`
`RESEARCH
`
`APPLICATION NUMBER:
`
`21-450
`
`APPROVED LABELING
`
`
`
`
`
`
`
`Rcv 09MB
`
`Rx only
`
`SIC
`
`ZOMIG (zolmitriptan) Nasal Spray
`
`For Nasal Use Only
`
`DESCRIPTION
`
`ZOMIG" (zolmitn'ptan) Nasal Spray contains zolmitriptan, which
`is a selective Shydroxytryptmhe lB/lD (5-HT1 13/11)) receptor
`
`agonist. Zolmitn'ptan is chemically dcsignated as (S)-4-[[3-[2—
`(d'nnethylaminokthyfl- 1H- indol-S»yl]methyl] -2-oxazolidinone and
`has the following chemical structure:
`
`
`
`NOW:
`
`The empirical formula is C15H21N302, representing a molecular
`
`‘ weight of 287.36. Zolmitriplsn is a white to almost white powder
`that is readily soluble in water. ZOMIG Nasal Spray is supplied as
`a clear to pale yellow solution of zolmitriptan, buffered to a pH
`5.0. Each ZOMIG Nasal Spray contains 5 mg of zolmitriptan in a
`lOO-pL unit dose aqueous buffered solution containing citric acid,
`anhydrous, USP, disodium phosphate dodccahydmte USP and
`purified water USP.
`
`ZOMIG Nasal Spray is hypertonic. The osmolarity of ZOMIG
`Nasal Spray 5 mg is 420 to 470 mOsmol.
`
`
`
`
`
`
`
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action: Zolmitriptan binds with high affinity to
`human recombinant 5-HT") and 5-HT"; receptors. Zolmitriptan
`exhibits modest affinity for 5—HT“
`receptors, but has no
`significant affinity (as measured by radioligand binding assays) or
`pharmacological activity at 5-HT}, 5-HT3, 5-HT}, alpha“, alpha;.
`or betaI-adrenergic; H, H;, histaminic; mnscan'nic; dopamine], or
`
`dopamine; receptors. The N-desmethyl metabolite also has high
`
`affinity for 5-HT13]“) and modest amnity for 5-HT“ receptors.
`
`theories proposed to explain the etiology of migraine
`Current
`headache suggest
`that
`symptoms are due to local cranial
`vasodilatation andlor to the release of sensory neuropeptides
`(vasoactive intestinal peptide, substance P and calcitonin gene-
`related peptide) through nerve endings in me trigeminai system.
`The therapeutic activity of zolmitriptan for the treatment of
`migraine headache can most likely be attributed to the agonist
`efi'ects at the 5-HT13/lp receptors on intractanial blood vessels
`(including the arterio—venous anastomoses) and sensory nerves of
`the trigeminal system which result in cranial vessel constriction
`and inhibition of pro- inflarnmatory neuropeptide release.
`
`Clinical Phannacoklnetiee and Bioavailability:
`Absorption: Zolmilriptan nasal spray is rapidly absorbed via the
`nasopharynx as detected in a Photon Emission Tomography (PET)
`study using ”C zolmitn'ptan. 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 alter single (1 day) or
`multiple
`(4 day) nasal
`dosing. Plasma
`concentrations of
`mlmitn'ptan are
`sustained for 4 to 6 hours afier dosing.
`Zolmitriptan displays linear kinetics alter multiple doses of 2.5 mg,
`5 mg, or 10 mg. The mean relative bioavailability of the nasal
`spray formulation is 102%, compared to the oral tablet.
`l.
`
`Zolmitriptan and its active metabolite display dose proportionality
`alter single or multiple dosing. Dose proportional
`increases in
`zolmitriptan and N-desmethyl metabolite Cm... and AUC were
`observed
`for
`2.5
`and
`5 mg
`nasal
`spray
`doses. The
`phannacokinetics for elimination of zolmilriptan and its active N-
`desmethyl metabolite are similar for all nasal spray dosages. The
`N-desmethyl metabolite is detected in plasma by 15 minutes and
`peak plasma concentration is generally achieved by 3 hours afier
`administration.
`
`
`
`
`
`Food has no significant
`mlmitriptan.
