HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use ZOMIG
`Nasal Spray safely and effectively. See full prescribing information for
`ZOMIG Nasal Spray.
`
` Recent (within 24 hours) use of another 5-HT1 agonist (e.g., another
`triptan) or of an ergot-type medication (4)
` MAO-A inhibitor used in past 2 weeks (4)
` Hypersensitivity to ZOMIG (4)
`
`ZOMIG (zolmitriptan) nasal spray
`INITIAL US APPROVAL: 1997
`
`----------------------------RECENT MAJOR CHANGES------------------------- 
`Dosage and Administration, Dosing Information (2.1, 2.2, 2.3)
`09/2013
`Warnings And Precautions, Medication Overuse Headache (5.6) 09/2013
`
`----------------------------INDICATIONS AND USAGE---------------------------
`ZOMIG Nasal Spray is a serotonin (5-HT)1B/1D receptor agonist (triptan)
`indicated for the acute treatment of migraine with or without aura in adults (1)
`Limitations of Use:
` Use only after a clear diagnosis of migraine has been established (1)
` Not intended for the prophylactic therapy of migraine (1)
` Not indicated for the treatment of cluster headache (1)
` Not recommended in patients with moderate to severe hepatic impairment
`(1)
`------------------------DOSAGE AND ADMINISTRATION----------------------
` Recommended starting dose: 2.5 mg. (2.1)
` Maximum single dose: 5 mg (2.1)
` May repeat dose after 2 hours if needed; not to exceed 10 mg in any
`24-hour period (2.1)
`
`-----------------------DOSAGE FORMS AND STRENGTHS--------------------
`Nasal Spray: 2.5 mg, and 5 mg (3)
`
`-------------------------WARNINGS AND PRECAUTIONS----------------------
` Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina:
`Perform cardiac evaluation in patients with multiple cardiovascular risk
`factors (5.1)
` Arrhythmias: Discontinue dosing if occurs (5.2)
` Chest/throat/neck/jaw pain, tightness, pressure, or heaviness: Generally
`not associated with myocardial ischemia; evaluate for coronary artery
`disease in patients at high risk (5.3)
` Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue
`dosing if occurs (5.4)
`ischemic events, peripheral vasospastic reactions:
` Gastrointestinal
`Discontinue dosing if occurs (5.5)
` Medication Overuse Headache: Detoxification may be necessary (5.6)
` Serotonin syndrome: Discontinue dosing if occurs (5.7, 7.5)
` Increase in blood pressure: very rarely associated with significant events
`(5.8)
`
`------------------------------ADVERSE REACTIONS-------------------------------
` The most common adverse reactions ( 5% and  placebo) were unusual
`taste, paresthesia, dizziness, and hyperesthesia (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Impax
`Pharmaceuticals at 1-877-994-6729 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch
`
`------------------------------DRUG INTERACTIONS-------------------------------
` If co-administered with cimetidine: Maximum single dose of 2.5 mg, not to
`exceed 5 mg in any 24-hour period (2.3, 7.4)
`
`-------------------------USE IN SPECIFIC POPULATIONS----------------------
` Pregnancy: Based on animal data, may cause fetal harm.(8.1)
`
`-------------------------------CONTRAINDICATIONS------------------------------
` History of ischemic heart disease or coronary artery vasospasm (4)
` Symptomatic Wolff-Parkinson-White syndrome or other cardiac accessory
`conduction pathway disorders (4)
` History of stroke, transient ischemic attack, or hemiplegic or basilar
`migraine (4)
` Peripheral Vascular Disease (4)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
` Ischemic bowel disease (4)
`approved patient labeling.
` Uncontrolled hypertension (4)
`Revised: 09/2013
`________________________________________________________________________________
`7.4 Cimetidine
`FULL PRESCRIBING INFORMATION: CONTENTS*
`7.5 Selective Serotonin Reuptake Inhibitors/Serotonin
`1
`INDICATIONS AND USAGE
`Norepinephrine Reuptake Inhibitors and Serotonin Syndrome
`2
`DOSAGE AND ADMINISTRATION
`2.1 Dosing Information
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`2.2 Dosing in Patients with Hepatic Impairment
`8.3 Nursing Mothers
`2.3 Dosing in Patients taking Cimetidine
`8.4 Pediatric Use
`DOSAGE FORMS AND STRENGTHS
`8.5 Geriatric Use
`CONTRAINDICATIONS
`8.6 Patients With Hepatic Impairment
`WARNINGS AND PRECAUTIONS
`5.1 Myocardial Ischemia, Myocardial Infarction, and
`OVERDOSAGE
`Prinzmetal's Angina
`DESCRIPTION
`5.2 Arrhythmias
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`5.3 Chest, Throat, Neck,and/or Jaw Pain/Tightness/Pressure
`12.3 Pharmacokinetics
`5.4 Cerebrovascular Events
`5.5 Other Vasospasm Reactions
`NONCLINICAL TOXICOLOGY
`5.6 Medication Overuse Headache
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`5.7 Serotonin Syndrome
`CLINICAL STUDIES
`14
`5.8
`Increase in Blood Pressure
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`ADVERSE REACTIONS
`PATIENT COUNSELING INFORMATION
`17
`FDA-APPROVED PATIENT LABELING
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`*Sections or subsections omitted from the full prescribing information are not
`DRUG INTERACTIONS
`listed.
`7.1 Ergot-containing drugs
`7.2 MAO-A Inhibitors
`7.3 5-HT1B/1D agonists
`_______________________________________________________________________________
`
`8
`
`10
`11
`12
`
`13
`
`3
`4
`5
`
`6
`
`7
`
`Reference ID: 3374105
`
`Opiant Exhibit 2048
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 1
`
`

