1
` IMITREX®
`
`2
`(sumatriptan)
`3
`4 Nasal Spray
`
`5
`
`PRESCRIBING INFORMATION
`
`6 DESCRIPTION
`
`7
` IMITREX (sumatriptan) Nasal Spray contains sumatriptan, a selective 5-hydroxytryptamine1
`
`receptor subtype agonist. Sumatriptan is chemically designated as 3-[2-(dimethylamino)ethyl]­
`8
`9 N-methyl-1H-indole-5-methanesulfonamide, and it has the following structure:
`
`10
`
`11
`12
`13
`14
`15
`16
`17
`18
`19
`
`
`
`
`The empirical formula is C14H21N3O2S, representing a molecular weight of 295.4.
`
`Sumatriptan is a white to off-white powder that is readily soluble in water and in saline. Each
`IMITREX Nasal Spray contains 5 or 20 mg of sumatriptan in a 100-L unit dose aqueous
`buffered solution containing monobasic potassium phosphate NF, anhydrous dibasic sodium
`
`phosphate USP, sulfuric acid NF, sodium hydroxide NF, and purified water USP. The pH of the
`solution is approximately 5.5. The osmolality of the solution is 372 or 742 mOsmol for the 5-
`and 20-mg IMITREX Nasal Spray, respectively.
`
`CLINICAL PHARMACOLOGY
`20
`21 Mechanism of Action: Sumatriptan is an agonist for a vascular 5-hydroxytryptamine1
`
`receptor subtype (probably a member of the 5-HT1D family) having only a weak affinity for
`22
`23
`5-HT1A, 5-HT5A, and 5-HT7 receptors and no significant affinity (as measured using standard
`radioligand binding assays) or pharmacological activity at 5-HT2, 5-HT3, or 5-HT4 receptor
`24
`subtypes or at alpha1-, alpha2-, or beta-adrenergic; dopamine1; dopamine2; muscarinic; or
`25
`26
`benzodiazepine receptors.
`27
`The vascular 5-HT1 receptor subtype that sumatriptan activates is present on cranial arteries in
`
`both dog and primate, on the human basilar artery, and in the vasculature of human dura mater
`28
`29
`and mediates vasoconstriction. This action in humans correlates with the relief of migraine
`30
`headache. In addition to causing vasoconstriction, experimental data from animal studies show
`that sumatriptan also activates 5-HT1 receptors on peripheral terminals of the trigeminal nerve
`31
`32
`innervating cranial blood vessels. Such an action may contribute to the antimigrainous effect of
`
`33
`sumatriptan in humans.
`34
`In the anesthetized dog, sumatriptan selectively reduces the carotid arterial blood flow with
`
`little or no effect on arterial blood pressure or total peripheral resistance. In the cat, sumatriptan
`35
`
`Reference ID: 3087904
`
`1
`
`Opiant Exhibit 2047
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 1
`
`