`
`effect on the bioavailability of
`
`Distribution: Plasma protein binding of zolmitriptan is 25% over
`the concentration range of lO-lOOOng/mL. The mean (:|:SD)
`apparent volume of distribution for zolluilriptan nasal
`spray
`formulation is 8.6fl.3 Ulrg.
`
`' Metabolism: Zolmitriptan is converted to an active N—desmethyl
`metabolite such that the metabolite concentrations are about two-
`thirds that of zolmitriptan. Because the SHTlann 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
`afier zolmitriptan administration.
`
`Excretlon: The mean elimination half- life for zohnitriptan and its
`active
`N—desmethyl, metabolite
`following
`nasal
`spray
`administration are approximately 3 hours,'which is similar to the
`halillife values seen afier oral tablet administration. The half- life
`
`for zohnitriptan and the N—desmethyl
`values were similar
`metabolite after single (1 day) and multiple (4 day) nasal dosing.
`
`Mean total plasma clearance 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.
`
`Special Populations
`Age: The phannacokinetics of oral zolmitriptan in healthy elderly
`non- migraineur volunteers (age 65 - 76 yrs) was similar to those in
`younger non-migraineur volunteers (age 18-39 yrs).
`
`Gender: Mean plasma concentrations of orally administered
`zolmitriptan were up to 15-fold higher in females than males.
`
`impairment on the
`Impairment: The effect of renal
`Renal
`phannacokinetics of zolrnitriptan nasal
`spray has not been
`evaluated. Afier orally dosing zolmitriptan, renal clearance was
`reduced by 25% in patients with severe renal impairment (Clcr 2 5
`S 25 mUmin) compared to the normal group (Clcr 2 70 lemin);
`no significant change in renal clearance was observed in the
`_ moderately renally impaired group (C lcr 2 26 S 50 mUmin).
`
`
`
`
`
`
`
`
`
`Hepatic Impainnent: The effect of hepatic disease on the
`pharrnacokinetics of zolmitriptan nasal
`spray has not been
`evaluated. In severely hepatically impaired patients, the mean Cm“,
`Tm, and AUCo-.. of zolmitriptan dosed orally were increased 1.5,
`2, and 3-fold, respectively, compued to normals. Seven out of 27
`patients experienced 20 to 80 mm Hg elevations in systolic and/or
`diastolic blood pressure after a 10 mg dose. Because of the
`similarity in exposure, zolmitriptan tablets and nasal spray should
`have similar dosage adjustments and should be administered with
`caution in subjects with liver disease, generally using doses less
`than 2.5 mg. Doses lower than 5 mg can only be achieved through
`the use of
`an oral
`formulation.
`(see WARNINGS and
`PRECAUTIONS).
`
`Hypertensive Patients: No differences in the pharmacokinetics
`of oral zolmitriptan or its effects on blood pressure were seen in
`mild
`to moderate
`hypertensive
`volunteers
`compared
`to
`norrnotensive controls.
`
`Race: Retrospective analysis of pharmacokinetic data between
`Japanese and Caucasians revealed no significant differences for
`orally dosed zolmitriptan.
`
`Drug Interactions: All drug interaction studies were performed
`in healthy volunteers using a single 10 mg dose of zolmitr'ptan and
`a single dose of the other drug except where otherwise noted.
`Eight drug interaction studies have been performed with
`zolrnitriptan tablets and one study (xylometazoline) was performed
`with nasal spray.
`
`Xylometazoline: An in vivo drug interaction study with ZOMIG
`Nasal Spray indicated that 1 spray (lOOpL dose) of xylometazoline
`(0.1% WV), :1 decongestant, administered 30 minutes prior to a 5
`mg nasal dose of zolrnilriptan did not alter the pharmacokinetics of
`zolmitriptan.
`
`Fluoxetine: The phannacokinefics of zolmitriptan, as well as its
`effect on blood pressure, were unaffected by 4 weeks of
`pretreatment with oral fluoxetine (20 mglday).
`
`
`
`MAO Inhibitors: Following one week of administration of 150
`mg bid moclobemide, a specific MAO-A inhibitor, here was an
`increase of about 25% in both C“, and AUC for zolmitriptan and
`a 3-fold increase in the C...“ and‘AUC of the active N-desmethyl
`metabolite of zolmiln'ptan (see CONTRAINDICATIONS and
`PRECAUTIONS).
`
`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.