`

`FULL PRESCRIBING INFORMATION
`
` 1
`
`
`
`INDICATIONS AND USAGE
`ZOMIG Nasal Spray is indicated for the acute treatment of migraine with or without aura
`in adults.
`
`2
`
`
`Limitations of Use
` Only use ZOMIG if a clear diagnosis of migraine has been established.If a patient has no
`response to ZOMIG treatment for the first migraine attack, reconsider the diagnosis of
`migraine before ZOMIG is administered to treat any subsequent attacks.
` ZOMIG is not indicated for the prevention of migraine attacks.
` Safety and effectiveness of ZOMIG have not been established for cluster headache.
` Not recommended in patients with moderate or severe hepatic impairment [see Dosage
`and Administration (2.2)].
`
`
`DOSAGE AND ADMINISTRATION
`
`2.1 Dosing Information
`The recommended starting dose for ZOMIG nasal spray is 2.5 mg. As the individual
`response to ZOMIG Nasal spray may vary, the dose should be adjusted on an individual
`basis. The maximum recommended single dose of ZOMIG is 5 mg.
`
`In controlled clinical trials, a greater proportion of patients had headache response
`following a 2.5 mg or 5 mg dose than following a 1 mg dose. There was little added
`benefit from the 5 mg dose compared to the 2.5 mg dose, but adverse reactions were
`more frequent with the 5 mg dose.
`
`If the migraine has not resolved by 2 hours after taking ZOMIG, or returns after a
`transient improvement, another dose may be administered at least 2 hours after the
`previous dose.
`
`The maximum daily dose should not exceed 10 mg in any 24-hour period.
`
`The safety of ZOMIG in the treatment of an average of more than four headaches in a
`30-day period has not been established.
`
`Reference ID: 3374105
`
`Opiant Exhibit 2048
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 2
`
`

