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  • CLASSES

    Selective Serotonin 1B/1D Receptor Agonists (Triptans)

    DEA CLASS

    Rx

    DESCRIPTION

    Serotonin-receptor 1B and 1D agonist (triptan)
    Used for acute treatment of migraine with or without aura and cluster headaches
    Potential for serious cardiac adverse effects

    COMMON BRAND NAMES

    Alsuma, Imitrex, Imitrex STAT dose, Migraine Pack, ONZETRA, Sumavel DosePro System, Tosymra, ZEMBRACE

    HOW SUPPLIED

    Alsuma/Imitrex/Imitrex STAT dose/Sumatriptan/Sumatriptan Succinate/Sumavel DosePro System/ZEMBRACE Subcutaneous Inj Sol: 0.5mL, 3mg, 4mg, 6mg
    Imitrex/Migraine Pack/Sumatriptan/Sumatriptan Succinate Oral Tab: 25mg, 50mg, 100mg
    Imitrex/Sumatriptan/Tosymra Nasal Spray Met: 1actuation, 5mg, 10mg, 20mg
    ONZETRA/Sumatriptan Nasal Pwd: 1actuation, 11mg

    DOSAGE & INDICATIONS

    For the acute treatment of migraine attacks with or without aura.
    NOTE: Sumatriptan is not indicated for hemiplegic or basilar migraine.
    Subcutaneous dosage (Alsuma, Sumavel DosePro, Imitrex, and generic equivalents)
    Adults

    6 mg subcutaneously. May repeat dose once with a minimum 1-hour interval between doses if migraine symptoms return. The maximum dose within 24 to 48 hours is 12 mg. If side effects are limiting, a lower dose may be used. Controlled clinical trials have failed to show that clear benefit is associated with the administration of a second 6 mg dose in patients who have failed to respond to first injection.[31921] A dose-ranging efficacy study showed that although pain relief occurred faster with 6 and 8 mg, doses as low as 1 mg were significantly more efficacious than placebo. The incidence of adverse effects was highest (93%) with the 8 mg dose compared to the 6, 4, or 3 mg doses (about 80%).[24985] Headache relief within 1 hour (defined as a reduction in pain from severe or moderately severe to mild or no headache) was achieved in 73% of patients who received a single 6 mg subcutaneous dose of sumatriptan compared to 50% of patients who received a single 4 mg subcutaneous dose.[31921]

    Subcutaneous dosage (Zembrace SymTouch)
    Adults

    3 mg subcutaneously. May repeat dose up to 4 times/day with each injection at least 1 hour apart. The maximum cumulative daily dose is 12 mg.

    Oral dosage
    Adults

    25, 50, or 100 mg PO once. May repeat a dose 2 hours after the first dose if the headache has not resolved or returns after transient improvement. The maximum daily dose is 200 mg. If headache returns after initial treatment with sumatriptan injection, may give up to 100 mg/day PO with intervals of at least 2 hours between oral doses. Doses of 50 or 100 mg may provide a greater effect than 25 mg; however, 100 mg may not provide a greater effect than 50 mg.[28583]

    Intranasal dosage (Imitrex nasal spray and generic equivalents)
    Adults

    5, 10, or 20 mg into 1 nostril as a single dose. May repeat dose once after 2 hours if headache returns up to a maximum of 40 mg/day. In controlled clinical trials, a greater proportion of patients had headache response after a 20 mg dose than 5 or 10 mg doses.[29523]

    Intranasal dosage (Tosymra nasal spray)
    Adults

    10 mg into 1 nostril. May repeat dose as needed with at least 1 hour between doses up to a maximum of 30 mg/day.

    Intranasal dosage (Onzetra Xsail nasal powder)
    Adults

    22 mg (2 nosepieces with 11 mg into each nostril) nasally. May repeat dose after at least 2 hours after the first dose if the headache has not resolved or returns after transient improvement. Do not exceed a total daily dose of 44 mg (4 nosepieces) or 1 dose of nasal powder and 1 dose of another sumatriptan product.[60543]

    For the acute treatment of cluster headache.
    Subcutaneous dosage (Alsuma, Sumavel DosePro, Imitrex, and generic equivalents)
    Adults

    Initially, 6 mg subcutaneously. If headache symptoms return, a second 6 mg dose may be given with a minimum 1-hour interval between doses. Consider giving a second dose only if some response to the first dose was observed. The maximum dose within 24 to 48 hours is two 6 mg injections. A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease).