`
`Propranolol: CIm and AUC of zolmitriptan increased 15-fold
`afier one week of dosing with propranolol (160 nag/day). Cmax 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
`zolmitn'ptan.
`'
`
`Acetaminophen: A single 1 g dose of acetaminophen does not
`alter the pharmcolcinetics of zolmiuiptan and its N-desmethyl
`metabolite.
`However,
`zolmitriptan delayed
`the
`Tmax
`of
`acetaminophen by one hour.
`
`Metoclopramide: A single 10 mg dose of metoclopramide had no
`effect on the pharmacokinetics of zolmiuiptan or its metabolites.
`
`Oral Contraceptives: Retrospective analysis of pharmacokinetie
`data across studies indicated that mean plasma concentrations of
`zolmitriptan were generally higher
`in females
`taking oral
`contraceptives compared to those not taking oral contraceptives.
`Mean C1mm and AUC of zolmitriptan were found to be higher by
`30% and 50%, respectively, and T...“ was delayed by one-half hour
`in females taking oral contraceptives. The effect of zolmitriptan
`on the pharmacokinetics of oral contraceptives has not been
`studied.
`
`the
`Following the administration of cimetidine,
`Cimetidine:
`half-life and AUC of a 5 mg dose of zolmitriptan and its active
`metabolite were approximately doubled (see PRECAUTIONS).
`
`Cllnlcal Studles:
`
`The efficacy of ZOMIG Nasal Spray 5 mg in the acute treatment of
`migraine headache with or without aura was demonstrated in a
`randomized, outpatient, double—blind, placebo—controlled trial.
`
`
`
`Patients were instructed to treat a moderate to severe headache.
`
`Headache response, defined as a reduction in headache severity
`from moderate or severe pain to mild or no pain, was assessed 15,
`30, 45 minutes and l, 2, and 4 hours afier dosing. Pain free
`response
`rates
`and associated symptoms
`such as nausea,
`photophobia, and phonophobia were also assessed. A dose of
`escape medication was allowed 4 to 24 hours after the initial
`treatment for persistent and recurrent headache.
`
`0f the 1372 patients treated in the study, 83% were female and
`99% were Caucasian, with a mean age of 40.6 years (range 18 to
`65 years).
`
`The two hour headache response rates in patients treated with
`ZOMIG Nasal Spray were statistically significant among patients
`receiving ZOMIG Nasal Spray compared to placebo. There was a
`greater percentage of patients with a headache response at 2 hours
`in the higher dose groups.
`The headache response efficacy
`endpoints of the controlled clinical study, analyzed from the first
`attack data, are shown in Table 1.
`
`Table 1: First Attack Data: Percentage of Patients with
`Headache Response to ZOMIG Nasal Spray (Mild or No
`Headache) 2 Hours Following Treatment
`(N = number of randomized patients treating a migraine attack).
`The 2 hour headache response was the primary end-point
`
`PLACEBO
`
`ZOMIG
`
`235 um— 69%
`
`226
`
`5 mg
`
`Ip <0.0001 in comparison with placebo
`
`The estimated probability of achieving an initial headache response
`by 4 hours following treatment with ZOMIG Nasal Spray is
`depicted in Figure 1.
`
`
`
`MummdM—wmmmlmdmw
`
` “Minn—lullausslsaasi
`
`”III-w-
`
`shows the Kaplan—Meier plot of the
`Figure 1
`Note:
`time of obtaining headache response
`probability over
`(moderate or severe headache improving to mild or no
`pain) following treatment with zolmitn'ptan nasal spray.
`The averages displayed are based on a placebo controlled,
`outpatient trial providing evidence of efficacy. Patients not
`achieving headache response or taking additional treatment
`prior to 4 hours were censored to 4 hours.
`
`For patients with migraine associated photophobia, phonophobia,
`and nausea at baseline, there was a decreased incidence of these
`
`symptoms following administration of ZOMIG Nasal Spray as
`compared to placebo.
`
`Four to 24 hours following the initial dose of study treatment,
`patients were allowed to use additional treatment for pain relief in
`the form of a second dose of study treatment or other medication.
`The estimated probability of patients taking a second dose or other
`medication for migraine over the 24 hours following the initial
`dose of study treatment is summarized in Figure 2.