`

`4
`
`3
`
`
`2.2 Dosing in Patients with Hepatic Impairment
`ZOMIG nasal spray is not recommended in patients with moderate to severe hepatic
`impairment because of increased zolmitriptan blood levels in these patients and elevation
`of blood pressure in some of these patients. The recommended dosage of ZOMIG nasal
`spray in patients with mild hepatic impairment is the same as for patients with normal
`hepatic function [see Dosage and Administration (2.1), Warnings and Precautions (5.8),
`Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
`
`2.3 Dosing in Patients taking Cimetidine
`If ZOMIG is co-administered with cimetidine, limit the maximum single dose of ZOMIG
`to 2.5 mg, not to exceed 5 mg in any 24-hour period [see Drug Interactions (7.4) and
`Clinical Pharmacology (12.3)].
`
`
`DOSAGE FORMS AND STRENGTHS
`Nasal Spray 2.5 mg and 5 mg.
`
`
`CONTRAINDICATIONS
`ZOMIG is contraindicated in patients with:
`
`Ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or
`documented silent ischemia), other significant underlying cardiovascular disease, or
`coronary artery vasospasm including Prinzmetal’s angina [see Warnings and
`Precautions (5.1)]
` Wolff-Parkinson-White Syndrome or arrhythmias associated with other cardiac
`accessory conduction pathway disorders [see Warnings and Precautions (5.2)]
` History of stroke, transient ischemic attack (TIA) or history of hemiplegic or basilar
`migraine because these patients are at higher risk of stroke [see Warnings and
`Precautions (5.4)]
` Peripheral vascular disease (PVD) [see Warnings and Precautions (5.5)]
`
`Ischemic bowel disease [see Warnings and Precautions (5.5)]
` Uncontrolled hypertension [see Warnings and Precautions (5.8)]
` Recent use (i.e., within 24 hours) of another 5-HT1 agonist, ergotamine-containing
`medication, or ergot-type medication (such as dihydroergotamine or methysergide)
`[see Drug Interactions (7.1, 7.3)]
` Concurrent administration of an MAO-A inhibitor or recent discontinuation of a
`MAO-A inhibitor (that is within 2 weeks) [see Drug Interactions (7.2) and Clinical
`Pharmacology (12.3)]
` Known hypersensitivity to ZOMIG (angioedema and anaphylaxis seen) [see Adverse
`Reactions (6.2)]
`
`
`
` 5
`
`
`
`WARNINGS AND PRECAUTIONS
`
`
`Reference ID: 3374105
`
`Opiant Exhibit 2048
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 3
`
`

`

`5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina
`ZOMIG is contraindicated in patients with ischemic or vasospastic coronary artery
`disease (CAD). There have been rare reports of serious cardiac adverse reactions,
`including acute myocardial infarction, occurring within a few hours following
`administration of ZOMIG. Some of these reactions occurred in patients without known
`CAD. 5-HT1 agonists including ZOMIG may cause coronary artery vasospasm
`(Prinzmetal’s Angina), even in patients without a history of CAD.
`
`Perform a cardiovascular evaluation in triptan-naïve patients who have multiple
`cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity,
`strong family history of CAD) prior to receiving ZOMIG. Do not administer ZOMIG if
`there is evidence of CAD or coronary artery vasospasm [see Contraindications (4)]. For
`patients with multiple cardiovascular risk factors who have a negative cardiovascular
`evaluation, consider administrating the first ZOMIG dose in a medically-supervised
`setting and performing an electrocardiogram (ECG) immediately following ZOMIG
`administration. For such patients, consider periodic cardiovascular evaluation in
`intermittent long-term users of ZOMIG.
`
`5.2 Arrhythmias
`Life-threatening disturbances of cardiac rhythm including ventricular tachycardia and
`ventricular fibrillation leading to death have been reported within a few hours following
`the administration of 5-HT1 agonists. Discontinue ZOMIG if these disturbances occur.
`Patients with Wolff-Parkinson-White Syndrome or arrhythmias associated with other
`cardiac accessory conduction pathway disorders should not receive ZOMIG [see
`Contraindications (4)].
`
`5.3 Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure
`As with other 5-HT1 agonists, sensations of tightness, pain, pressure, and heaviness in the
`precordium, throat, neck, and jaw commonly occur after treatment with ZOMIG and is
`usually non-cardiac in origin. However, if a cardiac origin is suspected, patients should
`be evaluated. Patients shown to have CAD and those with Prinzmetal’s variant angina
`should not receive 5-HT1 agonists [see Contraindications (4)].
`
`5.4 Cerebrovascular Events
`Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients
`treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it
`appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having
`been administered in the incorrect belief that the symptoms experienced were a
`consequence of migraine, when they were not. Discontinue ZOMIG if a cerebrovascular
`event occurs.
`
`As with other acute migraine therapies, before treating headaches in patients not
`previously diagnosed as migraineurs, and in migraineurs who present with symptoms
`atypical for migraine, other potentially serious neurological conditions should be
`excluded. ZOMIG should not be administered to patients with a history of stroke or
`transient ischemic attack [see Contraindications (4)].
`
`Reference ID: 3374105
`
`Opiant Exhibit 2048
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 4
`
`