`

`selectively constricts the carotid arteriovenous anastomoses while having little effect on blood
`36
`flow or resistance in cerebral or extracerebral tissues.
`37
`38 Pharmacokinetics: In a study of 20 female volunteers, the mean maximum concentration
`
`following a 5- and 20-mg intranasal dose was 5 and 16 ng/mL, respectively. The mean Cmax
`39
`
`following a 6-mg subcutaneous injection is 71 ng/mL (range: 49 to 110 ng/mL). The mean Cmax
`40
`41
`is 18 ng/mL (range: 7 to 47 ng/mL) following oral dosing with 25 mg and 51 ng/mL (range: 28
`42
`to 100 ng/mL) following oral dosing with 100 mg of sumatriptan. In a study of 24 male
`43
`volunteers, the bioavailability relative to subcutaneous injection was low, approximately 17%,
`44
`primarily due to presystemic metabolism and partly due to incomplete absorption.
`
`45
`Protein binding, determined by equilibrium dialysis over the concentration range of 10 to
`1,000 ng/mL, is low, approximately 14% to 21%. The effect of sumatriptan on the protein
`46
`47
`binding of other drugs has not been evaluated, but would be expected to be minor, given the low
`48
`rate of protein binding. The mean volume of distribution after subcutaneous dosing is 2.7 L/kg
`49
`and the total plasma clearance is approximately 1,200 mL/min.
`
`50
`The elimination half-life of sumatriptan administered as a nasal spray is approximately
`2 hours, similar to the half-life seen after subcutaneous injection. Only 3% of the dose is excreted
`51
`52
`in the urine as unchanged sumatriptan; 42% of the dose is excreted as the major metabolite, the
`53
`indole acetic acid analogue of sumatriptan.
`
`54
`Clinical and pharmacokinetic data indicate that administration of two 5-mg doses, 1 dose in
`each nostril, is equivalent to administration of a single 10-mg dose in 1 nostril.
`55
`56 Special Populations: Renal Impairment: The effect of renal impairment on the
`
`pharmacokinetics of sumatriptan has not been examined, but little clinical effect would be
`57
`58
`expected as sumatriptan is largely metabolized to an inactive substance.
`Hepatic Impairment: The effect of hepatic disease on the pharmacokinetics of
`
`59
`subcutaneously and orally administered sumatriptan has been evaluated, but the intranasal
`60
`61
`dosage form has not been studied in hepatic impairment. There were no statistically significant
`62
`differences in the pharmacokinetics of subcutaneously administered sumatriptan in hepatically
`63
`impaired patients compared to healthy controls. However, the liver plays an important role in the
`64
`presystemic clearance of orally administered sumatriptan. In 1 small study involving oral
`65
`sumatriptan in hepatically impaired patients (N = 8) matched for sex, age, and weight with
`66
`healthy subjects, the hepatically impaired patients had an approximately 70% increase in AUC
`
`and Cmax and a Tmax 40 minutes earlier compared to the healthy subjects. The bioavailability of
`67
`nasally absorbed sumatriptan following intranasal administration, which would not undergo first­
`68
`69
`pass metabolism, should not be altered in hepatically impaired patients. The bioavailability of the
`70
`swallowed portion of the intranasal sumatriptan dose has not been determined, but would be
`71
`increased in these patients. The swallowed intranasal dose is small, however, compared to the
`72
`usual oral dose, so that its impact should be minimal.
`Age: The pharmacokinetics of oral sumatriptan in the elderly (mean age: 72 years, 2 males
`
`73
`and 4 females) and in patients with migraine (mean age: 38 years, 25 males and 155 females)
`74
`
`Reference ID: 3087904
`
`
`2
`
`
`Opiant Exhibit 2047
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 2
`
`

`

`75 were similar to that in healthy male subjects (mean age: 30 years). Intranasal sumatriptan has not
`76
`been evaluated for age differences (see PRECAUTIONS: Geriatric Use).
`Race: The systemic clearance and Cmax of sumatriptan were similar in black (n = 34) and
`
`77
`78 Caucasian (n = 38) healthy male subjects. Intranasal sumatriptan has not been evaluated for race
`79
`differences.
` 80 Drug Interactions: Monoamine Oxidase Inhibitors: Treatment with monoamine oxidase
`
`81
`inhibitors (MAOIs) generally leads to an increase of sumatriptan plasma levels (see
`82 CONTRAINDICATIONS and PRECAUTIONS).
`
`83
`MAOI interaction studies have not been performed with intranasal sumatriptan. Due to gut
`and hepatic metabolic first-pass effects, the increase of systemic exposure after coadministration
`84
`85
`of an MAO-A inhibitor with oral sumatriptan is greater than after coadministration of the MAOI
`86 with subcutaneous sumatriptan. The effects of an MAOI on systemic exposure after intranasal
`87
`sumatriptan would be expected to be greater than the effect after subcutaneous sumatriptan but
`88
`smaller than the effect after oral sumatriptan because only swallowed drug would be subject to
`89
`first-pass effects.
`90
`In a study of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the
`
`clearance of subcutaneous sumatriptan. Under the conditions of this experiment, the result was a
`91
`92
`2-fold increase in the area under the sumatriptan plasma concentration x time curve (AUC),
`93
`corresponding to a 40% increase in elimination half-life. This interaction was not evident with an
`94 MAO-B inhibitor.
`95
`A small study evaluating the effect of pretreatment with an MAO-A inhibitor on the
`
`bioavailability from a 25-mg oral sumatriptan tablet resulted in an approximately 7-fold increase
`96
`97
`in systemic exposure.
`Xylometazoline: An in vivo drug interaction study indicated that 3 drops of xylometazoline
`98
`99
`(0.1% w/v), a decongestant, administered 15 minutes prior to a 20-mg nasal dose of sumatriptan
`100
`did not alter the pharmacokinetics of sumatriptan.
`
`101 CLINICAL TRIALS
`102
`The efficacy of IMITREX Nasal Spray in the acute treatment of migraine headaches was
`
`demonstrated in 8, randomized, double-blind, placebo-controlled studies, of which 5 used the
`103
`104
`recommended dosing regimen and used the marketed formulation. Patients enrolled in these 5
`105
`studies were predominately female (86%) and Caucasian (95%), with a mean age of 41 (range of
`106
`18 to 65). Patients were instructed to treat a moderate to severe headache. Headache response,
`107
`defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was
`108
`assessed up to 2 hours after dosing. Associated symptoms such as nausea, photophobia, and
`109
`phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours
`110
`postdose. A second dose of IMITREX Nasal Spray or other medication was allowed 2 to
`111
`24 hours after the initial treatment for recurrent headache. The frequency and time to use of these
`112
`additional treatments were also determined. In all studies, doses of 10 and 20 mg were compared
`
`Reference ID: 3087904
`
`
`3
`
`
`Opiant Exhibit 2047
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 3
`
`

