Zolmitriptan Odt (zolmitriptan)

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

5-Ht1d Agonists/Ergot Alkaloids

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The 5-HT1D agonists and ergot alkaloids can produce vasospastic reactions.

CLINICAL EFFECTS: Concurrent therapy may produce additive vasospastic effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that sumatriptan should not be used within 24 hours of an ergotamine-containing or ergotamine-like medication (such as dihydroergotamine or methysergide).(1,2) The Australian(3) and UK(4,5) manufacturers state that 24 hours should elapse before sumatriptan is administered following an ergotamine-containing preparation and 6 hours should elapse before an ergotamine-containing preparation is administered following sumatriptan. The US manufacturer states that zolmitriptan should not be used within 24 hours of an ergotamine-containing or ergotamine-like medication.(6) The UK manufacturer states that zolmitriptan should not be used within 6 hours of an ergotamine-containing or ergotamine-like medication.(7) The The Australian manufacturer states that 24 hours should elapse before zolmitriptan is administered following an ergotamine-containing preparation and 6 hours should elapse before an ergotamine-containing medication is administered following zolmitriptan.(8) The US manufacturer states that the use of rizatriptan within 24 hours of an ergotamine-containing or ergot-type medication is contraindicated.(9) The US manufacturer states that the use of naratriptan within 24 hours of an ergotamine-containing or ergot-type medication is contraindicated.(10) The Australian manufacturer states that concurrent use of naratriptan and ergotamine or ergotamine derivatives is not recommended.(11) The US manufacturer states that the use of eletriptan within 24 hours of an ergotamine-containing or ergot-type medication is contraindicated.(12) The UK manufacturer states that the use of eletriptan within 24 hours of an ergotamine-containing or ergot-type medication is not recommended.(13)

DISCUSSION: Because of the theoretical risk of additive vasospastic effects, the US manufacturer states that the use of sumatriptan within 24 hours of an ergotamine-containing or ergotamine-like medication is contraindicated.(1,2) The Australian(3) and UK(4,5) manufacturer states that 24 hours should elapse before sumatriptan is administered following an ergotamine-containing preparation and 6 hours should elapse before an ergotamine-containing medication is administered following sumatriptan. Although the pharmacokinetics of zolmitriptan were not affected by ergotamine, the UK manufacturer of zolmitriptan recommends that 6 hours should elapse between the administration of zolmitriptan and an ergotamine preparation.(7) The US manufacturer of zolmitriptan states under contraindications that zolmitriptan should not be used within 24 hours of an ergotamine-containing or ergot-type medication.(6) The Australian manufacturer states that 24 hours should elapse before zolmitriptan is administered following an ergotamine-containing preparation and 6 hours should elapse before an ergotamine-containing medication is administered following zolmitriptan.(8) Because of the additive risk of prolonged vasospastic reactions, the manufacturers of rizatriptan(9) and naratriptan(10) in the US state that the use of ergotamine-containing or ergot-type medications and these agents is contraindicated. The Australian manufacturer states that concurrent use of naratriptan and ergotamine or ergotamine derivatives is not recommended.(11) Administration of oral ergotamine one and two hours after eletriptan resulted in additive increases in blood pressure.(13)

Selected 5-Ht1d Agonists/Mao Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: MAOIs inhibit the metabolism of rizatriptan,(1) sumatriptan,(2-9) and zolmitriptan.(10-11)

CLINICAL EFFECTS: Concurrent use of MAOIs may result in increased levels and effects of rizatriptan, sumatriptan or zolmitriptan.(1-11)

PREDISPOSING FACTORS: Patients with a history of cardiovascular disease, e.g., coronary artery disease (CAD), transient ischemic attack (TIA), stroke, cardiac conduction disorders or poorly controlled hypertension are not considered candidates for 5-HT1D agonist therapy and would be at greater risk for toxicity due to this interaction.