`
`
`
`
`
`mothhfl-lmfl-fllflmowflwuummhfldmdm
`
`*5!) MG nasal spray
`AAAAAA
`
`:sssllassi mfldmaw—lfllm
`
`*This Kaplan-Meier plot is based on data obtained from the
`placebo controlled clinical
`trial.
`Patients not using
`additional treatments were censored at 24 hours. The plot
`includes both patients who had headache response at 2
`hours and those who had no response to the initial dose. It
`should be noted that
`the
`protocol
`did not
`allow
`remedication within 4 hours post dose.
`
`'
`
`The efficacy of ZOMIG was unaffected by presence of aura;
`presence of headache upon awakening, relationship to menses;
`gender, age or weight of the patient; or presence of pretreatment
`nausea.
`
`The efficacy of ZOMIG Nasal Spray 5 mg was firrther supported by an
`interim analysis of another similarly designed trial. The 2 hour headache
`response rates for the first 210 subjects in that study for ZOMIG 5 mg
`and placebo were 70% and 47%,
`respectively (N=108 and 102,
`respectively, p=0.0006).
`
`. INDICATIONS AND USAGE:
`
`ZOMIG Nasal Spray is indicated for the acute treatment of
`migraine with or without aura in adults.
`
`ZOMIG is not intended for the prophylactic therapy of migraine or
`for use in the management of hemiplegic or basilar migraine (see
`CONTRAINDICATIONS). Safety and effectiveness of ZOMIG
`have not been established for cluster headache, which is present in
`an older, predominantly male pOpulation.
`
`
`
`CONTRAINDICATIONS
`
`ZOMIG should not be given to patients with ischemic heart
`disease (angina pectoris, history of myocardial infarction, or
`documented silent ischemia) or to patients who have symptoms
`or findings consistent with ischemic heart disease, coronary
`artery vasospasm, including Prinzmetal’s variant angina, or
`other
`significant underlying cardiovascular disease
`(see
`WARNINGS).
`
`ZOMIG should not be given to patients with cerebrovascular
`syndromes including (but not limited to) stroke of any type as
`well as transient ischemic attacks.
`
`Because ZOMIG may increase blood pressure, it should not be
`given
`to
`patients with
`uncontrolled
`hypertension
`(see
`WARNINGS).
`
`ZOMIG should not he used within 24 hours of treatment with
`
`another 5-HT; agonist, or an ergotamine-containing or target-
`type medication like dihydroergotamine or methysergide.
`ZOMIG should not
`be
`administered to patients with
`hemiplegic or basilar migraine.
`
`Concurrent administration of MAO-A inhibitors or use of
`
`zolmitriptan within 2 weeks of discontinuation of MAO-A
`inhibitor
`therapy
`is
`contraindicated
`(see CLINICAL
`PHARMACOLOGY: Drug Interactions and PRECAUTIONS:
`Drug Interactions).
`
`ZOMIG is contraindicated in patients who are hypersensitive
`to zolmitriptan or any of its inactive ingredients.
`
`WARNINGS
`
`ZOMIG should only be used where a clear diagnosis of
`migraine has been established.
`
`
`
`Risk of Myocardial lschemia andlor Infarction and Other
`Adverse Cardiac Events:
`
`ZOMIG should not be given to patients with documented
`ischemic or
`vasospastic
`coronary
`artery
`disease
`(see
`CONTRAINDICATIONS).
`It is strongly recommended that
`zolmitriptan not be given to patients in whom unrecognized
`coronary artery disease (CAD) is predicted by the presence of
`risk factors (eg, hypertension, hypercholesterolemia, smoker,
`obesity, diabetes, strong family history of CAD, female with
`surgical or physiological menopause, or male over 40 years of
`age) unless a cardiovascular evaluation provides satisfactory
`clinical evidence that the patient is reasonably free of coronary
`artery and ischemic myocardial disease or other significant
`underlying cardiovascular disease. The sensitivity of cardiac
`diagnostic procedures to detect cardiovascular disease or
`predisposition to coronary artery vasospasm is modest, at best.
`If, during the cardiovascular evaluation, the patient’s medical
`history, electrocardiographic or other investigations reveal
`findings indicative of, or consistent with, coronary artery
`vasospasm or myocardial ischemia, zolmitriptan should not be
`administered (see CONTRAINDICATIONS). For patients with
`risk factors predictive of CAD, who are determined to have a
`satisfactory
`cardiovascular
`evaluation,
`it
`is
`strongly
`recommended that administration of
`the first dose of
`
`zolmitriptan take place in the setting of a physician’s office or
`Similar medically staffed and equipped facility unless the
`patient has previously received zolmitriptan.
