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  • CLASSES

    Selective Serotonin Agonists/Triptans

    DEA CLASS

    Rx

    DESCRIPTION

    Oral serotonin agonist for migraine; similar to sumatriptan, but with a higher patient acceptability rating regarding ADRs; FDA approved in adults and pediatrics 12—17 years of age.

    COMMON BRAND NAMES

    Axert

    HOW SUPPLIED

    Almotriptan/Almotriptan Malate/Axert Oral Tab: 6.25mg, 12.5mg

    DOSAGE & INDICATIONS

    For the acute treatment of migraine attacks in patients with a history of migraine with or without aura .
    NOTE: Use almotriptan only when a clear diagnosis of migraine is established. If a patient does not respond to almotriptan for the first migraine attack, the diagnosis of migraine should be re-evaluated prior to subsequent use of the drug. Almotriptan is not indicated for migraine prophylaxis or for the treatment of hemiplegic or basilar migraines or cluster headaches.
    For the acute treatment of migraine headache pain in patients with a history of migraine attacks with or without aura usually lasting 4 hours or more (when untreated).
    Oral dosage
    Adolescents and Children 12 to 17 years

    6.25 mg or 12.5 mg PO once. If the headache returns, the dose may be repeated after 2 hours. The maximum dosage is 2 doses per 24-hour period (25 mg/day). Controlled trials have not adequately established the effectiveness of a second dose if the initial dose is ineffective. Single doses more than 12.5 mg do not improve efficacy. The safety of treating more than 4 headaches in a 30-day period has not been established. Efficacy for migraine associated symptoms such as nausea, photophobia, and phonophobia has not been established.

    Oral dosage
    Adults

    6.25 mg or 12.5 mg PO once; a higher percentage of patients reported pain relief with the 12.5 mg dose in clinical trials. If the headache returns, the dose may be repeated after 2 hours. The maximum dosage is 2 doses per 24-hour period (25 mg/day). Controlled trials have not adequately established the effectiveness of a second dose if the initial dose is ineffective. Single doses more than 12.5 mg do not improve efficacy. The safety of treating more than 4 headaches in a 30-day period has not been established.

    MAXIMUM DOSAGE

    Adults

    25 mg/day PO.

    Elderly

    25 mg/day PO.

    Adolescents

    25 mg/day PO.

    Children

    >= 12 years: 25 mg/day PO.
    < 12 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    The recommended initial dose is 6.25 mg PO; the maximum dosage is 12.5 mg/day.

    Renal Impairment

    CrCl > 30 ml/min: No dosage adjustment is needed.
    CrCl 10—30 ml/min: Initial dose is 6.25 mg PO; maximum dosage is 12.5 mg/day.
     
    Intermittent hemodialysis
    See dosage for renal impairment. It is not known whether hemodialysis removes almotriptan from plasma.
     
    Peritoneal dialysis
    The effects of peritoneal dialysis on plasma concentrations of almotriptan are unknown.

    ADMINISTRATION

    Avoid or use with caution with other serotonergic drugs to prevent serotonin syndrome (see Drug Interactions).

    Oral Administration
    Oral Solid Formulations

    May be administered without regard to meals.

    STORAGE

    Axert:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Almotriptan is contraindicated in patients who have received ergotamine-containing or ergot-type medications within 24 hours of almotriptan administration. Almotriptan and other 5-HT1 agonists should not be administered within 24 hours of each other.
     
    Serotonin syndrome may occur during the use of 5-HT1 agonists, including almotriptan, particularly during concurrent administration of serotonin norepinephrine reuptake inhibitors or selective serotonin reuptake inhibitors. If concomitant use is necessary, careful observation of the patient is advised, particularly during treatment initiation and dose escalation.
     
    Results from animal studies suggest that almotriptan and/or its metabolites may bind to melanin in the eye. Although adverse retinal effects were not observed during a toxicity study in animals, in theory, toxicity to melanin-rich tissue, such as the eye, may occur during chronic use of the drug. Systematic evaluation of ophthalmologic function has not been conducted in clinical trials, and there are presently no specific recommendations regarding ophthalmologic monitoring during almotriptan use.
     
    During a 52-week toxicity study in animals, slight corneal opacities developed in 3 of 14 almotriptan-treated animals. Further study is needed to determine the significance of this finding, if any, in humans receiving standard doses of the drug.