    MAXIMUM DOSAGE

    Adults

    6 mg/dose or 12 mg/day subcutaneously (Alsuma, Sumavel DosePro, Imitrex, and generic equivalents); 3 mg/dose or 12 mg/day subcutaneously (Zembrace SymTouch); 100 mg/dose PO or 200 mg/day PO; 40 mg/day intranasally (Imitrex nasal spray and generic equivalents); 30 mg/day intranasally (Tosymra nasal spray); or 44 mg/day intranasally (nasal powder). The safety of treating more than 4 headaches in a 30-day period has not been established.

    Geriatric

    6 mg/dose or 12 mg/day subcutaneously (Alsuma, Sumavel DosePro, Imitrex, and generic equivalents); 3 mg/dose or 12 mg/day subcutaneously (Zembrace SymTouch); 100 mg/dose PO or 200 mg/day PO; 40 mg/day intranasally (Imitrex nasal spray and generic equivalents); 30 mg/day intranasally (Tosymra nasal spray); or 44 mg/day intranasally (nasal powder). The safety of treating more than 4 headaches in a 30 day period has not been established.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Hepatic impairment may cause unpredictable increases in the bioavailability of orally administered sumatriptan. Do not exceed 50 mg/dose PO. Hepatic impairment does not significantly affect intranasal or subcutaneous sumatriptan. All formulations are contraindicated for use in patients with severe hepatic impairment.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
     
    Intermittent hemodialysis
    It is not known whether hemodialysis removes sumatriptan from plasma.
     
    Peritoneal dialysis
    It is not known whether peritoneal dialysis removes sumatriptan from plasma.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    To avoid unpleasant taste swallow tablets whole; do not crush or chew.
    Take with fluids.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    For subcutaneous administration only; do NOT administer intravenously or intramuscularly.

    Subcutaneous Administration

    Imitrex injectable solution and generic equivalents:
    In patients with identifiable cardiovascular risk factors, the initial dose should be given in the physician's office in order to observe if there is any unrecognized cardiovascular disease.
    In patients receiving doses other than 4 or 6 mg, only the 6 mg single dose vial should be used.
    Inject subcutaneously preferably into the lateral portion of the thigh or deltoid area.
    For patients who are self administering sumatriptan, adequate oral as well as written instructions on the use of the auto-injector should be supplied before they self-administer a dose.
     
    Sumavel DosePro needle-free system:
    Sumavel is provided as a single use system; discard after use.
    Visually inspect device prior to administration. Snap-off tip should sit firmly on end of clear medication chamber; if the snap-off tip is tilted or broken, do not use product.
    Visually inspect product within clear medication chamber for particulate matter and discoloration. Product should be clear to pale yellow; if product appears dark-colored or cloudy, do not use product.
    Clean and dry delivery site prior to administration.
    Remove the snap-off tip using a firm downward motion; do not twist or pull. Prepare the dose by pressing the green lever down until it clicks and locks into the handle. From this point on, do not touch the end of the medication chamber; keep chamber pointed away from face and eyes.
    Pinch 2 inches of skin on the thigh or abdomen; do not administer into scars or moles, or within 2 inches of the navel. Place medication chamber against skin and press device straight down to deliver the subcutaneous dose.
    Rotate delivery site with each use. Avoid administration into other areas of the body, including the arm.
     
    Zymbrace SymTouch autoinjector:
    The autoinjector is a prefilled, ready-to-use, single dose device; discard after use.
    Inspect the appearance of the medicine through the medicine window. The solution should be a clear, colorless to pale yellow. Do not use if the solution is discolored or contains lumps, flakes, or particles.
    The needle penetrates approximately one-fourth inch (6 mm). Use injection sites with adequate skin and subcutaneous thickness. Recommended injection sites are the lateral portion of the thigh or deltoid area.
    Hold the autoinjector in one hand, and pull the red cap straight off.
    Place the autoinjector at a 90 degree angle at the skin injection site with the yellow needle guard gently pressed against the skin.
    Press and hold the autoinjector down against the skin. Continue to hold the device down until 2 audible clicks occur. After the second click, wait 5 seconds before removing the autoinjector to ensure the full dose is delivered.
    Confirm that the red plunger rod has filled the medicine viewing window. This indicates a full dose has been delivered.

