Zolmitriptan (Systemic)


VA CLASSIFICATION
Primary: CN105

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antimigraine agent—

Indications

General considerations
Zolmitriptan should only be prescribed for patients who have an established clear diagnosis of migraine. Zolmitriptan is not intended for the prophylactic therapy of migraine. {01}.

Accepted

Headache, migraine (treatment)—Zolmitriptan is indicated to relieve (abort) acute migraine headaches (with or without aura) {01}.

Unaccepted
Zolmitriptan is not recommended for treatment of basilar artery migraine or hemiplegic migraine. Efficacy and safety of zolmitriptan in these conditions have not been established {01}.

Zolmitriptan is not recommended for treatment of cluster headaches. Efficacy and safety of zolmitriptan in this condition have not been established {01}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Synthetic. Zolmitriptan is structurally related to serotonin (5-hydroxytryptamine, 5-HT) {01}.
Molecular weight—
    287.36 {01}

Mechanism of action/Effect:

Zolmitriptan"s mechanism of action has not been established {01}. It is thought that agonist activity at the 5-HT 1D and 5-HT 1B receptor subtypes provides relief of headaches {01}. Zolmitriptan is a highly selective agonist at these receptor subtypes; it has no significant activity at 5-HT 2, 5-HT 3, or 5-HT 4 receptor subtypes or at adrenergic, dopaminergic, histamine, or muscarinic receptors {01}. However, zolmitriptan has moderate activity at the 5-HT 1A receptor subtype. It has been proposed that constriction of cerebral blood vessels resulting from 5-HT 1D/1B receptor stimulation reduces the pulsation that may be responsible for the pain of vascular headaches {01}. It has also been proposed that zolmitriptan may relieve migraines by decreasing the release of neuropeptides {01}.

Absorption:

Oral—Rapid; bioavailability is moderate (40%) {01}. The rate and extent of absorption are not affected by administration with food {01}.

Protein binding:

Low (25%) {01}.

Biotransformation:

Hepatic; three metabolites have been identified: indole acetic acid, N-oxide, and N-desmethyl metabolites. However, N-desmethyl is the only active metabolite {01}.

Half-life:


Elimination:

Zolmitriptan: Approximately 3 hours {01}

N-desmethyl metabolite: Approximately 3 hours {01}


Time to peak concentration:

Tablet—1.5 hours{02}.

Orally disintegrating tablet— 3 hours{02}.

Elimination:
    Renal—65% (8% of the dose as unchanged zolmitriptan; 31% as the indole acetic acid metabolite; 7% as the N-oxide metabolite; 4% as the N-desmethyl metabolite {01}.
    Fecal—30% {01}.


Precautions to Consider

Carcinogenicity/Tumorigenicity

In 85- and 92-week carcinogenicity studies in male and female mice, respectively, given zolmitriptan by oral gavage at doses of 400 mg per kg of body weight (mg/kg) (quantities sufficient to achieve peak concentrations of up to 800 times the maximum recommended human dose [MRHD]), no evidence of tumorigenicity was found {01}. However, in a 104- to 105-week study in rats, the high-dose male and female rats were sacrificed, due to excess mortality, after receiving zolmitriptan 400 mg/kg per day for 101 weeks and 86 weeks, respectively {01}. Although there was no evidence of tumorigenicity in male rats receiving 400 mg/kg per day of zolmitriptan (quantities sufficient to achieve peak concentrations approximately 3000 times the MRHD), an increased incidence of thyroid follicular cell hyperplasia and thyroid follicular cell adenomas occurred in male rats {01}.

Mutagenicity

Zolmitriptan demonstrated mutagenic effects in two of five strains of Salmonella typhimurium tested in an Ames test in the presence of metabolic activation {01}. However, no mutagenic activity was found in an in vitro mammalian gene cell mutation assay {01}. There was evidence of clastogenic activity in an in vitro human lymphocyte assay, with and without metabolic activation, but no evidence of clastogenic activity was observed in the in vivo mouse micronucleus assay {01}. Also, there was no genotoxicity observed in an unscheduled DNA synthesis study {01}.

