Zolmitriptan (Page 3 of 6)

6.2 Post marketing 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-HT1B/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 tablets.

7 DRUG INTERACTIONS

7.1 Ergot-containing Drugs

Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and zolmitriptan tablets 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 tablets and its active N-desmethyl metabolite. Therefore, the use of zolmitriptan tablets in patients receiving MAO-A inhibitors is contraindicated [ see Contraindications (4), Clinical Pharmacology (12.3)].

7.3 5-HT1B/1D agonists

Concomitant use of other 5-HT1B/1D agonists (including triptans) within 24 hours of 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) [see Warnings and Precautions (5.7) ].

7.5 Cimetidine

Following administration of cimetidine, the half-life and blood levels of zolmitriptan and its active N-desmethyl metabolite were approximately doubled [see Clinical Pharmacology (12.3) ]. If cimetidine and 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 [see Dosage and Administration, (2.4) and Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary
There are no adequate data on the developmental risk associated with the use of ZOLMITRIPTAN Tablets in pregnant women. In reproductive toxicity studies in rats and rabbits, oral administration of zolmitriptan to pregnant animals resulted in embryolethality and fetal abnormalities (malformations and variations) at clinically relevant exposures (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated rates of major birth defects (2.2%- 2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.

Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk Published data have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy.

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 Tablets and any potential adverse effects on the breastfed infant from Zolmitriptan Tablets or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness in pediatric patients have not been established. Therefore, zolmitriptan tablets are not recommended for use in patients under 18 years of age.

One randomized, placebo-controlled clinical trial of zolmitriptan tablets (2.5, 5 and 10 mg) evaluated 696 pediatric patients (aged 12 to 17 years) with migraines. This study did not demonstrate the efficacy of zolmitriptan tablets compared to placebo in the treatment of migraine in adolescents. Adverse reactions in the adolescent patients treated with zolmitriptan tablets were similar in nature and frequency to those reported in clinical trials in adults treated with zolmitriptan tablets. Zolmitriptan tablets have not been studied in pediatric patients less than 12 years old.

In the postmarketing experience with triptans, including zolmitriptan tablets, there were no additional adverse reactions seen in pediatric patients that were not seen in adults.

8.5 Geriatric Use

Clinical studies of zolmitriptan tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) prior to receiving zolmitriptan tablets [see Warnings and Precautions (5.1) ].

The pharmacokinetics of zolmitriptan were similar in geriatric patients (aged > 65 years) compared to younger patients [see Clinical Pharmacology (12.3) ].

8.6 Patients with Hepatic Impairment:

After oral zolmitriptan tablets administration, zolmitriptan blood levels were increased in patients with moderate to severe hepatic impairment, and significant elevation in blood pressure was observed in some of these patients [see Warnings and Precautions (5.8) ]. Therefore, adjust the zolmitriptan tablets dose and administer with caution in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

10 OVERDOSAGE

There is no experience with acute overdose of zolmitriptan tablets. Clinical study subjects who received single 50 mg oral doses of zolmitriptan tablets commonly experienced sedation.

There is no specific antidote to zolmitriptan tablets. In cases of severe intoxication, intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system.

The elimination half-life of zolmitriptan tablets is 3 hours [see Clinical Pharmacology (12.1) ]; therefore, monitor patients after overdose with zolmitriptan tablets for at least 15 hours or until symptoms or signs resolve. It is unknown what effect hemodialysis or peritoneal dialysis has on the plasma concentrations of zolmitriptan.

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