    Sulfonamide hypersensitivity

    Almotriptan is contraindicated in patients with known hypersensitivity to almotriptan or any of its ingredients. Because the chemical structure of almotriptan contains a sulfonyl group, caution is recommended when administering almotriptan to patients with a sulfonamide hypersensitivity. It should be noted that cross-sensitivity to almotriptan in patients allergic to sulfonamides has not been formally evaluated by the manufacturer.

    Angina, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, hypercholesterolemia, myocardial infarction, 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. Almotriptan and other 5-HT1 agonists may cause coronary vasospasm, and therefore are contraindicated in patients with coronary artery disease (CAD), angina pectoris, vasospastic angina such as Prinzmetal's variant angina, silent myocardial ischemia, history of myocardial infarction, or other significant underlying 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 males older than 40 years) should not be given almotriptan 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 almotriptan 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 almotriptan 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 almotriptan administration in patients with risk factors. In addition, patients with cardiac arrhythmias should not receive almotriptan 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 almotriptan because serious cardiac events have been reported within a few hours of receiving 5-HT1 agonists.

    Hypertension

    Almotriptan 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

    Almotriptan is contraindicated in patients with cerebrovascular disease, including stroke or history of transient ischemic attack. Intracranial hemorrhage, intracranial bleeding, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with 5-HT1 agonists; some have resulted in fatal events. In these cases, cerebrovascular events may have preceded administration of the 5-HT1 agonist. Patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, intracranial bleeding, transient ischemic attack).

    Basilar/hemiplegic migraine

    Almotriptan is contraindicated for use in basilar/hemiplegic migraine because safe and effective use has not been established.

    Geriatric

    Almotriptan should be used with caution in geriatric patients with migraine. Elderly patients are more likely to have unrecognized risk factors for coronary artery disease than younger adults. Clearance of almotriptan is lower in elderly volunteers than in younger individuals, but there are no observed differences in the safety and tolerability between the two populations; however, sufficient numbers of elderly patients receiving almotriptan have not been studied. In general, dosage selection for almotriptan should be cautious, usually starting at the lower end of the adult dosage range.

    Hepatic disease

    Almotriptan should be used cautiously in patients with hepatic disease. The pharmacokinetics of almotriptan have not been assessed in patients with hepatic impairment; however, drug clearance would be expected to be reduced, since up to 60% of the dose may be eliminated by hepatic metabolism (see Dosage).

    Renal disease, renal failure, renal impairment

    Almotriptan should be used cautiously in patients with renal impairment (renal disease or renal failure). Patients with severe renal impairment require dosage reduction.

    Colitis, peripheral vascular disease, Raynaud's phenomenon

    Almotriptan is contraindicated in patients with peripheral vascular disease, including but not limited to ischemic bowel disease (ischemic colitis). Almotriptan may cause vasospastic reactions other than coronary artery vasospasm, such as peripheral and gastrointestinal vascular ischemia with abdominal pain and bloody diarrhea. Rare reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1-agonists. Visual disorders may also be part of a migraine attack. Patients who experience signs or symptoms suggestive of decreased arterial flow, such as Raynaud's phenomenon or ischemic bowel syndrome, after the use of almotriptan should be further evaluated.

    Driving or operating machinery

    Patients should be warned to avoid driving or operating machinery until they know how almotriptan affects them.

    Children, infants, neonates

    The safety and efficacy of almotriptan have not been established in neonates, infants, or children less than 12 years of age. Post-marketing experience with other 'triptans' include a limited number of reports that describe pediatric patients who have experienced serious adverse events that are similar in nature to rare adverse events reported in adults.

    Pregnancy

    Almotriptan is classified as FDA pregnancy risk category C. There have been no adequate and well controlled studies in pregnant women; therefore, almotriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known if almotriptan crosses the placenta, but the low molecular weight and minimal protein binding of the drug suggest that placental transfer in humans is likely. In animal studies, almotriptan produced developmental toxicity (increased embryolethality, fetal skeletal variations (decreased ossification), and decreased offspring body weight) at doses greater than those used clinically. During administration to rats throughout gestation and lactation, gestation length was increased and litter size and offspring body weight were decreased at the highest dose. The decrease in pup weight persisted throughout lactation. Patients should be instructed to notify their physician if they become pregnant or intend to become pregnant during treatment with almotriptan. The effects of almotriptan during labor and delivery are unknown.

