Zolmitriptan

Included as part of the PRECAUTIONS section.

Zolmitriptan may be found in some form under the following brand names:

• Zomig

Tell your doctor about all the medicines you take or plan to take, including prescription and nonprescription medicines, supplements, and herbal remedies.

Tell your doctor if you are taking selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), two types of drugs for depression or other disorders. Common SSRIs are:

• Celexa (citalopram)
• Lexapro (escitalopram)
• Paxil (paroxetine) 
• Prozac (fluoxetine) 
• Symbyax (olanzapine/fluoxetine)
• Zoloft (sertraline) 
• Sarafem (fluoxetine) 
• Luvox (fluvoxamine). 

Common SNRIs are Cymbalta (duloxetine) and Effexor (venlafaxine).

Your doctor will decide if you can take zolmitriptan with your other medicines.

Tell your doctor about all the medicines you take or plan to take, including prescription and nonprescription medicines, supplements, and herbal remedies.

Tell your doctor if you:

• have heart disease or a history of heart disease
• have uncontrolled high blood pressure
• have hemiplegic or basilar migraine (if you are not sure about this, ask your doctor)
• have or had a stroke or problems with your blood circulation
• have serious liver problems
• have taken any of the following medications in the last 24 hours: almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), sumatriptan (Imitrex), sumatriptan/naproxen (Treximet); ergotamines like Bellergal-S, Cafergot, Ergomar, Wigraine; dihydroergotamine like D.H.E. 45 or Migranal; or methysergide (Sansert). These medications have side effects similar to zolmitriptan.
• have taken monoamine oxidase (MAO) inhibitors such as phenelzine sulfate (Nardil) or tranylcypromine sulfate (Parnate) for depression or other conditions, or if it has been less than 2 weeks since you stopped taking a MAO inhibitor.

Tell your doctor if you know that you have any of the following risk factors for heart disease:

• high cholesterol
• diabetes
• smoking
• obesity (overweight)
• menopause
• a family history of heart disease or stroke

Tell your doctor if you are pregnant, planning to become pregnant, breast feeding, planning to breast feed, or not using effective birth control.

Tell your doctor if you are pregnant or plan to become pregnant. 

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Zolmitriptan falls into category C. No well-controlled studies have been done in humans. It is not known if zolmitriptan will harm your unborn baby. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if zolmitriptan is excreted in human breast milk or if it will harm your nursing baby. Because many drugs are excreted in human milk, caution should be exercised when zolmitriptan is administered to a nursing woman. 

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using zolmitriptan and call your doctor at once if you have:

• feeling of tightness in your jaw, neck, throat, or chest;

• fast or pounding heartbeats, dizziness;

• sudden and severe stomach pain and bloody diarrhea;

• heart attack symptoms--chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating; or

• high levels of serotonin in the body--agitation, hallucinations, fever, fast heart rate, overactive reflexes, nausea, vomiting, diarrhea, loss of coordination, fainting.

Common side effects may include:

• pain or tightness in your throat or chest;

• dry mouth, upset stomach;

• pressure or heavy feeling anywhere in your body;

• drowsiness, feeling tired; or

• flushing (warmth, redness, or tingly feeling).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Usual Adult Dose for Migraine:

Oral:
-Initial dose: 1.25 or 2.5 mg orally once (may break the scored 2.5 mg tablet in half to obtain 1.25 mg dose); may repeat in 2 hours if migraine has not resolved or returns after a transient improvement
-Maintenance Dose: Adjust dose based on individual response
Maximum single dose: 5 mg
Maximum daily dose: 10 mg in a 24-hour period

Orally Disintegrating Tablets:
-Initial dose: 2.5 mg orally once; may repeat in 2 hours if migraine has not resolved or returns after a transient improvement
-Maintenance Dose: Adjust dose based on individual response
Maximum single dose: 5 mg
Maximum daily dose: 10 mg in a 24-hour period

Nasal Spray:
-Initial dose: 2.5 mg intranasally once; may repeat in 2 hours if migraine has not resolved or returns after a transient improvement
-Maintenance Dose: Adjust dose based on individual response
Maximum single dose: 5 mg
Maximum daily dose: 10 mg in a 24-hour period

Comments:
-This drug should only be used after a clear diagnosis of migraine has been established; if a patient has no response for the first migraine attack, reconsider the diagnosis of migraine before treating any subsequent attacks.
-Do not break the oral disintegrating tablet, they are not scored.
-In trials, the majority of patients had headache response following a 2.5 mg or 5 mg dose compared with a 1 mg dose; little added benefit was observed with the 5 mg dose compared to the 2.5 mg dose, but adverse events were more frequent.
-The safety of treating an average of more than 4 headaches in a 30-day period has not been established.