`

`
`5.5 Other Vasospasm Reactions
`5-HT1 agonists, including ZOMIG, may cause non-coronary vasospastic reactions, such
`as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction
`(presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s
`syndrome. In patients who experience symptoms or signs suggestive of vasospasm
`reaction following the use of any 5-HT1 agonist, the suspected vasospasm reaction should
`be ruled out before receiving additional ZOMIG doses [see Contraindications (4)].
`
`Reports of transient and permanent blindness and significant partial vision loss have been
`reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine
`attack, a causal relationship between these events and the use of 5-HT1 agonists have not
`been clearly established.
`
`
`5.6 Medication Overuse Headache
`Overuse of acute migraine drugs (e.g. ergotamine, triptans, opioids, or a combination of
`drugs for 10 or more days per month) may lead to exacerbation of headache (medication
`overuse headache). Medication overuse headache may present as migraine-like daily
`headaches, or as a marked increase in frequency of migraine attacks. Detoxification of
`patients, including withdrawal of the overused drugs, and treatment of withdrawal
`symptoms (which often includes a transient worsening of headache) may be necessary.
`
`
`5.7 Serotonin Syndrome
`Serotonin syndrome may occur with triptans, including ZOMIG, particularly during co-
`administration with selective serotonin
`reuptake
`inhibitors
`(SSRIs), serotonin
`norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO
`inhibitors [see Drug Interactions (7.5)]. Serotonin syndrome symptoms may include
`mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g.,
`tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g.,
`hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting,
`diarrhea). The onset of symptoms usually rapidly occurs within minutes to hours of
`receiving a new or a greater dose of a serotonergic medication. ZOMIG treatment should
`be discontinued if serotonin syndrome is suspected [see Drug Interactions (7.5) and
`Patient Counseling Information (17)].
`
`Increase in Blood Pressure
`Significant elevations in systemic blood pressure have been reported in patients treated
`with 5-HT1 agonists including patients without a history of hypertension. Very rarely
`these increases in blood pressure have been associated with significant clinical events. In
`healthy subjects treated with 5 mg of ZOMIG oral tablet, an increase of 1 and 5 mm Hg
`in the systolic and diastolic blood pressure, respectively, was seen. In a study of patients
`with moderate to severe liver impairment, 7 of 27 patients experienced 20 to 80 mm Hg
`elevations in systolic and/or diastolic blood pressure after a dose of 10 mg of ZOMIG
`oral tablet. As with all triptans, blood pressure should be monitored in ZOMIG-treated
`patients. ZOMIG is contraindicated in patients with uncontrolled hypertension [see
`Contraindications (4)].
`
`5.8
`
`Reference ID: 3374105
`
`Opiant Exhibit 2048
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 5
`
`

