Zolmitriptan

Tablet, Film Coated · Oral, Nasal

Prescription (Rx) Serotonin-1b and Serotonin-1d Receptor Agonist

Uses

1 INDICATIONS 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)

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) 2.1 Dosing Information The recommended starting dose for ZOLMITRIPTAN NASAL SPRAY in adult and pediatric patients 12 years of age and older is 2.5 mg. As the individual response to ZOLMITRIPTAN NASAL SPRAY may vary, the dose should be adjusted on an individual basis. The maximum recommended single dose of ZOLMITRIPTAN NASAL SPRAY is 5 mg. If the migraine has not resolved by 2 hours after taking ZOLMITRIPTAN NASAL SPRAY, 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 ZOLMITRIPTAN NASAL SPRAY in the treatment of an average of more than four headaches in a 30-day period has not been established. 2.2 Dosing in Patients with Hepatic Impairment ZOLMITRIPTAN 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 ZOLMITRIPTAN 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 ZOLMITRIPTAN NASAL SPRAY is co-administered with cimetidine, limit the maximum single dose of ZOLMITRIPTAN NASAL SPRAY 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. Nasal Spray: 2.5 mg and 5 mg (3)

Contraindications

Zolmitriptan 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-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 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 zolmitriptan (angioedema and anaphylaxis seen) [see Adverse Reactions (6.2) ] 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) Ischemic bowel disease (4) Uncontrolled hypertension (4) Recent (within 24 hours) use of another 5-HT 1 agonist (e.g., another triptan) or of an ergot-type medication (4) MAO-A inhibitor used in past 2 weeks (4) Hypersensitivity to zolmitriptan (4)

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) Gastrointestinal ischemic events, peripheral vasospastic reactions: 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) 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina Zolmitriptan 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 zolmitriptan. Some of these reactions occurred in patients without known CAD. 5-HT 1 agonists including zolmitriptan 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. Do not administer zolmitriptan 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 zolmitriptan dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following zolmitriptan administration. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of zolmitriptan. 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 if these disturbances occur. Patients with Wolff-Parkinson-White Syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders should not receive zolmitriptan [see Contraindications (4) ] . 5.3 Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure As with other 5-HT 1 agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with zolmitriptan 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-HT 1 agonists [see Contraindications (4) ] . 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. Discontinue zolmitriptan 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. Zolmitriptan should not be administered to patients with a history of stroke or transient ischemic attack [see Contraindications (4) ] . 5.5 Other Vasospasm Reactions 5-HT 1 agonists, including zolmitriptan, 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-HT 1 agonist, the suspected vasospasm reaction should be ruled out before receiving additional zolmitriptan doses [see Contraindications (4) ] . 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, 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).

Side effects

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, Throat, Neck and/or 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) ] The most common adverse reactions (≥ 5% and > placebo) were: Adults: unusual taste, paresthesia, dizziness, and hyperesthesia (6.1) Pediatrics: unusual taste (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 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. Adults 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 zolmitriptan nasal spray. The most common adverse reactions (≥ 5% and > placebo) in any dosage strength in clinical trials for zolmitriptan 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 in a Placebo-Controlled Study in Adult Patients with Migraine (Study 1) Body System Adverse Reaction Placebo (N=228) Zolmitriptan 2.5 mg (N=224) Zolmitriptan 5 mg (N=236) Atypical Sensations Hyperesthesia 0% 1% 5% Paraesthesia 6% 5% 10% Warm Sensation 2% 4% 0% Ear/Nose/Throat Disorder/Discomfort of nasal cavity 2% 1% 3% Pain and Pressure Sensations Pain Location Specified 1% 2% 4% Throat Pain 1% 4% 4% Throat Tightness 1% <1% 2% Digestive Dry Mouth <1% 3% 2% Nausea 1% 1% 4% Neurological Dizziness 4% 6% 3% Somnolence 2% 1% 4% Other Unusual Taste 3% 17% 21% Asthenia 1% 3% 3% In Study 1, adverse 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: abdominal pain, chills, throat pressure, facial edema, chest pressure, 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. Local Adverse Reactions: Among 460 patients using zolmitriptan 2.5 mg or 5 mg 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 zolmitriptan nasal spray. All nasopharyngeal adverse reactions with an incidence of ≥ 2% of patients in any zolmitriptan nasal spray dose groups are included in 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 zolmitriptan 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 zolmitriptan nasal spray and reported a reaction divided by the total number of patients exposed to zolmitriptan 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.