Pregnancy/Reproduction
Fertility—
Reproduction studies in male and female rats given zolmitriptan doses of up to 400 mg per kg of body weight (mg/kg) per day (approximately 3000 times the maximum recommended human dose [MRHD]) found no effect on fertility {01}.

Pregnancy—
Adequate and well-controlled trials have not been done in pregnant women {01}.

Reproductive toxicity studies in pregnant rats and rabbits found evidence of embryolethality and fetal abnormalities {01}. During the organogenesis period, studies in pregnant rats receiving doses of 100, 400, and 1200 mg/kg per day (approximately 280, 1100, and 5000 times the MRHD, respectively) resulted in a dose-related increase in embryolethality {01}. The higher dose was found to be maternotoxic, which resulted in decreased maternal body weight gain during gestation {01}. In a study in rabbits, embryolethality was increased at maternally toxic doses of 10 and 30 mg/kg per day (equivalent to 11 and 42 times the MRHD, respectively) {01}. In addition, at doses of 30 mg/kg per day there was evidence of an increase in fetal malformations, such as fused sternebrae, rib anomalies, major blood vessel variations, and an irregular ossification pattern of ribs {01}. Also, hydronephrosis was observed in the offspring of female rats receiving zolmitriptan 400 mg/kg per day (approximately 1100 times the MRHD) {01}.

FDA Pregnancy Category C {01}.

Breast-feeding

It is not known whether zolmitriptan is distributed into breast milk {01}.

Zolmitriptan was found to be distributed into the milk of lactating rats {01}. The concentration of zolmitriptan in the rat milk was equivalent to maternal plasma concentrations at 1 hour and four times higher than maternal plasma concentrations at 4 hours {01}.

Pediatrics

Appropriate studies on the relationship of age to the effects of zolmitriptan have not been performed in children up to 12 years of age.



Adolescents

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of zolmitriptan in adolescents.


Geriatrics


No information is available on the relationship of age to the effects of zolmitriptan in geriatric patients {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Cimetidine    (concurrent use of cimetidine and zolmitriptan may cause an increase in half-life and area under the plasma concentration–time curve of zolmitriptan {01})


Dihydroergotamine or
Ergotamine or
Methysergide or
Other 5-hydroxytryptamine agonists such as:
Sumatriptan     (a delay of 24 hours between administration of dihydroergotamine, ergotamine, methysergide, or other 5-hydroxytryptamine agonists and zolmitriptan is recommended because of the possibility of additive and/or prolonged vasoconstriction {01})


Selective serotonin reuptake inhibitors, such as:
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline    (concurrent use may result in weakness, hyperreflexia, and incoordination; monitoring is recommended {01})


» Monoamine oxidase-A (MAO-A) inhibitors, including furazolidone, procarbazine, and selegiline    (concurrent use may increase systemic exposure of zolmitriptan; zolmitriptan should not be taken during or within 14 days following administration of an MAO-A inhibitor)

{01}

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Blood pressure    (may be increased; in healthy volunteers blood pressure elevations [increase in systolic and diastolic by 1 mm Hg and 5 mm Hg, respectively] occurred in patients receiving a 5-mg dose; however, a small study evaluating patients with moderate to severe liver disease receiving a 10-mg dose, resulted in elevations in systolic and/or diastolic pressure [20 mm Hg to 80 mm Hg] {01}; monitoring is recommended in patients with hepatic impairment and hepatic disease)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Cardiac arrythmias or
» Wolff-Parkinson-White syndrome    (may exacerbate condition {01})


» Coronary artery disease, especially:
Angina pectoris
Myocardial infarction, history of
Myocardial ischemia, silent, documented
Prinzmetal"s angina or
» Other conditions in which coronary vasoconstriction would be detrimental    (zolmitriptan may cause coronary vasospasms {01})


» Hypertension, uncontrolled    (may be exacerbated {01})


Risk-benefit should be considered when the following medical problems exist
» Cerebrovascular accident, history of    (zolmitriptan may cause cerebral hemorrhage, subarachnoid hemorrhage, or stroke; caution should be used when administering in patients at risk for cerebrovascular events {01})


