PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Selective Serotonin Agonists/Triptans

    DEA CLASS

    Rx

    DESCRIPTION

    Oral serotonin agonist
    Used for acute migraine in patients >= 6 years old
    Causes less sustained coronary artery constriction than ergot alkaloids

    COMMON BRAND NAMES

    Maxalt, Maxalt-MLT

    HOW SUPPLIED

    Maxalt/Rizatriptan/Rizatriptan Benzoate Oral Tab: 5mg, 10mg
    Maxalt-MLT/Rizatriptan/Rizatriptan Benzoate Oral Tab Orally Dis: 5mg, 10mg

    DOSAGE & INDICATIONS

    For the treatment of acute migraine attacks with or without aura.
    NOTE: Rizatriptan is not approved for prophylactic migraine therapy or for the treatment of hemiplegic or basilar migraines or cluster headaches.
    For acute treatment of migraine with or without aura using rizatriptan as a single agent.
    Oral dosage
    Adults

    5 to 10 mg PO as a single dose at migraine onset. In geriatric patients, initiate dosing at the low end of the range and use with caution due to a greater frequency of concomitant disease states, organ impairment, and drug therapies. May repeat every 2 hours with no more than 30 mg in any 24-hour period. There is evidence that the 10 mg dose may be more efficacious than the 5 mg dose; therefore, the appropriate dose should be based on an individual basis with consideration of the potential for side effects.

    Adolescents and Children 6 years and older weighing 40 kg or more

    10 mg PO as a single dose. Safety and efficacy of more than 1 dose per 24 hours have not been established.

    Adolescents and Children 6 years and older weighing less than 40 kg

    5 mg PO as a single dose. Safety and efficacy of more than 1 dose per 24 hours have not been established.

    For treatment of migraine in patients who are receiving concomitant therapy with propranolol.
    Oral dosage
    Adults

    5 mg PO at migraine onset. May repeat every 2 hours with no more than 15 mg PO in any 24-hour period. In general, use with caution in geriatric patients due to a greater frequency of concomitant disease states, organ impairment, and drug therapies.

    Adolescents and Children 6 years and older weighing 40 kg or more

    5 mg PO as a single dose. Administration of more than 1 dose per 24 hours is not recommended.

    Adolescents and Children 6 years and older weighing less than 40 kg

    Use is not recommended.

    MAXIMUM DOSAGE

    Adults

    30 mg/day PO per 24 hour period. If also receiving propranolol, do not exceed 15 mg/day PO. The safety of treating > 4 headaches in a 30-day period is not established.

    Geriatric

    30 mg/day PO per 24 hour period. If also receiving propranolol, do not exceed 15 mg/day PO. The safety of treating > 4 headaches in a 30-day period is not established.

    Adolescents

    >= 40 kg: 10 mg PO per 24 hour period. If also receiving propranolol, do not exceed 5 mg/day PO.
    < 40 kg: 5 mg PO per 24 hour period.

    Children

    >= 6 years and >= 40 kg: 10 mg PO per 24 hour period. If also receiving propranolol, do not exceed 5 mg/day PO.
    >= 6 years and < 40 kg: 5 mg PO per 24 hour period.
    < 6 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Use rizatriptan cautiously in patients with moderate to severe hepatic dysfunction due to increased plasma concentrations of at least 30%.

    Renal Impairment

    CrCl >= 10 ml/min: no dosage adjustment needed.
    CrCl < 10 ml/min: use rizatriptan with caution in dialysis patients as decreased clearance results in increased AUC.
     
    Intermittent hemodialysis
    See dosage for patients with renal impairment. It is not known whether hemodialysis (or peritoneal dialysis) removes rizatriptan from plasma.

    ADMINISTRATION

    Oral Administration

    Rizatriptan may be given without regard to food.

    Oral Solid Formulations

    Maxalt tablets: Swallow whole with liquid.
    Maxalt-MLT oral disintegrating tablets: Do not remove from packaging until immediately prior to use. Open packaging with dry hands and place on the tongue where it will dissolve and be swallowed with the saliva. Rizatriptan does not need to be taken with fluids. The patient may take with fluids if desired.

    STORAGE

    Maxalt:
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Maxalt-MLT:
    - Store at room temperature (between 59 to 86 degrees F)
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Rizatriptan is contraindicated in patients with a hypersensitivity to rizatriptan or any of its inactive ingredients.

    Colitis, peripheral vascular disease, Raynaud's phenomenon

    Rizatriptan should be given cautiously to patients with peripheral vascular disease including Raynaud's phenomenon and ischemic bowel disease (colitis). 5-HT agonists may cause vasospastic reactions leading to vascular and colonic ischemia with abdominal pain and bloody diarrhea.

    Acute myocardial infarction, angina, arteriosclerosis, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, hypercholesterolemia, obesity, tobacco smoking, vasospastic angina, Wolff-Parkinson-White syndrome

