methoxy--methyl-2-naphthaleneacetic
`
`acid, sodium salt, and it has the following structure:
`
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`32
`33
`34
`35
`36
`37
`38
`39
`40
`41
`
`
`
`
`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.
`
`Each TREXIMET Tablet for oral administration contains 119 mg of sumatriptan succinate
`equivalent to 85 mg of sumatriptan and 500 mg of naproxen sodium. Each tablet also contains
`the inactive ingredients croscarmellose sodium, dextrose monohydrate, dibasic calcium
`phosphate, FD&C Blue No. 2, lecithin, magnesium stearate, maltodextrin, microcrystalline
`
`cellulose, povidone, sodium bicarbonate, sodium carboxymethylcellulose, talc, and titanium
`dioxide.
`
`42 CLINICAL PHARMACOLOGY
`43 Mechanism of Action: TREXIMET contains sumatriptan, a 5-HT1 receptor agonist that
`44 mediates vasoconstriction of the human basilar artery and vasculature of human dura mater,
`45 which correlates with the relief of migraine headache. It also contains naproxen, an NSAID that
`46
`inhibits the synthesis of inflammatory mediators. Therefore, sumatriptan and naproxen contribute
`47
`to the relief of migraine through pharmacologically different mechanisms of action.
`
`
`Sumatriptan is a 5-HT1 receptor agonist that binds with high affinity to 5-HT1B and 5-HT1D
`48
`receptors. Sumatriptan has only a weak affinity for 5-HT1A, 5-HT5A, and 5-HT7 receptors and no
`49
`50
`significant affinity (as measured using standard radioligand binding assays) or pharmacological
`51
`activity at 5-HT2, 5-HT3, or 5-HT4 receptor subtypes or at alpha1-, alpha2-, or beta-adrenergic;
`
`52
`dopamine1; dopamine2; muscarinic; or benzodiazepine receptors. In addition to causing
`53
`vasoconstriction, experimental data from animal studies show that sumatriptan also activates 5­
`54 HT1 receptors on peripheral terminals of the trigeminal nerve innervating cranial blood vessels.
`55
`Such an action may contribute to the antimigrainous effect of sumatriptan in humans. In the
`56
`anesthetized dog, sumatriptan selectively reduces carotid arterial blood flow with little or no
`57
`effect on arterial blood pressure or total peripheral resistance.
`
`58
`Naproxen sodium is an NSAID with analgesic and antipyretic properties. The sodium salt of
`naproxen has been developed as a more rapidly absorbed formulation of naproxen for use as an
`59
`60
`analgesic. The mechanism of action of the naproxen anion, like that of other NSAIDs, is not
`61
`completely understood but may be related to prostaglandin synthetase inhibition.
`62 Pharmacokinetics: TREXIMET is a formulation of 85 mg of sumatriptan (as sumatriptan
`
`63
` succinate) and 500 mg of naproxen sodium with a distinct pharmacokinetic profile. Cmax
`64
`(median, range) for sumatriptan following administration of TREXIMET occurs at
`65
`approximately 1 hour (0.3 to 4.0 hours). Cmax (median, range) for naproxen following
`66
`administration of TREXIMET occurs at approximately 5 hours (0.3 to 12 hours). The
`67
`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
` TREXIMET is similar to that of sumatriptan when given as IMITREX® (sumatriptan succinate)
`
`69
`70
`Tablets 100 mg alone. The median sumatriptan Tmax is only slightly different (1 hour for
`
`TREXIMET and 1.5 hours for IMITREX). The Cmax for naproxen is approximately 36% lower,
`71
`and the Tmax occurs approximately 4 hours later from TREXIMET than from ANAPROX® DS
`72
`73
`(naproxen sodium tablets) 550 mg. AUC values for sumatriptan and for naproxen are similar for
`74
`TREXIMET compared to IMITREX or ANAPROX DS, respectively. In a crossover study in 16
`75
`patients, the pharmacokinetics of both components administered as TREXIMET were similar
`76
`during a migraine attack and during a migraine-free period.
`
`Absorption and Bioavailability: Bioavailability of sumatriptan is approximately 15%,
`77
`
`78
`primarily due to presystemic (first-pass) metabolism and partly due to incomplete absorption.
`
`79
`Naproxen is rapidly and completely absorbed from the gastrointestinal tract with an in vivo
`80
`bioavailability of 95%.
`Food Effects: Food had no significant effect on the bioavailability of sumatriptan or
`
`81
`82
`naproxen administered as TREXIMET, but slightly delayed the Tmax of sumatriptan by about
`83
`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
`
`84
`85
`is 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been
`86
`evaluated, but would be expected to be minor, given the low protein binding.