PATIENT MANAGEMENT: Concurrent administration of rizatriptan and a MAOI or administration of rizatriptan within two weeks of the discontinuation of a MAOI is contraindicated according to product labeling for rizatriptan.(1) Concurrent administration of sumatriptan and a MAOI or administration of sumatriptan within two weeks of the discontinuation of a MAOI is contraindicated according to the Australian, Canada, UK, and US product labeling for these agents.(2-9) Concurrent administration of zolmitriptan and a MAO-A inhibitor or the administration of zolmitriptan within two weeks of discontinuation of a MAO-A inhibitor is contraindicated according to US labeling.(10) The UK manufacturer states that a maximum of 7.5 mg of zolmitriptan should be administered within 24 hours of a MAO-A inhibitor.(11) Eletriptan and frovatriptan are not metabolized by MAO-A(12, 13) and may be an alternative in patients who require treatment with an MAO-A inhibitor.

DISCUSSION: Rizatriptan is metabolized by the 'A' subtype of monoamine oxidase. In a study with 12 subjects, the concurrent administration of rizatriptan (10 mg) with moclobemide (450 mg daily, a selective, reversible MAO-A inhibitor) resulted in increases in the rizatriptan area-under-curve (AUC) and maximum concentration (Cmax) by 119% and 41%, respectively. The AUC of the active metabolite, N-monodesmethyl rizatriptan, increased over 400%. Plasma concentrations of rizatriptan may be increased by selective MAO-A inhibitors or by nonselective MAO-A and MAO-B inhibitors, although the interaction is expected to be greater with selective MAO-A inhibitors. The manufacturer also states that no interaction is expected with selective MAO-B inhibitors.(1) Sumatriptan oral bioavailability is approximately 15%, primarily due to presystemic clearance by MAO-A in the gut and liver. A small study found an approximately 7-fold increase in systemic sumatriptan exposure when an MAO-A inhibitor was given prior to a 25 mg oral dose of sumatriptan.(4) In another study, pretreatment with an MAO-A inhibitor prior to administration of injectable sumatriptan resulted in a 2-fold increase in sumatriptan AUC and a 40% increase in elimination half-life.(8) Pretreatment with a MAO-B inhibitor did not produce any significant changes in sumatriptan pharmacokinetics. The effect of a MAOI on nasal sumatriptan systemic absorption is expected to be less than that seen with oral sumatriptan but greater than that seen with injectable sumatriptan.(6) Administration of moclobemide, a MAO-A inhibitor, for one week (150 mg twice daily) resulted in a 25% increase in zolmitriptan AUC and a three-fold increase in Cmax and AUC for zolmitriptan's active N-desmethyl metabolite.(10,11) Administration of selegiline for one week at a dosage of 10 mg daily had no effect on the pharmacokinetics of zolmitriptan or its metabolite.(10) At daily doses of 10 mg, selegiline is primarily a selective MAO-B inhibitor; however, at higher doses, selegiline is capable of inhibiting MAO-A. Hypertensive reactions to the addition of either tyramine or a sympathomimetic to recommended dosages of selegiline have been reported.(14) Therefore, patients receiving selegiline at dosages of greater than 10 mg daily should be considered to be receiving a MAO-A inhibitor. It would also be prudent to monitor patients receiving selegiline at recommended dosages for this interaction. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(15) Metaxalone is a weak inhibitor of MAO.(17,18) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Zolmitriptan (> 2.5 Mg)/Cimetidine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Cimetidine inhibits the CYP1A2 mediated metabolism of zolmitriptan and its active N-desmethyl metabolite.(1,2)

CLINICAL EFFECTS: Increased concentrations of zolmitriptan and its active N-desmethyl metabolite may increase the risk for adverse effects such as paresthesia, dizziness, or sensation of heaviness or tightness in the neck/throat/jaw, or chest.(1)

PREDISPOSING FACTORS: Due to the extended half-life associated with concurrent cimetidine use, multiple doses of zolmitriptan within a 24-hour period may lead to accumulation, increasing the risk for adverse effects.(1,2)

PATIENT MANAGEMENT: The manufacturer of zolmitriptan recommends the maximum single dose be reduced to 2.5 mg, not to exceed 5 mg in any 24-hour period.(1) When possible, consider use of an alternative acid reducing agent.