`

`113
`to placebo in the treatment of 1 to 3 migraine attacks. Patients received doses as a single spray
`114
`into 1 nostril. In 2 studies, a 5-mg dose was also evaluated.
`115
`
`In all 5 trials utilizing the market formulation and recommended dosage regimen, the
`116
`percentage of patients achieving headache response 2 hours after treatment was significantly
`117
`greater among patients receiving IMITREX Nasal Spray at all doses (with one exception)
`118
` compared to those who received placebo. In 4 of the 5 studies, there was a statistically significant
`
`119
`greater percentage of patients with headache response at 2 hours in the 20-mg group when
`120
`compared to the lower dose groups (5 and 10 mg). There were no statistically significant
`121
`differences between the 5- and 10-mg dose groups in any study. The results from the 5 controlled
`122
`clinical trials are summarized in Table 1. Note that, in general, comparisons of results obtained in
`123
`studies conducted under different conditions by different investigators with different samples of
`124
`patients are ordinarily unreliable for purposes of quantitative comparison.
`125
`
`126 Table 1. Percentage of Patients With Headache Response (No or Mild Pain) 2 Hours
`Following Treatment
`127
`
`
`IMITREX Nasal
`Spray
`10 mg
`
` 46%a
`(n = 112)
`
` 44%a
`(n = 273)
`54%a
`
`(n = 106)
`43%
`(n = 106)
`
` 53%a
`(n = 291)
`
`IMITREX Nasal
`Spray
`20 mg
`
` 64%abc
`(n = 118)
`55%ab
`
`(n = 277)
`63%a
`
`(n = 202)
`62%ab
`
`(n = 215)
`
` 60%ac
`(n = 286)
`
`
`
`Placebo
`Study 1
`25%
`(n = 63)
`
`Study 2
`25%
`(n = 138)
`
`Study 3
`35%
`(n = 100)
`
`Study 4
`29%
`
`(n = 112)
`Study 5d
`
`36%
`(n = 198)
`
`ap<0.05 in comparison with placebo.
`
`bp<0.05 in comparison with 10 mg.
`
`cp<0.05 in comparison with 5 mg.
`
`dData are for attack 1 only of multiattack study for comparison.
`
`
`The estimated probability of achieving an initial headache response over the 2 hours following
`
`
`treatment is depicted in Figure 1.
`
`
`
`IMITREX Nasal
`Spray
`5 mg
`49%a
`
`(n = 121)
`Not applicable
`
`Not applicable
`
`Not applicable
`
` 45%a
`
`(n = 296)
`
`128
`129
`130
`131
`132
`
`133
`134
`135
`
`
`Reference ID: 3087904
`
`
`4
`
`
`Opiant Exhibit 2047
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 4
`
`