Use: For the acute treatment of migraine with or without aura.

Usual Pediatric Dose for Migraine:

Age 12 years and older:

Nasal Spray:
-Initial dose: 2.5 mg intranasally once; may repeat in 2 hours if migraine has not resolved or returns after a transient improvement
-Maintenance Dose: Adjust dose based on individual response
Maximum single dose: 5 mg
Maximum daily dose: 10 mg in a 24-hour period

Comments:
-This drug should only be used after a clear diagnosis of migraine has been established; if a patient has no response to this drug for the first migraine attack, reconsider the diagnosis of migraine before treating any subsequent attacks.
-The safety of treating an average of more than 4 headaches in a 30-day period has not been established.

Use: For the acute treatment of migraine with or without aura.

Zolmitriptan Tablets, USP 2.5 mg: Yellow colored, round, biconvex, film-coated, debossed with ‘AC 322’ on one side and score line on other side.

Zolmitriptan Tablets, USP 5 mg: Pink colored, round, biconvex, film-coated, debossed with ‘AC 323’ on one side and plain on other side.

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 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.

When Zolmitriptan was administered to pregnant rats during the period of organogenesis at oral doses of 100, 400, and 1,200 mg/kg/day (plasma exposures (AUCs) ≈280, 1,100, and 5,000 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 1,100 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.

Nursing Mothers

It is not known whether Zolmitriptan is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Zolmitriptan, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. In rats, oral dosing with Zolmitriptan resulted in levels in milk up to 4 times higher than in plasma.

Pediatric Uses

The safety and effectiveness in pediatric patients have not been established. Therefore, Zolmitriptan is not recommended for use in patients under 18 years of age.

One randomized, placebo-controlled clinical trial of Zolmitriptan tablets (2.5, 5 and 10 mg) evaluated 696 pediatric patients (aged 12-17 years) with migraines. This study did not demonstrate the efficacy of Zolmitriptan compared to placebo in the treatment of migraine in adolescents. Adverse reactions in the adolescent patients treated with Zolmitriptan were similar in nature and frequency to those reported in clinical trials in adults treated with Zolmitriptan. Zolmitriptan has not been studied in pediatric patients less than 12 years old.

In the postmarketing experience with triptans, including Zolmitriptan, there were no additional adverse reactions seen in pediatric patients that were not seen in adults.

Geriatric Use

Clinical studies of Zolmitriptan did not include sufficient numbers of subjects aged 65 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.

A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) prior to receiving Zolmitriptan [see Warnings and Precautions (5.1)].

The pharmacokinetics of Zolmitriptan were similar in geriatric patients (aged > 65 years) compared to younger patients [see Clinical Pharmacology (12.3)].

Patients with Hepatic Impairment:

After oral Zolmitriptan administration, Zolmitriptan blood levels were increased in patients with moderate to severe hepatic impairment, and significant elevation in blood pressure was observed in some of these patients [see Warnings and Precautions (5.8)]. Therefore, adjust the Zolmitriptan dose and administer with caution in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

There is no experience with acute overdose of Zolmitriptan. Clinical study subjects who received single 50 mg oral doses of Zolmitriptan commonly experienced sedation.I

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.

The elimination half-life of Zolmitriptan is 3 hours [see Clinical Pharmacology (12.1)]; therefore, monitor patients after overdose with Zolmitriptan for at least 15 hours or until symptoms or signs resolve. It is unknown what effect hemodialysis or peritoneal dialysis has on the plasma concentrations of Zolmitriptan.

Mechanism of Action

Zolmitriptan binds with high affinity to human recombinant 5­ HT1D and 5-HT1B receptors, and moderate affinity for 5-HT1A receptors. The N-desmethyl metabolite also has high affinity for 5-HT11B/1D and moderate affinity for 5-HT1A receptors.

Migraines are likely 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-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.

Pharmacokinetics

Absorption, Distribution, Metabolism, and Excretion

Absorption
Zolmitriptan is well absorbed after oral administration for both Zolmitriptan tablets and Zolmitriptan orally disintegrating tablets. Zolmitriptan displays linear kinetics over the dose range of 2.5 to 50 mg.

