ZOMIPTAN

Zolmitriptan is a member of the triptan class of 5-hydroxytryptamine(5-HT) 1B/1D/(1F) receptor agonists used to treat acute migraine. 1, 14 Sumatriptan was the first triptan to be developed, but had poor oral bioavailability and lipophilicity.

This led to the development of second-generation triptans, including almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, and zolmitriptan.

Triptans can be administered alone or in combination with an NSAID like naproxen, and represent the current "gold standard" for acute migraine treatment.

Zolmitriptan was first approved by the FDA for sale by Zeneca Pharmaceuticals under the trade name Zomig® on November 25, 1997.

It is currently available in both tablet and nasal spray forms.

Zolmitriptan is indicated for the acute treatment of migraine with or without auras in patients aged and over.

Zolmitriptan, like other triptans, is a serotonin (5-hydroxytryptamine; 5-HT) receptor agonist, with enhanced specificity for the 5-HT 1B and 5-HT 1D receptor subtypes.

It is through the downstream effects of 5-HT 1B/1D activation that triptans are proposed to provide acute relief of migraines. 14, 1, 2 Zolmitriptan is also a vasoconstrictor, 5 leading to possible adverse cardiovascular effects such as myocardial ischemia/infarction, arrhythmias, cerebral and subarachnoid hemorrhage, stroke, gastrointestinal ischemia, and peripheral vasospastic reactions.

In addition, chest/throat/neck/jaw pain, tightness, and/or pressure has been reported, along with the possibility of medication overuse headaches and serotonin syndrome.

Patients with phenylketonuria should be advised that ZOMIG-ZMT contains phenylalanine.

5-hydroxytryptamine receptor 1B Agonist 5-hydroxytryptamine receptor 1D Agonist 5-hydroxytryptamine receptor 1F Agonist.

Zolmitriptan tablets have a mean absolute oral bioavailability of approximately 40%, with food having no effect on the rate or extent of absorption. 1, 9, 14 The dosing kinetics are linear over a range of 2.5-50 mg with 75% of the eventual C max being attained within 1 hour of dosing.

The median

T max for the tablet form is 1.5 hours, while for the Oral disintegrating tablet form, it is 3 hours. 9, 14 The AUC across studies was in the range of 84.4-173.8 ng/mL*h while the C max was between and 25.2 ng/mL. 9, 12 Zolmitriptan administered as a nasal spray is detected in the plasma within 2-5 minutes, compared to 10-15 minutes for the tablet form; the faster kinetics likely reflect fast absorption across the nasal mucosa.

The bioavailability compared to the tablet is 102%, and plasma zolmitriptan concentration is maintained for 4-6 hours after intranasal delivery. 10, 14 The active N-desmethyl metabolite of zolmitriptan has a mean plasma concentration that is roughly two-thirds of zolmitriptan, regardless of dosage route or concentration. 9, 14.

Zolmitriptan has a volume of distribution between and 8.4 L/kg.

Zolmitriptan is metabolized in the liver, and studies using cytochrome P450 inhibitors like cimetidine suggest that it is likely metabolized by CYP1A2, as well as by monoamine oxidase (MAO). 14, 11, 13 Zolmitriptan metabolism results in three major metabolites: an active N-desmethyl metabolite (183C91) as well as inactive N-oxide (1652W92) and indole acetic acid (2161W92) metabolites. 14, 12, 9 Hover over products below to view reaction partners Zolmitriptan Zolmitriptan N-oxide N-Desmethylzolmitriptan Indole ethyl alcohol zolmitriptan derivative Indole acetic acid zolmitriptan derivative.

Zolmitriptan is primarily excreted in urine (approximately 65%) and feces (approximately 30%).

Within urine, the most common form is the indole acetic acid metabolite (31%), followed by the N-oxide (7%), and N-desmethyl (4%) metabolites; the majority of zolmitriptan recovered in feces remains unchanged. 14, 12.

Zolmitriptan has a mean elimination half-life of approximately three hours following oral or nasal administration.

Its active

N-desmethyl metabolite has a slightly longer (approximately 3.5 hours) half-life. 14, 12.

Zolmitriptan has a clearance of 31.5 mL/min/kg for oral tablets and 25.9 mL/min/kg for nasal administration; one-sixth of the clearance is renal.

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information regarding zolmitriptan is not readily available.

Patients experiencing an overdose are at an increased risk of severe adverse effects such as cardiovascular symptoms due to excessive vasoconstriction and activation of serotonergic receptors.

Patients receiving a single 50 mg oral dose of zolmitriptan often experienced sedation.