    Breast-feeding

    Use caution when administering almotriptan to a breast-feeding woman. Almotriptan is excreted into the breast milk of lactating rats, however, it is not known if almotriptan is distributed into human breast milk. In rats, concentrations of almotriptan were up to 7 times higher in breast milk compared to plasma. During administration of almotriptan to rats throughout gestation and lactation, pup weight was decreased at the highest dose, and the decrease in weight persisted throughout lactation. Low molecular weight and low protein binding suggest the drug will be excreted into human breast milk. Pumping or expressing breast milk and discarding it after a dose would help to avoid maximum infant exposure to almotriptan. Additionally, almotriptan is typically given as a 1 or 2 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 almotriptan for the acute treatment of migraines in breast-feeding mothers.

    ADVERSE REACTIONS

    Severe

    serotonin syndrome / Delayed / 0-1.0
    laryngospasm / Rapid / 0.1-1.0
    bowel ischemia / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    coronary vasospasm / Early / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    stroke / Early / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    visual impairment / Early / Incidence not known

    Moderate

    dyspnea / Early / 0.1-1.0
    sinus tachycardia / Rapid / 0.1-1.0
    palpitations / Early / 0.1-1.0
    chest pain (unspecified) / Early / 0.1-1.0
    hyperglycemia / Delayed / 0.1-1.0
    colitis / Delayed / 0-0.1
    gastritis / Delayed / 0-0.1
    hyperreflexia / Delayed / 0-0.1
    hypertonia / Delayed / 0-0.1
    depression / Delayed / 0-0.1
    euphoria / Early / 0-0.1
    nystagmus / Delayed / 0-0.1
    erythema / Early / 0-0.1
    myopathy / Delayed / 0-0.1
    myasthenia / Delayed / 0-0.1
    hypertension / Early / 0-0.1
    hypercholesterolemia / Delayed / 0-0.1
    scotomata / Delayed / 0-0.1
    hyperacusis / Delayed / 0-0.1
    conjunctivitis / Delayed / 0-0.1
    glossitis / Early / Incidence not known
    confusion / Early / Incidence not known
    withdrawal / Early / Incidence not known
    peripheral vasoconstriction / Rapid / Incidence not known
    angina / Early / Incidence not known
    chest pressure syndrome / Rapid / Incidence not known
    blepharospasm / Early / Incidence not known
    blurred vision / Early / Incidence not known

