2.1  Dosing Information

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

2.2   Administration of Zolmitriptan Orally Disintegrating Tablets

Instruct patients not to break zolmitriptan orally disintegrating tablets because they are not functionally-scored. Administration with liquid is not necessary.

Orally disintegrating tablets are packaged in a blister pack. Instruct patients not to remove the tablet from the blister until just prior to dosing. Subsequently, instruct patients to peel the blister pack open, and to place the orally disintegrating tablet on the tongue, where it will dissolve and it will be swallowed with the saliva.

2.3   Dosing in Patients with Hepatic Impairment

The recommended dose of zolmitriptan in 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. 

The use of zolmitriptan orally disintegrating tablets is not recommended in patients with moderate or severe hepatic impairment because these orally disintegrating tablets should not be broken in half [see Use in Specific Populations (8.6),and Clinical Pharmacology (12.3)].

2.4   Dosing in Patients taking Cimetidine

If zolmitriptan is co-administered with cimetidine, limit the maximum single dose of zolmitriptan to 2.5 mg, not to exceed 5 mg  in  any 24-hour  period  [see  Drug Interactions (7.5), Clinical Pharmacology (12.3)].

5.1   Myocardial Ischemia, Myocardial Infarction, and Prinzmetal 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-HT1 agonists including zolmitriptan may cause coronary artery vasospasm (Prinzmetal 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-HT1  agonists. Discontinue zolmitriptan if these   disturbances occur. Zolmitriptan is contraindicated  in patients  with  Wolff-Parkinson-White Syndrome  or arrhythmias  associated  with  other  cardiac  accessory conduction pathway disorders [see Contraindications(4)].

5.3   Chest, Throat, Neck and Jaw Pain/Tightness/Pressure

As with other 5-HT1  agonists, sensations of tightness, pain, and pressure in the chest, throat, neck, and jaw commonly occur after treatment with zolmitriptan  and is usually non-cardiac in origin.   However, perform a cardiac evaluation if these patients are at high cardiac risk.  5-HT1 agonists including zolmitriptan are contraindicated in patients with CAD or Prinzmetal’s variant angina [see Contraindications (4)].

5.4   Cerebrovascular Events

Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred 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 5-HT1 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 is contraindicated in patients with a history of stroke or transient ischemic attack [see Contraindications(4)].

5.5   Other Vasospasm Reactions

5-HT1 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 a vasospastic reaction following the use of any 5-HT1 agonist, rule out a vasospastic reaction  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-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 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). 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 if serotonin syndrome is suspected [see Drug Interactions (7.4)].

5.8   Increase in Blood Pressure

Significant elevations in systemic blood pressure have been reported in patients treated with 5-HT1 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, 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.

As with all triptans, blood pressure should be monitored in zolmitriptan-treated patients. Zolmitriptan is contraindicated in patients with uncontrolled hypertension [see Contraindications (4)].

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 > 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 1 mg, 2.5 mg, or 5 mg dose groups in the controlled clinical trials of zolmitriptan 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 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 Trials1

1 Only adverse reactions that were at least 2% more frequent in a zolmitriptan 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  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.

Adverse  Reactions  with  Zolmitriptan Orally Disintegrating Tablets  
The adverse reaction profile seen with zolmitriptan orally disintegrating tablets was similar to that seen with zolmitriptan tablets.

6.2   Postmarketing Experience

The following adverse reactions were identified during post approval use of zolmitriptan. 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. Zolmitriptan is contraindicated in patients with a history of hypersensitivity reaction to zolmitriptan.

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 and its active N-desmethyl metabolite. Therefore, the use of zolmitriptan in patients receiving MAO-A inhibitors is contraindicated [see Contraindications (4) and 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 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 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, (2.4)and Clinical Pharmacology (12.3)].

8.1  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 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.

8.3  Nursing Mothers

It is not known whether zolmitriptan is excreted in human milk.  Because many drugs are excreted in human milk, and because of the potential for  serious  adverse  reactions  in nursing infants from zolmitriptan, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. In rats, oral dosing with zolmitriptan resulted in levels in milk up to 4 times higher than in plasma. 

8.4   Pediatric Use

The safety and effectiveness in pediatric patients have not been established. Therefore, zolmitriptan is 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 12-17 years) with migraines. This study did not demonstrate the efficacy of zolmitriptan compared to placebo in the treatment of migraine in adolescents. Adverse reactions in the adolescent patients treated with zolmitriptan were similar in nature and frequency to those reported in clinical trials in adults treated with zolmitriptan. Zolmitriptan has not been studied in pediatric patients less than 12 years old.

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

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 [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 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 dose and administer with caution in patients with moderate or severe hepatic impairment [seeDosage and Administration (2.3) and Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Zolmitriptan binds with high affinity to human recombinant 5­-HT1D and 5-HT1B receptors, and moderate affinity for 5-HT1A receptors. The N-desmethyl metabolite also has high affinity for 5-HT1B/1D and moderate affinity for 5-HT1A receptors.  

Migraines are likely 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-HT1B/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.

12.3 Pharmacokinetics

Absorption, Distribution, Metabolism, and Excretion
Absorption
Zolmitriptan is well  absorbed  after  oral  administration for both zolmitriptan tablets and the zolmitriptan orally disintegrating tablets.  Zolmitriptan  displays  linear  kinetics over the dose range of 2.5 to 50 mg. 