DISCUSSION: Zolmitriptan is converted to several metabolites, but only the N-desmethyl metabolite is active. Although plasma concentrations are about 2/3 of the parent drug, the N-desmethyl metabolite is 2 to 6 times more potent at 5-HT1B/1D receptors than zolmitriptan and may contribute substantially to its pharmacologic effect.(1) Zolmitriptan added to therapeutic doses of cimetidine 400 mg three times a day increased the area-under-curve(AUC) for zolmitriptan and its active N-desmethyl metabolite of approximately 1.5 fold and 2 fold respectively.(1,2) An open 2 period crossover study in 16 volunteer subjects evaluated the pharmacokinetics of zolmitriptan and the N-desmethyl metabolite with or without cimetidine 400mg every 8 hours for 2 days. After cimetidine treatment, the AUC of zolmitriptan and the N-desmethyl metabolite increased 1.48 and 2.05 fold respectively. The half-life of zolmitriptan increased from 4.99 to 7.19 hours, while the active metabolite half-life increased from 3.81 to 8.00 hours after treatment with cimetidine.(2)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Selected 5-Ht1d Agonists/Linezolid

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Monoamine oxidase inhibitors (MAOIs) inhibit the metabolism of rizatriptan,(1) sumatriptan,(2-9) and zolmitriptan.(10) Linezolid is a weak, reversible, nonselective MAOI.(12)

CLINICAL EFFECTS: Concurrent use of linezolid may result in increased levels and effects of rizatriptan, sumatriptan or zolmitriptan.(1-11)

PREDISPOSING FACTORS: Patients with a history of cardiovascular disease, e.g. coronary artery disease (CAD), transient ischemic attack (TIA), stroke, cardiac conduction disorders or poorly controlled hypertension, are not considered candidates for 5-HT1D agonist therapy and would be at greater risk for toxicity due to this interaction.

PATIENT MANAGEMENT: Concurrent administration of rizatriptan and a MAOI or administration of rizatriptan within two weeks of the discontinuation of a MAOI is contraindicated according to product labeling for rizatriptan.(1) Concurrent administration of sumatriptan and a MAOI within two weeks of the discontinuation of a MAOI is contraindicated according to the Australian, Canada, UK, and US product labeling for these agents.(2-9) Concurrent administration of zolmitriptan and a MAO-A Inhibitor or the administration of zolmitriptan within two weeks of discontinuation of a MAO-A Inhibitor is contraindicated according to US labeling.(10) The UK manufacturer states that a maximum of 7.5 mg of zolmitriptan should be administered within 24 hours of a MAO-A inhibitor.(11) The manufacturer of linezolid does not contraindicated the use of 5-HT1D agonists but states that they should not be coadministered unless clinically appropriate and patients are carefully observed for signs and symptoms of serotonin syndrome.(12) Eletriptan and frovatriptan are not metabolized by MAO-A(13,14) and may be an alternative in patients who require treatment with linezolid.