`

`136
`137
`138
`
`Figure 1. Estimated Probability of Achieving Initial Headache Response Within
`120 Minutesa
`
`
`
`
`
` a The figure shows the probability over time of obtaining headache response (no or mild
`
`pain) following treatment with intranasal sumatriptan. The averages displayed are
`based on pooled data from the 5 clinical controlled trials providing evidence of
`efficacy. Kaplan-Meier plot with patients not achieving response within 120 minutes
`censored to 120 minutes.
`
`139
`140
`141
`142
`143
`144
`145
`
`
`For patients with migraine-associated nausea, photophobia, and phonophobia at baseline,
`146
`there was a lower incidence of these symptoms at 2 hours following administration of IMITREX
`147
`148 Nasal Spray compared to placebo.
`149
`Two to 24 hours following the initial dose of study treatment, patients were allowed to use
`
`additional treatment for pain relief in the form of a second dose of study treatment or other
`150
`151 medication. The estimated probability of patients taking a second dose or other medication for
`152 migraine over the 24 hours following the initial dose of study treatment is summarized in
`153
`Figure 2.
`154
`
`
`Reference ID: 3087904
`
`
`5
`
`
`Opiant Exhibit 2047
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 5
`
`

`

`Figure 2. The Estimated Probability of Patients Taking a Second Dose or Other
`155
`156 Medication for Migraine Over the 24 Hours Following the Initial Dose of Study
`157 Treatmenta
`158
`
`
`
`
`
`
` a Kaplan-Meier plot based on data obtained in the 3 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 remedication
`was allowed within 2 hours postdose.
`
`159
`160
`161
`162
`163
`164
`
`There is evidence that doses above 20 mg do not provide a greater effect than 20 mg. There
`165
`
`166 was no evidence to suggest that treatment with sumatriptan was associated with an increase in
`167
`the severity of recurrent headaches. The efficacy of IMITREX Nasal Spray was unaffected by
`168
`presence of aura; duration of headache prior to treatment; gender, age, or weight of the patient;
`169
`or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel
`170
`blockers, tricyclic antidepressants). There were insufficient data to assess the impact of race on
`171
`efficacy.
`
`172
`173
`174
`175
`176
`177
`178
`
`INDICATIONS AND USAGE
`IMITREX Nasal Spray is indicated for the acute treatment of migraine attacks with or without
`
`aura in adults.
`IMITREX Nasal Spray 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 IMITREX Nasal Spray have not been established for cluster headache, which is
`present in an older, predominantly male population.
`
`Reference ID: 3087904
`
`
`6
`
`
`Opiant Exhibit 2047
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 6
`
`

`

`179 CONTRAINDICATIONS
`
`IMITREX Nasal Spray should not be given to patients with history, symptoms, or signs
`180
`of ischemic cardiac, cerebrovascular, or peripheral vascular syndromes. In addition,
`181
`patients with other significant underlying cardiovascular diseases should not receive
`182
`IMITREX Nasal Spray. Ischemic cardiac syndromes include, but are not limited to, angina
`183
`pectoris of any type (e.g., stable angina of effort, vasospastic forms of angina such as the
`184
`Prinzmetal variant), all forms of myocardial infarction, and silent myocardial ischemia.
`185
`186 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,
`187
`ischemic bowel disease (see WARNINGS).
`188
`
`Because IMITREX Nasal Spray may increase blood pressure, it should not be given to
`189
`patients with uncontrolled hypertension.
`190
`
`
` Concurrent administration of MAO-A inhibitors or use within 2 weeks of
`191
`discontinuation of MAO-A inhibitor therapy is contraindicated (see CLINICAL
`192
`PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions).
`193
`IMITREX Nasal Spray and any ergotamine-containing or ergot-type medication (like
`
`194
`dihydroergotamine or methysergide) should not be used within 24 hours of each other, nor
`195
`should IMITREX Nasal Spray and another 5-HT1 agonist.
`196
`
`IMITREX Nasal Spray should not be administered to patients with hemiplegic or
`197
`basilar migraine.
`198
`IMITREX Nasal Spray is contraindicated in patients with hypersensitivity to
`
`199
`sumatriptan or any of its components.
`200
`
`IMITREX Nasal Spray is contraindicated in patients with severe hepatic impairment.
`
`201
`
`202 WARNINGS
`IMITREX Nasal Spray should only be used where a clear diagnosis of migraine
`
`
`203
`headache has been established.
`204
`205 Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events:
`
`Sumatriptan should not be given to patients with documented ischemic or vasospastic
`206
`coronary artery disease (CAD) (see CONTRAINDICATIONS). It is strongly recommended
`207
`that sumatriptan not be given to patients in whom unrecognized CAD is predicted by the
`208
`presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity,
`209
`diabetes, strong family history of CAD, female with surgical or physiological menopause,
`210
`211 male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical
`evidence that the patient is reasonably free of coronary artery and ischemic myocardial
`212
`disease or other significant underlying cardiovascular disease. The sensitivity of cardiac
`213
`diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery
`214
`vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient’s medical
`215
`history or electrocardiographic investigations reveal findings indicative of, or consistent
`216
`
`Reference ID: 3087904
`
`
`7
`
`
`Opiant Exhibit 2047
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 7
`
`