`

`6
`
`
`ADVERSE REACTIONS
`The following adverse reactions are discussed in more detail in other sections of labeling:
` Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina [see
`Warnings and Precautions (5.1)]
` Arrhythmias [see Warnings and Precautions (5.2)]
` Chest and or Throat, Neck and Jaw Pain/Tightness/Pressure [see Warnings and
`Precautions (5.3)]
` Cerebrovascular Events [see Warnings and Precautions (5.4)]
` Other Vasospasm Reactions [see Warnings and Precautions (5.5)]
` Medication Overuse Headache [see Warnings and Precautions (5.6)]
` Serotonin Syndrome [see Warnings and Precautions (5.7)]
`
`Increase in Blood Pressure [see Warnings and Precautions (5.8)]
`
`
`6.1 Clinical Trials Experience
`Because clinical studies are conducted under widely varying conditions, adverse reaction
`rates observed in the clinical studies of a drug cannot be directly compared to rates in the
`clinical studies of another drug and may not reflect the rates observed in practice.
`
`Among 460 patients treating 1180 single attacks with zolmitriptan nasal spray in a
`blinded placebo controlled trial (Study 1), there was a low withdrawal rate related to
`adverse reactions: 5 mg (1.3%), 2.5 mg (0%), and placebo (0.4%). None of the
`withdrawals were due to a serious event. One patient was withdrawn due to abnormal
`ECG changes from baseline that were incidentally found 23 days after the last dose of
`ZOMIG Nasal Spray.
`The most common adverse reactions ( 5% and > placebo) in any dosage strength in
`clinical trials for ZOMIG Nasal Spray were: unusual taste, paresthesia, hyperesthesia, and
`dizziness. The incidence of adverse reactions was generally dose-related.
`
`Table 1 lists the adverse reactions from the controlled clinical trial (Study 1) that
`occurred in  2% of patients in either the 2.5 or 5 mg zolmitriptan nasal spray dose
`groups and with an incidence greater than placebo.
`
`Table 1: Adverse reactions with an incidence of ≥2% and greater than placebo of patients
`in each of the ZOMIG 2.5 and 5 mg nasal spray treatment groups by body system.
`
`Body system and adverse reaction
`
` 
`Placebo
`
`(N=228)
`
`0%
`
`Zomig
`2.5 mg
`(N=224)
`
`Zomig
`5mg
`(N=236)
`
`1%
`
`5%
`
` 
`
`Atypical Sensations
`Hyperesthesia
`
`Reference ID: 3374105
`
`Opiant Exhibit 2048
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 6
`
`

`

`Body system and adverse reaction
`
` 
`
`Paraesthesia
`Sensation warm
`Ear/Nose/Throat
`Disorder/Discomfort of nasal cavity
`Pain and Pressure Sensations
`Pain Location Specified
`Pain Throat
`Tightness Throat
`
` 
`Placebo
`
`(N=228)
`6%
`2%
`
`2%
`
`1%
`1%
`1%
`
`Zomig
`2.5 mg
`(N=224)
`5%
`4%
`
`Zomig
`5mg
`(N=236)
`10%
`0%
`
`1%
`
`3%
`
`2%
`4%
`1%
`
`4%
`4%
`2%
`
`3%
`1%
`
`6%
`1%
`
`2%
`4%
`
`3%
`4%
`
`17%
`3%
`
`21%
`3%
`
`Digestive
`Dry Mouth
`Nausea
`Neurological
`Dizziness
`Somnolence
`Other
`Unusual Taste
`Asthenia
`
`In Study 1, adverse clinical reactions occurring in  1% and < 2% of patients in all
`attacks in either zolmitriptan nasal spray dose group and with incidence greater than that
`of placebo were pain abdominal, chills, pressure throat, edema face, pressure chest,
`palpitation, dysphagia, arthralgia, myalgia, and depersonalization.
`
`The incidence of adverse reactions in controlled clinical trials was not affected by gender,
`weight, or age of the patients (18-39 vs. 40-65 years of age), or presence of aura. There
`were insufficient data to assess the impact of race on the incidence of adverse reactions.
`
`
`
`1%
`1%
`
`4%
`2%
`
`3%
`1%
`
`Reference ID: 3374105
`
`Opiant Exhibit 2048
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 7
`
`