    Mild

    drowsiness / Early / 0-5.0
    dizziness / Early / 3.0-4.0
    nausea / Early / 1.0-3.0
    vomiting / Early / 0-2.0
    headache / Early / 1.0-2.0
    polydipsia / Early / 0.1-1.0
    diarrhea / Early / 0.1-1.0
    xerostomia / Early / 1.0-1.0
    abdominal pain / Early / 0.1-1.0
    dyspepsia / Early / 0.1-1.0
    tremor / Early / 0.1-1.0
    asthenia / Delayed / 0.1-1.0
    vertigo / Early / 0.1-1.0
    restlessness / Early / 0.1-1.0
    fatigue / Early / 0.1-1.0
    anxiety / Delayed / 0.1-1.0
    paresthesias / Delayed / 0-1.0
    hypoesthesia / Delayed / 0.1-1.0
    pruritus / Rapid / 0.1-1.0
    diaphoresis / Early / 0.1-1.0
    rash (unspecified) / Early / 0.1-1.0
    sinusitis / Delayed / 0.1-1.0
    rhinitis / Early / 0.1-1.0
    pharyngitis / Delayed / 0.1-1.0
    myalgia / Early / 0.1-1.0
    back pain / Delayed / 0.1-1.0
    flushing / Rapid / 0.1-1.0
    dysmenorrhea / Delayed / 0.1-1.0
    otalgia / Early / 0.1-1.0
    tinnitus / Delayed / 0.1-1.0
    chills / Rapid / 0.1-1.0
    gastroesophageal reflux / Delayed / 0-0.1
    hypersalivation / Early / 0-0.1
    insomnia / Early / 0-0.1
    nightmares / Early / 0-0.1
    photosensitivity / Delayed / 0-0.1
    epistaxis / Delayed / 0-0.1
    laryngitis / Delayed / 0-0.1
    sneezing / Early / 0-0.1
    hyperventilation / Early / 0-0.1
    arthralgia / Delayed / 0-0.1
    syncope / Early / 0-0.1
    ocular pain / Early / 0-0.1
    ocular irritation / Rapid / 0-0.1
    parosmia / Delayed / 0-0.1
    diplopia / Early / 0-0.1
    dysgeusia / Early / 0-0.1
    xerophthalmia / Early / 0-0.1
    fever / Early / 0-0.1
    hyperhidrosis / Delayed / Incidence not known
    mastalgia / Delayed / Incidence not known
    malaise / 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.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Clarithromycin may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and clarithromycin is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Clarithromycin may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and clarithromycin is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    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.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if almotriptan and aprepitant, fosaprepitant are used concurrently and monitor for an increase in almotriptan-related adverse effects for several days after administration of a multi-day aprepitant regimen. Almotriptan is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of almotriptan. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Artemether; Lumefantrine: (Major) Artemether; lumefantrine is an inhibitor and almotriptan is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased almotriptan concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    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.
    Atazanavir: (Major) Atazanavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Atazanavir is a potent CYP3A4 inhibitor and almotriptan is a substrate of CYP3A4. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    Atazanavir; Cobicistat: (Major) Atazanavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Atazanavir is a potent CYP3A4 inhibitor and almotriptan is a substrate of CYP3A4. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure. (Major) The plasma concentrations of almotriptan may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as serotonergic excess and triptan-related side effects, is recommended during coadministration. Cobicistat is a CYP3A4 and CYP2D6 inhibitor, while almotriptan is a CYP3A4 and CYP2D6 substrate.
    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.
    Boceprevir: (Major) Boceprevir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and boceprevir is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    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.
    Ceritinib: (Moderate) Monitor for almotriptan-related adverse reactions if coadministration with ceritinib is necessary; a dosage adjustment may be necessary. Almotriptan is primarily metabolized by CYP3A4 and ceritinib is a CYP3A4 inhibitor. The strength of inhibition of CYP3A4 by ceritinib is unknown; however, coadministration with a strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%, while coadministration with a moderate CYP3A4 inhibitor increased the almotriptan AUC and Cmax by 20% and 24%.
    Chloramphenicol: (Major) Chloramphenicol may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and chloramphenicol is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    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.
    Ciprofloxacin: (Major) The plasma concentrations of almotriptan may be elevated when administered concurrently with ciprofloxacin. Clinical monitoring for adverse effects, such as serotonergic excess and triptan-related side effects, is recommended during coadministration. Ciprofloxacin is a CYP3A4 inhibitor, while almotriptan is a CYP3A4 substrate.
    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., almotriptan). 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.
    Clarithromycin: (Major) Clarithromycin may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and clarithromycin is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    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.
    Cobicistat: (Major) The plasma concentrations of almotriptan may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as serotonergic excess and triptan-related side effects, is recommended during coadministration. Cobicistat is a CYP3A4 and CYP2D6 inhibitor, while almotriptan is a CYP3A4 and CYP2D6 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) The plasma concentrations of almotriptan may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as serotonergic excess and triptan-related side effects, is recommended during coadministration. Cobicistat is a CYP3A4 and CYP2D6 inhibitor, while almotriptan is a CYP3A4 and CYP2D6 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) The plasma concentrations of almotriptan may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as serotonergic excess and triptan-related side effects, is recommended during coadministration. Cobicistat is a CYP3A4 and CYP2D6 inhibitor, while almotriptan is a CYP3A4 and CYP2D6 substrate.
    Conivaptan: (Major) Avoid coadministration of conivaptan and almotriptan; subsequent almotriptan use should be initiated no sooner than 1 week after the infusion of conivaptan is complete. Conivaptan may increase the systemic exposure of almotriptan. Almotriptan is a CYP3A4 substrate and conivaptan is a potent CYP3A4 inhibitor.
    Dalfopristin; Quinupristin: (Major) Dalfopristin; quinupristin may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and quinupristin is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    Darunavir: (Major) Darunavir boosted with cobicistat or ritonavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a substrate of CYP3A4 and CYP2D6. Darunavir is an inhibitor of CYP3A4 and CYP2D6; when boosted with cobicistat or ritonavir, further inhibition is seen. In a drug interaction study, coadministration of almotriptan and ketoconazole, a potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    Darunavir; Cobicistat: (Major) Darunavir boosted with cobicistat or ritonavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a substrate of CYP3A4 and CYP2D6. Darunavir is an inhibitor of CYP3A4 and CYP2D6; when boosted with cobicistat or ritonavir, further inhibition is seen. In a drug interaction study, coadministration of almotriptan and ketoconazole, a potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure. (Major) The plasma concentrations of almotriptan may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as serotonergic excess and triptan-related side effects, is recommended during coadministration. Cobicistat is a CYP3A4 and CYP2D6 inhibitor, while almotriptan is a CYP3A4 and CYP2D6 substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Ombitasvir; paritaprevir; ritonavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and ritonavir is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure. (Major) Ritonavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and ritonavir is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    Delavirdine: (Major) Delavirdine may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a substrate of CYP3A4 and CYP2D6. Delavirdine is a potent CYP3A4 inhibitor; it may also inhibit CYP2D6. Delavirdine's inhibition of CYP3A4 activity appears to be reversible within 1 week after discontinuing the drug. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    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.
