
`
`
`
`
`
`
`Ischemic bowel disease (4)
`Uncontrolled hypertension (4)
`Recent (within 24 hours) use of another 5-HT1 agonist (e.g., another
`triptan), or an ergotamine-containing medication (4)
` Monoamine oxidase (MAO)-A inhibitor used in past 2 weeks (4)
`
`Known hypersensitivity to ZOMIG or ZOMIG-ZMT (4)
`
`-------------------------- WARNINGS AND PRECAUTIONS ------------------------
` Myocardial Ischemia/Infarction, and Prinzmetal Angina: Perform
`cardiac evaluation in patients with multiple cardiovascular risk factors
`(5.1)
`Arrhythmias: Discontinue ZOMIG if occurs (5.2)
`Chest/Throat/Neck /Jaw Pain, Tightness, and Pressure: Generally not
`associated with myocardial ischemia; evaluate for CAD in patients at
`high risk (5.3)
`Cerebral Hemorrhage, Subarachnoid Hemorrhage, and Strok e:
`Discontinue ZOMIG if occurs (5.4)
`Gastrointestinal Ischemic Reactions and Peripheral Vasospastic
`Reactions: Discontinue ZOMIG if occurs (5.5)
` Medication Overuse Headache: Detoxification may be necessary (5.6)
`
`Serotonin Syndrome: Discontinue ZOMIG if occurs (5.7, 7.4)
`
`Patients with Phenylk etonuria: ZOMIG-ZMT contains phenylalanine
`(5.9)
`
`
`
`
`
`
`---------------------------------- ADVERS E REACTIONS --------------------------------
`Most common adverse reactions (≥5% and > placebo) were neck/throat/jaw
`pain/tightness/pressure, dizziness, paresthesia, asthenia, somnolence,
`warm/cold sensation, nausea, heaviness sensation, and dry mouth (6.1)
`
`To report SUSPECTED ADVERS E REACTIONS, contact Impax
`Laboratories at 1-877-994-6729 or FDA at 1-800-FDA-1088 or
`www.fda.gov/ me dwatch.
`
`-------------------------- USE IN SPECIFIC POPULATIONS ------------------------
`Pregnancy: Based on animal data, may cause fetal harm (8.1)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approve d patient labeling.
`
`Revised: 12/2018
`
`
`
`7.3 5-HT1B/1D agonists
`7.4 Selective Serotonin Reuptake Inhibitors and Serotonin Norepinephrine
`Reuptake Inhibitors
`7.5 Cimetidine
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Patients with Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use ZOMIG
`or ZOMIG-ZMT safely and effectively. See full prescribing information
`for ZOMIG or ZOMIG-ZMT.
`
`ZOMIG (zolmitriptan) tablets, for oral use
`ZOMIG-ZMT (zolmitriptan), Orally Disintegrating Tablets
`Initial U.S. Approval: 1997
`
`------------------------------- INDICATIONS AND USAGE -----------------------------
`ZOMIG 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 indicated for the prophylactic therapy of migraine (1)
`
`Not indicated for the treatment of cluster headache (1)
`
`-------------------------- DOSAGE AND ADMINISTRATION ------------------------
`
`Recommended starting dose: 1.25 mg or 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)
`
`Do not break ZOMIG Orally Disintegrating Tablets (2.2)
` Moderate or Severe Hepatic Impairment: 1.25 mg recommended (2.3,
`8.6)
`
`
`------------------------ DOSAGE FORMS AND STRENGTHS ----------------------
`
`Tablets: 2.5 mg functionally-scored (3)
`
`Tablets: 5 mg (not scored) (3)
`
`Orally Disintegrating Tablets: 2.5 mg and 5 mg (3)
`
`---------------------------------- CONTRAINDICATIONS --------------------------------
`
`History of coronary artery disease (CAD) or coronary 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)
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS *
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Dosing Information
`2.2 Administration of ZOMIG-ZMT Orally Disintegrating Tablets
`2.3 Dosing in Patients with Hepatic Impairment
`2.4 Dosing in Patients taking Cimetidine
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal Angina
`5.2 Arrhythmias
`5.3 Chest, Throat, Neck and Jaw Pain/Tightness/Pressure
`5.4 Cerebrovascular Events
`5.5 Other Vasospasm Reactions
`5.6 Medication Overuse Headache
`5.7 Serotonin Syndrome
`5.8 Increase in Blood Pressure
`5.9 Risks in Patients with Phenylketonuria
`6 ADVERS E REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1 Ergot-containing Drugs
`7.2 MAO-A Inhibitors
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4367843
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`ZOMIG is indicated for the acute treatment of migraine with or without aura in adults.
`
`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.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Dosing Information
`
`The recommended starting dose of ZOMIG is 1.25 mg or 2.5 mg. The 1.25 mg dose can be achieved by manually
`breaking the functionally-scored 2.5 mg tablet in half. 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, a second dose
`may be administered at least 2 hours after the first dose. The maximum daily dose is 10 mg in any 24-hour period.
`
`The safety of ZOMIG in the treatment of an average of more than three migraines in a 30-day period has not been
`established.
`
`2.2 Administration of ZOMIG-ZMT Orally Disintegrating Tablets
`
`Instruct patients not to break ZOMIG-ZMT Orally Disintegrating Tablets because they are not functionally-scored.
`Administration with liquid is not necessary.
`
`Orally disintegrating tablets are packaged in a blister pack. Instruct patients not to remove the tablet from the blister until
`just prior to dosing. Subsequently, instruct patients to peel the blister pack open, and to place the orally disintegrating
`tablet on the tongue, where it will dissolve and it will be swallowed with the saliva.
`
`2.3 Dosing in Patients with Hepatic Impairment
`
`The recommended dose of ZOMIG in patients with moderate to severe hepatic impairment is 1.25 mg (one-half of one 2.5
`
`mg ZOMIG tablet) because of increased zolmitriptan blood levels in these patients and elevation of blood pressure in
`some of these patients. Limit the total daily dose in patients with severe hepatic impairment to no more than 5 mg per day.
`
`The use of ZOMIG-ZMT Orally Disintegrating Tablets is not recommended in patients with moderate or severe hepatic
`impairment because these orally disintegrating tablets should not be broken in half [see Use in Specific Populations (8.6),
`Clinical Pharmacology (12.3)].
`
`2.4 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 (7.5), Clinical Pharmacology (12.3)].
`
`Reference ID: 4367843
`
`

