Included as part of the PRECAUTIONS section.

Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events

Cardiac Events and Fatalities with 5-HT₁ Agonists

Serious adverse cardiac events, including acute myocardial infarction, have been reported within a few hours following administration of zolmitriptan. Life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of other 5-HT₁ agonists. Considering the extent of use of 5-HT₁ agonists in patients with migraine, the incidence of these events is extremely low.

ZOMIG (zolmitriptan nasal spray) can cause coronary artery vasospasm; at least one of these events occurred in a patient with no cardiac disease history and with documented absence of coronary artery disease. Because of the close proximity of the events to ZOMIG (zolmitriptan nasal spray) use, a causal relationship cannot be excluded. In the cases where there has been known underlying coronary artery disease, the relationship is uncertain. Patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of CAD or a predisposition to Prinzmetal's variant angina before receiving additional doses of medication, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur.

Patients with symptomatic Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders should not receive ZOMIG.

Premarketing experience with zolmitriptan

Among the more than 2,500 patients with migraine who participated in premarketing controlled clinical trials of ZOMIG (zolmitriptan nasal spray) Tablets, no deaths or serious cardiac events were reported. In a premar-keting controlled clinical trial of ZOMIG (zolmitriptan nasal spray) Nasal Spray, more than 1,300 patients participated and there were no deaths or serious cardiac events to report.

Postmarketing experience with zolmitriptan

Serious cardiovascular events have been reported in association with the use of ZOMIG (zolmitriptan nasal spray) Tablets, and in very rare cases, these events have occurred in the absence of known cardiovascular disease. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively the proportion of the reported cases that were actually caused by zolmitriptan or to reliably assess causation in individual cases.

Patients with documented coronary artery disease

Because of the potential of this class of compound (5-HT₁ agonists) to cause coronary vasospasm, ZOMIG (zolmitriptan nasal spray) should not be given to patients with documented ischemic or vasospastic coronary artery disease [see CONTRAINDICATIONS].

Patients with risk factors for CAD

It is strongly recommended that zolmitriptan not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of risk factors (eg, hypertension, hyper-cholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient's medical history, electrocardiographic or other investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, zolmitriptan should not be administered [see CONTRAINDICATIONS].

For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of zolmitriptan take place in the setting of a physician's office or similar medically staffed and equipped facility unless the patient has previously received zolmitriptan. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following ZOMIG (zolmitriptan nasal spray) , in these patients with risk factors.

It is recommended that patients who are intermittent long-term users of ZOMIG (zolmitriptan nasal spray) and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use ZOMIG (zolmitriptan nasal spray) .

The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to zolmitriptan.

Sensations of pain, tightness, pressure in the chest and or throat, neck, and jaw

As with other 5-HT₁ agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw have been reported after treatment with ZOMIG (zolmitriptan nasal spray) Tablets.

Because 5-HT₁ agonists may cause coronary vasospasm, patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of CAD or a predisposition to Prinzmetal's variant angina before receiving additional doses of medication, and should be monitored electrocardiographically if dosing is resumed and similar symptoms occur. Patients shown to have CAD and those with Prinzmetal's variant angina should not receive 5-HT₁ agonists [see CONTRAINDICATIONS].

Cerebrovascular Events

Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported 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 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 atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (eg, stroke, hemorrhage, transient ischemic attack) [see CONTRAINDICATIONS].

Other Vasospasm-Related Events, including Peripheral Vascular Ischemia and Colonic Ischemia

5-HT₁ agonists, including ZOMIG (zolmitriptan nasal spray) , may cause vasospastic reactions other than coronary artery vasospasm, such as peripheral and gastrointestinal vascular ischemia with abdominal pain and bloody diarrhea.

Very rare reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT₁ agonists. Visual disorders may also be part of a migraine attack. Patients who experience other symptoms or signs suggestive of decreased arterial flow following the use of any 5-HT agonist, such as ischemic bowel syndrome or Raynaud's syndrome, are candidates for further evaluation [see CONTRAINDICATIONS].