`
`Because cardiac ischemia can occur in the absence of clinical
`
`symptoms, consideration should be given to obtaining on the
`first occasion of use an electrocardiogram (ECG) during the
`interval immediately following ZOMIG, in these patients with
`risk factors.
`
`It is recommended that patients who are intermittent long-
`term users of ZOMIG and who have or acquire risk factors
`predictive of CAD, as described above, undergo periodic
`interval cardiovascular evaluation as they continue to use
`ZOMIG.
`
`The systematic approach described above is intended to reduce
`the likelihood that patients with unrecognized cardiovascular
`disease will be inadvertently exposed to zolmitriptan.
`
`10
`
`
`
`Cardiac Events and Fatalities:
`
`Serious adverse cardiac
`
`events, including acute myocardial infarction, have been reported
`within a few hours
`following administration of zolmitriptan.
`Life-threatening disturbances of cardiac rhythm, and death have
`been reported within a few hours following the administration of
`other 5-HT} agonists. Considering the extent of use of 5-HT1
`agonists in patients with migraine, the incidence of these events is
`extremely low.
`
`ZOMIG can cause coronary vasospasm; at least one of these events
`occurred in a patient with no cardiac disease history and with
`documented absence of coronary artery disease. Because of the
`close proximity of the events to ZOMIG use, a causal relationship
`cannot be excluded.
`In the cases where there has been known
`
`underlying coronary artery disease, the relationship is uncertain.
`
`Patients with symptomatic Wolff-ParkinsonWhite syndrome or
`arrhythmias associated with other cardiac accessory conduction
`pathway disorders should not receive ZOMIG.
`
`Premarketing experience with zolmitn'ptan: Among the more
`than 2,500 patients with migraine who participated in premarketing
`controlled clinical trials of ZOMIG Tablets, no deaths or serious
`
`cardiac events were reported. In premarketing controlled clinical
`trial of ZOMIG Nasal Spray, more than 1300 patients participated
`and there were no deaths or serious cardiac events to report.
`
`Serious
`zolmitriptan:
`with
`experience
`Postmarketing
`cardiovascular events have been reported in association with the
`use of ZOMIG Tablets, and in very rare cases, these events have
`occurred in the absence of known cardiovascular disease. The
`
`uncontrolled nature of postmarketing surveillance, however, makes
`it
`impossible to determine definitively the proportion of the
`reported cases that were actually caused by zolmitriptan or to
`reliably assess causation in individual cases.
`
`11
`
`
`
`
`
`
`
`5-HT1
`and Fatalities with
`Cerebrovascular Events
`agonists:
`Cereme hemorrhage,
`subarachnoid hemorrhage,
`stroke, and other cerebrovascular events have been reported in
`patients treated with 5-HT} agonists; and some have resulted in
`fatalities.
`In a number of cases,
`it appears possible that
`the
`cerebrovascular events were primary,
`the agonist having been
`administered in the incorrect belief that the symptoms experienced
`were a consequence of migraine, when they were not.
`It should be
`noted that patients with migraine may be at
`increased risk of
`certain cerebrovascular events (eg, stroke, hemorrhage, transient
`ischemic attack).
`
`5-Hr1 agonists may
`Other Vasospasm-Related Events:
`cause vasospastic reactions other than coronary artery vasospasm
`such as peripheral and gastrointestinal vascular ischemia. As with
`other serotonin SHTI agonists, very rare gastrointestinal ischemic
`events including ischemic colitis and gastrointestinal infarction or
`necrosis have been reported with ZOMIG Tablets;
`these may
`present as bloody diarrhea or abdominal pain.
`
`Increase in Blood Pressure: As with other SHT. agonists,
`
`in systemic blood pressure have been
`significant elevations
`reported on rare occasions with ZOMIG Tablet use, in patients
`with and without a history of hypertension; very rarely these
`increases in blood pressure have been associated with significant
`clinical events. Zolmitriptan is contraindicated in patients with
`uncontrolled hypertension.