`

`3 DOSAGE FORMS AND STRENGTHS
`
`2.5 mg Tablets: Yellow, biconvex, round, film-coated identified with “ZOMIG” and “2.5” debossed on one side
`(functionally-scored).
`
`5 mg Tablets: Pink, biconvex, round, film-coated identified with “ZOMIG” and “5” debossed on one side (not scored).
`
`2.5 mg Orally disintegrating tablets: White, flat-faced, round, uncoated, bevelled identified with a debossed “Z” on one
`side.
`
`5 mg Orally disintegrating tablets: White, flat-faced, round, uncoated, bevelled identified with a debossed “Z” and “5” on
`one side.
`
`4 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 a 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 a monoamine oxidase (MAO)-A inhibitor or recent use of a MAO-A inhibitor (that is
`within 2 weeks) [see Drug Interactions (7.2), Clinical Pharmacology (12.3)].
`
`Known hypersensitivity to ZOMIG or ZOMIG ZMT (angioedema and anaphylaxis seen) [see Adverse Reactions
`(6.2)].
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal 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 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.
`
`Reference ID: 4367843
`
`

`

`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. ZOMIG is contraindicated in patients with Wolff-Parkinson-White Syndrome or arrhythmias
`associated with other cardiac accessory conduction pathway disorders [see Contraindications (4)].
`
`5.3 Chest, Throat, Neck and Jaw Pain/Tightness/Pressure
`
`As with other 5-HT1 agonists, sensations of tightness, pain, and pressure in the chest, throat, neck, and jaw commonly
`occur after treatment with ZOMIG and is usually non-cardiac in origin. However, perform a cardiac evaluation if these
`patients are at high cardiac risk. 5-HT1 agonists including ZOMIG are contraindicated in patients with CAD or
`Prinzmetal’s variant angina [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.
`
`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, exclude other potentially serious neurological
`conditions. ZOMIG is contraindicated in patients with a history of stroke or transient ischemic attack [see
`Contraindications (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 a vasospastic reaction following
`the use of any 5-HT1 agonist, rule out a vasospastic reaction 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
`
`Reference ID: 4367843
`
`