    Dronedarone: (Moderate) Dronedarone is metabolized by CYP3A and is an inhibitor of CYP2D6 and CYP3A. Almotriptan is a substrate for CYP2D6 and CYP3A4. The concomitant administration of dronedarone with CYP2D6 and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    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.
    Elbasvir; Grazoprevir: (Moderate) Administering almotriptan with elbasvir; grazoprevir may result in elevated almotriptan plasma concentrations. Almotriptan is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    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.
    Erythromycin: (Major) Erythromycin may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and erythromycin is a CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, a potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    Erythromycin; Sulfisoxazole: (Major) Erythromycin may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and erythromycin is a CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, a potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    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., almotriptan). 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., almotriptan). 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. Co-administration of almotriptan and fluoxetine (60 mg daily for 8 days), a potent inhibitor of CYP2D6, had no effect on almotriptan clearance, but maximal concentrations of almotriptan were increased 18%. The difference is not considered clinically significant.
    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., almotriptan). 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. Co-administration of almotriptan and fluoxetine (60 mg daily for 8 days), a potent inhibitor of CYP2D6, had no effect on almotriptan clearance, but maximal concentrations of almotriptan were increased 18%. The difference is not considered clinically significant.
    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., almotriptan). 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.
    Fosamprenavir: (Major) Fosamprenavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and amprenavir, the active metabolite of fosamprenavir, is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    Grapefruit juice: (Major) Avoid grapefruit and grapefruit juice while taking almotriptan, as coadministration may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and grapefruit is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    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.
    Idelalisib: (Major) Idelalisib may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and idelalisib is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    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.
    Indinavir: (Major) Indinavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and indinavir is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with almotriptan may result in increased serum concentrations of almotriptan. Almotriptan is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isocarboxazid: (Severe) Whenever possible, do not give serotonin-receptor agonists like almotriptan concurrently with non-selective monoamine oxidase inhibitors (MAOIs) (e.g., phenelzine, tranylcypromine, isocarboxazid) or within 2 weeks of discontinuation of MAOI therapy. If use together is unavoidable, co-use should be approached with caution and the patient monitored for signs of serotonergic excess and triptan-related side effects. Inhibitors of MAO type A may potentiate the clinical effects of almotriptan by reducing the metabolism of almotriptan and also by decreasing the metabolism of serotonin. Although unlikely to occur with 5HT1 agonists when given alone, combining medications that potentiate serotonin neurotransmission could result in serotonin syndrome. Almotriptan is metabolized by one minor and two major pathways: Monoamine oxidase (MAO)-mediated oxidative deamination (approximately 27% of the dose), and CYP450-mediated oxidation (approximately 12% of the dose) are the two major routes of metabolism. The representative selective MAO-A inhibitor moclobemide decreases almotriptan clearance by 27% and increases Cmax roughly 6%; however, dosage adjustments of almotriptan are not necessary. It is not known whether selective monoamine oxidase B inhibitors (e.g., selegiline) interact with almotriptan at clinically relevant dosages; at higher selegiline doses (> 20 mg) the selectivity of selegiline may be lost.
    Itraconazole: (Major) Itraconazole may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and itraconazole is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    Ivacaftor: (Minor) Use caution when administering ivacaftor and almotriptan concurrently. Ivacaftor is an inhibitor of CYP3A and almotriptan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as almotriptan, can theoretically increase almotriptan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Ketoconazole: (Major) Ketoconazole may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and ketoconazole is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole resulted in an approximately 60% increase in almotriptan exposure.
    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.
    Lopinavir; Ritonavir: (Major) Lopinavir; ritonavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and lopinavir; ritonavir is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure. (Major) Ritonavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and ritonavir is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    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.
    Lumacaftor; Ivacaftor: (Minor) Lumacaftor; ivacaftor may reduce the efficacy of almotriptan by decreasing its systemic exposure. If used together, monitor the patient for appropriate clinical effects. Almotriptan is partially metabolized by CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Lumacaftor; Ivacaftor: (Minor) Use caution when administering ivacaftor and almotriptan concurrently. Ivacaftor is an inhibitor of CYP3A and almotriptan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as almotriptan, can theoretically increase almotriptan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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.
    Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as almotriptan may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    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.
    Mitotane: (Moderate) Use caution if mitotane and almotriptan are used concomitantly, and monitor for decreased efficacy of almotriptan and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and almotriptan is a CYP3A4 substrate (approximately 12%); coadministration may result in decreased plasma concentrations of almotriptan.
    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) Nefazodone may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and nefazodone is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    Nelfinavir: (Major) Nelfinavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and nelfinavir is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    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.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Ombitasvir; paritaprevir; ritonavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and ritonavir is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure. (Major) Ritonavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and ritonavir is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Ombitasvir; paritaprevir; ritonavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and ritonavir is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    Oritavancin: (Minor) Almotriptan is metabolized by CYP3A4 and CYP2D6; oritavancin is a weak CYP3A4 and CYP2D6 inducer. Plasma concentrations and efficacy of almotriptan may be reduced if these drugs are administered concurrently.
    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., almotriptan). 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.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and almotriptan, a CYP3A4 substrate, may cause an increase in systemic concentrations of almotriptan. Use caution when administering these drugs concomitantly.