Zolmitriptan is 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 Wolff-Parkinson-White Syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders History of stroke, transient ischemic attack (TIA) or history of hemiplegic or basilar migraine because these patients are at higher risk of stroke Peripheral vascular disease (PVD) Ischemic bowel disease Uncontrolled hypertension Recent use (i.e., within 24 hours) of another 5-HT 1 agonist, ergotamine-containing medication, or ergot-type medication (such as dihydroergotamine or methysergide) Concurrent administration of an MAO-A inhibitor or recent discontinuation of a MAO-A inhibitor (that is within 2 weeks) Known hypersensitivity to zolmitriptan (angioedema and anaphylaxis seen) History of ischemic heart disease or coronary artery vasospasm Symptomatic Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders History of stroke, transient ischemic attack, or hemiplegic or basilar migraine Peripheral Vascular Disease Ischemic bowel disease Uncontrolled hypertension Recent (within 24 hours) use of another 5-HT 1 agonist (e.g., another triptan) or of an ergot-type medication MAO-A inhibitor used in past 2 weeks Hypersensitivity to zolmitriptan.

Recommended starting dose: 2.5 mg Maximum single dose: 5 mg May repeat dose after 2 hours if needed; not to exceed 10 mg in any 24-hour period 2.1 Dosing Information The recommended starting dose for ZOLMITRIPTAN NASAL SPRAY in adult and pediatric patients 12 years of age and older is 2.5 mg. As the individual response to ZOLMITRIPTAN NASAL SPRAY may vary, the dose should be adjusted on an individual basis.

The maximum recommended single dose of ZOLMITRIPTAN NASAL SPRAY is 5 mg. If the migraine has not resolved by 2 hours after taking ZOLMITRIPTAN NASAL SPRAY, or returns after a transient improvement, another dose may be administered at least 2 hours after the previous dose.

The maximum daily dose should not exceed 10 mg in any 24-hour period.

The safety of ZOLMITRIPTAN NASAL

SPRAY in the treatment of an average of more than four headaches in a 30-day period has not been established. 2.2 Dosing in Patients with Hepatic Impairment ZOLMITRIPTAN NASAL SPRAY is not recommended in patients with moderate to severe hepatic impairment because of increased zolmitriptan blood levels in these patients and elevation of blood pressure in some of these patients.

The recommended dosage of ZOLMITRIPTAN NASAL

SPRAY in patients with mild hepatic impairment is the same as for patients with normal hepatic function. 2.3 Dosing in Patients taking Cimetidine If ZOLMITRIPTAN NASAL SPRAY is co-administered with cimetidine, limit the maximum single dose of ZOLMITRIPTAN NASAL SPRAY to 2.5 mg, not to exceed 5 mg in any 24-hour period.

SPRAY device is a blue-colored plastic device with a gray protection cap, labeled to indicate the nominal dose.

Each ZOLMITRIPTAN NASAL SPRAY device administers a single dose of ZOLMITRIPTAN NASAL SPRAY.

SPRAY is supplied as a clear to pale yellow solution of zolmitriptan, buffered to a pH 5.0.

SPRAY device contains 2.5 mg or 5 mg of zolmitriptan in a 100 μL unit dose aqueous buffered solution containing citric acid, anhydrous, USP, disodium phosphate dodecahydrate USP and purified water USP. 2.5 mg ZOLMITRIPTAN NASAL SPRAY is supplied in boxes of 6 single-use nasal spray units. (NDC 69238-2351-6) 5 mg ZOLMITRIPTAN NASAL SPRAY is supplied in boxes of 6 single-use nasal spray units. (NDC 69238-2352-6) Each ZOLMITRIPTAN NASAL SPRAY single dose unit spray supplies 2.5 and 5 mg, respectively, of zolmitriptan.

SPRAY unit must be discarded after use.

Store at controlled room temperature, 20-25°C (68-77°F) .

There are no adequate data on the developmental risk associated with the use of zolmitriptan 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.

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.

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

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.

Safety and effectiveness of zolmitriptan in pediatric patients under 12 years of age have not been established.

The efficacy of zolmitriptan nasal spray in the acute treatment of migraine in pediatric patients to 17 years of age was established in a placebo-controlled study with a total of 81 pediatric patients receiving zolmitriptan 2.5 mg and 229 pediatric patients receiving zolmitriptan 5 mg.

In an earlier study with a different design, zolmitriptan 5 mg nasal spray was evaluated in the acute treatment of migraine headache in 171 pediatric patients to 17 years of age.

In that study, the efficacy of zolmitriptan nasal spray was not established.

The safety of zolmitriptan nasal spray in the acute treatment of migraine in pediatric patients to 17 years of age was established in two placebo-controlled studies with a total of 81 pediatric patients receiving zolmitriptan 2.5 mg and 431 pediatric patients receiving zolmitriptan 5 mg.

The safety profile of zolmitriptan nasal spray in pediatric patients to 17 years of age is similar to the profile observed in adults.

In the postmarketing experience with triptans, including zolmitriptan, there are 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.

Clinical studies of zolmitriptan did not include sufficient numbers of subjects aged 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.

Geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) should have a cardiovascular evaluation prior to receiving zolmitriptan.

The pharmacokinetics of zolmitriptan were similar in geriatric patients (aged > 65 years) compared to younger patients.