    Rare, but serious adverse cardiac effects, including heart attacks, life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours of receiving 5-HT1 agonists. Many of these patients had concurrent cardiovascular risk factors; therefore, it is difficult to assess causality. Rizatriptan and other 5-HT agonists may cause coronary vasospasm, and therefore are contraindicated in patients with known or suspected coronary artery disease (CAD), angina pectoris, vasospastic angina such as Prinzmetal's variant angina, arteriosclerosis, silent myocardial ischemia, acute myocardial infarction, history of myocardial infarction, or other significant cardiac disease. Patients with CAD risk factors (e.g., high blood pressure, diabetes mellitus, hypercholesterolemia, obesity, tobacco smoking, family history of CAD, female with surgical or physiological menopause, or male > 40 yrs old) should not be given rizatriptan unless a cardiac evaluation determines they are reasonably free of CAD, myocardial ischemia or other significant cardiac disease. Patients who are long-term users of rizatriptan and who have or acquire risk factors predictive of CAD should undergo periodic cardiac evaluation. For patients with risk factors predictive of CAD who are determined to have a satisfactory cardiac evaluation, the first dose of rizatriptan should be given in a controlled setting such as a clinic or physician's office. ECG monitoring is strongly encouraged due to the possibility of asymptomatic cardiac ischemia during the time immediately following rizatriptan administration in patients with risk factors. In addition, patients with cardiac arrhythmias should not receive rizatriptan as rhythm disturbances have been reported with the use of 5-HT1 agonists. Patients with symptomatic Wolff-Parkinson-White syndrome or cardiac arrhythmias associated with other cardiac accessory conduction pathway disorders should not receive rizatriptan because serious cardiac events have been reported within a few hours of receiving 5-HT1 agonists.

    Hypertension

    Rizatriptan is contraindicated in uncontrolled hypertension. Serotonin agonists can produce an increase in blood pressure in patients with and without a history of hypertension. Patients with controlled hypertension may experience mild and transient elevations in blood pressure.

    Cerebrovascular disease, intracranial bleeding, stroke

    Rizatriptan should be used with extreme caution in patients with cerebrovascular disease, including intracranial bleeding, stroke or transient ischemic attacks, due to the vasospastic effects of 5-HT agonists. While stroke, cerebral hemorrhage, and related fatalities have been reported following administration of 5-HT1 agonists, these events may have been present prior to administration of the drug, and the drug was mistakenly given in response to the cerebrovascular symptoms. However, patients with migraines may be at an increased risk for cerebrovascular events (e.g., stroke, hemorrhage).

    Basilar/hemiplegic migraine

    Rizatriptan is contraindicated in basilar/hemiplegic migraine because safety and efficacy have not been established. Rizatriptan is not recommended for prophylaxis of migraine headaches or for the treatment of cluster headaches.

    Pregnancy

    Rizatriptan is classified as FDA pregnancy category C. Because pregnancy outcome data are too limited to be conclusive, the use of rizatriptan during pregnancy is not recommended unless the benefits outweigh the risks. Data were collected prospectively through the manufacturer's registry for 67 pregnancies with exposure to rizatriptan. The available outcomes included 3 spontaneous abortions during the first trimester, 1 elective abortion (chromosomal anomaly), 1 feta death due to cord accident, 1 neonatal death due to prematurity, 28 healthy term infants, and 1 premature infant with hypospadias. There are three cases of congenital anomalies collected prospectively through international reports, and three cases of congenital anomalies reported retrospectively. In clinical trials, there were 26 inadvertent exposures during pregnancy, of which there were 6 spontaneous abortions, 6 elective abortions, 13 healthy newborns, and 1 lost to follow-up. In animal studies at doses greater than those used clinically, rizatriptan was associated with reduced birth weight, reduced weight gain in the offspring, increased offspring mortality at birth, decreased learning capacity, and a decrease in maternal weight gain during gestation. In two animal species studied, rizatriptan crossed the placenta. The molecular weight of rizatriptan suggests that the drug can also undergo placental transfer in humans. The manufacturer maintains a registry to monitor the pregnancy outcomes of women exposed to rizatriptan while pregnant. Healthcare providers are encouraged to report any prenatal exposure to rizatriptan by calling the Pregnancy Registry at 800—986—8999. Patients should be instructed to notify their physician if they become pregnant or intend to become pregnant during treatment with rizatriptan. The effects of rizatriptan during labor and delivery are unknown.

    Breast-feeding

    According to the manufacturer, it is unknown whether rizatriptan is excreted into breast milk and caution is advisable when administering the drug during breast-feeding. Rizatriptan is excreted into the breast milk of rats at a level 5-fold or greater than maternal plasma levels. Due to a low molecular weight (roughly 269), rizatriptan will most likely enter the breast milk. Rizatriptan's bioavailability is 45% and undergoes first-pass metabolism, which in theory may lessen the total amount absorbed by the infant. Pumping or expressing breast milk and discarding it up to several hours after a dose would help to avoid maximum infant exposure to rizatriptan. Additionally, rizatriptan is typically given as a one or two time dose, which may lessen infant risk. Sumatriptan is classified as compatible with breast-feeding by the American Academy of Pediatrics and may be considered as an alternative to rizatriptan for the acute treatment of migraines in breast-feeding mothers. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Hepatic disease

    Rizatriptan should be used cautiously in patients with hepatic disease experiencing moderate hepatic insufficiency due to an increase in plasma concentrations of approximately 30%.

    Dialysis, renal disease, renal failure, renal impairment

    Rizatriptan should be used with caution in patients with significant renal disease including severe renal failure (CrCl < 2 ml/min/1.73 m2), including patients receiving dialysis. The AUC of rizatriptan in patients with renal impairment (CrCl 10—60 ml/min/1.73 m2) was not significantly different from healthy volunteers.

    Children, infants, neonates

    Rizatriptan is not FDA-approved for use in neonates, infants, and children < 6 years of age.

    Phenylketonuria

    Patients with phenylketonuria should be warned that Maxalt-MLT (rizatriptan) disintegrating tablets contain phenylalanine. Each 5 mg disintegrating tablet contains 1.05 mg phenylalanine and each 10 mg disintegrating tablet contains 2.1 mg phenylalanine.