DISCUSSION: The combination of linezolid and 5-HT1D agonists has not been studied. Other MAOIs have been reported to interact with 5-HT1D agonists. Rizatriptan is metabolized by the 'A' subtype of monoamine oxidase. In a study with 12 subjects, the concurrent administration of rizatriptan (10 mg) with moclobemide (450 mg daily, a selective, reversible MAO-A inhibitor) resulted in increases in the rizatriptan area-under-curve (AUC) and maximum concentration (Cmax) by 119% and 41%, respectively. The AUC of the active metabolite, N-monodesmethyl rizatriptan, increased over 400%. Plasma concentrations of rizatriptan may be increased by selective MAO-A inhibitors or by nonselective MAO-A&B inhibitors, although the interaction is expected to be greater with selective MAO-A inhibitors. The manufacturer also states that no interaction is expected with selective MAO-B inhibitors.(1) Sumatriptan oral bioavailability is approximately 15%, primarily due to presystemic clearance by MAO-A in the gut and liver. A small study found an approximately 7-fold increase in systemic sumatriptan exposure when an MAO-A inhibitor was given prior to a 25 mg oral dose of sumatriptan.(4) In another study, pretreatment with an MAO-A inhibitor prior to administration of injectable sumatriptan resulted in a 2-fold increase in sumatriptan AUC and a 40% increase in elimination half-life.(8) Pretreatment with a MAO-B inhibitor did not produce any significant changes in sumatriptan pharmacokinetics. The effect of a MAOI on nasal sumatriptan systemic absorption is expected to be less than that seen with oral sumatriptan but greater than that seen with injectable sumatriptan.(6) Administration of moclobemide, a MAO-A inhibitor, for one week (150 mg twice daily) resulted in a 25% increase in zolmitriptan AUC and a three-fold increase in Cmax and AUC for zolmitriptan's active N-desmethyl metabolite.(10,11)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Selected 5-Ht1d Agonists/Rasagiline

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Rasagiline may inhibit the monamine oxidase-A (MAO-A) mediated metabolism of rizatriptan,(2) sumatriptan,(3-10) and zolmitriptan.(11-12) At concentrations associated with recommended doses of 0.5 mg to 1 mg daily, rasagiline has a high specificity for MAO-B. Mild hepatic impairment, concomitant use of strong CYP1A2 inhibitors, or use of higher than recommended doses may substantially increase rasagiline systemic exposure and could result in MAO-A inhibition.

CLINICAL EFFECTS: Systemic concentrations of rizatriptan, sumatriptan or zolmitriptan may be increased.(2-12)

PREDISPOSING FACTORS: Rasagiline concentration may be increased 2-fold or more in patients also receiving a strong CYP1A2 inhibitor (e.g. ciprofloxacin, fluvoxamine).(1) Rasagiline plasma concentrations are higher in patients with any degree of hepatic impairment. Rasagiline should not be used in patients with moderate or severe hepatic impairment.(1) Patients with a history of cardiovascular disease, e.g. coronary artery disease (CAD), transient ischemic attack (TIA), stroke, cardiac conduction disorders or poorly controlled hypertension, are not considered candidates for 5-HT1D agonist therapy and would be at greater risk for toxicity due to this interaction.

PATIENT MANAGEMENT: Evaluate patient for predisposing risk factors, e.g. concomitant use with CYP1A2 inhibitors, cardiovascular disease, and hepatic impairment. Patients with mild hepatic impairment or receiving concurrent therapy with a CYP1A2 inhibitor (e.g. ciprofloxacin, fluvoxamine) should be receiving a maximum rasagiline dose of 0.5 mg daily.

