Maxalt-Mlt (rizatriptan benzoate)

Dosage of rizatriptan benzoate is expressed in terms of rizatriptan.

Rizatriptan benzoate is administered orally as conventional or orally disintegrating tablets without regard to meals.

Rizatriptan is also commercially available in fixed combination with meloxicam. Consult the prescribing information for additional information on this combination product.

The rizatriptan orally disintegrating tablet is packaged in a blister in an outer aluminum pouch. The blister should not be removed from the aluminum pouch until just prior to administration. With dry hands, the blister package should be peeled open and the tablet placed on the tongue to dissolve and be swallowed with saliva. Administration with liquid is not necessary.

Rizatriptan tablets and orally disintegrating tablets should be stored at 15-30degreesC.

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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)

Rizatriptan (>5 Mg)/Propranolol

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 exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent administration of rizatriptan and propranolol may increase the levels of rizatriptan.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients on concurrent propranolol should not use the 10 mg-dose of rizatriptan.(1) For adult patients receiving propranolol, the manufacturer of rizatriptan states that the 5 mg dose of rizatriptan should be used and that a maximum of three doses (15 mg) should be administered in a 24 hour period.(1) For pediatric patients 6-17 years old who weigh less than 40 kg (88 lb) and are receiving propranolol, rizatriptan should not be given.(1) For pediatric patients 6-17 years old who weigh at least 40 kg (88 lb) and are receiving propranolol, a single 5 mg dose of rizatriptan is recommended (maximum dose of 5 mg in a 24 hour period).(1)

DISCUSSION: In a study in 11 subjects, the concurrent use of rizatriptan (10 mg) with propranolol (240 mg daily) resulted in an increase in the area-under-curve (AUC) of rizatriptan by 70%. A 4-fold increase was observed in one subject. The AUC of the rizatriptan N-monodesmethyl metabolite was not affected by the concurrent administration of propranolol.(1,2) In a study in 12 healthy subjects, concurrent use of propranolol (80 mg twice daily) with almotriptan (12.5 mg) resulted in statistically significant changes in almotriptan AUC; however, the change was less than 7% and considered unlikely to be clinically significant.(3) In a study in 10 healthy subjects, concurrent propranolol (80 mg twice daily) with sumatriptan (300 mg) had no effects on the pharmacokinetics or pharmacodynamics of sumatriptan.(4) In a study in 12 healthy subjects, concurrent use of propranolol (160 mg daily) with zolmitriptan (10 mg) increased the AUC and maximum concentration (Cmax) of zolmitriptan by 56% and 37%, respectively. Propranolol had no effect on the pressor response to zolmitriptan. The authors stated that the effects are unlikely to be clinically significant and that no dosage adjustment is required during concurrent therapy.(5)

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.

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.

*Known or suspected ischemic heart disease (e.g., angina pectoris, history of myocardial infarction, documented silent ischemia), coronary artery vasospasm (e.g., Prinzmetal variant angina), uncontrolled hypertension, or other serious underlying cardiovascular disease.

*History of cerebrovascular syndromes (e.g., stroke of any type, transient ischemic attack).

*Peripheral vascular disease or ischemic bowel disease.

*Hemiplegic or basilar migraine.

*Recent (i.e., 24 hours or less) treatment with another 5-HT1 receptor agonist or an ergotamine-containing or ergot-type drug.

*Concurrent administration or recent discontinuation (i.e. within 2 weeks) of a monoamine oxidase (MAO) type A inhibitor.

*Known hypersensitivity to rizatriptan 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

• Tachyarrhythmia

• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Disease of liver
• Hypertension

The most common adverse reactions (incidence >=5% and greater than placebo) with rizatriptan include asthenia/fatigue, somnolence, pain/pressure sensation, and dizziness.