`

`217 with, coronary artery vasospasm or myocardial ischemia, sumatriptan should not be
`administered (see CONTRAINDICATIONS).
`218
`
`For patients with risk factors predictive of CAD, who are determined to have a
`219
` satisfactory cardiovascular evaluation, it is strongly recommended that administration of
`
`220
`the first dose of sumatriptan nasal spray take place in the setting of a physician’s office or
`221
`similar medically staffed and equipped facility unless the patient has previously received
`222
`sumatriptan. Because cardiac ischemia can occur in the absence of clinical symptoms,
`223
`consideration should be given to obtaining on the first occasion of use an electrocardiogram
`224
`(ECG) during the interval immediately following IMITREX Nasal Spray in these patients
`225
`226 with risk factors.
`
`It is recommended that patients who are intermittent long-term users of sumatriptan
`227
`and who have or acquire risk factors predictive of CAD, as described above, undergo
`228
`periodic interval cardiovascular evaluation as they continue to use sumatriptan.
`229
`
`The systematic approach described above is intended to reduce the likelihood that
`230
`patients with unrecognized cardiovascular disease will be inadvertently exposed to
`231
`sumatriptan.
`232
`233 Drug-Associated Cardiac Events and Fatalities: Serious adverse cardiac events,
`234
`including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death
`have been reported within a few hours following the administration of IMITREX® (sumatriptan
`235
`succinate) Injection or IMITREX® (sumatriptan succinate) Tablets. Considering the extent of use
`236
`237
`of sumatriptan in patients with migraine, the incidence of these events is extremely low.
`238
`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,
`239
`240
`and the close proximity of the events to sumatriptan use support the conclusion that some of
`241
`these cases were caused by the drug. In many cases, however, where there has been known
`242
`underlying coronary artery disease, the relationship is uncertain.
`Premarketing Experience With Sumatriptan: Among approximately 4,000 patients
`243
`
`244 with migraine who participated in premarketing controlled and uncontrolled clinical trials of
`
`245
`sumatriptan nasal spray, 1 patient experienced an asymptomatic subendocardial infarction
`246
`possibly subsequent to a coronary vasospastic event.
`247
`Of 6,348 patients with migraine who participated in premarketing controlled and uncontrolled
`
`clinical trials of oral sumatriptan, 2 experienced clinical adverse events shortly after receiving
`248
`249
`oral sumatriptan that may have reflected coronary vasospasm. Neither of these adverse events
`250 was associated with a serious clinical outcome.
`Among the more than 1,900 patients with migraine who participated in premarketing
`251
`
`controlled clinical trials of subcutaneous sumatriptan, there were 8 patients who sustained
`252
`
`clinical events during or shortly after receiving sumatriptan that may have reflected coronary
`253
`254
`artery vasospasm. Six of these 8 patients had ECG changes consistent with transient ischemia,
`255
`but without accompanying clinical symptoms or signs. Of these 8 patients, 4 had either findings
`256
`suggestive of CAD or risk factors predictive of CAD prior to study enrollment.
`
`Reference ID: 3087904
`
`8
`
`
`Opiant Exhibit 2047
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 8
`
`