DISCUSSION: Triptan interaction studies with other MAO inhibitors: Rizatriptan is metabolized by the 'A' subtype of monoamine oxidase. In a study with 12 subjects, the concurrent administration of rizatriptan (10 mg) with moclobemide (450 mg daily, a selective, reversible MAO-A inhibitor) resulted in increases in the rizatriptan area-under-curve (AUC) and maximum concentration (Cmax) by 119% and 41%, respectively. The AUC of the active metabolite, N-monodesmethyl rizatriptan, increased over 400%. Plasma concentrations of rizatriptan may be increased by selective MAO-A inhibitors or by nonselective MAO-A&B inhibitors, although the interaction is expected to be greater with selective MAO-A inhibitors. The manufacturer also states that no interaction is expected with selective MAO-B inhibitors.(2) Sumatriptan oral bioavailability is approximately 15%, primarily due to presystemic clearance by MAO-A in the gut and liver. A small study found an approximately 7-fold increase in systemic sumatriptan exposure when an MAO-A inhibitor was given prior to a 25 mg oral dose of sumatriptan.(5) In another study, pretreatment with an MAO-A inhibitor prior to administration of injectable sumatriptan resulted in a 2-fold increase in sumatriptan AUC and a 40% increase in elimination half-life.(9) Pretreatment with a MAO-B inhibitor did not produce any significant changes in sumatriptan pharmacokinetics. The effect of a MAOI on nasal sumatriptan systemic absorption is expected to be less than that seen with oral sumatriptan but greater than that seen with injectable sumatriptan.(6) Administration of moclobemide, a MAO-A inhibitor, for one week (150 mg twice daily) resulted in a 25% increase in zolmitriptan AUC and a three-fold increase in Cmax and AUC for zolmitriptan's active N-desmethyl metabolite.(11,12) Administration of selegiline for one week at a dosage of 10 mg daily had no effect on the pharmacokinetics of zolmitriptan or its metabolite.(11) At daily doses of 10 mg, selegiline is primarily a selective MAO-B inhibitor; however, at higher doses, selegiline is capable of inhibiting MAO-A. Hypertensive reactions to the addition of either tyramine or a sympathomimetic to recommended dosages of selegiline have been reported.(15) Therefore, patients receiving selegiline at dosages of greater than 10 mg daily should be considered to be receiving a MAO-A inhibitor. It would also be prudent to monitor patients receiving selegiline at recommended dosages for this interaction.

Zolmitriptan (<= 2.5 Mg)/Cimetidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cimetidine inhibits the CYP1A2 mediated metabolism of zolmitriptan and its active N-desmethyl metabolite.(1,2)

CLINICAL EFFECTS: Increased concentrations of zolmitriptan and its active N-desmethyl metabolite may increase the risk for adverse effects such as paresthesia, dizziness, or sensation of heaviness or tightness in the neck/throat/jaw, or chest.(1)

PREDISPOSING FACTORS: Due to the extended half-life associated with concurrent cimetidine use, multiple doses of zolmitriptan within a 24-hour period may lead to accumulation, increasing the risk for adverse effects.(1,2)

PATIENT MANAGEMENT: The manufacturer of zolmitriptan recommends the maximum single dose be reduced to 2.5 mg, not to exceed 5 mg in any 24-hour period.(1) When possible, consider use of an alternative acid reducing agent.

DISCUSSION: Zolmitriptan is converted to several metabolites, but only the N-desmethyl metabolite is active. Although plasma concentrations are about 2/3 of the parent drug, the N-desmethyl metabolite is 2 to 6 times more potent at 5-HT1B/1D receptors than zolmitriptan and may contribute substantially to its pharmacologic effect.(1) Zolmitriptan added to therapeutic doses of cimetidine 400 mg three times a day increased the area-under-curve(AUC) for zolmitriptan and its active N-desmethyl metabolite of approximately 1.5 fold and 2 fold respectively.(1,2) An open 2 period crossover study in 16 volunteer subjects evaluated the pharmacokinetics of zolmitriptan and the N-desmethyl metabolite with or without cimetidine 400mg every 8 hours for 2 days. After cimetidine treatment, the AUC of zolmitriptan and the N-desmethyl metabolite increased 1.48 and 2.05 fold respectively. The half-life of zolmitriptan increased from 4.99 to 7.19 hours, while the active metabolite half-life increased from 3.81 to 8.00 hours after treatment with cimetidine.(2)

Ischemic heart disease (e.g., angina pectoris, myocardial infarction, silent ischemia), coronary vasospasm (e.g., Prinzmetal variant angina), Wolff-Parkinson-White syndrome or cardiac arrhythmias associated with other accessory pathway conduction disorders, uncontrolled hypertension, other serious underlying cardiovascular disease, history of stroke or transient ischemic attack, peripheral vascular disease, or ischemic bowel disease. Basilar or hemiplegic migraine. Treatment within the previous 24 hours with another 5-HT1 receptor agonist or with an ergot alkaloid (e.g., ergotamine, dihydroergotamine, methysergide (no longer commercially available in the US)). Concurrent or recent (within 2 weeks) treatment with a monoamine oxidase-A (MAO-A) inhibitor. Known hypersensitivity to zolmitriptan or any ingredient in the formulation.