`

`greater dose of a serotonergic medication. Discontinue ZOMIG if serotonin syndrome is suspected [see Drug Interactions
`(7.4)].
`
`5.8 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 serious
`adverse reactions. In healthy subjects treated with 5 mg of ZOMIG, 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.
`
`As with all triptans, blood pressure should be monitored in ZOMIG-treated patients. ZOMIG is contraindicated in patients
`with uncontrolled hypertension [see Contraindications (4)].
`
`5.9 Risks in Patients with Phenylketonuria
`
`Phenylalanine can be harmful to patients with phenylketonuria (PKU). ZOMIG-ZMT Orally Disintegrating Tablets
`
`contain phenylalanine (a component of aspartame). Each 2.5 mg and 5 mg orally disintegrating tablet contains 2.81 and
`5.62 mg of phenylalanine, respectively. ZOMIG tablets do not contain phenylalanine.
`
`6 ADVERSE REACTIONS
`
`The following adverse reactions are described elsewhere in other sections of the prescribing information:
`
` Myocardial Ischemia, Myocardial Infarction, and Prinzmetal 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)].
` Risks in Patients with Phenylketonuria [see Warnings and Precautions (5.9)].
`
`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.
`In a long-term, open-label study where patients were allowed to treat multiple migraine attacks for up to 1 year, 8% (167
`out of 2,058) withdrew from the trial because of adverse reaction.
`The most common adverse reactions (≥5% and > placebo) in these trials were neck/throat/jaw pain, dizziness, paresthesia,
`
`asthenia, somnolence, warm/cold sensation, nausea, heaviness sensation, and dry mouth.
`Table 1 lists the adverse reactions that occurred in ≥ 2% of the 2,074 patients in any one of the ZOMIG 1 mg, 2.5 mg, or 5
`mg dose groups in the controlled clinical trials of ZOMIG in patients with migraines (Studies 1, 2, 3, 4, and 5) [see
`Clinical Studies (14)]. Only adverse reactions that were at least 2% more frequent in a ZOMIG group compared to the
`
`placebo group are included.
`Several of the adverse reactions appear dose related, notably paresthesia, sensation of heaviness or tightness in chest,
`neck, jaw, and throat, dizziness, somnolence and possibly asthenia and nausea.
`
`Reference ID: 4367843
`
`