`87
`The volume of distribution of naproxen is 0.16 L/kg. At therapeutic levels naproxen is greater
`
`88
`than 99% albumin bound. At doses of naproxen greater than 500 mg/day, there is a less than
`89
`proportional increase in plasma levels due to an increase in clearance caused by saturation of
`90
`plasma protein binding at higher doses (average trough Css = 36.5, 49.2, and 56.4 mg/L with 500,
`91
`1,000, and 1,500 mg daily doses of naproxen, respectively). However, the concentration of
`92
`unbound naproxen continues to increase proportionally to dose.
`Metabolism: Most of a radiolabeled dose of sumatriptan excreted in the urine is the major
`
`93
`94 metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive. Three
`95
`percent of the dose can be recovered as unchanged sumatriptan. In vitro studies with human
`96 microsomes suggest that sumatriptan is metabolized by monoamine oxidase (MAO),
`97
`predominantly the A isoenzyme, and inhibitors of that enzyme may alter sumatriptan
`98
`pharmacokinetics to increase systemic exposure (see CONTRAINDICATIONS and
`PRECAUTIONS: Drug Interactions: Monoamine Oxidase-A Inhibitors). No significant effect
`99
`100 was seen with an MAO-B inhibitor.
`101
`Naproxen is extensively metabolized to 6-0-desmethyl naproxen, and both parent and
`
`102 metabolites do not induce metabolizing enzymes.
`Elimination: Radiolabeled 14C-sumatriptan administered orally is largely renally excreted
`
`103
`(about 60%), with about 40% found in the feces. The elimination half-life of sumatriptan is
`104
`105
`approximately 2 hours.
`106
`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
`107
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`than 1%), or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in
`108
`humans is approximately 19 hours. The corresponding half-lives of both metabolites and
`109
`conjugates of naproxen are shorter than 12 hours, and their rates of excretion have been found to
`110
`coincide closely with the rate of naproxen disappearance from the plasma. In patients with renal
`111
`failure, metabolites may accumulate (see PRECAUTIONS: Renal Effects).
`112
`
` 113 Special Populations: Renal Impairment: TREXIMET is not recommended for use in
`patients with creatinine clearance less than 30 mL/min (see PRECAUTIONS: Renal Effects).
`114
`115
`The effect of renal impairment on the pharmacokinetics of TREXIMET has not been studied.
`
`116
`Minimal change in clinical effect would be expected with regard to sumatriptan as it is largely
`117 metabolized to an inactive substance.
`
`118
`Since naproxen and its metabolites and conjugates are primarily excreted by the kidney, the
`potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency.
`119
`120
`Elimination of naproxen is decreased in patients with severe renal impairment.
`Hepatic Impairment: Because TREXIMET is a fixed-dose combination that cannot be
`
`121
`adjusted for this patient population, it is contraindicated in patients with hepatic impairment (see
`122
`123 CONTRAINDICATIONS and PRECAUTIONS: Hepatic Effects). The effect of hepatic
`124
`impairment on the pharmacokinetics of TREXIMET has not been studied. Sumatriptan is
`125
`contraindicated in patients with severe hepatic impairment and the dose is limited to 50 mg in
`126
`patients with liver disease.
`Age: The effect of age (elderly or pediatric patients) on the pharmacokinetics of TREXIMET
`127
`
`has not been studied. Elderly patients are more likely to have decreased hepatic function and
`128
`129
`decreased renal function (see PRECAUTIONS: Geriatric Use).
`130
`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
`131
`132
`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
`133
`
`the systemic exposure of TREXIMET. In a study comparing the pharmacokinetics of
`134
`sumatriptan in females and males, no differences were observed between genders for AUC, Cmax,
`135
`136
`Tmax, and T½.
`Race: The effect of race on the pharmacokinetics of TREXIMET has not been studied. The
`
`137
`systemic clearance and Cmax of sumatriptan were similar in black (n = 34) and Caucasian (n = 38)
`138
`
`139
`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
`
`145
`been studied. Alcohol consumed 30 minutes prior to sumatriptan ingestion had no effect on the
`146
`147
`pharmacokinetics of sumatriptan.
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`148 CLINICAL TRIALS
`
`149
`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
`150
`151
`active component of TREXIMET (sumatriptan and naproxen sodium) as comparison treatments.