The AUC and Cmax of Zolmitriptan are similar following administration of Zolmitriptan tablets and Zolmitriptan orally disintegrating tablets, but the Tmax is somewhat later with Zolmitriptan orally disintegrating tablets, with a median Tmax of 3 hours for Zolmitriptan orally disintegrating tablet compared with 1.5 hours for the Zolmitriptan tablet. The AUC, Cmax, and Tmax for the active N-desmethyl metabolite are similar for the two formulations.

During a moderate to severe migraine attack, mean AUC0-4 and Cmax for Zolmitriptan, dosed as a Zolmitriptan tablet, were decreased by 40% and 25%, respectively, and mean Tmax was delayed by one-half hour compared to the same patients during a migraine free period.

Food has no significant effect on the bioavailability of Zolmitriptan. No accumulation occurred on multiple dosing.

Distribution
Mean absolute bioavailability is approximately 40%. The mean apparent volume of distribution is 7.0 L/kg. Plasma protein binding of Zolmitriptan is 25% over the concentration range of 10- 1,000 ng/mL.

Metabolism
Zolmitriptan is converted to an active N-desmethyl metabolite; 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
Total radioactivity recovered in urine and feces was 65% and 30% of the administered dose, respectively. About 8% of the dose was recovered in the urine as unchanged Zolmitriptan. Indole acetic acid metabolite accounted for 31% of the dose, followed by N-oxide (7%) and N-desmethyl (4%) metabolites. The indole acetic acid and N-oxide metabolites are inactive.

Mean total plasma clearance is 31.5 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
Hepatic Impairment

In patients with severe hepatic impairment, the mean Cmax Tmax, and AUC0-∞of Zolmitriptan 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 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a 10 mg Zolmitriptan dose. Adjust the Zolmitriptan dose in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].

Renal Impairment
Clearance of Zolmitriptan was reduced by 25% in patients with severe renal impairment (Clcr ≥5 ≤25 mL/min) compared to subjects with normal renal function (Clcr > = 70 mL/min); no significant change in clearance was observed in patients with moderate renal impairment (Clcr ≥26 ≤50 mL/min).

Age
Zolmitriptan pharmacokinetics in healthy elderly non­ migraineur volunteers (age 65–76 years) was similar to those in younger non-migraineur volunteers (age 18 - 39 years).

Sex
Mean plasma concentrations of Zolmitriptan were up to 1.5­ fold higher in females than males.

Race
Retrospective analysis of pharmacokinetic data between Japanese and Caucasians revealed no significant differences.

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

Drug Interaction Studies
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.

MAO Inhibitors
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 Cmax and AUC for Zolmitriptan and a 3-fold increase in the Cmax and AUC of the active N­ desmethyl metabolite of Zolmitriptan. MAO inhibitors are contraindicated in Zolmitriptan –treated patients [see Contraindications (4), Warnings and Precautions (5.7), and Drug Interactions (7.27.4)].

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.

Cimetidine
Following the administration of cimetidine, the half-life and AUC of Zolmitriptan (5 mg dose), and its active metabolite, were approximately doubled [see Dosage and Administration (2.4), Drug Interactions (7.5)].

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).

Propranolol
Cmax and AUC of Zolmitriptan were 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 changes in blood pressure or pulse rate following administration of propranolol with Zolmitriptan.

Acetaminophen
A single 1 gram dose of acetaminophen did not alter the pharmacokinetics of Zolmitriptan and its N-desmethyl metabolite. However, Zolmitriptan administration 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 Cmax and AUC of Zolmitriptan were increased by 30% and 50%, respectively, and Tmax was delayed by one-half hour in women taking oral contraceptives. The effect of Zolmitriptan on the pharmacokinetics of oral contraceptives has not been studied.

Selective agonist for serotonin (5-HT1B and 5-HT1D receptors) in cranial arteries and sensory nerves of the trigeminal system; causes vasoconstriction and reduces inflammation associated with antidromic neuronal transmission correlating with relief of migraine

Absorption

Well absorbed

Distribution

Vd: Oral: 7 L/kg; Nasal spray: 8.4 L/kg

Metabolism

Converted to an active N-desmethyl metabolite (2-6 times more potent than zolmitriptan at 5-HT1B and 5-HT1D receptors)

Excretion

Urine (~60% to 65% total dose; 8% of total dose as unchanged drug; 4% of total dose as N-desmethyl metabolite); feces (30%)

Time to Peak

Serum: Tablet: 1.5 hours; Orally-disintegrating tablet and nasal spray: 3 hours

Half-Life Elimination

3 hours

Protein Binding

25%

LactMed Record Number

579

Last Revision Date

20130907

Disclaimer

Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.