`In volunteers, an increase of land 5
`mm Hg in the systolic and diastolic blood pressure, respectively,
`was seen at 5 mg. In the headache trials, vital signs were measured
`only in the small inpatient study and no effect on blood pressure
`was seen.
`In a study of patients with moderate to severe liver
`disease, 7 of 27 experienced 20 to 80 mm Hg elevations in systolic
`and/or diastolic blood pressure after a dose of 10 mg of
`zolmitriptan (see CONTRAINDICATIONS).
`
`An 18% increase in mean pulmonary artery pressure was seen
`following dosing with another 5-HT; agonist in a study evaluating
`subjects undergoing cardiac catheterization.
`
`12
`
`
`
`
`
`
`
`Local Adverse Reactions: Among 922 patients using the
`zolmitriptan nasal spray to treat 2311 attacks in the controlled
`clinical study who were exposed, across all doses (05 to 5 mg),
`approximately 3% noted local irritation or soreness at the site of
`administration. Adverse events of any kind, perceived in the
`nasopharynx (which may include systemic effects of triptans) were
`severe in about 1 % of patients and approximately 60% 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 ciinically significant changes with
`repeated use of ZOMIG Nasal Spray.
`
`All nasopharyngeal adverse events with an incidence of 2 2% of
`patients in any zohnitriptan nasal spray dose groups are included in
`ADVERSE REACTIONS Table 2.
`
`PRECAUTIONS
`
`sensations of
`General: As with other 5-HTIBHD agonists,
`tightness, pain, pressure, and heaviness have been reported after
`treatment with ZOMIG Tablets in the precordium,
`throat, neck,
`and jaw. Because zolmitriptan may cause
`coronary artery
`vasospasm, patients who experience signs or symptoms suggestive
`of angina following dosing should be evaluated for the presence of
`CAD or a predisposition to Prinzmetal’s variant angina before
`receiving additional doses of medication, and should be monitored
`electrocardiographically
`if
`closing
`is
`resumed
`and
`similar
`symptoms
`recur. Similarly, patients who experience other
`symptoms or signs suggestive of decreased arterial flow following
`the use of any 5-HT agonist, such as ischemic bowel syndrome or
`Raynaud’s syndrome, are candidates for further evaluation. (see
`WARNINGS).
`
`Zolmitn'ptan should also be administered with caution to patients
`with diseases that may alter
`the absorption, metabolism, or
`excretion of drugs,
`such as
`impaired hepatic
`function (see
`CLINICAL PHARMACOLOGY).
`
`For a given attack, if a patient does not respond to the first dose of
`zolmitriptan,
`the diagnosis of migraine headache should be
`reconsidered before administration of a second dose.
`
`13
`
`
`
`
`
`Binding to Melanin-Containing Tissues: When pigmented
`rats were given a single oral dose of 10 mg/kg of radiolabeled
`zohnitriptan, the radioactivity in the eye after 7 days, the latest
`time point examined, was still 75% of the value measured alter 4
`hours. This suggests that zolmitriptan and/or its metabolites may
`bind to the melanin of the eye.
`Because there could be
`accumulation in melanin rich tissues over time,
`this raises the
`possibility that zolmitn'ptan could cause toxicity in these tissues
`after extended use. However, no effects on the retina related to
`treatment with zolmitriptan were noted in any of the toxicity
`studies including those conducted by the nasal route. Although no
`systematic monitoring of ophthalmologic function was undertaken
`in
`clinical
`trials,
`and
`no
`specific
`recommendations
`for
`ophthalmologic monitoring are offered, prescribers should be
`aware of the possibility of long-term ophthalmologic effects.
`
`lnfonnation for Patients: See PATIENT INFORMATION at
`
`the end of this labeling for the figures and text of the separate
`leaflet provided for patients.
`
`The ZOMIG Nasal Spray device is packaged in a carton and is a
`blue colored plastic device with a gray protection cap, labeled to
`indicate the nominal dose. Patients should be cautioned to not
`remove the gray protection cap until prior to dosing. The ZOMIG
`Nasal Spray device is placed in a nostril and actuated to deliver a
`single dose. Patients should be cautioned to avoid spraying the
`contents of the device in their eyes.
`
`Laboratory Tests: No monitoring of Specific laboratory tests is
`recommended.