    Driving or operating machinery

    Patients should be advised to avoid driving or operating machinery until they know how rizatriptan will affect them.

    Geriatric

    Rizatriptan should be used with caution in geriatric patients and dose selection should be cautious, starting at the low end of the dosage range. Elderly patients are more likely to have decreased hepatic function, decreased renal function, more pronounced blood pressure increases, and are at a higher risk for coronary artery disease (CAD) than younger adults. Geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) should have a cardiovascular evaluation prior to receiving rizatriptan.

    MAOI therapy

    Rizatriptan is contraindicated in patients currently receiving MAOI therapy (i.e., MAO-A inhibitors) or during use of an MAO-A inhibitor within the previous 2 weeks. Rizatriptan is contraindicated in patients who have received ergotamine-containing or ergot-type medications within 24 hours of sumatriptan administration (see Drug Interactions).

    ADVERSE REACTIONS

    Severe

    arrhythmia exacerbation / Early / 0.1-1.0
    bradycardia / Rapid / 0.1-1.0
    akinesia / Delayed / 0-0.1
    muscle paralysis / Delayed / 0-0.1
    seizures / Delayed / Incidence not known
    serotonin syndrome / Delayed / Incidence not known
    coronary vasospasm / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    bowel ischemia / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    stroke / Early / Incidence not known
    increased intracranial pressure / Early / Incidence not known

    Moderate

    chest pain (unspecified) / Early / 0-3.0
    chest pressure syndrome / Rapid / 0-3.0
    ataxia / Delayed / 0.1-1.0
    dysarthria / Delayed / 0.1-1.0
    hyperesthesia / Delayed / 0.1-1.0
    sinus tachycardia / Rapid / 0.1-1.0
    hypertension / Early / 0.1-1.0
    memory impairment / Delayed / 0.1-1.0
    confusion / Early / 0.1-1.0
    depression / Delayed / 0.1-1.0
    constipation / Delayed / 0.1-1.0
    edema / Delayed / 0.1-1.0
    dysphagia / Delayed / 0.1-1.0
    myasthenia / Delayed / 0.1-1.0
    blurred vision / Early / 0.1-1.0
    dehydration / Delayed / 0.1-1.0
    heat intolerance / Early / 0.1-1.0
    angina / Early / 0-0.1
    gastritis / Delayed / 0-0.1
    dysuria / Early / 0-0.1
    tachypnea / Early / 0-0.1
    erythema / Early / 0-0.1
    ocular inflammation / Early / 0-0.1
    hyperacusis / Delayed / 0-0.1
    photophobia / Early / 0-0.1
    photopsia / Delayed / 0-0.1
    palpitations / Early / 1.0
    euphoria / Early / 1.0
    hot flashes / Early / 1.0
    dyspnea / Early / 1.0
    withdrawal / Early / Incidence not known
    hyperthermia / Delayed / Incidence not known
    peripheral vasoconstriction / Rapid / Incidence not known
    wheezing / Rapid / Incidence not known