`

`Local Adverse Reactions:
`Among 460 patients using ZOMIG 2.5mg or 5mg in the controlled clinical trial,
`approximately 3% noted local irritation or soreness at the site of administration. Adverse
`reactions of any kind, perceived in the nasopharynx (which may include systemic effects
`of triptans) were severe in about 1% of patients and approximately 57% resolved in 1
`hour. Nasopharyngeal examinations, in a subset of patients participating in two long
`term trials of up to one year duration, failed to demonstrate any clinically significant
`changes with repeated use of ZOMIG Nasal Spray.
`
`All nasopharyngeal adverse reactions with an incidence of  2% of patients in any
`zolmitriptan nasal spray dose groups are included in ADVERSE REACTIONS Table 1.
`
`Other Adverse Reactions:
`In the paragraphs that follow, the frequencies of less commonly reported adverse clinical
`reactions are presented. Because the reports include reactions observed in open and
`uncontrolled studies, the role of ZOMIG in their causation cannot be reliably determined.
`Furthermore, variability associated with adverse reaction reporting, the terminology used
`to describe adverse reactions, etc., limit the value of the quantitative frequency estimates
`provided. Reaction frequencies are calculated as the number of patients who used
`ZOMIG Nasal Spray and reported a reaction divided by the total number of patients
`exposed to ZOMIG Nasal Spray (n=3059). All reported reactions are included except
`those already listed in the previous table, those too general to be informative, and those
`not reasonably associated with the use of the drug. Reactions are further classified
`within body system categories and enumerated in order of decreasing frequency using the
`following definitions: infrequent adverse reactions are those occurring in 1/100 to
`1/1,000 patients and rare adverse reactions are those occurring in fewer than 1/1,000
`patients.
`
`General: Infrequent: allergic reactions.
`
`Cardiovascular: Infrequent: arrhythmias, hypertension, syncope and tachycardia. Rare:
`angina pectoris and myocardial infarct.
`
`Digestive: Rare: stomatitis.
`
`Neurological: Infrequent: agitation, amnesia, anxiety, depression, insomnia, and
`nervousness. Rare: convulsions.
`
`Respiratory: Infrequent: bronchitis, increased cough, dyspnea, epistaxis, laryngeal
`edema, pharyngitis, rhinitis, and sinusitis.
`
`Skin: Infrequent: pruritus, rash, and urticaria.
`
`Urogenital: Infrequent: polyuria and urinary urgency. Rare: urinary frequency.
`
`Special senses: Infrequent: tinnitus. Rare: conjunctivitis, dry eye, and visual field defect.
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3374105
`
`Opiant Exhibit 2048
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 8
`
`

`

`
`
`The adverse experience profile seen with ZOMIG Nasal Spray is similar to that seen with
`ZOMIG tablets and ZOMIG-ZMT tablets except for the occurrence of local adverse
`reactions from the nasal spray (see ZOMIG tablet/ZOMIG-ZMT oral disintegrating tablet
`Prescribing Information).
`
`6.2 Postmarketing Experience
`The following adverse reactions were identified during post approval use of ZOMIG.
`Because these reactions are reported voluntarily from a population of uncertain size, it is
`not always possible to reliably estimate their frequency or establish a causal relationship
`to drug exposure.
`
`The reactions enumerated include all except those already listed in the Clinical Trials
`Experience section above or the Warnings and Precautions section.
`
`Hypersensitivity Reactions:
`As with other 5-HT1B/1D agonists, there have been reports of anaphylaxis, anaphylactoid,
`and hypersensitivity reactions including angioedema in patients receiving ZOMIG.
`ZOMIG is contraindicated in patients with a history of hypersensitivity reaction to
`ZOMIG.
`
`
`
`DRUG INTERACTIONS
`
`7.1 Ergot-containing drugs
`Ergot-containing drugs have been reported to cause prolonged vasospastic reactions.
`Because these effects may be additive, use of ergotamine-containing or ergot-type
`medications (like dihydroergotamine or methysergide) and ZOMIG within 24 hours of
`each other is contraindicated [see Contraindications (4)].
`
`7.2 MAO-A Inhibitors
`MAO-A inhibitors increase the systemic exposure of zolmitriptan. Therefore, the use of
`[see
`ZOMIG
`in patients
`receiving MAO-A
`inhibitors
`is
`contraindicated
`Contraindications (4) and Clinical Pharmacology (12.3)].
`
`5-HT1B/1D agonists (e.g. triptans)
`Concomitant use of other 5-HT1B/1D agonists (including triptans) within 24 hours of
`ZOMIG treatment is contraindicated because the risk of vasospastic reactions may be
`additive [see Contraindications (4)].
`
`7.4 Cimetidine
`Following administration of cimetidine, the half-life and AUC of ZOMIG and its active
`metabolites were approximately doubled [see Clinical Pharmacology (12.3)]. If
`cimetidine and ZOMIG are used concomitantly, limit the maximum single dose of
`ZOMIG to 2.5 mg, not to exceed 5 mg in any 24-hour period [see Dosage and
`Administration (2.3) and Clinical Pharmacology (12.3)].
`
`
`7.3
`
` 7
`
`
`
`Reference ID: 3374105
`
`Opiant Exhibit 2048
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 9
`
`