    Peginterferon Alfa-2b: (Major) Monitor for adverse effects associated with increased exposure to almotriptan if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while almotriptan is a CYP2D6 substrate.
    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) Whenever possible, do not give serotonin-receptor agonists like almotriptan concurrently with non-selective monoamine oxidase inhibitors (MAOIs) (e.g., phenelzine, tranylcypromine, isocarboxazid) or within 2 weeks of discontinuation of MAOI therapy. If use together is unavoidable, co-use should be approached with caution and the patient monitored for signs of serotonergic excess and triptan-related side effects. Inhibitors of MAO type A may potentiate the clinical effects of almotriptan by reducing the metabolism of almotriptan and also by decreasing the metabolism of serotonin. Although unlikely to occur with 5HT1 agonists when given alone, combining medications that potentiate serotonin neurotransmission could result in serotonin syndrome. Almotriptan is metabolized by one minor and two major pathways: Monoamine oxidase (MAO)-mediated oxidative deamination (approximately 27% of the dose), and CYP450-mediated oxidation (approximately 12% of the dose) are the two major routes of metabolism. The representative selective MAO-A inhibitor moclobemide decreases almotriptan clearance by 27% and increases Cmax roughly 6%; however, dosage adjustments of almotriptan are not necessary. It is not known whether selective monoamine oxidase B inhibitors (e.g., selegiline) interact with almotriptan at clinically relevant dosages; at higher selegiline doses (> 20 mg) the selectivity of selegiline may be lost.
    Posaconazole: (Major) Posaconazole may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and posaconazole is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    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 agonists and monoamine oxidase inhibitors (MAOIs). Since rasagiline selectively inhibits MAO-B at recommended doses, no interaction with almotriptan 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. However, whether or not 5-HT1B/1D agonists such as almotriptan 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. Approximately 27% of a dose of almotriptan is metabolized by MAO-A. Theoretically, use of high dose rasagiline could increase systemic exposure to almotriptan through MAO-A inhibition, although a significant interaction appears remote based on results of an interaction study between almotriptan and the selective MAO-A inhibitor moclobemide.
    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.
    Ritonavir: (Major) Ritonavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and ritonavir is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    Rolapitant: (Major) Use caution if almotriptan and rolapitant are used concurrently, and monitor for almotriptan-related adverse effects. Almotriptan is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration.
    Saquinavir: (Major) Saquinavir boosted with ritonavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate. Saquinavir is an inhibitor of CYP3A4; when boosted with ritonavir, CYP3A4 inhibition is potent. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    Selegiline: (Major) Serotonin syndrome has been reported during co-administration of serotonin-receptor agonists and monoamine oxidase inhibitors (MAOIs). Since oral selegiline selectively inhibits MAO-B at recommended doses, no interaction with almotriptan would be expected with normal prescription use. However, there is a decline in MAO-B selectivity with increasing doses. Therefore, high dose treatment with oral selegiline may increase central serotonin levels through MAO-A inhibition. In addition, selegiline, transdermal inhibits both MAO-A and MAO-B at the usual antidepressant doses. However, whether or not 5-HT1B/1D agonists such as almotriptan 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. Approximately 27% of a dose of almotriptan is metabolized by MAO-A. Theoretically, use of high dose selegiline could increase systemic exposure to almotriptan through MAO-A inhibition, although a significant interaction appears remote based on results of an interaction study between almotriptan and the selective MAO-A inhibitor moclobemide.
    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., almotriptan). 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.
    Simeprevir: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of almotriptan, which is a CYP3A4 substrate. Monitor patients for adverse effects of almotriptan, such as serotonin syndrome.
    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.
    Streptogramins: (Major) Dalfopristin; quinupristin may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and quinupristin is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    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 almotriptan. 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.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering almotriptan with telaprevir due to an increased potential for almotriptan-related adverse events. If almotriptan dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of almotriptan. Almotriptan is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated almotriptan plasma concentrations.
    Telithromycin: (Major) Avoid coadministration of telithromycin and almotriptan, as coadministration may increase the systemic exposure of almotriptan. If coadministration is necessary, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and telithromycin is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and almotriptan is necessary, as the systemic exposure of almotriptan may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of almotriptan; consider increasing the dose of almotriptan if necessary. Almotriptan is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Tipranavir: (Major) Tipranavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 and CYP2D6 substrate and tipranavir is a potent inhibitor of both CYP3A4 and CYP2D6. In a drug interaction study, coadministration of almotriptan and ketoconazole, a potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    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.
    Trandolapril; Verapamil: (Minor) Verapamil, a moderate CYP3A4 inhibitor, increases AUC and peak plasma concentrations of almotriptan by 20% and 24%, respectively; however, per the manufacturer, the changes are not clinically significant and no dosage adjustment of almotriptan is needed. Some patients might rarely have an increase in common side effects of almotriptan, such as dizziness, nausea or drowsiness.
    Tranylcypromine: (Severe) Whenever possible, do not give serotonin-receptor agonists like almotriptan concurrently with non-selective monoamine oxidase inhibitors (MAOIs) (e.g., phenelzine, tranylcypromine, isocarboxazid) or within 2 weeks of discontinuation of MAOI therapy. If use together is unavoidable, co-use should be approached with caution and the patient monitored for signs of serotonergic excess and triptan-related side effects. Inhibitors of MAO type A may potentiate the clinical effects of almotriptan by reducing the metabolism of almotriptan and also by decreasing the metabolism of serotonin. Although unlikely to occur with 5HT1 agonists when given alone, combining medications that potentiate serotonin neurotransmission could result in serotonin syndrome. Almotriptan is metabolized by one minor and two major pathways: Monoamine oxidase (MAO)-mediated oxidative deamination (approximately 27% of the dose), and CYP450-mediated oxidation (approximately 12% of the dose) are the two major routes of metabolism. The representative selective MAO-A inhibitor moclobemide decreases almotriptan clearance by 27% and increases Cmax roughly 6%; however, dosage adjustments of almotriptan are not necessary. It is not known whether selective monoamine oxidase B inhibitors (e.g., selegiline) interact with almotriptan at clinically relevant dosages; at higher selegiline doses (> 20 mg) the selectivity of selegiline may be lost.
    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.
    Verapamil: (Minor) Verapamil, a moderate CYP3A4 inhibitor, increases AUC and peak plasma concentrations of almotriptan by 20% and 24%, respectively; however, per the manufacturer, the changes are not clinically significant and no dosage adjustment of almotriptan is needed. Some patients might rarely have an increase in common side effects of almotriptan, such as dizziness, nausea or drowsiness.
    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