• Acute myocardial infarction
• Angina
• Cerebral ischemia
• Cerebrovascular accident
• Coronary artery disease
• Hemiplegic migraine
• Ischemic bowel disease
• Myocardial ischemia
• Peripheral vascular disease
• Prinzmetal angina
• Serotonin syndrome
• Severe uncontrolled hypertension

• Raynaud's phenomenon
• Severe hepatic disease
• Tachyarrhythmia

• Hypertension
• Severe renal impairment

Adverse effects occurring in 2% or more of patients receiving orally administered zolmitriptan and more frequently (by at least 2 percentage points) with zolmitriptan than with placebo include dizziness, paresthesia, neck/throat/jaw/chest symptoms (e.g., pain, tightness, pressure, heaviness), other sensations of heaviness/pressure/tightness, nausea, somnolence, warm or cold sensation, asthenia, dry mouth, dyspepsia, dysphagia, vertigo, and sweating.

Adverse effects occurring in 2% or more of patients receiving intranasal zolmitriptan and more frequently with zolmitriptan than with placebo include paresthesia, hyperesthesia, unusual taste, throat pain, pain of specified location, nausea, somnolence, disorder or discomfort of the nasal cavity, asthenia, tightness of the throat, and dry mouth.

More Frequent

• Chest pain
• Paresthesia

Less Frequent

• Cardiac arrhythmia
• Gastroenteritis
• Hypertension

Rare or Very Rare

• Acute myocardial infarction
• Anaphylaxis
• Angioedema
• Cerebrovascular accident
• Coronary artery spasm
• Gastrointestinal vascular ischemia
• Hypersensitivity drug reaction
• Intracerebral hemorrhage
• Ischemic bowel disease
• Ischemic colitis
• Leukopenia
• Myocardial ischemia
• Peripheral vascular disease
• Serotonin syndrome
• Splenic infarction
• Ventricular fibrillation
• Ventricular tachycardia

More Frequent

• Dizziness
• Drowsy
• General weakness
• Jaw pain
• Nausea

Less Frequent

• Agitation
• Depression
• Dysgeusia
• Dyspepsia
• Dysphagia
• Ecchymosis
• Edema
• Hyperhidrosis
• Mouth irritation
• Myalgia
• Palpitations
• Polyuria
• Pruritus of skin
• Skin rash
• Symptoms of anxiety
• Syncope
• Xerostomia

Rare or Very Rare

• Medication overuse headache
• Raynaud's phenomenon

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Safety and efficacy of zolmitriptan have not been established in children younger than 18 years of age. Randomized, placebo-controlled studies in adolescents 12-17 years of age with migraine headaches failed to demonstrate efficacy of the drug. Adverse effects reported in adolescents were similar to those reported in adults. Serious adverse events have been reported during postmarketing experience in a limited number of pediatric patients receiving 5-HT1 receptor agonists, including zolmitriptan. Zolmitriptan has not been studied in children younger than 12 years of age,

Category C. (See Users Guide.)

Zolmitriptan is distributed into milk in rats. It is not known whether zolmitriptan is distributed into milk in humans. A decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Experience in patients 65 years of age and older is insufficient to determine whether they respond differently than younger adults; dosage in geriatric patients should be selected with caution.

Pharmacokinetic profile of zolmitriptan in geriatric patients is similar to that in younger adults.