    Mild

    dizziness / Early / 4.0-9.0
    drowsiness / Early / 4.0-8.0
    fatigue / Early / 4.0-7.0
    asthenia / Delayed / 4.0-7.0
    nausea / Early / 4.0-6.0
    paresthesias / Delayed / 3.0-4.0
    xerostomia / Early / 3.0-3.0
    headache / Early / 0-2.0
    insomnia / Early / 0.1-1.0
    vertigo / Early / 0.1-1.0
    agitation / Early / 0.1-1.0
    irritability / Delayed / 0.1-1.0
    anxiety / Delayed / 0.1-1.0
    flatulence / Early / 0.1-1.0
    gastroesophageal reflux / Delayed / 0.1-1.0
    dyspepsia / Early / 0.1-1.0
    musculoskeletal pain / Early / 0.1-1.0
    arthralgia / Delayed / 0.1-1.0
    myalgia / Early / 0.1-1.0
    muscle cramps / Delayed / 0.1-1.0
    menstrual irregularity / Delayed / 0.1-1.0
    polyuria / Early / 0.1-1.0
    increased urinary frequency / Early / 0.1-1.0
    nasal congestion / Early / 0.1-1.0
    nasal irritation / Early / 0.1-1.0
    throat irritation / Early / 0.1-1.0
    infection / Delayed / 0.1-1.0
    nasal dryness / Early / 0.1-1.0
    epistaxis / Delayed / 0.1-1.0
    yawning / Early / 0.1-1.0
    pharyngitis / Delayed / 0.1-1.0
    urticaria / Rapid / 0.1-1.0
    hyperhidrosis / Delayed / 0.1-1.0
    pruritus / Rapid / 0.1-1.0
    rash (unspecified) / Early / 0.1-1.0
    xerophthalmia / Early / 0.1-1.0
    ocular pain / Early / 0.1-1.0
    otalgia / Early / 0.1-1.0
    lacrimation / Early / 0.1-1.0
    ocular irritation / Rapid / 0.1-1.0
    tinnitus / Delayed / 0.1-1.0
    polydipsia / Early / 0.1-1.0
    chills / Rapid / 0.1-1.0
    hyporeflexia / Delayed / 0-0.1
    dysesthesia / Delayed / 0-0.1
    hyperkinesis / Delayed / 0-0.1
    eructation / Early / 0-0.1
    anorexia / Delayed / 0-0.1
    appetite stimulation / Delayed / 0-0.1
    hoarseness / Early / 0-0.1
    cough / Delayed / 0-0.1
    sneezing / Early / 0-0.1
    hiccups / Early / 0-0.1
    rhinorrhea / Early / 0-0.1
    acne vulgaris / Delayed / 0-0.1
    photosensitivity / Delayed / 0-0.1
    parosmia / Delayed / 0-0.1
    ocular pruritus / Rapid / 0-0.1
    syncope / Early / 0-0.1
    fever / Early / 0-0.1
    tremor / Early / 1.0
    hypoesthesia / Delayed / 1.0
    diarrhea / Early / 1.0
    vomiting / Early / 1.0
    dysgeusia / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Acetaminophen; Dextromethorphan: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Acetaminophen; Oxycodone: (Major) Serotonin syndrome can occur during concomitant use of opiate agonists with serotonergic drugs, such as serotonin-receptor agonists. Symptoms may occur hours to days after concomitant use, particularly after dose increases. Serotonin syndrome may occur within recommended dose ranges. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during initiation of the second therapy and after dosage increases of either agent. Instruct patients to immediately report symptoms of agitation, hallucinations, tachycardia, fever, excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, nausea, vomiting, or diarrhea.
    Acetaminophen; Tramadol: (Moderate) Caution is advised when tramadol is coadministered with serotonin-receptor agonists because of the potential for serotonin syndrome. If concomitant treatment of tramadol and a serotonin-receptor agonist is clinically warranted, careful observation of the patient is advised, especially during the initial time both drugs are used together and during a dose increase of either tramadol or the serotonin-receptor agonist.
    Amitriptyline: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases.
    Amitriptyline; Chlordiazepoxide: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases.
    Amoxapine: (Moderate) Amoxapine should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Amoxapine, a tetracyclic antidepressant, shares some pharmacologic properties with tricyclic antidepressants (TCAs), including reducing the uptake of norepinephrine and serotonin. Amoxapine rarely causes serotonin syndrome when used alone, but the risk may be increased when combined with other serotonergic agents.
    Amphetamine: (Major) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. Serotonin syndrome, while uncommon, can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Although unlikely to occur during monotherapy with serotonin-receptor agonists (or "triptans"), serotonin syndrome may occur from combining these drugs with other medications that potentiate serotonin activity. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Amphetamine; Dextroamphetamine Salts: (Major) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. Serotonin syndrome, while uncommon, can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Although unlikely to occur during monotherapy with serotonin-receptor agonists (or "triptans"), serotonin syndrome may occur from combining these drugs with other medications that potentiate serotonin activity. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Amphetamine; Dextroamphetamine: (Major) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. Serotonin syndrome, while uncommon, can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Although unlikely to occur during monotherapy with serotonin-receptor agonists (or "triptans"), serotonin syndrome may occur from combining these drugs with other medications that potentiate serotonin activity. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Aspirin, ASA; Oxycodone: (Major) Serotonin syndrome can occur during concomitant use of opiate agonists with serotonergic drugs, such as serotonin-receptor agonists. Symptoms may occur hours to days after concomitant use, particularly after dose increases. Serotonin syndrome may occur within recommended dose ranges. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during initiation of the second therapy and after dosage increases of either agent. Instruct patients to immediately report symptoms of agitation, hallucinations, tachycardia, fever, excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, nausea, vomiting, or diarrhea.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Theoretically, concurrent use of methylene blue and serotonin-receptor agonists may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and serotonin-receptor agonists increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Theoretically, concurrent use of methylene blue and serotonin-receptor agonists may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and serotonin-receptor agonists increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
    Benzphetamine: (Major) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. Serotonin syndrome, while uncommon, can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Although unlikely to occur during monotherapy with serotonin-receptor agonists (or "triptans"), serotonin syndrome may occur from combining these drugs with other medications that potentiate serotonin activity. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Bromocriptine: (Major) Bromocriptine is an ergot alkaloid derivative. Serotonin-receptor agonists (e.g., "triptans" such as almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) are contraindicated for use within 24 hours of treatment with traditional ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of serotonin-receptor agonists. While interactions have not been specifically reported between bromocriptine and triptans, combined use of these agents should be avoided if possible.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Buprenorphine: (Major) Concurrent use of opioids with other drugs that modulate serotonergic function, such as selective serotonin-receptor agonists ('triptans'), has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment with buprenorphine and a triptan is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected.
    Buprenorphine; Naloxone: (Major) Concurrent use of opioids with other drugs that modulate serotonergic function, such as selective serotonin-receptor agonists ('triptans'), has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment with buprenorphine and a triptan is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected.