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) 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 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 zolmitriptan in patients receiving MAO-A inhibitors is contraindicated [see Contraindications (4) and Clinical Pharmacology (12.3) ] . 7.3 5-HT 1B/1D agonists (e.g. triptans) Concomitant use of other 5-HT 1B/1D agonists (including triptans) within 24 hours of zolmitriptan 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 zolmitriptan and its active metabolites were approximately doubled [see Clinical Pharmacology (12.3) ] . If cimetidine and zolmitriptan are used concomitantly, limit the maximum single dose of zolmitriptan 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) ] . 7.5 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

Pregnancy: Based on animal data, may cause fetal harm (8.1) 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of zolmitriptan 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. 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. Data 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 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. 8.2 Lactation 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 zolmitriptan and any potential adverse effects on the breastfed infant from zolmitriptan or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness of zolmitriptan in pediatric patients under 12 years of age have not been established. The efficacy of zolmitriptan nasal spray in the acute treatment of migraine in pediatric patients 12 to 17 years of age was established in a placebo-controlled study with a total of 81 pediatric patients receiving zolmitriptan 2.5 mg and 229 pediatric patients receiving zolmitriptan 5 mg [see Clinical Studies (14.2) ] . In an earlier study with a different design, zolmitriptan 5 mg nasal spray was evaluated in the acute treatment of migraine headache in 171 pediatric patients 12 to 17 years of age. In that study, the efficacy of zolmitriptan nasal spray was not established. The safety of zolmitriptan nasal spray in the acute treatment of migraine in pediatric patients 12 to 17 years of age was established in two placebo-controlled studies with a total of 81 pediatric patients receiving zolmitriptan 2.5 mg and 431 pediatric patients receiving zolmitriptan 5 mg [see Adverse Reactions (6.1) ] . The safety profile of zolmitriptan nasal spray in pediatric patients 12 to 17 years of age is similar to the profile observed in adults [see Adverse Reactions (6.1) ] . In the postmarketing experience with triptans, including zolmitriptan, there are 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 zolmitriptan 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 zolmitriptan [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 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) ] . Zolmitriptan nasal spray is not recommended in patients with moderate to severe hepatic impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ] .

Pregnancy

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of zolmitriptan 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. 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. Data 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 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.

Pediatric use

8.4 Pediatric Use Safety and effectiveness of zolmitriptan in pediatric patients under 12 years of age have not been established. The efficacy of zolmitriptan nasal spray in the acute treatment of migraine in pediatric patients 12 to 17 years of age was established in a placebo-controlled study with a total of 81 pediatric patients receiving zolmitriptan 2.5 mg and 229 pediatric patients receiving zolmitriptan 5 mg [see Clinical Studies (14.2) ] . In an earlier study with a different design, zolmitriptan 5 mg nasal spray was evaluated in the acute treatment of migraine headache in 171 pediatric patients 12 to 17 years of age. In that study, the efficacy of zolmitriptan nasal spray was not established. The safety of zolmitriptan nasal spray in the acute treatment of migraine in pediatric patients 12 to 17 years of age was established in two placebo-controlled studies with a total of 81 pediatric patients receiving zolmitriptan 2.5 mg and 431 pediatric patients receiving zolmitriptan 5 mg [see Adverse Reactions (6.1) ] . The safety profile of zolmitriptan nasal spray in pediatric patients 12 to 17 years of age is similar to the profile observed in adults [see Adverse Reactions (6.1) ] . In the postmarketing experience with triptans, including zolmitriptan, there are 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.

Geriatric use

8.5 Geriatric Use Clinical studies of zolmitriptan 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 zolmitriptan [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) ] .

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 zolmitriptan is 3 hours [see Clinical Pharmacology (12.1) ] and therefore monitoring of patients after overdose with zolmitriptan should continue for at least 15 hours or while symptoms or signs persist. 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

11 DESCRIPTION ZOLMITRIPTAN NASAL SPRAY contains zolmitriptan, 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 empirical formula is C 16 H 21 N 3 O 2 , representing a molecular weight of 287.36. Zolmitriptan is a white to almost white powder that is readily soluble in water. ZOLMITRIPTAN NASAL SPRAY is supplied as a clear to pale yellow solution of zolmitriptan, buffered to a pH 5.0. Each ZOLMITRIPTAN 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. ZOLMITRIPTAN NASAL SPRAY is hypertonic. The osmolarity of ZOLMITRIPTAN NASAL SPRAY for 2.5 mg is 360 to 420 mOsmol, and for 5 mg is 420 to 470 mOsmol. Chemical Structure