`

`Table 1: Adverse Reaction Incidence in Five Pooled Placebo-Controlled Migraine Clinical Trials*
`
`
`
`Placebo
`
`(n=401)
`
`ATYPICAL
`SENSATIONS
`
`Paresthesia (all types)
`
`Warm/cold sensation
`
`PAIN AND PRESSURE
`SENSATIONS
`
`Chest -
`pain/tightness/pressure
`and/or heaviness
`
`Neck/throat/jaw -
`pain/tightness/pressure
`
`Heaviness other than chest
`or neck
`
`Other-
`Pressure/tightness/heaviness
`
`DIGESTIVE
`
`6%
`
`2%
`
`4%
`
`7%
`
`1%
`
`3%
`
`1%
`
`0%
`
`8%
`
`ZOMIG
`
`1 mg
`
`(n=163)
`
`12%
`
`ZOMIG
`
`2.5 mg
`
`(n=498)
`
`12%
`
`5%
`
`6%
`
`13%
`
`2%
`
`4%
`
`1%
`
`2%
`
`7%
`
`5%
`
`14%
`
`3%
`
`7%
`
`2%
`
`2%
`
`11%
`
`16%
`
`ZOMIG
`
`5 mg
`
`(n=1012)
`
`18%
`
`9%
`
`7%
`
`22%
`
`4%
`
`10%
`
`5%
`
`2%
`
`14%
`
`3%
`
`Dry mouth
`
`Dyspepsia
`
`Dysphagia
`
`Nausea
`
`2%
`
`1%
`
`0%
`
`4%
`
`5%
`
`3%
`
`0%
`
`4%
`
`NEUROLOGICAL
`
`10%
`
`11%
`
`Dizziness
`
`Somnolence
`
`Vertigo
`
`OTHER
`
`Asthenia
`
`Sweating
`
`4%
`
`3%
`
`0%
`
`
`
`3%
`
`1%
`
`6%
`
`5%
`
`0%
`
`
`
`5%
`
`0%
`
`3%
`
`2%
`
`0%
`
`9%
`
`17%
`
`8%
`
`6%
`
`0%
`
`
`
`3%
`
`2%
`
`1%
`
`2%
`
`6%
`
`21%
`
`10%
`
`8%
`
`2%
`
`
`
`9%
`
`3%
`
`* Only adverse reactions that were at least 2% more frequent in a ZOMIG group compared to the placebo group are included.
`
`There were no differences in the incidence of adverse reactions in controlled clinical trials in the following subgroups:
`gender, weight, age, use of prophylactic medications, or presence of aura. There were insufficient data to assess the
`impact of race on the incidence of adverse reactions.
`
`
`Less Common Adverse Reactions with ZOMIG Tablets:
`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. Adverse reaction frequencies were
`calculated as the number of patients who used ZOMIG tablets and reported a reaction divided by the total number of
`
`Reference ID: 4367843
`
`

`

`patients exposed to ZOMIG tablets (n=4,027). Reactions were further classified within body system categories and
`enumerated in order of decreasing frequency using the following definitions: infrequent adverse reactions (those occurring
`in 1/100 to 1/1,000 patients) and rare adverse reactions (those occurring in less than 1/1,000 patients).
`
`General: Infrequent were allergic reactions.
`Cardiovascular: Infrequent were arrhythmias, hypertension, and syncope. Rare was tachycardia.
`Neurological: Infrequent were agitation, anxiety, depression, emotional lability and insomnia; Rare were amnesia,
`hallucinations, and cerebral ischemia.
`
`Skin: Infrequent were pruritus, rash and urticaria.
`Urogenital: Infrequent were polyuria, urinary frequency and urinary urgency.
`
`
`Adverse Reactions with ZOMIG-ZMT Orally Disintegrating Tablets
`The adverse reaction profile seen with ZOMIG-ZMT Orally Disintegrating Tablets was similar to that seen with ZOMIG
`tablets.
`
`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.
`
`7 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 and its active N-desmethyl metabolite. Therefore, the
`use of ZOMIG in patients receiving MAO-A inhibitors is contraindicated [see Contraindications (4), Clinical
`Pharmacology (12.3)].
`
`7.3 5-HT1B/1D agonists
`
`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 Selective Serotonin Reuptake Inhibitors and Serotonin Norepinephrine Reuptake Inhibitors
`
`Cases of life-threatening serotonin syndrome have been reported during co-administration of triptans and selective
`serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [see Warnings and
`Precautions (5.7)].
`
`Reference ID: 4367843
`
`