`152
`Patients enrolled in these 2 trials were predominately female (87%) and Caucasian (88%), with a
`153 mean age of 40 years (range 18 to 65 years). Patients were instructed to treat a migraine of
`154 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;
`155
`
`headache relief was defined as a reduction in headache severity from moderate or severe pain to
`156
`157 mild or no pain. Associated symptoms of nausea, photophobia, and phonophobia were also
`158
`evaluated. Sustained pain free was defined as a reduction in headache severity from moderate or
`159
`severe pain to no pain at 2 hours postdose without a return of mild, moderate, or severe pain and
`160
`no use of rescue medication for 24 hours postdose. The results from the 2 controlled clinical
`161
`trials are summarized in Table 1. In both trials, the percentage of patients achieving headache
`162
`pain relief 2 hours after treatment was significantly greater among patients receiving
`163
`TREXIMET (65% and 57%) compared with those who received placebo (28% and 29%).
`164
`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
`165
`166
`TREXIMET (25% and 23%) compared with those who received placebo (8% and 7%) or either
`
`sumatriptan (16% and 14%) or naproxen sodium (10%) alone.
`167
`168
`
`169 Table 1. Percentage of Patients With 2-Hour Pain Relief and Sustained Pain Free
`Following Treatmenta
`
`170
`
`
`
`TREXIMET
`
`
` Sumatriptan
`
`85 mg
`
`
`
` Naproxen Sodium
`500 mg
`
`
`Placebo
`
`2-Hour Pain Relief
`Study 1 (all patients)
`
`Study 2 (all patients)
`
`Study 2
`
`171
`172
`173
`174
`
`
` 65%b
`
`n = 364
`57%b
`
`n = 362
`Sustained Pain Free (2-24 Hours)
`25%c
`Study 1
`16%
`
`n = 361
`n = 364
`23%c
`14%
`
`n = 362
`n = 362
`ap values provided only for prespecified comparisons.
`
`bp<0.05 versus placebo and sumatriptan.
`
`cp<0.01 versus placebo, sumatriptan, and naproxen sodium.
`
`
`
`55%
`n = 361
`50%
`n = 362
`
`44%
`n = 356
`43%
`n = 364
`
`10%
`n = 356
`10%
`n = 364
`
`28%
`n = 360
`29%
`n = 382
`
`8%
`n = 360
`7%
`n = 382
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`177
`178
`179
`180
`181
`182
`183
`184
`185
`186
`
` 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.
` 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
`
`
`187
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`188
`
`189
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`190
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`191
`
`192
`
`
`
` 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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`193
`194
`195
`
`Figure 2. Estimated Probability of Taking a Rescue Medication Over the 24 Hours
`Following the First Dose*
`
`
`
`196
`197
`198
`199
`200
`201
`202
`203
`204
`205
`
`
`* Kaplan-Meier plot based on data obtained in the 2 clinical controlled trials providing evidence
`of efficacy with patients not using additional treatments censored to 24 hours. Plot also
`includes patients who had no response to the initial dose. No rescue medication was allowed
`within 2 hours postdose.
`
`
` 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).
`
`INDICATIONS AND USAGE
`206
` TREXIMET is indicated for the acute treatment of migraine attacks with or without aura in
`207
`adults. Carefully consider the potential benefits and risks of TREXIMET and other treatment
`208
`options when deciding to use TREXIMET.
`209
` TREXIMET is not intended for the prophylactic therapy of migraine or for use in the
`210
`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
`214 Cardiac, Cerebrovascular, or Peripheral Vascular Disease: TREXIMET should not
`
`be given to patients with history, symptoms, or signs of ischemic cardiac, cerebrovascular,
`215
`or peripheral vascular syndromes. In addition, patients with other significant underlying
`216
`cardiovascular diseases should not receive TREXIMET, nor should patients who have had
`217
`coronary artery bypass graft (CABG) surgery. Ischemic cardiac syndromes include, but
`218
`are not limited to, angina pectoris of any type (e.g., stable angina of effort and vasospastic
`219
`forms of angina, such as the Prinzmetal variant), all forms of myocardial infarction, and
`220
`silent myocardial ischemia. Cerebrovascular syndromes include, but are not limited to,
`221
`strokes of any type as well as transient ischemic attacks. Peripheral vascular disease
`222
`includes, but is not limited to, ischemic bowel disease (see WARNINGS: Cardiovascular
`223
`224 Effects).
`225 Uncontrolled Hypertension: TREXIMET should not be given to patients with
`uncontrolled hypertension because the components have been shown to increase blood
`226
`pressure.
`227
`228 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
`229
`contraindicated (see CLINICAL PHARMACOLOGY: Drug Interactions and
`230
`PRECAUTIONS: Drug Interactions).