    Buspirone: (Moderate) Buspirone should be used cautiously with serotonin-receptor agonists. Pharmacologically, buspirone is a serotonin agonist, and using in conjunction with other serotonin agonists could result in serotonin syndrome, which can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonin-agonists and buspirone should be informed of the signs and symptoms of serotonin syndrome.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Chlorpheniramine; Dextromethorphan: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Citalopram: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., rizatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Clomipramine: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases.
    Desipramine: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases.
    Desvenlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like desvenlafaxine with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) because of the potential risk and severity of serotonin syndrome. Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SNRI or the addition of other serotonergic medications to an existing SNRI regimen.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Dextroamphetamine: (Major) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. Serotonin syndrome, while uncommon, can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Although unlikely to occur during monotherapy with serotonin-receptor agonists (or "triptans"), serotonin syndrome may occur from combining these drugs with other medications that potentiate serotonin activity. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Dextromethorphan: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Dextromethorphan; Guaifenesin: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Dextromethorphan; Promethazine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Dextromethorphan; Quinidine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome.
    Doxepin: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases.
    Droxidopa: (Major) Coadministration of droxidopa with other agents that increase blood pressure, such as serotonin-receptor agonists, would be expected to increase the risk for supine hypertension. Monitor supine blood pressure. Reduce or discontinue droxidopa if supine hypertension persists. If supine hypertension is not well-managed, droxidopa may increase the risk of cardiovascular events.
    Duloxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like duloxetine with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) because of the potential risk and severity of serotonin syndrome. Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SNRI or the addition of other serotonergic medications to an existing SNRI regimen.
    Ergot alkaloids: (Severe) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.
    Escitalopram: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., rizatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Fluoxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., rizatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Fluoxetine; Olanzapine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., rizatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Fluvoxamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., rizatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Hydrochlorothiazide, HCTZ; Propranolol: (Major) Concurrent administration of propranolol 240 mg/day and a single dose of rizatriptan 10 mg resulted in a 70% increase in the mean rizatriptan AUC. The AUC of the active N-monodesmethyl metabolite was not affected by propranolol. This interaction is most likely due to first-pass metabolic interaction between rizatriptan and propranolol. Based on in vitro data, no pharmacokinetic interaction is expected with timolol or atenolol. This interaction requires a dose adjustment of rizatriptan when it is given concurrently with propranolol. The recommended dose of rizatriptan 5 mg up to a maximum of 15 mg in 24 hours when given with propranolol. Patients receiving concomitant administration of other antimigraine agents (e.g., beta-blockers including propranolol) with rizatriptan had similar adverse reaction rates as compared to those who did not receive these medications concomitantly.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Theoretically, concurrent use of methylene blue and serotonin-receptor agonists may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and serotonin-receptor agonists increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
    Ibuprofen; Oxycodone: (Major) Serotonin syndrome can occur during concomitant use of opiate agonists with serotonergic drugs, such as serotonin-receptor agonists. Symptoms may occur hours to days after concomitant use, particularly after dose increases. Serotonin syndrome may occur within recommended dose ranges. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during initiation of the second therapy and after dosage increases of either agent. Instruct patients to immediately report symptoms of agitation, hallucinations, tachycardia, fever, excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, nausea, vomiting, or diarrhea.
    Imipramine: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases.
    Isocarboxazid: (Severe) The administration of rizatriptan to patients currently receiving a monoamine oxidase A inhibitor or within 2 weeks of discontinuing a monoamine oxidase A inhibitor is contraindicated. Rizatriptan is principally metabolized by monoamine oxidase A (MAO-A); therefore, plasma concentrations of rizatriptan may be increased by concurrent use of selective MAO-A inhibitors (e.g., meclobemide) or non-selective MAO-A and MAO-B inhibitors (e.g., phenelzine, tranylcypromine, isocarboxazid) and rizatriptan. During a drug interaction study with meclobemide, the mean increase in rizatriptan Cmax was 41%, and the mean increases in the AUC of rizatriptan and its metabolite were 119% and 400%, respectively. According to the manufacturer, no interaction is expected between rizatriptan and selective MAO-B inhibitors.
    Levomilnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like levomilnacipran with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) because of the potential risk and severity of serotonin syndrome. Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SNRI or the addition of other serotonergic medications to an existing SNRI regimen.
    Linezolid: (Major) Linezolid is an antibiotic that is also a reversible, non-selective inhibitor of MAO and should not be administered with serotonin-receptor agonists. The monoamine oxidase type A enzyme metabolizes serotonin. Non-selective MAO inhibitors increase the plasma concentrations of these drugs and some of their active metabolites, thus increasing levels of serotonin. This interaction could lead to serotonin syndrome. The manufacturers of serotonin agonists contraindicate the administration of their drugs to patients receiving non-selective MAO inhibitors like linezolid or within 2 weeks of discontinuation of a MAO inhibitor.
    Lisdexamfetamine: (Major) Serotonin syndrome may occur during coadministration of drugs with serotonergic properties such as amphetamines and serotonin-receptor agonists. Serotonin syndrome, while uncommon, can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Although unlikely to occur during monotherapy with serotonin-receptor agonists (or "triptans"), serotonin syndrome may occur from combining these drugs with other medications that potentiate serotonin activity. Discontinue all serotonergic drugs if serotonin syndrome occurs and implement appropriate medical management.