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome may occur with triptans, including ZOMIG (zolmitriptan nasal spray) treatment, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with ZOMIG (zolmitriptan nasal spray) and an SSRI (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. 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) [see DRUG INTERACTIONS].

Increase in Blood Pressure

As with other 5-HT₁ agonists, significant elevations in systemic blood pressure have been reported on rare occasions with ZOMIG (zolmitriptan nasal spray) Tablet use, in patients with and without a history of hypertension; very rarely these increases in blood pressure have been associated with significant clinical events. Zolmitriptan is contraindicated in patients with uncontrolled hypertension. In volunteers, an increase of 1 and 5 mm Hg in the systolic and diastolic blood pressure, respectively, was seen at 5 mg. In the headache trials, vital signs were measured only in the small inpatient study and no effect on blood pressure was seen. In a study of patients with moderate to severe liver disease, 7 of 27 experienced 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a dose of 10 mg of zolmitriptan [see CONTRAINDICATIONS].

An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5-HT₁ agonist in a study evaluating subjects undergoing cardiac catheterization.

Binding to Melanin-Containing Tissues

When pigmented rats were given a single oral dose of 10 mg/kg of radiolabeled zolmitriptan, the radioactivity in the eye after 7 days, the latest time point examined, was still 75% of the value measured after 4 hours. This suggests that zolmitriptan and/or its metabolites may bind to the melanin of the eye. Because there could be accumulation in melanin rich tissues over time, this raises the possibility that zolmitriptan could cause toxicity in these tissues after extended use. However, no effects on the retina related to treatment with zolmitriptan were noted in any of the toxicity studies including those conducted by the nasal route. Although no systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic monitoring are offered, prescribers should be aware of the possibility of long-term ophthalmologic effects.

Laboratory Tests

No monitoring of specific laboratory tests is recommended.

Drug/Laboratory Test Interactions

Zolmitriptan is not known to interfere with commonly employed clinical laboratory tests.

Patient Counseling Information

See FDA-Approved Patient Labeling

Risk of Myocardial Ischemia and/or Infarction, Other Adverse Cardiac Events, Other Vasospasm-related Event, and Cerebrovascular Events

Patients should be informed that ZOMIG (zolmitriptan nasal spray) 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. Patients should be apprised of the importance of this follow-up [see WARNINGS AND PRECAUTIONS].

Serotonin Syndrome

Patients should be cautioned about the risk of serotonin syndrome with the use of ZOMIG (zolmitriptan nasal spray) or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [see WARNINGS AND PRECAUTIONS].

Device Use

The ZOMIG (zolmitriptan nasal spray) 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. Patients should be cautioned to not remove the gray protection cap until prior to dosing. The ZOMIG (zolmitriptan nasal spray) Nasal Spray device is placed in a nostril and actuated to deliver a single dose. Patients should be cautioned to avoid spraying the contents of the device in their eyes.

Pregnancy

ZOMIG (zolmitriptan nasal spray) should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

Nonclinical Toxicology

Carcinogenesis

Zolmitriptan was administered to mice and rats at doses up to 400 mg/kg/day. Mice were dosed for 85 weeks (males) and 92 weeks (females); rats were dosed for 101 weeks (males) and 86 weeks (females). There was no evidence of drug-induced tumors in mice at plasma exposures (AUC) up to approximately 700 times that in humans at the maximum recommended human dose (MRHD) of 10 mg/day. In rats, there was an increase in the incidence of thyroid follicular cell hyperplasia and thyroid follicular cell adenomas seen in male rats receiving 400 mg/kg/day. The no-effect dose for tumors in rats (100 mg/kg/day) was associated with a plasma AUC ≈700 times that in humans at the MRHD.

Mutagenesis

Zolmitriptan was positive in an in vitro bacterial reverse mutation (Ames) assay and in an in vitro chromosomal aberration assay in human lymphocytes. Zolmitriptan was negative in an in vitro mammalian gene cell mutation (CHO/HGPRT) assay and in oral in vivo micronucleus assays in mouse and rat.

