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Zomig (Zolmitriptan) - Warnings and Precautions

 
 



WARNINGS

Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events: ZOMIG should not be given to patients with documented ischemic or vasospastic coronary artery disease (see CONTRAINDICATIONS). 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 (e.g., hypertension, hypercholesterolemia, 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, in these patients with risk factors.

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

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

Cardiac Events and Fatalities:

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 can cause coronary 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 use, a causal relationship cannot be excluded. In the cases where there has been known underlying coronary artery disease, the relationship is uncertain.

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 Tablets, no deaths or serious cardiac events were reported.

Postmarketing experience with zolmitriptan:

Serious cardiovascular events have been reported in association with the use of ZOMIG 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.

Cerebrovascular Events and Fatalities with 5-HT agonists:

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. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack). (See CONTRAINDICATIONS.)

Serotonin Syndrome:

The development of a potentially life-threatening serotonin syndrome may occur with triptans, including ZOMIG treatment, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with ZOMIG 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 PRECAUTIONS, Drug Interactions).

Other Vasospasm-Related Events:

5-HT1 agonists may cause vasospastic reactions other than coronary artery vasospasm such as peripheral and gastrointestinal vascular ischemia. As with other serotonin 5HT1 agonists, very rare gastrointestinal ischemic events including ischemic colitis and gastrointestinal infarction or necrosis have been reported with ZOMIG Tablets; these may present as bloody diarrhea or abdominal pain. (See CONTRAINDICATIONS.)

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.

Increase in Blood Pressure:

As with other 5-HT1 agonists, significant elevations in systemic blood pressure have been reported on rare occasions with ZOMIG 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.

PRECAUTIONS

General:

As with other 5-HT1B/1D agonists, sensations of tightness, pain, pressure, and heaviness have been reported after treatment with ZOMIG Tablets in the precordium, throat, neck, and jaw. Because zolmitriptan may cause coronary artery 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 recur. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud’s syndrome following the use of any 5-HT1 agonist are candidates for further evaluation. (see CONTRAINDICATIONS and WARNINGS.)

Zolmitriptan should also be administered with caution to patients with diseases that may alter the absorption, metabolism, or excretion of drugs, such as impaired hepatic function (see CLINICAL PHARMACOLOGY).

For a given attack, if a patient does not respond to the first dose of zolmitriptan, the diagnosis of migraine headache should be reconsidered before administration of a second dose.

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. 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.

Phenylketonurics:

Phenylketonuric patients should be informed that ZOMIG-ZMT contain phenylalanine (a component of aspartame). Each 2.5 mg orally disintegrating tablet contains 2.81 mg phenylalanine. Each 5 mg orally disintegrating tablet contains 5.62 mg phenylalanine.

Information for Patients

See PATIENT INFORMATION at the end of this labeling for the text of the separate leaflet provided for patients.

ZOMIG-ZMT Orally Disintegrating Tablets

The orally disintegrating tablet is packaged in a blister. Patients should be instructed not to remove the tablet from the blister until just prior to dosing. The blister pack should then be peeled open, and the orally disintegrating tablet placed on the tongue, where it will dissolve and be swallowed with the saliva.

Patients should be cautioned about the risk of serotonin syndrome with the use of ZOMIG or other triptans, especially during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).

Laboratory Tests:

No monitoring of specific laboratory tests is recommended.

Drug Interactions

Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that 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 should be avoided (see CONTRAINDICATIONS).

MAO-A inhibitors increase the systemic exposure of zolmitriptan. Therefore, the use of zolmitriptan in patients receiving MAO-A inhibitors is contraindicated (see CLINICAL PHARMACOLOGY and CONTRAINDICATIONS).

Concomitant use of other 5-HT1B/1D agonists within 24 hours of ZOMIG treatment is not recommended. (see CONTRAINDICATIONS).

Following administration of cimetidine, the half-life and AUC of zolmitriptan and its active metabolites were approximately doubled (see CLINICAL PHARMACOLOGY).

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).

Drug/Laboratory Test Interactions:

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

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Carcinogenesis:

Carcinogenicity studies by oral gavage were carried out in mice and rats at doses up to 400 mg/kg/day. Mice were dosed for 85 weeks (males) and 92 weeks (females). The exposure (plasma AUC of parent drug) at the highest dose level was approximately 800 times that seen in humans after a single 10 mg dose (the maximum recommended total daily dose). There was no effect of zolmitriptan on tumor incidence. Control, low dose, and middle dose rats were dosed for 104-105 weeks; the high dose group was sacrificed after 101 weeks (males) and 86 weeks (females) due to excess mortality. Aside from an increase in the incidence of thyroid follicular cell hyperplasia and thyroid follicular cell adenomas seen in male rats receiving 400 mg/kg/day, an exposure approximately 3000 times that seen in humans after dosing with 10 mg, no tumors were noted.

Mutagenesis:

Zolmitriptan was mutagenic in an Ames test, in 2 of 5 strains of S. typhimurium tested, in the presence of, but not in the absence of, metabolic activation. It was not mutagenic in an in vitro mammalian gene cell mutation (CHO/HGPRT) assay. Zolmitriptan was clastogenic in an in vitro human lymphocyte assay both in the absence of and the presence of metabolic activation; it was not clastogenic in an in vivo mouse micronucleus assay. It was also not genotoxic in an unscheduled DNA synthesis study.

Impairment of Fertility:

Studies of male and female rats administered zolmitriptan prior to and during mating and up to implantation have shown no impairment of fertility at doses up to 400 mg/kg/day. Exposure at this dose was approximately 3000 times exposure at the maximum recommended human dose of 10 mg/day.

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 was associated with embryolethality and fetal abnormalities. When pregnant rats were administered oral zolmitriptan during the period of organogenesis at doses of 100, 400, and 1200 mg/kg/day, there was a dose-related increase in embryolethality which became statistically significant at the high dose. The maternal plasma exposures at these doses were approximately 280, 1100, and 5000 times the exposure in humans receiving the maximum recommended total daily dose of 10 mg. The high dose was maternally toxic, as evidenced by a decreased maternal body weight gain during gestation. In a similar study in rabbits, embryolethality was increased at the maternally toxic doses of 10 and 30 mg/kg/day (maternal plasma exposures equivalent to 11 and 42 times exposure in humans receiving the maximum recommended total daily dose of 10 mg), and increased incidences of fetal malformations (fused sternebrae, rib anomalies) and variations (major blood vessel variations, irregular ossification pattern of ribs) were observed at 30 mg/kg/day. Three mg/kg/day was a no effect dose (equivalent to human exposure at a dose of 10 mg). When female rats were given zolmitriptan during gestation, parturition, and lactation, an increased incidence of hydronephrosis was found in the offspring at the maternally toxic dose of 400 mg/kg/day (1100 times human exposure).

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 milk levels 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 Tablets in pediatric patients have not been established. Therefore, ZOMIG is not recommended for use in patients under 18 years of age.

One randomized, placebo-controlled clinical trial evaluating zolmitriptan tablets (2.5, 5 and 10 mg) in pediatric patients aged 12-17 years evaluated a total of 696 adolescent migraineurs. This study did not establish the efficacy of zolmitriptan compared to placebo in the treatment of migraine in adolescents. Adverse events observed were similar in nature and frequency to those reported in clinical trials in adults.

Postmarketing experience with ZOMIG and other triptans includes a limited number of reports that describe pediatric patients who have experienced clinically serious adverse events that 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: Special Populations)

Page last updated: 2008-10-29

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