ZOMIPTAN

contains zolmitriptan, which is a selective 5-hydroxytryptamine 1B/1D (5-HT 1B/1D ) receptor agonist.

Zolmitriptan is chemically designated as (S)-4-[[3-[2-(dimethylamino) ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone and has the following chemical structure: The empirical formula is C 16 H 21 N 3 O 2, representing a molecular weight of 287.36.

Zolmitriptan is a white to almost white powder that is readily soluble in water.

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

SPRAY 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.

SPRAY is hypertonic.

The osmolarity of ZOLMITRIPTAN NASAL

SPRAY for 2.5 mg is to 420 mOsmol, and for 5 mg is to 470 mOsmol.

is indicated for the acute treatment of migraine with or without aura in adults and pediatric patients 12 years of age and older.

Limitations of Use Only use ZOLMITRIPTAN NASAL SPRAY if a clear diagnosis of migraine has been established.

If a patient has no response to ZOLMITRIPTAN NASAL SPRAY treatment for the first migraine attack, reconsider the diagnosis of migraine before ZOLMITRIPTAN NASAL SPRAY is administered to treat any subsequent attacks.

SPRAY is not indicated for the prevention of migraine attacks.

Safety and effectiveness of ZOLMITRIPTAN NASAL

SPRAY have not been established for cluster headache.

Not recommended in patients with moderate or severe hepatic impairment.

SPRAY is a serotonin (5-HT) 1B/1D receptor agonist (triptan) indicated for the acute treatment of migraine with or without aura in adults and pediatric patients 12 years and older Limitations of Use: Use only after a clear diagnosis of migraine has been established Not intended for the prophylactic therapy of migraine Not indicated for the treatment of cluster headache Not recommended in patients with moderate to severe hepatic impairment.

Zolmitriptan binds with high affinity to human recombinant 5-HT 1D and 5-HT 1B receptors, and moderate affinity for 5-HT 1A receptors.

N-desmethyl metabolite also has high affinity for 5-HT 1B/1D and moderate affinity for 5-HT1A receptors.

Current theories proposed to explain the etiology of migraine headache suggest that symptoms are 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-HT 1B/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 nasal spray is rapidly absorbed via the nasopharynx as detected in a Photon Emission Tomography (PET) study using 11 C zolmitriptan.

The mean relative bioavailability of the nasal spray formulation is 102%, compared with the oral tablet.

Zolmitriptan was detected in plasma by 5 minutes and peak plasma concentration generally was achieved by 3 hours.

The time at which maximum plasma concentrations were observed was similar after single (1 day) or multiple (4 days) nasal dosing.

Plasma concentrations of zolmitriptan are sustained for to 6 hours after dosing.

Zolmitriptan and its active

N-desmethyl metabolite display linear kinetics after single or multiple doses of zolmitriptan nasal spray over the dose range of 0.1 to 10 mg. The pharmacokinetics of the N-desmethyl metabolite are similar to that of zolmitriptan for all nasal spray dosages.

N-desmethyl metabolite is detected in plasma by 15 minutes and peak plasma concentration is generally achieved by 3 hours after administration.

Food has no significant effect on the bioavailability of zolmitriptan.

Plasma protein binding of zolmitriptan is 25% over the concentration range of 10-1000 ng/mL.

The mean apparent volume of distribution for zolmitriptan nasal spray formulation is 8.4 L/kg. Metabolism Zolmitriptan is converted to an active N-desmethyl metabolite such that the metabolite concentrations are about two-thirds that of zolmitriptan.

Because the 5HT 1B/1D potency of the metabolite is to 6 times that of the parent compound, the metabolite may contribute a substantial portion of the overall effect after zolmitriptan administration.

Excretion The mean elimination half-life for zolmitriptan and N-desmethyl metabolite following single or multiple nasal spray administration are approximately 3 hours, similar to the half-life values seen after oral tablet administration.

In a study with orally administered zolmitriptan, total radioactivity recovered in urine and feces was 65% and 30% of the administered dose, respectively.

In urine, unchanged zolmitriptan and N-desmethyl metabolite accounted for 8% and 4% of the dose, respectively, whereas the inactive indole acetic acid and N-oxide metabolites accounted for 31% and 7% of the dose, respectively.

Mean total plasma clearance for zolmitriptan nasal spray is 25.9 mL/min/kg, of which one-sixth is renal clearance.