More Frequent

• Dyspnea
• Palpitations

Less Frequent

• Bradycardia
• Cardiac arrhythmia
• Chest pain
• Chest tightness
• Paresthesia
• Tachycardia

Rare or Very Rare

• Acute myocardial infarction
• Anaphylaxis
• Angina
• Angioedema
• Cerebrovascular accident
• Hearing loss
• Hypersensitivity drug reaction
• Intracerebral hemorrhage
• Pharyngeal edema
• Seizure disorder
• Serotonin syndrome
• Subarachnoid intracranial hemorrhage
• Tongue swelling
• Toxic epidermal necrolysis
• Ventricular arrhythmias
• Wheezing

More Frequent

• Dizziness
• Drowsy
• Fatigue
• General weakness
• Nausea
• Vomiting

Less Frequent

• Acute cognitive impairment
• Arthralgia
• Constipation
• Depression
• Diarrhea
• Dry eye
• Dyspepsia
• Dysphagia
• Euphoria
• Flatulence
• Flushing
• Hyperhidrosis
• Hypertension
• Hypoesthesia
• Irritability
• Jaw pain
• Muscle rigidity
• Muscle spasm
• Myalgia
• Neck stiffness
• Non-cardiac chest pain
• Ocular irritation
• Pain
• Pruritus of skin
• Sensation of cold
• Sensation of warmth
• Tremor
• Xerostomia

Rare or Very Rare

• Abdominal distension
• Acute abdominal pain
• Agitation
• Ataxia
• Blurred vision
• Chills
• Disturbance of attention
• Drug-induced hot flash
• Dysgeusia
• Edema
• Erythema
• Facial edema
• Gait abnormality
• Hallucinations
• Medication overuse headache
• Memory impairment
• Periorbital edema
• Polydipsia
• Polyuria
• Skin rash
• Symptoms of anxiety
• Syncope
• Tinnitus
• Urticaria
• Vertigo

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Safety and efficacy have not been established in pediatric patients younger than 6 years of age. The efficacy and safety of rizatriptan for the acute treatment of migraine in pediatric patients 6 to 17 years of age were established in a controlled trial. Adverse effects in pediatric patients are expected to be similar to those reported in adults.

Human data are insufficient to draw conclusions regarding the risk of rizatriptan for major birth defects and miscarriage. In animal studies, developmental toxicity (e.g., decreased fetal body weight, increased mortality, neurobehavioral impairment) was seen following rizatriptan administration during pregnancy or throughout pregnancy and lactation at maternal plasma exposures greater than that expected at therapeutic doses in humans.

Results from an evaluation of pregnancy registry data (1998 to 2018) did not reveal any pattern of congenital anomalies or other adverse birth outcomes with rizatriptan use. However, the number of prospective reports in this registry with outcome information was low. In addition, a significant number of patients were lost to follow-up.

In another study involving data from the Swedish Medical Birth Register, 7 infants were born with malformations among 157 births with maternal first trimester exposure to rizatriptan. In an evaluation of data from the Medical Birth Registry of Norway, 10 infants had major congenital malformations among 310 women who filled rizatriptan prescriptions during the first trimester of pregnancy and 12 infants had major congenital malformation among 271 women who filled rizatriptan prescriptions, before, but not during pregnancy.

There are no data on the presence of rizatriptan or its metabolites in human milk; its effects on the breastfed infant and on milk production are also unknown. Rizatriptan is reported to be present in rat milk, with levels approximately 6 times those seen in maternal plasma.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for rizatriptan and any potential adverse effects on the breastfed infant from rizatriptan or the underlying maternal condition.

Dosage selection for geriatric patients should be cautious, usually starting at the low end of the dosage range, and reflect the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in such patients.

Pharmacokinetic profile is similar to that in younger adults. Clinical studies of rizatriptan did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently than younger patients. While other clinical experience has not revealed age-related differences in response, dosage should be selected with caution in geriatric patients starting at the low end of the dosage range.

Geriatric patients with other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) should have a cardiovascular evaluation prior to rizatriptan administration.