`
`Drug Interactions: Ergot-containing drugs have been reported
`to cause prolonged vasospastic reactions. Because there is a
`theoretical basis that
`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
`should
`be
`avoided
`(see
`CONTRAINDICATIONS).
`
`MAO-A inhibitors increase the systemic exposure of zolmitriptan.
`Therefore, the use of zolmitriptan in patients receiving MAO-A
`inhibitors is contraindicated (see CLINICAL PHARMACOLOGY
`and CONTRAINDICATIONS).
`
`14
`
`
`
`Concomitant use of other 5-HT lB/lD agonists within 24 hours of
`ZOMIG
`treatment
`is
`not
`recommended.
`(see
`CONTRAINDICATIONS).
`
`Following administration of cimetidine, the half-life and AUC of
`zolmitriptan and its active metabolites were approximately doubled
`(see CLINICAL PHARMACOLOGY).
`
`(eg, fluoxetine,
`Selective serotonin reuptake inhibitors (SSRIS)
`fluvoxamine, paroxetine, sertraline) have been reported, rarely, to
`cause weakness,
`hyperreflexia,
`and
`incoordination when
`coadrninistered with 5-HT} agonists.
`If concomitant treatment
`with zolmitriptan’and an SSRl is clinically warranted, appropriate
`observation of the patient is advised.
`
`Zolmitriptan is not
`DrugILaboratory Test Interactions:
`known to interfere with commonly employed clinical laboratory
`tests.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility:
`Carcinogenesis: Carcinogenicity studies by oral gavage were
`carried out in mice and rats at doses up to 400 mg/kg/day. Mice
`were dosed for 85 weeks (males) and 92 weeks (females). The
`exposure (plasma AUC of parent drug) at the highest dose level
`was approximately 800 times that seen in humans after a single 10
`mg dose (the maximum recommended total daily close). There was
`no effect of :olmitiiptan on tumor incidence. Control, low dose,
`and middle dose rats were closed for 104—105 weeks; the high dose
`group was sacrificed after 101 weeks (males) and 86 weeks
`(females) due to excess modality. Aside from an increase in the
`incidence of thyroid follicular cell hyperplasia and thyroid
`follicular cell
`adenomas
`seen in male rats
`receiving 400
`mgfkg/day, an exposure approximately 3000 times that seen in
`humans afier dosing with 10 mg, no tumors were noted.
`
`Mulagenesis: Zolmitriptan was mutaganic in an Ames test, in 2
`of 5 strains of S. typhimurium tested, in the presence of, but not in
`the absence of, metabolic activation. It was not mutagenic in an in
`vitro mammalian gene
`cell mutation (CHOIHGPRT)
`assay.
`Zolmitriptan was clastogenic in an in vitro human lymphocyte
`assay both in the absence of and the presence of metabolic
`activation. Zolrnitriptan was not clastogenic in in viva mouse and
`rat micronucleus assays. Zolmiuiptan was not genotoxic in an
`unscheduled DNA synthesis study.
`
`15
`
`
`
`
`
`
`
`Studies of male and female rats
`Impairment of Fertility:
`administered zolmitriptan prior to and during mating and up to
`implantation have shown no impairment of fertility at doses up to
`400 mg/kg/day. Exposure at this dose was approximately 3000
`times exposure at the maximum recommended human dose of 10
`mg/day.
`
`Pregnancy: Pregnancy Category C: There are no adequate
`and well
`controlled studies
`in pregnant women;
`therefore,
`zolrnitriptan should be used during pregnancy only if the potential
`benefit justifies the potential risk to the fetus.
`
`and rabbits, oral
`in rats
`toxicity studies
`In reproductive
`administration of zolmitriptan to pregnant animals was associated
`with embryolethality and fetal abnormalities. When pregnant rats
`were administered oral
`zolmitn'ptan during the period of
`organogenesis at doses of 100, 400, and 1200 mg/kg/day, there
`was a dose-related increase in embryolethality which became
`statistically significant at the high dose. The maternal plasma
`exposures at these doses were approximately 280, 1100, and 5000
`times
`the
`exposure
`in
`humans
`receiving
`the maximum
`recommended total daily dose of 10 mg. The high dose was
`maternally toxic, as evidenced by a decreased maternal body
`weight gain during gestation.
