SIC
`
`Rev 09/03
`
`Rx only
`
`ZOMIG (zolmitriptan) Nasal Spray
`
`For Nasal Use Only
`
`DESCRIPTION
`ZOMIG® (zolmitriptan) Nasal Spray contains zolmitriptan, which
`is a selective 5-hydroxytryptamine 1B/1D (5-HT1B/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 C16H21N3O2, representing a molecular
`weight of 287.36. Zolmitriptan 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
`100-µL unit dose aqueous buffered solution containing citric acid,
`anhydrous, USP, disodium phosphate dodecahydrate 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-HT1D and 5-HT1B receptors. Zolmitriptan
`exhibits modest affinity for 5-HT1A receptors, but has no
`significant affinity (as measured by radioligand binding assays) or
`pharmacological activity at 5-HT2, 5-HT3, 5-HT4, alpha1-, alpha2-
`or beta1-adrenergic; H1, H2, histaminic; muscarinic; dopamine1, or
`dopamine2 receptors. The N-desmethyl metabolite also has high
`affinity for 5-HT1B/1D and modest 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 can most likely be attributed to the agonist
`effects at the 5-HT1B/1D receptors on intracranial blood vessels
`(including the arterio-venous anastomoses) and sensory nerves of
`the trigeminal system which result in cranial vessel constriction
`and inhibition of pro-inflammatory neuropeptide release.
`
`Clinical Pharmacokinetics and Bioavailability:
`Absorption: Zolmitriptan nasal spray is rapidly absorbed via the
`nasopharynx as detected in a Photon Emission Tomography (PET)
`study using 11C zolmitriptan. 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 day) nasal dosing. Plasma concentrations of
`zolmitriptan are sustained for 4
`to 6 hours after dosing.
`Zolmitriptan displays linear kinetics after 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.
`
`Zolmitriptan and its active metabolite display dose proportionality
`after single or multiple dosing. Dose proportional increases in
`zolmitriptan and N-desmethyl metabolite Cmax and AUC were
`observed
`for 2.5 and 5 mg nasal
`spray doses. The
`pharmacokinetics for elimination of zolmitriptan 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 after
`administration.
`
`
`
`
`2
`
`

`

`the bioavailability of
`
`Food has no significant effect on
`zolmitriptan.
`
`Distribution: Plasma protein binding of zolmitriptan is 25% over
`the concentration range of 10-1000ng/mL. The mean (±SD)
`apparent volume of distribution for zolmitriptan nasal spray
`formulation is 8.6– 3.3 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 5HT1B/1D potency of the
`metabolite is 2 to 6 times that of the parent compound, the
`metabolite may contribute a substantial portion of the overall effect
`after zolmitriptan administration.
`
`
`Excretion: The mean elimination half-life for zolmitriptan and its
`active N-desmethyl metabolite
`following
`nasal
`spray
`administration are approximately 3 hours, which is similar to the
`half-life values seen after oral tablet administration. The half-life
`values were similar for zolmitriptan and
`the N-desmethyl
`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 pharmacokinetics 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 1.5-fold higher in females than males.
`
`Renal Impairment: 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 to the normal group (Clcr ‡
` 70 mL/min);
`no significant change in renal clearance was observed in the
`moderately renally impaired group (Clcr ‡
` 26 £
` 50 mL/min).
`
`
`
`
`3
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`

`Hepatic Impairment: The effect of hepatic disease on the
`pharmacokinetics of zolmitriptan nasal spray has not been
`evaluated. In severely hepatically impaired patients, the mean Cmax,
`Tmax, and AUC0-¥ of zolmitriptan dosed orally were increased 1.5,
`2, and 3-fold, respectively, compared 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
`normotensive 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 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.
`
`Xylometazoline: An in vivo drug interaction study with ZOMIG
`Nasal Spray indicated that 1 spray (100µL 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.
`
`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).
`
`
`
`
`4
`
`

`

`MAO Inhibitors: Following one week of administration of 150
`mg bid moclobemide, a specific MAO-A inhibitor, there was an
`increase of about 25% in both Cmax and AUC for zolmitriptan and
`a 3-fold increase in the Cmax and AUC of the active N-desmethyl
`metabolite of zolmitriptan (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: Cmax and AUC of zolmitriptan 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 interactive effects on blood
`pressure or pulse rate following administration of propranolol with
`zolmitriptan.
`
`Acetaminophen: A single 1 g dose of acetaminophen does not
`alter the pharmacokinetics of zolmitriptan 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 zolmitriptan or its metabolites.
`
`Oral Contraceptives: Retrospective analysis of pharmacokinetic
`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 Cmax and AUC of zolmitriptan were found to be higher by
`30% and 50%, respectively, and Tmax 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.
`
`Cimetidine: Following the administration of cimetidine, the
`half-life and AUC of a 5 mg dose of zolmitriptan and its active
`metabolite were approximately doubled (see PRECAUTIONS).
`
`Clinical Studies:
`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.
`
`
`
`5
`
`

`

`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 1, 2, and 4 hours after 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.
`
`Of 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
`
`(226)
`31%
`
`ZOMIG
`5 mg
`(235)
`69% ‡
`
`
`
` N
`
`
`2 hours
`
`.
`‡p <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.
`
`
`
`6
`
`