The renal clearance is greater than the glomerular filtration rate suggesting renal tubular secretion.

The pharmacokinetics of orally administered zolmitriptan in healthy elderly non-migraineur volunteers (age 65-76 yrs) was similar to those in younger non-migraineur volunteers (age 18-39 yrs).

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

There are no significant differences in the pharmacokinetics of orally administered zolmitriptan in Japanese and Caucasians.

The effect of renal impairment on the pharmacokinetics of zolmitriptan nasal spray has not been evaluated.

After orally dosing zolmitriptan, renal clearance was reduced by 25% in patients with severe renal impairment (Clcr ≥ 5 ≤ 25 mL/min) compared with the normal group (Clcr ≥ 70 mL/min); no significant change in clearance was observed in the moderately renally impaired group (Clcr ≥ 26 ≤ 50 mL/min).

The effect of hepatic disease on the pharmacokinetics of zolmitriptan nasal spray has not been evaluated.

In patients with severe hepatic impairment, the mean C max, T max, and AUC of zolmitriptan dosed orally 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 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a 10 mg zolmitriptan dose.

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

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.

Eight drug interaction studies have been performed with zolmitriptan tablets and one study (xylometazoline) was performed with nasal spray.

An in vivo drug interaction study with zolmitriptan nasal spray indicated that 1 spray (100 μL dose) of xylometazoline (0.1% w/v), a decongestant, administered 30 minutes prior to a 5 mg nasal dose of zolmitriptan did not alter the pharmacokinetics of zolmitriptan.

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

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 C max and AUC for zolmitriptan and a 3-fold increase in the C max and AUC of the active N-desmethyl metabolite of zolmitriptan.

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.

C max and AUC of zolmitriptan increased 1.5-fold after one week of dosing with propranolol (160 mg/day).

C max and AUC of the

N-desmethyl metabolite were reduced by 30% and 15%, respectively.

There were no interactive effects on blood pressure or pulse rate following administration of propranolol with zolmitriptan.

A single 1g dose of acetaminophen does not alter the pharmacokinetics of zolmitriptan and its N-desmethyl metabolite.

However, zolmitriptan delayed the T max of acetaminophen by one hour.

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

Retrospective analysis of pharmacokinetic data across studies indicated that mean C max and AUC of zolmitriptan were 30% and 50% higher, respectively, and T max was delayed by one-half hour in females taking oral contraceptives compared to females not taking oral contraceptives.

The effect of zolmitriptan on the pharmacokinetics of oral contraceptives has not been studied.

Following the administration of cimetidine, the half-life and AUC of a 5 mg dose of zolmitriptan and its active metabolite were approximately doubled.

A dosage adjustment is therefore required.

fda.gov/medwatch. 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.

Among 460 patients treating 1180 single attacks with zolmitriptan nasal spray in a blinded placebo controlled trial (Study 1), there was a low withdrawal rate related to adverse reactions: 5 mg (1.3%), 2.5 mg (0%), and placebo (0.4%).

None of the withdrawals were due to a serious event.

One patient was withdrawn due to abnormal ECG changes from baseline that were incidentally found 23 days after the last dose of zolmitriptan nasal spray.

The most common adverse reactions (≥ 5% and > placebo) in any dosage strength in clinical trials for zolmitriptan nasal spray were: unusual taste, paresthesia, hyperesthesia, and dizziness.

The incidence of adverse reactions was generally dose-related.

Table 1 lists the adverse reactions from the controlled clinical trial (Study 1) that occurred in ≥ 2% of patients in either the 2.5 or 5 mg zolmitriptan nasal spray dose groups and with an incidence greater than placebo.

Table 1: Adverse reactions in a Placebo-Controlled Study in Adult Patients with Migraine (Study 1) Body System Adverse Reaction Placebo (N=228) Zolmitriptan 2.5 mg (N=224) Zolmitriptan 5 mg (N=236) Atypical Sensations Hyperesthesia 0% 1% 5% Paraesthesia 6% 5% 10% Warm Sensation 2% 4% 0% Ear/Nose/Throat Disorder/Discomfort of nasal cavity 2% 1% 3% Pain and Pressure Sensations Pain Location Specified 1% 2% 4% Throat Pain 1% 4% 4% Throat Tightness 1% <1% 2% Digestive Dry Mouth <1% 3% 2% Nausea 1% 1% 4% Neurological Dizziness 4% 6% 3% Somnolence 2% 1% 4% Other Unusual Taste 3% 17% 21% Asthenia 1% 3% 3% In Study 1, adverse reactions occurring in ≥ 1% and < 2% of patients in all attacks in either zolmitriptan nasal spray dose group and with incidence greater than that of placebo were: abdominal pain, chills, throat pressure, facial edema, chest pressure, palpitation, dysphagia, arthralgia, myalgia, and depersonalization.