» Coronary artery disease, predisposition to    (zolmitriptan may cause serious coronary adverse effects; patients in whom coronary artery disease is a possibility on the basis of age or the presence of other risk factors, such as diabetes, hypercholesterolemia, obesity, a strong family history of coronary artery disease, or tobacco smoking, should be evaluated for the presence of cardiovascular disease before zolmitriptan is prescribed; even after a satisfactory evaluation, the advisability of administering the patient"s first dose under medical supervision should be considered {01})


» Hepatic disease or
» Hepatic function impairment, severe or
Renal function impairment, severe    (studies have shown a decreased clearance in zolmitriptan in patients with severe renal or hepatic impairment; caution is recommended; a dosage adjustment is recommended in patients with hepatic impairment and hepatic disease {01})


» Hypertension, controlled    (may precipitate an increase in systolic and diastolic blood pressure {01})


» Hypersensitivity to zolmitriptan
» Phenylketonuria (PKU)    ( Zomig-ZMT brand of oral disintegrating tablets contains aspartame, which is metabolized to phenylalanine, and must be used with caution in patients with PKU)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood pressure determinations    (monitoring is recommended for patients with hepatic impairment)


Electrocardiogram (ECG)    (monitoring is recommended for long-term intermittent users of zolmitriptan )




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Chest pain, severe
    
heaviness, tightness, or pressure in chest and/or neck
    
paresthesias (sensation of burning, warmth, heat, numbness, tightness, or tingling)

Note: Although chest pain and heaviness, tightness, or pressure in the chest and/or neck are suggestive of angina pectoris, monitoring of the electrocardiogram (ECG) during such symptoms in clinical studies failed to detect evidence of myocardial ischemia or arrythmias. Zolmitriptan-induced coronary artery vasospasm resulting in symptomatic myocardial ischemia and myocardial infarction have not been documented in patients taking zolmitriptan.


Incidence less frequent
    
Arrythmias (irregular heartbeat)
    
gastroenteritis (severe abdominal pain; diarrhea; loss of appetite; nausea; weakness)

Incidence rare
    
Leukopenia (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Asthenia (unusual tiredness or muscle weakness)
    
dizziness
    
nausea
    
somnolence (sleepiness)

Incidence less frequent
    
Central nervous system effects, including agitation
anxiety
and depression
    
discomfort in jaw, mouth, or throat
    
dry mouth
    
dyspepsia (heartburn)
    
dysphagia (difficulty swallowing)
    
ecchymosis (large, nonelevated blue or purplish patches in the skin)
    
edema (swelling of face, fingers, feet and/or lower legs)
    
hypertension (increased blood pressure)
    
myalgia (muscle aches)
    
palpitations (pounding heartbeat)
    
polyuria (sudden, large increase in frequency and quantity of urine)
    
pruritus (itching of the skin)
    
skin rash
    
sweating
    
syncope (fainting)





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
Monitoring—Patients should be monitored for at least 15 hours after an overdose of zolmitriptan {01}.

Supportive care—Maintaining an open airway and breathing, maintaining proper fluid and electrolyte balance, and/or correcting hypertension {01}. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Zolmitriptan (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to zolmitriptan
Other medications, especially monamine oxidase inhibitors
Other medical problems, especially cardiac arrythmias, cerebrovascular accident (history of), coronary artery disease, predisposition to coronary artery disease, or other conditions that may be adversely affected by coronary artery constriction, hepatic disease, hepatic function impairment (severe), hypertension, phenylketonuria, Wolf-Parkinson-White syndrome

Proper use of this medication
» Not administering if atypical headache symptoms are present; checking with physician instead

Administering after onset of headache pain

Additional benefit may be obtained if the patient lies down in a quiet, dark room after administering medication

» Not using additional doses if first dose does not provide substantial relief; additional zolmitriptan is not likely to be effective in these circumstances; taking alternate medication as previously advised by physician, then checking with physician as soon as possible

Taking additional doses, if needed, for return of migraine after initial relief was obtained, provided that prescribed limits (quantity used and frequency of administration) are not exceeded