Mechanism of action

12.1 Mechanism of Action Zolmitriptan binds with high affinity to human recombinant 5-HT 1D and 5-HT 1B receptors, and moderate affinity for 5-HT 1A receptors. The N-desmethyl metabolite also has high affinity for 5-HT 1B/1D and moderate affinity for 5-HT1A receptors. Current theories proposed to explain the etiology of migraine headache suggest that symptoms are 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 zolmitriptan for the treatment of migraine headache is thought to be due to the agonist effects at the 5-HT 1B/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.

How supplied

The ZOLMITRIPTAN NASAL SPRAY device is a blue-colored plastic device with a gray protection cap, labeled to indicate the nominal dose. Each ZOLMITRIPTAN NASAL SPRAY device administers a single dose of ZOLMITRIPTAN NASAL SPRAY. ZOLMITRIPTAN NASAL SPRAY is supplied as a clear to pale yellow solution of zolmitriptan, buffered to a pH 5.0. Each ZOLMITRIPTAN NASAL SPRAY device 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. 2.5 mg ZOLMITRIPTAN NASAL SPRAY is supplied in boxes of 6 single-use nasal spray units. (NDC 69238-2351-6) 5 mg ZOLMITRIPTAN NASAL SPRAY is supplied in boxes of 6 single-use nasal spray units. (NDC 69238-2352-6) Each ZOLMITRIPTAN NASAL SPRAY single dose unit spray supplies 2.5 and 5 mg, respectively, of zolmitriptan. The ZOLMITRIPTAN NASAL SPRAY unit must be discarded after use. Store at controlled room temperature, 20-25°C (68-77°F) [see USP].

Patient information

Advise the patient to read the FDA-approved patient labeling ( Patient Information ). Risk of Myocardial Ischemia and/or Infarction, Prinzmetal's angina, Other Vasospasm-related Events, and Cerebrovascular Events Inform patients that zolmitriptan may cause serious cardiovascular side effects such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms [see Warnings and Precautions (5.1 , 5.2 , 5.4 , 5.5) ] . Medication Overuse Headache Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [see Warnings and Precautions (5.6) ] . Serotonin Syndrome Inform patients about the risk of serotonin syndrome with the use of zolmitriptan or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.7) ] . Pregnancy Advise patients to notify their healthcare provider if they are pregnant or plan to become pregnant. Lactation Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations (8.2) ] . Handling of zolmitriptan nasal spray device The zolmitriptan nasal spray device is packaged in a carton and is a blue-colored plastic device with a gray protection cap, labeled to indicate the nominal dose. Caution patients to not remove the gray protection cap until prior to dosing. The zolmitriptan nasal spray device is placed in a nostril and actuated to deliver a single dose. Caution patients to avoid spraying the contents of the device in their eyes.

Label text from the FDA structured product label by Amneal Pharmaceuticals NY LLC (revised Apr 30, 2019). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Zolmitriptan in 38 products

Zolmitriptan NDC products (38)