`

`7.5 Cimetidine
`
`Following administration of cimetidine, the half-life and blood levels of zolmitriptan and its active N-desmethyl
`metabolite 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 (2.4), Clinical Pharmacology (12.3)].
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`Risk Summary
`There are no adequate data on the developmental risk associated with the use of ZOMIG in pregnant women. 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 (see Data).
`
`In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically
`
`recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated rates of major birth defects (2.2%-
`2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women
`without migraine.
`
`Clinical Considerations
`
`Disease-Associated Maternal and/or Embryo/Fetal Risk
`
`Published data have suggested that women with migraine may be at increased risk of preeclampsia during
`pregnancy.
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`Data
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`Animal Data
`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 embryofetal 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.
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`8.2 Lactation
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`Risk Summary
`
`There are no data on the presence of zolmitriptan or its metabolites in human milk, the effects on the breastfed infant, or
`the effects of zolmitriptan and its metabolites on milk production. In rats, oral dosing with zolmitriptan resulted in levels
`in milk up to 4 times that in maternal plasma.
`
`The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for
`ZOMIG and any potential adverse effects on the breastfed infant from ZOMIG or from the underlying maternal condition.
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` 8.4 Pediatric Use
`
`The safety and effectiveness in pediatric patients have not been established. Therefore, ZOMIG is not recommended for
`use in patients under 18 years of age.
`
`One randomized, placebo-controlled clinical trial of ZOMIG tablets (2.5, 5 and 10 mg) evaluated 696 pediatric patients
`(aged 12-17 years) with migraines. This study did not demonstrate the efficacy of ZOMIG compared to placebo in the
`
`treatment of migraine in adolescents. Adverse reactions in the adolescent patients treated with ZOMIG were similar in
`nature and frequency to those reported in clinical trials in adults treated with ZOMIG. ZOMIG has not been studied in
`pediatric patients less than 12 years old.
`
`In the postmarketing experience with triptans, including ZOMIG, there were no additional adverse reactions seen in
`pediatric patients that were not seen 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.
`
`A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g.,
`
`diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) 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
`
`After oral ZOMIG 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)]. Therefore, adjust the ZOMIG dose and administer with caution in patients with moderate or severe
`hepatic impairment [see Dosage and Administration (2.3), Clinical Pharmacology (12)].
`
`10 OVERDOSAGE
`
`There is no experience with acute overdose of ZOMIG. Clinical study subjects who received single 50 mg oral doses of
`ZOMIG commonly experienced sedation.
`
`There is no specific antidote to ZOMIG. 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.
`
`The elimination half-life of ZOMIG is 3 hours [see Clinical Pharmacology (12.1)]; therefore, monitor patients after
`overdose with ZOMIG for at least 15 hours or until symptoms or signs resolve. It is unknown what effect hemodialysis or
`peritoneal dialysis has on the plasma concentrations of zolmitriptan.
`
`11 DESCRIPTION
`
`ZOMIG® (zolmitriptan) tablets and ZOMIG-ZMT® (zolmitriptan) Orally Disintegrating Tablets contain zolmitriptan,
`which is a selective 5-hydroxytryptamine1B/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:
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`The empirical formula is C
`
`H
`
`16
`21
`3
`2
`powder that is readily soluble in water.
`
`N
`
`O
`
`, representing a molecular weight of 287.36. Zolmitriptan is a white to almost white
`
`ZOMIG tablets are available as 2.5 mg (yellow and functionally-score) and 5 mg (pink, not scored) film-coated tablets for
`oral administration. The film-coated tablets contain anhydrous lactose NF, microcrystalline cellulose NF, sodium starch
`glycolate NF, magnesium stearate NF, hydroxypropyl methylcellulose USP, titanium dioxide USP, polyethylene glycol
`400 NF, yellow iron oxide NF (2.5 mg tablet), red iron oxide NF (5 mg tablet), and polyethylene glycol 8000 NF.
`
`ZOMIG-ZMT® Orally Disintegrating Tablets are available as 2.5 mg and 5 mg white uncoated tablets. T he orally
`disintegrating tablets contain mannitol USP, microcrystalline cellulose NF, crospovidone NF, aspartame NF [see
`Warnings and Precautions (5.9)], sodium bicarbonate USP, citric acid anhydrous USP, colloidal silicon dioxide NF,
`magnesium stearate NF and orange flavor SN 027512.
`
`12 CLINICAL PHARMACOLOGY
`
`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.
`
`Migraines are likely due to local cranial vasodilatation and/or to the release of sensory neuropeptides (vasoactive
`intestinal peptide, substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system. The
`therapeutic activity of ZOMIG for the treatment of migraine headache is thought to be due to the agonist effects at the
`5-HT1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the
`trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.
`
`12.3 Pharmacokinetics
`
`Absorption, Distribution, Metabolism, and Excretion
`
`Absorption
`
`Zolmitriptan is well absorbed after oral administration for both ZOMIG tablets and the ZOMIG-