    Lithium: (Major) There is an increased risk of serotonin syndrome during concurrent use of drugs with central serotonergic properties such as lithium and serotonin-receptor agonists. Signs and symptoms of serotonin syndrome include autonomic instability (e.g., labile blood pressure, tachycardia, diaphoresis, dizziness, hyperthermia), mental status changes (e.g., delirium, confusion, coma), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), gastrointestinal effects (e.g., nausea, vomiting, diarrhea), seizures, and in rare cases, death. If concurrent use is necessary, monitor for the emergence of serotonin syndrome and inform patients of the increased risk. If serotonin syndrome is suspected, serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Lorcaserin: (Major) Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, serotonin-receptor agonists. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS) like signs and symptoms.
    Maprotiline: (Moderate) Maprotiline should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Maprotiline, a tetracyclic antidepressant, shares some pharmacologic properties with tricyclic antidepressants (TCAs). However, as maprotiline primarily blocks norepinephrine uptake vs. serotonin uptake, the drug rarely causes serotonin side effects or serotonin syndrome when used alone. However, combination therapy with agents with serotonergic actions might increase the risk for serotonergic side effects.
    Meperidine: (Moderate) Serotonin-receptor agonists are associated with decreased serotonin reuptake and thus, increased serotonin concentrations. They should be used cautiously in conjunction with meperidine, as meperidine blocks the neuronal reuptake of serotonin. Taking these drugs together may increase the risk for serotonin syndrome. While uncommon, serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever
    Meperidine; Promethazine: (Moderate) Serotonin-receptor agonists are associated with decreased serotonin reuptake and thus, increased serotonin concentrations. They should be used cautiously in conjunction with meperidine, as meperidine blocks the neuronal reuptake of serotonin. Taking these drugs together may increase the risk for serotonin syndrome. While uncommon, serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever
    Methamphetamine: (Major) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. Serotonin syndrome, while uncommon, can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Although unlikely to occur during monotherapy with serotonin-receptor agonists (or "triptans"), serotonin syndrome may occur from combining these drugs with other medications that potentiate serotonin activity. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Theoretically, concurrent use of methylene blue and serotonin-receptor agonists may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and serotonin-receptor agonists increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
    Methylene Blue: (Major) Theoretically, concurrent use of methylene blue and serotonin-receptor agonists may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and serotonin-receptor agonists increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
    Milnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like milnacipran with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) because of the potential risk and severity of serotonin syndrome. Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SNRI or the addition of other serotonergic medications to an existing SNRI regimen.
    Mirtazapine: (Major) Based on the mechanism of action of mirtazapine and the potential for serotonin syndrome, caution is advised when mirtazapine is coadministered with other drugs that may affect these neurotransmitter systems, including the serotonin-receptor agonists ("triptans"). The co-use of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
    Morphine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin-receptor agonists. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the serotonin-receptor agonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Morphine; Naltrexone: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin-receptor agonists. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the serotonin-receptor agonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Nefazodone: (Major) Medications that augment release, decrease the metabolism of, or decrease the reuptake of serotonin, like the serotonin-receptor agonists, may interact with nefazodone by causing serotonin-related side effects, including serotonin syndrome. Whenever possible, these drug combinations should be avoided. If serotonin-syndrome is suspected, offending agents should be discontinued.
    Nortriptyline: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases.
    Oxycodone: (Major) Serotonin syndrome can occur during concomitant use of opiate agonists with serotonergic drugs, such as serotonin-receptor agonists. Symptoms may occur hours to days after concomitant use, particularly after dose increases. Serotonin syndrome may occur within recommended dose ranges. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during initiation of the second therapy and after dosage increases of either agent. Instruct patients to immediately report symptoms of agitation, hallucinations, tachycardia, fever, excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, nausea, vomiting, or diarrhea.
    Paroxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., rizatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Perphenazine; Amitriptyline: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases.
    Phenelzine: (Severe) The administration of rizatriptan to patients currently receiving a monoamine oxidase A inhibitor or within 2 weeks of discontinuing a monoamine oxidase A inhibitor is contraindicated. Rizatriptan is principally metabolized by monoamine oxidase A (MAO-A); therefore, plasma concentrations of rizatriptan may be increased by concurrent use of selective MAO-A inhibitors (e.g., meclobemide) or non-selective MAO-A and MAO-B inhibitors (e.g., phenelzine, tranylcypromine, isocarboxazid) and rizatriptan. During a drug interaction study with meclobemide, the mean increase in rizatriptan Cmax was 41%, and the mean increases in the AUC of rizatriptan and its metabolite were 119% and 400%, respectively. According to the manufacturer, no interaction is expected between rizatriptan and selective MAO-B inhibitors. However, it should be noted that selegiline, a selective MAO-B inhibitor, may interact with rizatriptan at higher doses (> 20 mg) since the MAO-B selectivity of the drug diminishes at higher doses.
    Propranolol: (Major) Concurrent administration of propranolol 240 mg/day and a single dose of rizatriptan 10 mg resulted in a 70% increase in the mean rizatriptan AUC. The AUC of the active N-monodesmethyl metabolite was not affected by propranolol. This interaction is most likely due to first-pass metabolic interaction between rizatriptan and propranolol. Based on in vitro data, no pharmacokinetic interaction is expected with timolol or atenolol. This interaction requires a dose adjustment of rizatriptan when it is given concurrently with propranolol. The recommended dose of rizatriptan 5 mg up to a maximum of 15 mg in 24 hours when given with propranolol. Patients receiving concomitant administration of other antimigraine agents (e.g., beta-blockers including propranolol) with rizatriptan had similar adverse reaction rates as compared to those who did not receive these medications concomitantly.
    Protriptyline: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases.
    Rasagiline: (Minor) Serotonin syndrome has been reported during co-administration of serotonin-receptor agonistsand monoamine oxidase inhibitors (MAOIs) with MAO-A inhibitory effects. Because rasagiline selectively inhibits MAO-B at recommended doses, no interaction with rizatriptan would be expected with normal prescription use. However, there is a decline in MAO-B selectivity with increasing doses. Therefore, high dose treatment with rasagiline may increase central serotonin levels through MAO-A inhibition, thereby increasing the risk of serotonin syndrome. However, whether or not 5-HT1B/1D agonists such as rizatriptan can cause serious cases of serotonin syndrome when combined with serotonergic drugs has been debated since serotonin syndrome is thought to result primarily from 5-HT2A activation. In vitro data indicate that rizatriptan is primarily metabolized by MAO-A. Theoretically, use of high doses of rasagiline could increase systemic exposure to rizatriptan through MAO-A inhibition.
