ZOLMITRIPTAN: 1,622 Adverse Event Reports & Safety Profile

Zolmitriptan orally disintegrating tablets, USP contain zolmitriptan, USP, which is a selective 5-hydroxytryptamine 1B/1D (5-HT 1B/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: The molecular formula is C­ 16 ­H­ 21 ­N ­3 ­O ­­2 ­, representing a molecular weight of 287.36. Zolmitriptan is white to cream colored crystalline powder that is freely soluble in methanol, slightly soluble in ethyl acetate and very slightly soluble in water. Zolmitriptan orally disintegrating tablets, USP are available for oral administration as 2.5 mg and 5 mg, white colored, round shaped, flat faced, beveled edged tablets. Each orally disintegrating tablet contains acesulfame potassium, aminomethacrylate copolymer, colloidal silicon dioxide, crospovidone, low-substituted hydroxypropyl cellulose, magnesium aluminometasilicate, magnesium stearate, mannitol, peppermint flavor, sodium lauryl sulfate, and talc. zolmitriptan structure

AND USAGE ZOLMITRIPTAN NASAL SPRAY is indicated for the acute treatment of migraine with or without aura in adults and pediatric patients 12 years of age and older. Limitations of Use Only use ZOLMITRIPTAN NASAL SPRAY if a clear diagnosis of migraine has been established. If a patient has no response to ZOLMITRIPTAN NASAL SPRAY treatment for the first migraine attack, reconsider the diagnosis of migraine before ZOLMITRIPTAN NASAL SPRAY is administered to treat any subsequent attacks. ZOLMITRIPTAN NASAL SPRAY is not indicated for the prevention of migraine attacks. Safety and effectiveness of ZOLMITRIPTAN NASAL SPRAY have not been established for cluster headache. Not recommended in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.2) ] . ZOLMITRIPTAN 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 and pediatric patients 12 years and older (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)

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) Moderate or Severe Hepatic Impairment: 1.25 mg recommended (2.3 , 8.6)

2.1 Dosing Information The recommended starting dose of zolmitriptan tablets 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 zolmitriptan tablets 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 zolmitriptan tablets, 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 zolmitriptan tablets in the treatment of an average of more than three migraines in a 30-day period has not been established.

2.3 Dosing in Patients with Hepatic Impairment The recommended dose of zolmitriptan tabletsin patients with moderate to severe hepatic impairment is 1.25 mg (one-half of one 2.5 mg zolmitriptan 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.

2.4 Dosing in Patients taking Cimetidine If zolmitriptan tablets are co-administered with cimetidine, limit the maximum single dose of zolmitriptan tablets to 2.5 mg, not to exceed 5 mg in any 24-hour period <span class="opacity-50 text-xs">[see Drug Interactions (7.5) , Clinical Pharmacology (12.3) ]</span> .

2.1 Dosing Information The recommended starting dose of zolmitriptan tablets 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 zolmitriptan tablets 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 zolmitriptan tablets, 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 zolmitriptan tablets in the treatment of an average of more than three migraines in a 30-day period has not been established.

2.3 Dosing in Patients with Hepatic Impairment The recommended dose of zolmitriptan tabletsin patients with moderate to severe hepatic impairment is 1.25 mg (one-half of one 2.5 mg zolmitriptan 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.

2.4 Dosing in Patients taking Cimetidine If zolmitriptan tablets are co-administered with cimetidine, limit the maximum single dose of zolmitriptan tablets to 2.5 mg, not to exceed 5 mg in any 24-hour period <span class="opacity-50 text-xs">[see Drug Interactions (7.5) , Clinical Pharmacology (12.3) ]</span> .

Zolmitriptan orally disintegrating tablets are contraindicated in patients with:

• Ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), other significant underlying cardiovascular disease, or c oronary 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-HT 1 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 ) and Clinical Pharmacology ( 12.3 ) ].
• Known hypersensitivity to zolmitriptan orally disintegrating tablets (angioedema and anaphylaxis seen) [see Adverse Reactions ( 6.2 ) ].
• 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 )
• Ischemic bowel disease ( 4 )
• Uncontrolled hypertension ( 4 )
• Recent (within 24 hours) use of another 5-HT 1 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 zolmitriptan ( 4 )

REACTIONS The following adverse reactions are described elsewhere in other sections of the prescribing information: 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) ] . 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 ADVERSE REACTIONS, contact Avéma Pharma Solutions at 1-877-753-3935 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 &gt; 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 zolmitriptan tablets 1 mg, 2.5 mg, or 5 mg dose groups in the controlled clinical trials of zolmitriptan tablets 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 zolmitriptan tablets 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.