`

`Postmarketing Experience With Sumatriptan: Serious cardiovascular events, some
`
`257
`resulting in death, have been reported in association with the use of IMITREX Injection or
`258
`IMITREX Tablets. The uncontrolled nature of postmarketing surveillance, however, makes it
`259
`impossible to determine definitively the proportion of the reported cases that were actually
`260
`caused by sumatriptan or to reliably assess causation in individual cases. On clinical grounds, the
`261
`longer the latency between the administration of IMITREX and the onset of the clinical event,
`262
`the less likely the association is to be causative. Accordingly, interest has focused on events
`263
`beginning within 1 hour of the administration of IMITREX.
`264
`
`Cardiac events that have been observed to have onset within 1 hour of sumatriptan
`265
`administration include: coronary artery vasospasm, transient ischemia, myocardial infarction,
`266
`ventricular tachycardia and ventricular fibrillation, cardiac arrest, and death.
`267
`
`Some of these events occurred in patients who had no findings of CAD and appear to
`268
`represent consequences of coronary artery vasospasm. However, among domestic reports of
`269
`serious cardiac events within 1 hour of sumatriptan administration, almost all of the patients had
`270
`risk factors predictive of CAD and the presence of significant underlying CAD was established
`271
`in most cases (see CONTRAINDICATIONS).
`272
`273 Drug-Associated Cerebrovascular Events and Fatalities: Cerebral hemorrhage,
`274
`subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in
`275
`patients treated with oral or subcutaneous sumatriptan, and some have resulted in fatalities. The
`276
`relationship of sumatriptan to these events is uncertain. In a number of cases, it appears possible
`277
`that the cerebrovascular events were primary, sumatriptan having been administered in the
`278
`incorrect belief that the symptoms experienced were a consequence of migraine when they were
`279
`not. As with other acute migraine therapies, before treating headaches in patients not previously
`280
`diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should
`281
`be taken to exclude other potentially serious neurological conditions. It should also be noted that
`282
`patients with migraine may be at increased risk of certain cerebrovascular events (e.g.,
`283
`cerebrovascular accident, transient ischemic attack).
`284 Other Vasospasm-Related Events: Sumatriptan may cause vasospastic reactions other than
`285
`coronary artery vasospasm. Both peripheral vascular ischemia and colonic ischemia with
`286
`abdominal pain and bloody diarrhea have been reported. Very rare reports of transient and
`287
`permanent blindness and significant partial vision loss have been reported with the use of
`288
`sumatriptan. Visual disorders may also be part of a migraine attack.
`289 Serotonin Syndrome: Serotonin syndrome may occur with triptans, including IMITREX,
`290
`particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or
`291
`serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome symptoms may
`292
`include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g.,
`293
`tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia,
`294
`incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of
`295
`symptoms can occur within minutes to hours of receiving a new or a greater dose of a
`
`Reference ID: 3087904
`
`
`9
`
`
`Opiant Exhibit 2047
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 9
`
`

`

`serotonergic medication. Treatment with IMITREX should be discontinued if serotonin
`296
`syndrome is suspected.
`297
`Increase in Blood Pressure: Significant elevation in blood pressure, including hypertensive
`298
`crisis, has been reported on rare occasions in patients with and without a history of hypertension.
`299
`Sumatriptan is contraindicated in patients with uncontrolled hypertension (see
`300
`301 CONTRAINDICATIONS). Sumatriptan should be administered with caution to patients with
`302
`controlled hypertension as transient increases in blood pressure and peripheral vascular resistance
`303
`have been observed in a small proportion of patients.
`Local Irritation: Of the 3,378 patients using the nasal spray (5-, 10-, or 20-mg doses) on 1 or 2
`304
`305
`occasions in controlled clinical studies, approximately 5% noted irritation in the nose and throat.
`306
`Irritative symptoms such as burning, numbness, paresthesia, discharge, and pain or soreness were
`
`307
` noted to be severe in about 1% of patients treated. The symptoms were transient and in
`308
`approximately 60% of the cases, the symptoms resolved in less than 2 hours. Limited
`309
`examinations of the nose and throat did not reveal any clinically noticeable injury in these
`310
`patients.
`311
`The consequences of extended and repeated use of IMITREX Nasal Spray on the nasal and/or
`
`respiratory mucosa have not been systematically evaluated in patients. No increase in the
`312
`313
`incidence of local irritation was observed in patients using IMITREX Nasal Spray repeatedly for
`314
`up to 1 year.
`315
`In inhalation studies in rats dosed daily for up to 1 month at exposures as low as one half the
`
`316 maximum daily human exposure (based on dose per surface area of nasal cavity), epithelial
`317
`hyperplasia (with and without keratinization) and squamous metaplasia were observed in the
`318
`larynx at all doses tested. These changes were partially reversible after a 2-week drug-free
`319
`period. When dogs were dosed daily with various formulations by intranasal instillation for up to
`320
`13 weeks at exposures of 2 to 4 times the maximum daily human exposure (based on dose per
`321
`surface area of nasal cavity), respiratory and nasal mucosa exhibited evidence of epithelial
`322
`hyperplasia, focal squamous metaplasia, granulomata, bronchitis, and fibrosing alveolitis. A no­
`323
`effect dose was not established. The changes observed in both species are not considered to be
`324
`signs of either preneoplastic or neoplastic transformation.
`325
`Local effects on nasal and respiratory tissues after chronic intranasal dosing in animals have
`
`not been studied.
`326
`327 Concomitant Drug Use: In patients taking MAO-A inhibitors, sumatriptan plasma levels
`328
`attained after treatment with recommended doses are 2-fold (following subcutaneous
`329
`administration) to 7-fold (following oral administration) higher than those obtained under other
`330
`conditions. Accordingly, the coadministration of IMITREX Nasal Spray and an MAO-A
`331
`inhibitor is contraindicated (see CLINICAL PHARMACOLOGY and
`332 CONTRAINDICATIONS).
`333 Hypersensitivity: Hypersensitivity (anaphylaxis/anaphylactoid) reactions have occurred on
`334
`rare occasions in patients receiving sumatriptan. Such reactions can be life threatening or fatal. In
`
`
`Reference ID: 3087904
`
`
`10
`
`
`Opiant Exhibit 2047
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 10
`
`