`

`7.5 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine
`Reuptake Inhibitors and Serotonin Syndrome
`Cases of life-threatening serotonin syndrome have been reported during combined use of
`selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake
`inhibitors (SNRIs) and triptans [see Warnings and Precautions (5.7)].
`
`USE IN SPECIFIC POPULATIONS
`8
`8.1 Pregnancy
`Pregnancy Category C. There are no adequate and well controlled studies in pregnant
`women; therefore, zolmitriptan should be used during pregnancy only if the potential
`benefit justifies the potential risk to the fetus. In reproductive toxicity studies in rats and
`rabbits, oral administration of zolmitriptan
`to pregnant animals
`resulted
`in
`embryolethality and fetal abnormalities (malformations and variations) at clinically
`relevant exposures.
`
`When zolmitriptan was administered to pregnant rats during the period of organogenesis
`at oral doses of 100, 400, and 1200 mg/kg/day (plasma exposures (AUCs) ≈280, 1100,
`and 5000 times the human AUC at the maximum recommended human dose (MRHD) of
`10 mg/day), there was a dose-related increase in embryolethality. A no-effect dose for
`embryolethality was not established. When zolmitriptan was administered to pregnant
`rabbits during the period of organogenesis at oral doses of 3, 10, and 30 mg/kg/day
`(plasma AUCs ≈1, 11, and 42 times the human AUC at the MRHD), there were increases
`in embryolethality and in fetal malformations and variations. The no-effect dose for
`adverse effects on embryo-fetal development was associated with a plasma AUC similar
`to that in humans at the MRHD. When female rats were given zolmitriptan during
`gestation, parturition, and lactation at oral doses of 25, 100, and 400 mg/kg/day (plasma
`AUCs ≈70, 280, and 1100 times that in human at the MRHD), an increased incidence of
`hydronephrosis was found in the offspring. The no-effect dose was associated with a
`plasma AUC ≈280 times that in humans at the MRHD.
`
`8.3 Nursing Mothers
`It is not known whether zolmitriptan is excreted in human milk. Because many drugs are
`excreted in human milk, and because of the potential for serious adverse reactions in
`nursing infants from ZOMIG, a decision should be made whether to discontinue nursing
`or to discontinue the drug, taking into account the importance of the drug to the mother.
`In rats, oral dosing with zolmitriptan resulted in levels in milk up to 4 times higher than
`in plasma.
`
`8.4 Pediatric Use
`Safety and effectiveness in pediatric patients have not been established.
`
` A
`
` single, multicenter, double-blind, randomized placebo-controlled, study was conducted
`to evaluate the efficacy of ZOMIG 5 mg nasal spray in the acute treatment of migraine
`headache in 171 evaluable adolescent subjects 12 to 17 years of age. Efficacy was not
`established in that study.
`
`Reference ID: 3374105
`
`Opiant Exhibit 2048
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 10
`
`