The AUC and Cmax of zolmitriptan are similar following administration of zolmitriptan tablets and zolmitriptan orally disintegrating tablets, but the Tmax is somewhat later with zolmitriptan orally disintegrating tablets,   with   a   median   Tmax     of   3   hours   for zolmitriptan orally disintegrating tablets compared with 1.5 hours for the zolmitriptan tablet.  The AUC, Cmax, and Tmax for the active N-desmethyl metabolite are similar for the two formulations.

During a moderate to severe migraine attack, mean AUC0-4 and Cmax for zolmitriptan, dosed as a zolmitriptan tablet, were decreased by 40% and 25%, respectively, and mean Tmax was delayed by one-half hour compared to  the  same  patients during a migraine free period. 

Food has no significant effect on the bioavailability of zolmitriptan. No accumulation occurred on multiple dosing.

Distribution
Mean  absolute  bioavailability  is  approximately  40%.  The mean apparent volume of distribution is 7.0 L/kg. Plasma protein binding of zolmitriptan is 25% over the concentration range of 10-1000 ng/mL. 

Metabolism
Zolmitriptan  is  converted  to  an  active  N-desmethyl metabolite; the metabolite concentrations are about two-thirds that of zolmitriptan.  Because the 5HT1B/1D potency of the metabolite is 2 to 6 times that of the parent compound, the metabolite may contribute a substantial portion of the overall effect after zolmitriptan  administration.

Excretion
Total radioactivity recovered in urine and feces was 65% and 30% of the administered dose, respectively.  About 8% of the dose was recovered in the urine as unchanged zolmitriptan. Indole acetic acid metabolite accounted for 31% of the dose, followed by N-oxide (7%) and N-desmethyl (4%) metabolites. The indole acetic acid and N-oxide metabolites are inactive. 

Mean total plasma clearance is 31.5 mL/min/kg, of which one-sixth is renal clearance. The renal clearance is greater than the glomerular filtration rate suggesting renal tubular secretion.

Special Populations
Hepatic Impairment

In patients with severe hepatic impairment, the mean Cmax, Tmax, and AUC0-∞of zolmitriptan were increased 1.5-fold, 2-fold (2 vs. 4 hours), and 3-fold, respectively, compared to subjects with normal hepatic function. Seven out of 27 patients experienced 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a 10 mg zolmitriptan dose. Adjust the zolmitriptan dose in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].

Renal Impairment
Clearance of zolmitriptan was  reduced by  25%  in patients with  severe  renal  impairment  (Clcr  ≥  5  ≤  25  mL/min) compared to subjects with normal renal function (Clcr ≥ 70 mL/min); no significant change in clearance was observed in patients with moderate renal impairment (Clcr ≥ 26 ≤ 50 mL/min).

Age
Zolmitriptan      pharmacokinetics      in     healthy     elderly     non-migraineur volunteers (age 65–76 years) was similar to those in younger non-migraineur volunteers (age 18-39 years). 

Sex
Mean plasma concentrations of zolmitriptan were up to 1.5-fold higher in females than males. 

Race
Retrospective  analysis   of   pharmacokinetic  data   between Japanese and Caucasians revealed no significant differences. 

Hypertensive Patients
No differences in the pharmacokinetics of zolmitriptan or its effects on blood pressure were seen in mild to moderate hypertensive  volunteers  compared  with  normotensive controls.

Drug Interaction Studies
All drug interaction studies were performed in healthy volunteers using a single 10 mg dose of zolmitriptan and a single dose of the other drug except where otherwise noted.

MAO Inhibitors
Following one week of administration of moclobemide (150 mg twice daily), a specific MAO-A inhibitor, there was an increase of about 25% in both Cmax and AUC for zolmitriptan and a 3-fold increase in the Cmax  and AUC of the active N­-desmethyl metabolite of zolmitriptan. MAO inhibitors are contraindicated in zolmitriptan-treated patients [see Contraindications(4), Warnings and Precautions (5.7), and Drug Interactions (7.2, 7.4)]. 

Selegiline,  a  selective  MAO-B  inhibitor,  at  a  dose  of  10 mg/day for 1 week, had no effect on the pharmacokinetics of zolmitriptan and its metabolite. 

Cimetidine
Following the administration of cimetidine, the half-life and AUC of zolmitriptan (5 mg dose), and its active metabolite, were approximately doubled [see Dosage and Administration (2.4), Drug Interactions (7.5)]. 

Fluoxetine
The pharmacokinetics of zolmitriptan, as well as its effect on blood pressure, were unaffected by 4 weeks of pretreatment with oral fluoxetine (20 mg/day). 

Propranolol
Cmax and AUC of zolmitriptan were increased 1.5-fold after one week of dosing with propranolol (160 mg/day).  Cmax and AUC of the N-desmethyl metabolite were reduced by 30% and 15%, respectively. There were no changes in blood pressure or pulse rate following administration of propranolol with zolmitriptan. 

Acetaminophen
A single 1 gram dose of acetaminophen did not alter the pharmacokinetics of zolmitriptan and its N-desmethyl metabolite. However, zolmitriptan   administration delayed  the Tmax of acetaminophen by one hour. 

Metoclopramide
A single 10 mg dose of metoclopramide had no effect on the pharmacokinetics of zolmitriptan or its metabolites. 

Oral Contraceptives
Retrospective analysis of pharmacokinetic data across studies indicated that mean Cmax and AUC of zolmitriptan were increased by 30% and 50%, respectively, and Tmax   was delayed by one-half hour in women taking oral contraceptives. The effect of zolmitriptan on the pharmacokinetics of oral contraceptives has not been studied.

13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility

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 in male rats receiving 400 mg/kg/day. No increase in tumors was observed in rats at 100 mg/kg/day, a dose associated with a plasma AUC approximately 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 mouse 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 MRHD.