Table

1: Adverse Reaction Incidence in Five Pooled Placebo-Controlled Migraine Clinical Trials * Placebo (n=401)

Zolmitriptan Tablets

1 mg (n=163)

Zolmitriptan Tablets

2.5 mg (n=498)

Zolmitriptan Tablets

5 mg (n=1012) ATYPICAL SENSATIONS 6% 12% 12% 18% Paresthesia (all types) 2% 5% 7% 9% Warm/cold sensation 4% 6% 5% 7% PAIN AND PRESSURE SENSATIONS 7% 13% 14% 22% Chest - pain/tightness/pressure and/or heaviness 1% 2% 3% 4% Neck/throat/jaw - pain/tightness/pressure 3% 4% 7% 10% Heaviness other than chest or neck 1% 1% 2% 5% Other- Pressure/tightness/heaviness 0% 2% 2% 2% DIGESTIVE 8% 11% 16% 14% Dry mouth 2% 5% 3% 3% Dyspepsia 1% 3% 2% 1% Dysphagia 0% 0% 0% 2% Nausea 4% 4% 9% 6% NEUROLOGICAL 10% 11% 17% 21% Dizziness 4% 6% 8% 10% Somnolence 3% 5% 6% 8% Vertigo 0% 0% 0% 2% OTHER Asthenia 3% 5% 3% 9% Sweating 1% 0% 2% 3% * Only adverse reactions that were at least 2% more frequent in a zolmitriptan tablet 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 Zolmitriptan 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 zolmitriptan tablets 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 zolmitriptan tablets and reported a reaction divided by the total number of patients exposed to zolmitriptan 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.

6.2 Postmarketing Experience The following adverse reactions were identified during post approval use of zolmitriptan tablets. 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-HT 1B/1D agonists, there have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving zolmitriptan tablets. Zolmitriptan tablets are contraindicated in patients with a history of hypersensitivity reaction to zolmitriptan.

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 &gt; 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 zolmitriptan tablets 1 mg, 2.5 mg, or 5 mg dose groups in the controlled clinical trials of zolmitriptan tablets 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 zolmitriptan tablets 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.

Table

1: Adverse Reaction Incidence in Five Pooled Placebo-Controlled Migraine Clinical Trials * Placebo (n=401)

Zolmitriptan Tablets

1 mg (n=163)

Zolmitriptan Tablets

2.5 mg (n=498)

Zolmitriptan Tablets

5 mg (n=1012) ATYPICAL SENSATIONS 6% 12% 12% 18% Paresthesia (all types) 2% 5% 7% 9% Warm/cold sensation 4% 6% 5% 7% PAIN AND PRESSURE SENSATIONS 7% 13% 14% 22% Chest - pain/tightness/pressure and/or heaviness 1% 2% 3% 4% Neck/throat/jaw - pain/tightness/pressure 3% 4% 7% 10% Heaviness other than chest or neck 1% 1% 2% 5% Other- Pressure/tightness/heaviness 0% 2% 2% 2% DIGESTIVE 8% 11% 16% 14% Dry mouth 2% 5% 3% 3% Dyspepsia 1% 3% 2% 1% Dysphagia 0% 0% 0% 2% Nausea 4% 4% 9% 6% NEUROLOGICAL 10% 11% 17% 21% Dizziness 4% 6% 8% 10% Somnolence 3% 5% 6% 8% Vertigo 0% 0% 0% 2% OTHER Asthenia 3% 5% 3% 9% Sweating 1% 0% 2% 3% * Only adverse reactions that were at least 2% more frequent in a zolmitriptan tablet 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 Zolmitriptan 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 zolmitriptan tablets 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 zolmitriptan tablets and reported a reaction divided by the total number of patients exposed to zolmitriptan 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.

6.2 Postmarketing Experience The following adverse reactions were identified during post approval use of zolmitriptan tablets. 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-HT 1B/1D agonists, there have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving zolmitriptan tablets. Zolmitriptan tablets are contraindicated in patients with a history of hypersensitivity reaction to zolmitriptan.

AND PRECAUTIONS Myocardial Ischemia/Infarction, and Prinzmetal’s Angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors (5.1) Arrhythmias: Discontinue zolmitriptan tablets 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 Stroke: Discontinue zolmitriptan tablets if occurs (5.4)

Gastrointestinal Ischemic

Reactions and Peripheral Vasospastic Reactions: Discontinue zolmitriptan tablets if occurs (5.5)

Medication Overuse

Headache: Detoxification may be necessary (5.6)

Serotonin

Syndrome: Discontinue zolmitriptan tablets if occurs (5.7 , 7.4)

5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina Zolmitriptan tablets are 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 zolmitriptan tablets. Some of these reactions occurred in patients without known CAD. 5-HT 1 agonists including zolmitriptan tablets 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 zolmitriptan tablets. Do not administer zolmitriptan tablets if there is evidence of CAD or coronary artery vasospasm <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first zolmitriptan tablets dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following zolmitriptan tablets administration. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of zolmitriptan tablets.