`

`Adverse reactions observed in this study were similar in nature and frequency to those
`reported in clinical trials of ZOMIG Nasal Spray in adults. The most commonly reported
`adverse reactions ( 2% and  placebo) were dysgeusia (7%), nasal discomfort (3%),
`dizziness (2%), nasal congestion (2%), nausea (2%), and throat irritation (2%).
`
`ZOMIG Nasal Spray has not been studied in pediatric patients age 11 years and under.
`
`In the postmarketing experience with triptans, including ZOMIG, there is a limited
`number of reports that describe pediatric patients who have experienced clinically serious
`adverse events; those that were reported are similar in nature to those reported rarely in
`adults.
`
`8.5 Geriatric Use
`Clinical studies of ZOMIG did not include sufficient numbers of subjects aged 65 and
`over to determine whether they respond differently from younger subjects. Other reported
`clinical experience has not identified differences in responses between the elderly and
`younger patients. In general, dose selection for an elderly patient should be cautious,
`usually starting at the low end of the dosing range, reflecting the greater frequency of
`decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug
`therapy. Geriatric patients who have other cardiovascular risk factors (e.g., diabetes,
`hypertension, smoking, obesity, strong family history of coronary artery disease) should
`have a cardiovascular evaluation prior to receiving ZOMIG [see Warnings and
`Precautions (5.1)]. The pharmacokinetics of zolmitriptan were similar in geriatric
`patients (aged > 65 years) compared to younger patients [see Clinical Pharmacology
`(12.3)].
`
`8.6 Patients With Hepatic Impairment:
`The effect of hepatic disease on the pharmacokinetics of zolmitriptan nasal spray has not
`been evaluated. After oral administration, zolmitriptan blood levels were increased in
`patients with moderate to severe hepatic impairment, and significant elevation in blood
`pressure was observed in some of these patients [see Warnings and Precautions (5.8)].
`ZOMIG nasal spray is not recommended in patients with moderate to severe hepatic
`impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
`
`
`OVERDOSAGE
`There is no experience with acute overdose. Clinical study subjects receiving single
`50 mg oral doses of zolmitriptan commonly experienced sedation.
`
`The elimination half-life of ZOMIG is 3 hours [see Clinical Pharmacology (12.1)] and
`therefore monitoring of patients after overdose with ZOMIG should continue for at least
`15 hours or while symptoms or signs persist.
`
`
`10
`
`Reference ID: 3374105
`
`Opiant Exhibit 2048
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 11
`
`

`

`There is no specific antidote to zolmitriptan. In cases of severe intoxication, intensive
`care procedures are recommended, including establishing and maintaining a patent
`airway, ensuring adequate oxygenation and ventilation, and monitoring and support of
`the cardiovascular system.
`
`It is unknown what effect hemodialysis or peritoneal dialysis has on the plasma
`concentrations of zolmitriptan.
`
`DESCRIPTION
`ZOMIG® (zolmitriptan) Nasal Spray contains zolmitriptan, which is a selective
`5-hydroxytryptamine 1B/1D (5-HT1B/1D) receptor agonist. Zolmitriptan is chemically
`designated as (S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone
`and has the following chemical structure:
`
`
`11
`
`
`
`
`The empirical formula is C16H21N3O2, representing a molecular weight of 287.36.
`Zolmitriptan is a white to almost white powder that is readily soluble in water. ZOMIG
`Nasal Spray is supplied as a clear to pale yellow solution of zolmitriptan, buffered to a
`pH 5.0. Each ZOMIG Nasal Spray contains 2.5 mg or 5 mg of zolmitriptan in a 100-µL
`unit dose aqueous buffered solution containing citric acid, anhydrous, USP, disodium
`phosphate dodecahydrate USP and purified water USP.
`
`ZOMIG Nasal Spray is hypertonic. The osmolarity of ZOMIG Nasal Spray for 2.5 mg is
`360 to 420 mOsmol, and for 5 mg is 420 to 470 mOsmol.
`
`
`CLINICAL PHARMACOLOGY
`12
`12.1 Mechanism of Action
`Zolmitriptan binds with high affinity to human recombinant 5-HT1D and 5-HT1B
`receptors, and moderate affinity for 5-HT1A receptors. The N-desmethyl metabolite also
`has high affinity for 5-HT1B/1D and moderate affinity for 5-HT1A receptors.
`
`Current theories proposed to explain the etiology of migraine headache suggest that
`symptoms