Compliance with prophylactic therapy, if prescribed

Proper handling/administration of oral disintegrating tablets

» Proper dosing

» Proper storage

Precautions while using this medication
Avoiding alcohol, which aggravates headache

» Caution when driving or doing anything else requiring alertness because of possible drowsiness, dizziness, lightheadedness, impairment of physical or mental abilities


Side/adverse effects
Signs of potential side effects, especially chest pain, severe; heaviness, tightness, or pressure in chest and/or neck; paresthesias; arrhythmias; gastroenteritis; leukopenia


For oral dosing forms:
The orally disintegrating tablet is packaged in a blister. Patients should be instructed not to remove the tablet from the blister until just prior to dosing. The blister pack should be peeled open and the orally disintegrating tablet placed on the tongue, where it is dissolved and swallowed with the saliva.{02}

Unlike the swallow tablets, the orally disintegrating tablets should not be broken.{02}

Oral disintegrating tablets may contain aspartame, which is metabolized to phenylalanine. This substance must be used with caution in patients with phenylketonuria (PKU).{02}


Oral Dosage Forms

ZOLMITRIPTAN TABLETS

Usual adult
Antimigraine agent
Oral, initially 2.5 mg or lower (tablet may be broken in half) {01}. If necessary, additional doses may be taken at intervals of at least two hours {01}.
A single dose of less than 2.5 mg is recommended for patients with hepatic disease or impairment {01}.


Usual adult limits
10 mg in twenty-four hours {01}.

Usual pediatric dose
Safety and efficacy have not been established in children under 18 years of age {02}.

Usual geriatric dose
See Usual adult dose .

Strength(s) usually available
U.S.—


2.5 mg (Rx) [Zomig (anhydrous lactose) (microcrystalline cellulose) ( sodium starch glycolate) (magnesium stearate) (hydroxypropyl methylcellulose) (titanium dioxide) (polyethylene glycol 400) (yellow iron oxide) (red iron oxide ) (polyethylene glycol 8000)]{01}


5 mg (Rx) [Zomig (anhydrous lactose) (microcrystalline cellulose) ( sodium starch glycolate) (magnesium stearate) (hydroxypropyl methylcellulose) (titanium dioxide) (polyethylene glycol 400) (yellow iron oxide) (red iron oxide ) (polyethylene glycol 8000)]{01}

Packaging and storage:
Store at room temperature, preferably between 20 and 25 ºC (68 and 77 ºF) {01}.


ZOLMITRIPTAN ORAL DISINTEGRATING TABLETS

Usual adult dose
Antimigraine agent
Oral, initially 2.5 mg. If necessary, additional doses may be taken at intervals of at least two hours to a maximum of 10 mg in a twenty-four-hour period..{02}

Note: Patients with moderate to severe hepatic function impairment should receive a low dose. Blood pressure monitoring is recommended.{02}



Usual adult limits
See Zolmitriptan Tablets.

Usual pediatric dose
Safety and efficacy have not been established in children under 18 years of age.
{02}
Usual geriatric dose
See Usual adult dose .

Strength(s) usually available
U.S.—


2.5 mg (Rx) [Zomig-ZMT (Orally disintegrating tablets) (mannitol USP) (microcrystalline cellulose NF) (crospovidone anhydrous NF) (aspartame NF) ( sodium bicarbonate USP) (citric acid anhydrousUSP ) (colloidal silicon dioxide NF) ( magnesium stearate NF) (orange flavor SN 027512 )]{02}

Packaging and storage:
Store at controlled room temperature 20 to 25°C (68 to 77°F). Protect from light and moisture.{02}

Note: Each Zomig-ZMT tablet contains 2.81 mg of phenylalanine.{02}
Liquid is not necessary for administration. The tablet will dissolve when placed directly on the patients tongue. {02}




Developed: 04/09/98
Revised: 05/21/2001



References
  1. Zomig package insert (Zeneca—US), Rec 12/97, Rev 11/97.
  1. Product Information: Zomig-ZMT, zolmitriptan. AstraZeneca, Wilmington, DE. (PI revised 02/2001) revised 05/2001
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