NDC	Strength & form	Labeler	Type
27241-021	Zolmitriptan 2.5 mg/1 Tablet	Ajanta Pharma USA Inc.	ANDA
27241-022	Zolmitriptan 5 mg/1 Tablet	Ajanta Pharma USA Inc.	ANDA
62332-181	Zolmitriptan 2.5 mg/1 Tablet, Orally Disintegrating	Alembic Pharmaceuticals Inc.	ANDA
62332-182	Zolmitriptan 5 mg/1 Tablet, Orally Disintegrating	Alembic Pharmaceuticals Inc.	ANDA
62332-462	Zolmitriptan 2.5 mg/1 Tablet, Film Coated	Alembic Pharmaceuticals Inc.	ANDA
62332-463	Zolmitriptan 5 mg/1 Tablet, Film Coated	Alembic Pharmaceuticals Inc.	ANDA
46708-181	Zolmitriptan 2.5 mg/1 Tablet, Orally Disintegrating	Alembic Pharmaceuticals Limited	ANDA
46708-182	Zolmitriptan 5 mg/1 Tablet, Orally Disintegrating	Alembic Pharmaceuticals Limited	ANDA
46708-462	Zolmitriptan 2.5 mg/1 Tablet, Film Coated	Alembic Pharmaceuticals Limited	ANDA
46708-463	Zolmitriptan 5 mg/1 Tablet, Film Coated	Alembic Pharmaceuticals Limited	ANDA
76420-337	Zolmitriptan 5 mg/1 Tablet	Asclemed USA, Inc.	ANDA
76420-336	Zolmitriptan 2.5 mg/1 Tablet	Asclemed USA, Inc.	ANDA
65862-915	Zolmitriptan 5 mg/1 Tablet, Film Coated	Aurobindo Pharma Limited	ANDA
65862-914	Zolmitriptan 2.5 mg/1 Tablet, Film Coated	Aurobindo Pharma Limited	ANDA
68001-250	Zolmitriptan 5 mg/1 Tablet, Film Coated	BluePoint Laboratories	ANDA
68001-249	Zolmitriptan 2.5 mg/1 Tablet, Film Coated	BluePoint Laboratories	ANDA
63629-9575	Zolmitriptan 5 mg/1 Spray	Bryant Ranch Prepack	ANDA
72162-1425	Zolmitriptan 5 mg/1 Spray	Bryant Ranch Prepack	ANDA
71335-2947	Zolmitriptan 5 mg/1 Spray	Bryant Ranch Prepack	ANDA
69097-863	Zolmitriptan 2.5 mg/1 Tablet, Film Coated	Cipla USA Inc.	ANDA
69097-864	Zolmitriptan 5 mg/1 Tablet, Film Coated	Cipla USA Inc.	ANDA
72189-435	Zolmitriptan 5 mg/1 Tablet	Direct_Rx	ANDA
72189-434	Zolmitriptan 2.5 mg/1 Tablet	Direct_Rx	ANDA
68462-497	Zolmitriptan 2.5 mg/1 Tablet, Film Coated	Glenmark Pharmaceuticals Inc.,USA	ANDA
68462-498	Zolmitriptan 5 mg/1 Tablet, Film Coated	Glenmark Pharmaceuticals Inc.,USA	ANDA
71626-101	Zolmitriptan 2.5 mg/1 Tablet, Film Coated	Medstone Pharma LLC	ANDA
71626-102	Zolmitriptan 5 mg/1 Tablet, Film Coated	Medstone Pharma LLC	ANDA
45802-711	Zolmitriptan 5 mg/1 Spray	Padagis Israel Pharmaceuticals Ltd	ANDA
63548-0102	Zolmitriptan 5 mg/1 Tablet, Film Coated	PLD Acquisitions LLC DBA Avma Pharma Solutions	ANDA
63548-0101	Zolmitriptan 2.5 mg/1 Tablet, Film Coated	PLD Acquisitions LLC DBA Avma Pharma Solutions	ANDA
16571-803	Zolmitriptan 2.5 mg/1 Tablet, Film Coated	Rising Pharma Holdings, Inc.	ANDA
16571-804	Zolmitriptan 5 mg/1 Tablet, Film Coated	Rising Pharma Holdings, Inc.	ANDA
65841-768	Zolmitriptan 5 mg/1 Tablet, Orally Disintegrating	Zydus Lifesciences Limited	ANDA
65841-767	Zolmitriptan 2.5 mg/1 Tablet, Orally Disintegrating	Zydus Lifesciences Limited	ANDA
68382-715	Zolmitriptan 2.5 mg/1 Tablet, Orally Disintegrating	Zydus Pharmaceuticals USA Inc.	ANDA
68382-717	Zolmitriptan 5 mg/1 Tablet, Orally Disintegrating	Zydus Pharmaceuticals USA Inc.	ANDA
69238-2352	Zolmitriptan 5 mg/1 Spray, Metered	Amneal Pharmaceuticals NY LLC	NDA AUTHORIZED GENERIC
69238-2351	Zolmitriptan 2.5 mg/1 Spray, Metered	Amneal Pharmaceuticals NY LLC	NDA AUTHORIZED GENERIC

Frequently asked questions

What is Zolmitriptan used for?

What are the side effects of Zolmitriptan?

Who makes Zolmitriptan?

Zolmitriptan is listed by 17 labelers in the FDA NDC directory, including Ajanta Pharma USA Inc., Alembic Pharmaceuticals Inc., Alembic Pharmaceuticals Limited, Asclemed USA, Inc..