`In a similar study in rabbits,
`embryobthality was increased at the maternally toxic doses of 10
`and 30 mg/kg/day (maternal plasma exposures equivalent to 11
`and 42 times exposure in humans
`receiving the maximum
`recommended total daily dose of 10 mg), and increased incidences
`of fetal malformations (fiJsed sternebrae,
`rib anomalies) and
`variations (major blood vessel variations,
`irregular ossification
`pattern of ribs) were observed at 30 mg/kg/day. Three mgfkg/day
`was a no effect dose (equivalent to human exposure at a dose of 10
`mg). When female rats were given zolmitn'ptan during gestation,
`parturition, and lactation, an increased incidence of hydronephrosis
`was found in the offspring at the maternally toxic dose of 400
`mg/kg/day (1100 times human exposure).
`
`is not known whether zolmitriptan is
`It
`Nursing Mothers:
`excreted in human milk. Because many drugs are excreted in
`human milk, caution should be exercised when zolmin-iptan is
`administered to a nursing woman.
`Lactating rats dosed with
`zolmitriptan had levels in milk equivalent
`to materml plasma
`levels at 1 hour and 4 times higher than plasma levels at 4 hours.
`
`16
`
`
`
`Pediatric Use: Safety and effectiveness of ZOMIG in pediatric
`patients have not been established therefore ZOMIG is not
`recommended for use in patients under 18 years of age.
`
`Postmarketing experience with other triptans includes a limited
`number of reports that describe pediatric patients who have
`experienced clinically serious adverse events that are similar in
`nature to those reported rarely in adults.
`
`Geriatric Use: Although the pharmacokinetic disposition of the
`drug in the elderly is similar to that seen in younger adults, there is
`no information about the safety and effectiveness of zolmitriptan in
`this population because patients over age 65 were excluded from
`the controlled clinical trials (see CLINICAL PHARMACOLOGY:
`Special Populations).
`
`ADVERSE REACTIONS:
`
`Serious cardiac events, including myocardial infarction, have
`occurred following the use of ZOMIG Tablets. These events
`are extremely rare and most have been reported in patients
`with risk factors predictive of CAD. Events reported,
`in
`association with drugs of this class, have included coronary
`artery vasospasm, transient myocardial ischemia, myocardial
`infarction, ventricular tachycardia, and ventricular fibrillation
`(see
`CONTRAINDICATIONS,
`WARNINGS,
`and
`PRECAUTIONS).
`
`464
`Among
`Incidence in Controlled Clinical Trials:
`patients treating single attacks with zolmitriptan nasal spray in a
`blinded placebo controlled trial, there was a low withdrawal rate
`related to adverse events:
`5 mg (1.3%),
`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 ZOMIG
`Nasal Spray. The most common adverse events in clinical trials for
`ZOMIG Nasal Spray were:
`unusual
`taste,
`paresthesia,
`, hyperesthesia, and dizziness. Table 2 lists the adverse events that
`occurred in 2 2% of the 236 patients in the 5 mg dose group of
`the controlled clinical trial.
`
`17
`
`
`
`Table 2:
`
`Adverse events with an incidence of 2 2% of patients in the
`zolmitriptan 5 mg nasal spray treatment group by body system and
`greater than placebo.
`
`Body system and
`Adverse event
`
`Zolmilriptan nasal spray
`
`Placebo
`(N=228)
`
`5.0 mg
`(N=236)
`
`ATYPICAL SENSATIONS
`
`Hyperesthesia
`Paraesthesia
`EAR/NOSE/THROAT
`Disorder/Discomfort of nasal
`
`0%
`6%
`
`2%
`
`cavity
`PAIN AND PRESSURE SENSATIONS
`
`Pain Location Specified
`Pain Throat
`
`Tightness Throat
`DIGESTIVE
`
`Dry Mouth
`Nausea
`NEUROLOGICAL
`Dizziness
`Somnolence
`Unusual Taste
`OTHER
`Asthenia
`
`'
`
`1%
`, 1%
`
`1%
`
`0%
`1%
`
`4%
`2%
`3%
`
`1%
`
`5%
`10%
`
`3%
`
`4%
`4%
`
`2%
`
`2%
`4%
`
`3%
`4%
`21%
`
`3%
`
`Adverse clinical events occurring in 2 1% and < 2% of patients in
`all attacks of the controlled clinical trial were pain abdominal,
`pressure moat, vomiting, headache, tightness chest, d