The incidence of adverse reactions in controlled clinical trials was not affected by gender, weight, or age of the patients (18-39 vs. 40-65 years of age), or presence of aura.

There were insufficient data to assess the impact of race on the incidence of adverse reactions.

Among 460 patients using zolmitriptan 2.5 mg or 5 mg in the controlled clinical trial, approximately 3% noted local irritation or soreness at the site of administration.

Adverse reactions of any kind, perceived in the nasopharynx (which may include systemic effects of triptans) were severe in about 1% of patients and approximately 57% resolved in 1 hour.

Nasopharyngeal examinations, in a subset of patients participating in two long term trials of up to one-year duration, failed to demonstrate any clinically significant changes with repeated use of zolmitriptan nasal spray.

All nasopharyngeal adverse reactions with an incidence of ≥ 2% of patients in any zolmitriptan nasal spray dose groups are included in Table 1.

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.

Reaction frequencies are calculated as the number of patients who used zolmitriptan nasal spray and reported a reaction divided by the total number of patients exposed to zolmitriptan nasal spray (n=3059).

All reported reactions are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug.

Reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients and rare adverse reactions are those occurring in fewer than 1/1,000 patients.

Infrequent: allergic reactions.

Infrequent: arrhythmias, hypertension, syncope and tachycardia.

• Rare: angina pectoris and myocardial infarct.

• Rare: stomatitis.

Infrequent: agitation, amnesia, anxiety, depression, insomnia, and nervousness.

• Rare: convulsions.

Infrequent: bronchitis, increased cough, dyspnea, epistaxis, laryngeal edema, pharyngitis, rhinitis, and sinusitis.

Infrequent: pruritus, rash, and urticaria.

Infrequent: polyuria and urinary urgency.

• Rare: urinary frequency.

Special senses

Infrequent: tinnitus.

• Rare: conjunctivitis, dry eye, and visual field defect.

The adverse reaction profile seen with zolmitriptan nasal spray is similar to that seen with zolmitriptan tablets and zolmitriptan orally disintegrating tablets except for the occurrence of local adverse reactions from the nasal spray.

Patients to 17 Years of Age The safety of zolmitriptan nasal spray in the acute treatment of migraine in pediatric patients to 17 years of age was established in two studies.

The most common adverse reactions (incidence of ≥ 2% of pediatric patients receiving 2.5 mg and 5 mg zolmitriptan nasal spray and numerically greater than placebo) after a single dose are summarized in Table 2.

Dysgeusia (unusual taste) was the most common adverse reaction, with a numerically greater incidence for patients receiving zolmitriptan compared to placebo (10% vs. 2%).

Other common adverse reactions were nasal discomfort, dizziness, oropharyngeal pain, and nausea.

Table 2 lists the adverse reactions from the pooled placebo-controlled studies that occurred in ≥ 2% of pediatric patients to 17 years of age in either the 2.5 mg or 5 mg zolmitriptan dose groups and with an incidence greater than placebo.

Table 2: Adverse reactions in Pooled Placebo-Controlled Studies in Pediatric Patients to 17 years of Age with Migraine Adverse Reaction Placebo (N=437) Zolmitriptan 2.5 mg (N=81) Zolmitriptan 5 mg (N=431) Unusual taste 2% 6% 10% Nasal discomfort 1% 3% 3% Dizziness 1% 0% 2% Oropharyngeal pain 2% 0% 2% Nausea 1% 1% 2% The adverse reaction profile was similar across gender.

There were insufficient data to assess the impact of race on the incidence of adverse reactions. 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.

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.

There is no experience with acute overdose.

Clinical study subjects receiving single 50 mg oral doses of zolmitriptan commonly experienced sedation.

The elimination half-life of zolmitriptan is 3 hours and therefore monitoring of patients after overdose with zolmitriptan should continue for at least 15 hours or while symptoms or signs persist.

There is no specific antidote to zolmitriptan.

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.

It is unknown what effect hemodialysis or peritoneal dialysis has on the plasma concentrations of zolmitriptan.

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.