    Remifentanil: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Selective serotonin reuptake inhibitors: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., rizatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Selegiline: (Severe) Rizatriptan is partially metabolized by MAO-A, and is contraindicated for use with non-selective MAOIs, including selegiline in its transdermal form, which inhibits both MAO-A and MAO-B at antidepressant doses. Serotonin syndrome has been reported during co-administration of serotonin-receptor agonists and monoamine oxidase inhibitors (MAOIs), due to the inhibitory effects of MAOIs on MAO-A, which decreases central serotonin degradation. Since oral selegiline selectively inhibits MAO-B at recommended doses, no interaction with serotonin-receptor agonists is expected with usual prescription use. However, there is a decline in MAO-B selectivity with increasing doses. Therefore, when recommended oral doses are exceeded (i.e., > 10 mg/day), there is the potential for selegiline to increase central serotonin levels through MAO-A inhibition. However, whether or not 5-HT1B/1D agonists such as serotonin-receptor agonists can cause serious cases of serotonin syndrome when used with serotonergic drugs has been debated since serotonin syndrome is thought to result primarily from 5-HT2A activation.
    Sertraline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., rizatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Sibutramine: (Major) Sibutramine is a serotonin reuptake inhibitor. Concomitant use of two serotonin-augmenting drugs has been associated with serotonin syndrome, so concurrent use of the serotonin-receptor agonists with sibutramine is not recommended.
    St. John's Wort, Hypericum perforatum: (Major) Although unlikely to occur during monotherapy with 5-HT1 agonists such as sumatriptan, serotonin syndrome may occur from combining medications that potentiate serotonin activity. Serotonin syndrome, while uncommon, can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. St. John's wort, Hypericum perforatum can potentiate the effects of serotonin through inhibiting serotonin reuptake.
    Tapentadol: (Major) Caution is advised when tapentadol is coadministered with serotonin-receptor agonists, as this combination may increase the potential for serotonin syndrome development. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during initiation of the second therapy and after dosage adjustments (increases) of either agent.
    Tedizolid: (Minor) Caution is warranted with the concurrent use of tedizolid and serotonin-receptor agonists such as rizatriptan. Tedizolid is an antibiotic that is also a weak reversible, non-selective inhibitor of MAO. The monoamine oxidase (MAO) type A enzyme metabolizes serotonin. Non-selective traditional MAO inhibitors increase the plasma concentrations of these drugs and some of their active metabolites, thus increasing levels of serotonin. Serious CNS reactions, such as serotonin syndrome, have been reported during the concurrent use of linezolid, which is structurally similar to tedizolid, and psychiatric medications that enhance central serotonergic activity; therefore, caution is warranted with concomitant use of other agents with serotonergic activity. This interaction could lead to 'serotonin syndrome' (presenting as agitation, restlessness, aggressive behavior, insomnia, poor concentration, headache, paresthesia, incoordination, worsening of obsessive thoughts or compulsive behavior, nausea, abdominal cramps, diarrhea, palpitations, or chills). The manufacturers of serotonin agonists contraindicate the administration of their drugs to patients receiving non-selective MAO inhibitors or within 2 weeks of discontinuation of a MAO inhibitor.
    Tramadol: (Moderate) Caution is advised when tramadol is coadministered with serotonin-receptor agonists because of the potential for serotonin syndrome. If concomitant treatment of tramadol and a serotonin-receptor agonist is clinically warranted, careful observation of the patient is advised, especially during the initial time both drugs are used together and during a dose increase of either tramadol or the serotonin-receptor agonist.
    Tranylcypromine: (Severe) The administration of rizatriptan to patients currently receiving a monoamine oxidase A inhibitor or within 2 weeks of discontinuing a monoamine oxidase A inhibitor is contraindicated. Rizatriptan is principally metabolized by monoamine oxidase A (MAO-A); therefore, plasma concentrations of rizatriptan may be increased by concurrent use of selective MAO-A inhibitors (e.g., meclobemide) or non-selective MAO-A and MAO-B inhibitors (e.g., phenelzine, tranylcypromine, isocarboxazid) and rizatriptan. During a drug interaction study with meclobemide, the mean increase in rizatriptan Cmax was 41%, and the mean increases in the AUC of rizatriptan and its metabolite were 119% and 400%, respectively. According to the manufacturer, no interaction is expected between rizatriptan and selective MAO-B inhibitors. However, it should be noted that selegiline, a selective MAO-B inhibitor, may interact with rizatriptan at higher doses (> 20 mg) since the MAO-B selectivity of the drug diminishes at higher doses.
    Trazodone: (Major) Based on the mechanism of action of trazodone and the potential for serotonin syndrome, caution is advised when trazodone is coadministered with other drugs that may affect these neurotransmitter systems, including the serotonin-receptor agonists ("triptans"). The co-use of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
    Tricyclic antidepressants: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases.
    Trimipramine: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases.
    Venlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like venlafaxine with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) because of the potential risk and severity of serotonin syndrome. Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SNRI or the addition of other serotonergic medications to an existing SNRI regimen.
    Vilazodone: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering vilazodone with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan). Serotonin syndrome has been reported during concurrent use of serotonin norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) with serotonin-receptor agonists. Of the 27 cases reviewed by the FDA, 2 were considered life-threatening and 13 required hospitalization. Some patients had used the combination previously without incident. Eight of 27 cases involved a recent dose increase or addition of another serotonergic drug to the regimen, with a median onset of 1 day (range: 10 minutes to 6 days). It is thought that the interaction between SNRIs or SSRIs and serotonin-receptor agonists is the result of increased serotonergic activity by each of the drug classes. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. At least 6 patients taking an SSRI antidepressant are known to have received sumatriptan for migraine where no apparent adverse effects were seen. In another case report, the addition of fluoxetine lead to loss of migraine control with sumatriptan. Patients receiving vilazodone and a serotonin-receptor agonist should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. Vilazodone and the serotonin-receptor agonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Vortioxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering vortioxetine with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan). Serotonin syndrome has been reported during concurrent use of serotonergic antidepressants with the serotonin-receptor agonists. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the sertonergic antidepressant or the addition of other serotonergic medications to an existing antidepressant regimen.