    Almotriptan is classified as FDA pregnancy risk category C. There have been no adequate and well controlled studies in pregnant women; therefore, almotriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known if almotriptan crosses the placenta, but the low molecular weight and minimal protein binding of the drug suggest that placental transfer in humans is likely. In animal studies, almotriptan produced developmental toxicity (increased embryolethality, fetal skeletal variations (decreased ossification), and decreased offspring body weight) at doses greater than those used clinically. During administration to rats throughout gestation and lactation, gestation length was increased and litter size and offspring body weight were decreased at the highest dose. The decrease in pup weight persisted throughout lactation. Patients should be instructed to notify their physician if they become pregnant or intend to become pregnant during treatment with almotriptan. The effects of almotriptan during labor and delivery are unknown.

    Use caution when administering almotriptan to a breast-feeding woman. Almotriptan is excreted into the breast milk of lactating rats, however, it is not known if almotriptan is distributed into human breast milk. In rats, concentrations of almotriptan were up to 7 times higher in breast milk compared to plasma. During administration of almotriptan to rats throughout gestation and lactation, pup weight was decreased at the highest dose, and the decrease in weight persisted throughout lactation. Low molecular weight and low protein binding suggest the drug will be excreted into human breast milk. Pumping or expressing breast milk and discarding it after a dose would help to avoid maximum infant exposure to almotriptan. Additionally, almotriptan is typically given as a 1 or 2 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 almotriptan for the acute treatment of migraines in breast-feeding mothers.