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-HT 1 agonists. Discontinue zolmitriptan tablets if these disturbances occur. Zolmitriptan tablets are contraindicated in patients with Wolff-Parkinson-White Syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.3 Chest, Throat, Neck and Jaw Pain/Tightness/Pressure As with other 5-HT 1 agonists, sensations of tightness, pain, and pressure in the chest, throat, neck, and jaw commonly occur after treatment with zolmitriptan tablets and is usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. 5-HT 1 agonists including zolmitriptan tablets are contraindicated in patients with CAD or Prinzmetal’s variant angina <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT 1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT 1 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. Zolmitriptan tablets are contraindicated in patients with a history of stroke or transient ischemic attack <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.5 Other Vasospasm Reactions 5-HT 1 agonists, including zolmitriptan tablets, 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-HT 1 agonist, rule out a vasospastic reaction before receiving additional zolmitriptan tablets doses <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT 1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT 1 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 zolmitriptan tablets, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors <span class="opacity-50 text-xs">[see Drug Interactions (7.5) ]</span> . 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. Discontinue zolmitriptan tablets if serotonin syndrome is suspected <span class="opacity-50 text-xs">[see Drug Interactions (7.4) ]</span> .

5.8 Increase in Blood Pressure Significant elevations in systemic blood pressure have been reported in patients treated with 5-HT 1 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 zolmitriptan tablets, 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 zolmitriptan tablets. As with all triptans, blood pressure should be monitored in zolmitriptan tablets-treated patients. Zolmitriptan tablets are contraindicated in patients with uncontrolled hypertension <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina Zolmitriptan tablets are 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 zolmitriptan tablets. Some of these reactions occurred in patients without known CAD. 5-HT 1 agonists including zolmitriptan tablets 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 zolmitriptan tablets. Do not administer zolmitriptan tablets if there is evidence of CAD or coronary artery vasospasm <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first zolmitriptan tablets dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following zolmitriptan tablets administration. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of zolmitriptan tablets.

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-HT 1 agonists. Discontinue zolmitriptan tablets if these disturbances occur. Zolmitriptan tablets are contraindicated in patients with Wolff-Parkinson-White Syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.3 Chest, Throat, Neck and Jaw Pain/Tightness/Pressure As with other 5-HT 1 agonists, sensations of tightness, pain, and pressure in the chest, throat, neck, and jaw commonly occur after treatment with zolmitriptan tablets and is usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. 5-HT 1 agonists including zolmitriptan tablets are contraindicated in patients with CAD or Prinzmetal’s variant angina <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT 1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT 1 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. Zolmitriptan tablets are contraindicated in patients with a history of stroke or transient ischemic attack <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.5 Other Vasospasm Reactions 5-HT 1 agonists, including zolmitriptan tablets, 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-HT 1 agonist, rule out a vasospastic reaction before receiving additional zolmitriptan tablets doses <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT 1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT 1 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 zolmitriptan tablets, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors <span class="opacity-50 text-xs">[see Drug Interactions (7.5) ]</span> . 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. Discontinue zolmitriptan tablets if serotonin syndrome is suspected <span class="opacity-50 text-xs">[see Drug Interactions (7.4) ]</span> .

5.8 Increase in Blood Pressure Significant elevations in systemic blood pressure have been reported in patients treated with 5-HT 1 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 zolmitriptan tablets, 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 zolmitriptan tablets. As with all triptans, blood pressure should be monitored in zolmitriptan tablets-treated patients. Zolmitriptan tablets are contraindicated in patients with uncontrolled hypertension <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

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 zolmitriptan tablets within 24 hours of each other is contraindicated <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

7.2 MAO-A Inhibitors MAO-A inhibitors increase the systemic exposure of zolmitriptan and its active N-desmethyl metabolite. Therefore, the use of zolmitriptan tablets in patients receiving MAO-A inhibitors is contraindicated <span class="opacity-50 text-xs">[see Contraindications (4) , Clinical Pharmacology (12.3) ]</span> . 7.3 5-HT1B/1D agonists Concomitant use of other 5-HT 1B/1D agonists (including triptans) within 24 hours of zolmitriptan tablets treatment is contraindicated because the risk of vasospastic reactions may be additive <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

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) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) ]</span> .

7.5 Cimetidine Following administration of cimetidine, the half-life and blood levels of zolmitriptan and its active N-desmethyl metabolite were approximately doubled <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . If cimetidine and zolmitriptan tablets are used concomitantly, limit the maximum single dose of zolmitriptan tablets to 2.5 mg, not to exceed 5 mg in any 24-hour period <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ]</span> .

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 zolmitriptan tablets within 24 hours of each other is contraindicated <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

7.2 MAO-A Inhibitors MAO-A inhibitors increase the systemic exposure of zolmitriptan and its active N-desmethyl metabolite. Therefore, the use of zolmitriptan tablets in patients receiving MAO-A inhibitors is contraindicated <span class="opacity-50 text-xs">[see Contraindications (4) , Clinical Pharmacology (12.3) ]</span> .

7.3 5-HT1B/1D agonists Concomitant use of other 5-HT 1B/1D agonists (including triptans) within 24 hours of zolmitriptan tablets 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) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) ]</span> .

7.5 Cimetidine Following administration of cimetidine, the half-life and blood levels of zolmitriptan and its active N-desmethyl metabolite were approximately doubled <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . If cimetidine and zolmitriptan tablets are used concomitantly, limit the maximum single dose of zolmitriptan tablets to 2.5 mg, not to exceed 5 mg in any 24-hour period <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ]</span> .