    PREGNANCY AND LACTATION

    Pregnancy

    Rizatriptan is classified as FDA pregnancy category C. Because pregnancy outcome data are too limited to be conclusive, the use of rizatriptan during pregnancy is not recommended unless the benefits outweigh the risks. Data were collected prospectively through the manufacturer's registry for 67 pregnancies with exposure to rizatriptan. The available outcomes included 3 spontaneous abortions during the first trimester, 1 elective abortion (chromosomal anomaly), 1 feta death due to cord accident, 1 neonatal death due to prematurity, 28 healthy term infants, and 1 premature infant with hypospadias. There are three cases of congenital anomalies collected prospectively through international reports, and three cases of congenital anomalies reported retrospectively. In clinical trials, there were 26 inadvertent exposures during pregnancy, of which there were 6 spontaneous abortions, 6 elective abortions, 13 healthy newborns, and 1 lost to follow-up. In animal studies at doses greater than those used clinically, rizatriptan was associated with reduced birth weight, reduced weight gain in the offspring, increased offspring mortality at birth, decreased learning capacity, and a decrease in maternal weight gain during gestation. In two animal species studied, rizatriptan crossed the placenta. The molecular weight of rizatriptan suggests that the drug can also undergo placental transfer in humans. The manufacturer maintains a registry to monitor the pregnancy outcomes of women exposed to rizatriptan while pregnant. Healthcare providers are encouraged to report any prenatal exposure to rizatriptan by calling the Pregnancy Registry at 800—986—8999. Patients should be instructed to notify their physician if they become pregnant or intend to become pregnant during treatment with rizatriptan. The effects of rizatriptan during labor and delivery are unknown.

    According to the manufacturer, it is unknown whether rizatriptan is excreted into breast milk and caution is advisable when administering the drug during breast-feeding. Rizatriptan is excreted into the breast milk of rats at a level 5-fold or greater than maternal plasma levels. Due to a low molecular weight (roughly 269), rizatriptan will most likely enter the breast milk. Rizatriptan's bioavailability is 45% and undergoes first-pass metabolism, which in theory may lessen the total amount absorbed by the infant. Pumping or expressing breast milk and discarding it up to several hours after a dose would help to avoid maximum infant exposure to rizatriptan. Additionally, rizatriptan is typically given as a one or two time dose, which may lessen infant risk. Sumatriptan is classified as compatible with breast-feeding by the American Academy of Pediatrics and may be considered as an alternative to rizatriptan for the acute treatment of migraines in breast-feeding mothers. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Rizatriptan is a selective 5-hydroxytryptamine 1B/1D (5-HT 1B/1D) receptor agonist. It has very weak activity at other 5-HT receptors, but has no activity at alpha, beta, dopaminergic, histaminergic, muscarinic, or benzodiazepine receptors. The pathophysiology of migraine is not completely understood, and therefore the action of the serotonin-agonists (i.e., 'triptans' ) in treating migraine is not completely certain. Multiple pharmacological actions have been derived that appear important for antimigraine effects.. 'Triptans' stimulate presynaptic 5-HT1D receptors, an action that inhibits both dural vasodilation and inflammation. They directly inhibit trigeminal nuclei cell nociceptive neurotransmission via 5-HT1B/D receptor agonism within the trigeminocervical complex of the brainstem and upper spinal cord. Additionally, vascular 5-HT1B receptor agonism results in vasoconstriction of painfully dilated intracranial extracerebral vessels.. Although rizatriptan has little effect on other 5-HT receptors, activation of coronary 5-HT 1B receptors could result in clinically significant cardiac events in patients with cardiac disease or risk factors for cardiac disease. However, it appears the cardiac effects of rizatriptan in vitro are less than those of sumatriptan.

    PHARMACOKINETICS

    Rizatriptan is administered orally; there are two distinct solid oral dosage forms. There is no accumulation of rizatriptan with repeated dosing. Rizatriptan is metabolized via oxidative deamination by monoamine oxidase-A (MAO-A) to the inactive indoleacetic acid metabolite and to a small degree, to N-monodesmethyl-rizatriptan which has similar activity as the parent compound. Rizatriptan undergoes significant first pass metabolism with only 14% of the oral dose excreted in the urine as unchanged drug and 51% is excreted as the indole acetic acid metabolite. The half-life of rizatriptan averages 2—3 hours. Rizatriptan is a competitive inhibitor of cytochrome P450 2D6 but only at high, clinically irrelevant concentrations. Rizatriptan does not inhibit P450 isoforms 3A4/5, 1A2, 2C9, 2C19, or 2E1.

    Oral Route

    Rizatriptan is rapidly absorbed orally with a bioavailability of about 45%. The time to peak plasma concentrations is approximately 1—1.5 hours. Food does not affect the availability of rizatriptan but delays the time to peak concentration by an hour and increases AUC. The bioavailability and peak plasma concentrations are similar between Maxalt tablets and Maxalt-MLT disintegrating tablets; however, the time to peak plasma concentration is longer with the Maxalt-MLT disintegrating tablets with a time to peak plasma concentration of 1.6—2.5 hours.