`231
`232 Ergotamine-Containing or Ergot-Type Medications: TREXIMET and any
`
`ergotamine-containing or ergot-type medication (like dihydroergotamine or methysergide)
`233
`should not be used within 24 hours of each other (see PRECAUTIONS: Drug Interactions).
`234
`235 Other 5-HT1 Agonists: Since TREXIMET contains sumatriptan, it should not be
`
`administered within 24 hours of another 5-HT1 agonist.
`236
`237 Hemiplegic or Basilar Migraine: TREXIMET should not be administered to patients
`238 with hemiplegic or basilar migraine.
`
` 239 Hepatic Impairment: TREXIMET is contraindicated in patients with hepatic impairment
` (see CLINICAL PHARMACOLOGY: Special Populations, PRECAUTIONS: Hepatic
`
`240
`241 Effects, and PRECAUTIONS: Geriatric Use).
`242 Allergy to Naproxen/Asthma, Nasal Polyps, Urticaria, and Hypotension
`
` 243 Associated With Nonsteroidal Anti-inflammatory Drugs: TREXIMET is
`
`contraindicated in patients who have had allergic reactions to prescription as well as to
`244
`over-the-counter products containing naproxen. It is also contraindicated in patients in
`245
`246 whom aspirin or other nonsteroidal anti-inflammatory/analgesic drugs induce the
`syndrome of asthma, rhinitis, and nasal polyps. Anaphylactic/anaphylactoid reactions to
`247
`naproxen, whether of the true allergic type or the pharmacologic idiosyncratic type (e.g.,
`248
`aspirin hypersensitivity syndrome), usually but not always occur in patients with a known
`249
`history of such reactions. Both types of reactions have the potential of being fatal.
`250
`251 Therefore, careful questioning of patients for medical conditions such as asthma, nasal
`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
`
`cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac
`291
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`292
`rhythm, and death have been reported within a few hours following the administration of
`293
`sumatriptan. Considering the extent of use of 5-HT1 agonists in patients with migraine, the
`294
`incidence of these events is extremely low.
`295
`
`The fact that sumatriptan can cause coronary vasospasm, that some of these events have
`296
`occurred in patients with no prior cardiac disease history and with documented absence of CAD,
`297
`and the close proximity of the events to sumatriptan use support the conclusion that some of
`298
`these cases were caused by the drug. In cases, however, where there has been known underlying
`299
`coronary artery disease, the relationship is uncertain.
`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
`
`
`serious cardiovascular thrombotic events associated with NSAID use. The concurrent use of
`312
`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
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`received TREXIMET in premarketing controlled and uncontrolled clinical trials, a 47-year-old
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`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
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`subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in
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`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
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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).
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`Other Vasospasm-Related Events: Sumatriptan may cause vasospastic reactions other
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`331
`than coronary artery vasospasm. Both peripheral vascular ischemia and colonic ischemia with
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`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
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`336
`hypertension (see CONTRAINDICATIONS). TREXIMET should be used with caution in
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`338
`patients with controlled hypertension.
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`339
`Significant elevation in blood pressure, including hypertensive crisis, has been reported in
`patients with and without a history of hypertension receiving sumatriptan. Sumatriptan­
`340
`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.
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`343
`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
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`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
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`patients with fluid retention or heart failure. Fluid retention and edema have been observed in
`350
`351
`some patients taking NSAIDs. Since each TREXIMET tablet contains 61.2 mg of sodium (about
`352
`2.7 mEq/500 mg 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.
`
`369
`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
`370
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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 months 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. However, even short-term therapy is not
`376 without risk. Among 3,302 patients with migraine who received TREXIMET in premarketing
`377
`controlled and uncontrolled clinical trials, 1 patient experienced a recurrence of gastric ulcer
`378
`after taking 8 doses over 3 weeks, and 1 patient developed a gastric ulcer after treating an
`379
`average of 8 attacks per month over 7 months.
`380
` NSAID-containing products, including TREXIMET, should be prescribed with extreme
`381
`caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a
`382
`prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a
`383
`greater than 10-fold increased risk for developing gastrointestinal bleeding compared to patients
`384 with neither of these risk factors. Other factors that increase the risk for gastrointestinal bleeding
`385
`in patients treated with NSAIDs include concomitant use of oral corticosteroids or
`386
`anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor
`387
`general health status. Most spontaneous reports of fatal gastrointestinal events are in elderly or
`388
`debilitated patients, and therefore special care should be taken in treating this population.
`389
`To minimize the potential risk for an adverse gastrointestinal event in patients treated with an
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`390 NSAID-containing product, the lowest effective dose should be used for the shortest possib