`

`Figure 1: Estimated probability of achieving an initial headache response within 4 hours of initial treatment
`
`5.0 MG nasal spray
`Placebo
`
`0.5
`
`1.0
`
`1.5
`
`2.0
`
`2.5
`
`3.0
`
`3.5
`
`4.0
`
`Hours from initial dose
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`Estimated probability of response (%)
`
`0
`
`0.0
`
`
`
`
`
`Note: Figure 1 shows the Kaplan-Meier plot of the
`probability over time of obtaining headache response
`(moderate or severe headache improving to mild or no
`pain) following treatment with zolmitriptan 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.
`
`
`
`
`7
`
`

`

`Figure 2: Estimated probability of patients taking a escape medication over the 24 hours following the initial dose of study
`treatment
`
`5.0 MG nasal spray
`Placebo
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Estimated probability of taking a escape medication (%)
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`Hours from initial dose
`
`14
`
`16
`
`18
`
`20
`
`22
`
`24
`
`
`
`*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 further 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.
`
`
`
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`

`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 be used within 24 hours of treatment with
`another 5-HT1 agonist, or an ergotamine-containing or ergot-
`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.
`
`
`
`
`9
`
`

`

`Risk of Myocardial Ischemia and/or 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.
`
`
`
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`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-HT1 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-Parkinson-White syndrome or
`arrhythmias associated with other cardiac accessory conduction
`pathway disorders should not receive ZOMIG.
`
`Premarketing experience with zolmitriptan: 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:
`experience with
`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.
`
`
`
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`11
`
`

`

`Cerebrovascular Events and Fatalities with 5-HT1
`agonists: Cerebral hemorrhage, subarachnoid hemorrhage,
`stroke, and other cerebrovascular events have been reported 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 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).
`
`Other Vasospasm-Related Events: 5-HT1 agonists may
`cause vasospastic reactions other than coronary artery vasospasm
`such as peripheral and gastrointestinal vascular ischemia. As with
`other serotonin 5HT1 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 5-HT1 agonists,
`significant elevations in systemic blood pressure have been
`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 1 and 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-HT1 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 (0.5 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 clinically significant changes with
`repeated use of ZOMIG Nasal Spray.
`
`All nasopharyngeal adverse events with an incidence of ‡
` 2% of
`patients in any zolmitriptan nasal spray dose groups are included in
`ADVERSE REACTIONS Table 2.
`
`
`PRECAUTIONS
`General: As with other 5-HT1B/1D agonists, sensations of
`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 dosing
`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).
`
`Zolmitriptan 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
`zolmitriptan, the radioactivity in the eye after 7 days, the latest
`time point examined, was still 75% of the value measured after 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 zolmitriptan 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.
`
`Information 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 1B/1D 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).
`
`Selective serotonin reuptake inhibitors (SSRIs) (eg, fluoxetine,
`fluvoxamine, paroxetine, sertraline) have been reported, rarely, to
`cause weakness, hyperreflexia,
`and
`incoordination when
`coadministered with 5-HT1 agonists. If concomitant treatment
`with zolmitriptan and an SSRI is clinically warranted, appropriate
`observation of the patient is advised.
`
`Drug/Laboratory Test Interactions: Zolmitriptan is not
`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 dose). There was
`no effect of zolmitriptan on tumor incidence. Control, low dose,
`and middle dose rats were dosed for 104-105 weeks; the high dose
`group was sacrificed after 101 weeks (males) and 86 weeks
`(females) due to excess mortality. Aside from an increase in the
`incidence of thyroid follicular cell hyperplasia and thyroid
`follicular cell adenomas seen
`in male rats receiving 400
`mg/kg/day, an exposure approximately 3000 times that seen in
`humans after dosing with 10 mg, no tumors were noted.
`
`Mutagenesis: Zolmitriptan was mutagenic 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 (CHO/HGPRT) assay.
`Zolmitriptan was clastogenic in an in vitro human lymphocyte
`assay both in the absence of and the presence of metabolic
`activation. Zolmitriptan was not clastogenic in in vivo mouse and
`rat micronucleus assays. Zolmitriptan was not genotoxic in an
`unscheduled DNA synthesis study.
`
`
`
`
`15
`
`

`

`Impairment of Fertility: Studies of male and female rats
`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,
`zolmitriptan should be used during pregnancy only if the potential
`benefit justifies the potential risk to the fetus.
`
`in rats and rabbits, oral
`toxicity studies
`In reproductive
`administration of zolmitriptan to pregnant animals was associated
`with embryolethality and fetal abnormalities. When pregnant rats
`were administered oral zolmitriptan 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,
`embryolethality 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 (fused sternebrae, rib anomalies) and
`variations (major blood vessel variations, irregular ossification
`pattern of ribs) were observed at 30 mg/kg/day. Three mg/kg/day
`was a no effect dose (equivalent to human exposure at a dose of 10
`mg). When female rats were given zolmitriptan 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).
`
`Nursing Mothers: It is not known whether zolmitriptan is
`excreted in human milk. Because many drugs are excreted in
`human milk, caution should be exercised when zolmitriptan is
`administered to a nursing woman. Lactating rats dosed with
`zolmitriptan had levels in milk equivalent to maternal 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).
`
`Incidence in Controlled Clinical Trials: Among 464
`patients treating single attacks with zolmitriptan nasal spray in a
`blinded placebo controlled trial, there was a low withdrawal rate
`related to adverse event