Zolmitriptan tablets are indicated for the acute treatment of migraine with or without aura in adults.

Limitations of Use

• Only use zolmitriptan if a clear diagnosis of migraine has been established. If a patient has no response to zolmitriptan treatment for the first migraine attack, reconsider the diagnosis of migraine before zolmitriptan is administered to treat any subsequent attacks.
• Zolmitriptan tablets are not indicated for the prevention of migraine attacks.
• Safety and effectiveness of zolmitriptan have not been established for cluster
• headache.

2.1 Dosing Information

The recommended starting dose of zolmitriptan tablets 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 tablets 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 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.

2.3 Dosing in Patients taking Cimetidine

If zolmitriptan is coadministered 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)].

2.5 mg tablets are light yellow to yellow colored, round-shaped, biconvex, film-coated tablets with breakline on one side and debossed with "7" on other side.

5 mg tablets are light orange to orange colored, round-shaped, biconvex beveled edge, film-coated tablets debossed with '714' on one side and plain on other side.

Zolmitriptan tablets are 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 a 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-HT1  agonist, ergotamine-containing medication, or ergot-type medication (such as dihydroergotamine or methysergide) [see Drug Interactions (7.1, 7.3) ]
• Concurrent administration of a monoamine oxidase (MAO)-A inhibitor or recent use 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) ]

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-nave 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 coadministration 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 mmHg 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 mmHg 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)].

The following adverse reactions are described elsewhere in other sections of the prescribing information:

• Myocardial Ischemia, Myocardial Infarction, and Prinzmetal Angina [see Warnings and Precautions (5.1) ].
• Arrthymias [see Warnings and Precautions (5.2) ].
• Chest and or Throat, Neck and 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) ].

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.

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 coadministration 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 to 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 [see Dosage 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 arteriovenous 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 tablet 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 L/kg. Plasma protein binding of zolmitriptan is 25% over the concentration range of 10 to 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 5-HT1B/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 mmHg 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 to 76 years) was similar to those in younger non-migraineur volunteers (age 18 to 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 Ndesmethyl 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 (2.4122), 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.

13.3 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.

Manufactured by:

Cadila Healthcare Ltd.

Ahmedabad, India

Distributed by:

Zydus Pharmaceuticals (USA) Inc.

Pennington, NJ 08534

Rev.: 07/18