    MECHANISM OF ACTION

    Mechanism of Action: Almotriptan acts therapeutically as an agonist at central serotonin 5-HT1 type B and D receptors. Almotriptan binds with high affinity to 5-HT1D, 5-HT1B, and 5-HT1F 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. In addition, vascular 5-HT1B receptor agonism results in vasoconstriction of painfully dilated intracranial extracerebral vessels.. Like other 5-HT1B/D receptor agonists, almotriptan has a high affinity for 5-HT1F; however, the pharmacological effects of this serotonin receptor subtype have not been determined.

    PHARMACOKINETICS

    Almotriptan is administered orally. Almotriptan is minimally protein bound (about 35%) with a mean Vd of approximately 180 to 200 L. One minor and two major pathways contribute to the metabolism of almotriptan. Monoamine oxidase (MAO)-mediated oxidative deamination (about 27% of the dose) and cytochrome P450-mediated oxidation (about 12% of the dose) are the major routes of metabolism, while flavin monooxygenase is the minor route. MAO-A is responsible for the formation of the indoleacetic acid metabolite, whereas cytochrome P450 (CYP3A4 and CYP2D6) catalyzes the hydroxylation of the pyrrolidine ring to an intermediate that is further oxidized by aldehyde dehydrogenase to the gamma-amino-butyric acid derivative; both metabolites are inactive. Renal clearance exceeds the glomerular filtration rate by 3-fold, indicating an active process. The mean elimination half-life of almotriptan is 3 to 4 hours. Almotriptan is primarily eliminated by the kidney (about 75%), with approximately 40% of the dose excreted unchanged in the urine. Approximately 13% of the administered dose is excreted in the feces.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4 and CYP2D6
    Cytochrome P450-mediated oxidation (about 12% of the dose) is one of the major routes of almotriptan metabolism. CYP3A4 and CYP2D6 catalyze the hydroxylation of the pyrrolidine ring to an intermediate that is further oxidized by aldehyde dehydrogenase to the gamma-amino-butyric acid derivative. Concomitant use of almotriptan and potent CYP3A4 inhibitors is expected to increase almotriptan exposure.

    Oral Route

    Almotriptan is well absorbed and has a bioavailability of 70%. Peak plasma levels of almotriptan occur 1 to 3 hours after oral administration; food does not affect its pharmacokinetics.