`

`335
`336
`
`general, hypersensitivity reactions to drugs are more likely to occur in individuals with a history
`of sensitivity to multiple allergens (see CONTRAINDICATIONS).
`
`337 PRECAUTIONS
`338 General: Chest discomfort and jaw or neck tightness have been reported infrequently following
`339
`the administration of IMITREX Nasal Spray and have also been reported following use of
`340
`IMITREX Tablets. Chest, jaw, or neck tightness is relatively common after administration of
`341
`IMITREX Injection. Only rarely have these symptoms been associated with ischemic ECG
`342
`changes. However, because sumatriptan may cause coronary artery vasospasm, patients who
`343
`experience signs or symptoms suggestive of angina following sumatriptan should be evaluated
`344
`for the presence of CAD or a predisposition to Prinzmetal variant angina before receiving
`345
`additional doses of sumatriptan, and should be monitored electrocardiographically if dosing is
`346
`resumed and similar symptoms recur. Similarly, patients who experience other symptoms or
`347
`signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud
`348
`syndrome following sumatriptan should be evaluated for atherosclerosis or predisposition to
`349
`vasospasm (see WARNINGS).
`350
`IMITREX Nasal Spray should also be administered with caution to patients with diseases that
`
`351 may alter the absorption, metabolism, or excretion of drugs, such as impaired hepatic or renal
`352
`function.
`353
`There have been rare reports of seizure following administration of sumatriptan. Sumatriptan
`
`should be used with caution in patients with a history of epilepsy or conditions associated with a
`354
`355
`lowered seizure threshold.
`356
`Care should be taken to exclude other potentially serious neurologic conditions before treating
`
`headache in patients not previously diagnosed with migraine headache or who experience a
`357
`358
`headache that is atypical for them. There have been rare reports where patients received
`359
`sumatriptan for severe headaches that were subsequently shown to have been secondary to an
`360
`evolving neurologic lesion (see WARNINGS).
`361
`For a given attack, if a patient does not respond to the first dose of sumatriptan, the diagnosis
`
`of migraine headache should be reconsidered before administration of a second dose.
`362
`363 Overuse: Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or a combination
`364
`of drugs for 10 or more days per month) may lead to exacerbation of headache (medication
`365
`overuse headache). Medication overuse headache may present as migraine-like daily headaches,
`366
`or as a marked increase in frequency of migraine attacks. Detoxification of patients, including
`367 withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes
`368
`a transient worsening of headache) may be necessary. Migraine patients should be informed
`369
`about the risks of medication overuse and encouraged to record headache frequency and drug
`370
`use.
`Information for Patients: See PATIENT INFORMATION at the end of this labeling for the
`
`371
`text of the separate leaflet provided for patients.
`372
`
`Reference ID: 3087904
`
`
`11
`
`
`Opiant Exhibit 2047
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 11
`
`

`

`Patients should be cautioned about the risk of serotonin syndrome with the use of sumatriptan
`
`373
`or other triptans, especially during combined use with SSRIs or SNRIs.
`374
`Laboratory Tests: No specific laboratory tests are recommended for monitoring p