Impairment of Fertility

Studies of male and female rats administered zolmitriptan prior to and during mating and up to implantation showed no impairment of fertility at oral doses up to 400 mg/kg/day. The plasma exposure (AUC) at this dose was approximately 3000 times that in humans at the maximum recommended human dose of 10 mg/day.

Use Inspecific Populations

Pregnancy

Pregnancy Category C. There are no adequate and well controlled studies in pregnant women; therefore, zolmitriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In reproductive toxicity studies in rats and rabbits, oral administration of zolmitriptan to pregnant animals resulted in embryolethality and fetal abnormalities (malformations and variations) at clinically relevant exposures.

When zolmitriptan was administered to pregnant rats during the period of organogenesis at oral doses of 100, 400, and 1200 mg/kg/day (plasma exposures (AUCs) ≈280, 1100, and 5000 times the human AUC at the maximum recommended human dose (MRHD) of 10 mg/day), there was a dose-related increase in embryolethality. A no-effect dose for embryolethality was not established. When zolmitriptan was administered to pregnant rabbits during the period of organogenesis at oral doses of 3, 10, and 30 mg/kg/day (plasma AUCs ≈1, 11, and 42 times the human AUC at the MRHD), there were increases in embryolethality and in fetal malformations and variations. The no-effect dose for adverse effects on embryo-fetal development was associated with a plasma AUC similar to that in humans at the MRHD. When female rats were given zolmitriptan during gestation, parturition, and lactation at oral doses of 25, 100, and 400 mg/kg/day (plasma AUCs ≈70, 280, and 1100 times that in humans 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.

Nursing Mothers

It is not known whether zolmitriptan is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when zolmitriptan is administered to a nursing woman. Lactating rats dosed with zolmitriptan had levels in milk equivalent to maternal plasma levels at 1 hour and 4 times higher than plasma levels at 4 hours.

Pediatric Use

Safety and effectiveness of ZOMIG (zolmitriptan nasal spray) in pediatric patients have not been established; therefore, ZOMIG (zolmitriptan nasal spray) is not recommended for use in patients under 18 years of age.

A single, multicenter, double-blind, randomized placebo-controlled study was conducted to evaluate the efficacy of zolmitriptan 5 mg nasal spray in the acute treatment of migraine headache in 171 evaluable adolescent subjects 12 to 17 years of age. Efficacy was not established in that study.

Adverse reactions observed in this study were similar in nature and frequency to those reported in ZOMIG (zolmitriptan nasal spray) Nasal Spray adult clinical trials. The most commonly reported adverse reactions (≥ 2% and > placebo) were dysgeusia (7%), nasal discomfort (3%), dizziness (2%), nasal congestion (2%), nausea (2%), and throat irritation (2%).

ZOMIG (zolmitriptan nasal spray) Nasal Spray has not been studied in pediatric patients under 12 years of age.

In the postmarketing experience with triptans, including ZOMIG (zolmitriptan nasal spray) , there is a limited number of reports that describe pediatric patients who have experienced clinically serious adverse events; those that were reported are similar in nature to those reported rarely in adults.

Geriatric Use

Although the pharmacokinetic disposition of the drug in the elderly is similar to that seen in younger adults, there is no information about the safety and effectiveness of zolmitriptan in this population because patients over age 65 were excluded from the controlled clinical trials [see CLINICAL PHARMACOLOGY].

Hepatic Impairment

The effect of hepatic disease on the pharmacokinetics of zolmitriptan nasal spray has not been evaluated. After oral administration, zolmitriptan exposure was increased in patients with severe hepatic impairment, and significant elevation in blood pressure was observed in some patients. Because of the similarity in exposure, zolmitriptan tablets and nasal spray should have similar dosage adjustments and should be administered with caution in subjects with liver disease, generally using doses less than 2.5 mg. Doses lower than 5 mg can only be achieved through the use of an oral formulation [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 12/22/2008
This monograph has been modified to include the generic and brand name in many instances.