    Inhalation Administration
    Intranasal Inhalation Administration

    Imitrex nasal spray solution and generic equivalents:
    Instruct patient on proper administration technique.
    After administration, rinse the tip of the bottle with hot water, taking care not to suck water into the bottle, and dry with a clean tissue. Replace the cap right after cleaning.
    To avoid the spread of infection, do not use the container for more than 1 person.[29523]
     
    Tosymra nasal spray solution:
    Each spray delivers 10 mg of sumatriptan.
    Administer as single spray in 1 nostril.
    While sitting upright, gently blow nose to clear nostrils.
    Gently press 1 nostril with a finger to keep closed.
    Hold device upright and between thumb and first 2 fingers.
    Insert half of the spray nozzle into the open nostril and angle outward.
    While keeping the device in nose, tilt head back slightly.
    While slowly breathing through nose, firmly press plunger all the way up.
    Remove device from nostril, and gently breathe through nose and out through mouth for 10 to 20 seconds.
    Immediately discard the single-dose unit following administration.
    Separate doses by at least 1 hour. May also administer at least 1 hour after a dose of another sumatriptan product.[63912]
     
    Onzetra Xsail nasal powder:
    Each nosepiece contains 1 dose of 11 mg of sumatriptan.
    Remove the clear device cap from the reusable delivery device.
    Remove a nosepiece from the foil pouch, and click the nosepiece into the device body.
    Fully press and then release the white piercing button on the device to pierce the capsule in the nosepiece. Only press the button once.
    Insert the nosepiece into the nostril and create a tight seal.
    Rotate the device to place the mouthpiece into the mouth. Blow forcefully into the mouthpiece to deliver the nasal powder into the nostril. Vibration may occur, which indicates that the patient is blowing forcefully as directed.
    Once the medication has been delivered, discard the nosepiece.
    Repeat the process to administer the drug into the other nostril.[60543]

    STORAGE

    Alsuma:
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until time of use
    Imitrex:
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until time of use
    Imitrex STAT dose:
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until time of use
    Migraine Pack:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original package until time of use
    ONZETRA:
    - Do not freeze
    - Do not refrigerate
    - Product should always be stored in the blister and only removed immediately before use
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Sumavel DosePro System:
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until time of use
    Tosymra:
    - Do not refrigerate
    - Protect from freezing
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Zecuity:
    - Do not freeze
    - Do not refrigerate
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    ZEMBRACE:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    The sumatriptan iontophoretic transdermal system (TDS) should not be applied in areas near or over electrically-active implantable or body-worn medical devices (e.g., implantable cardiac pacemaker, body-worn insulin pump, implantable deep brain stimulator).

    Latex hypersensitivity, sumatriptan hypersensitivity

    Sumatriptan is contraindicated in patients with sumatriptan hypersensitivity or any components of the commercially available products. In general, anaphylactic reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. Use sumatriptan cautiously in patients who have experienced allergic contact dermatitis (ACD) with the iontophoretic transdermal system (TDS).   Patients sensitized from use of the sumatriptan TDS, as evidenced by development of ACD, may develop systemic sensitization or other systemic reactions if sumatriptan-containing products are taken via other routes, e.g., orally or subcutaneously. It is possible that some patients who developed ACD with sumatriptan by exposure to the sumatriptan TDS, and who have developed systemic sensitization, may not be able to take sumatriptan in any form. Patients who develop ACD with the sumatriptan TDS and require treatment with sumatriptan via other routes should receive their first subsequent dose under close medical supervision. The needle shield of the Imitrex Statdose prefilled syringe contains dry natural rubber (a latex derivative) and may cause allergic reactions in patients with latex hypersensitivity.

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

    Rare, but serious adverse cardiac effects, including heart attacks, life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours of receiving 5-HT1 agonists. Many of these patients had concurrent cardiovascular risk factors; therefore, it is difficult to assess causality. Sumatriptan and other 5-HT agonists may cause coronary vasospasm, and therefore are contraindicated in patients with known or suspected coronary artery disease (CAD), angina pectoris, vasospastic angina such as Prinzmetal's variant angina, arteriosclerosis, silent myocardial ischemia, acute myocardial infarction, history of myocardial infarction, or other significant cardiac disease. Patients with CAD risk factors (e.g., high blood pressure, diabetes mellitus, hypercholesterolemia, obesity, tobacco smoking, family history of CAD, female with surgical or physiological menopause, or male > 40 years old) should not be given sumatriptan 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 sumatriptan 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 sumatriptan 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 sumatriptan administration in patients with risk factors. Inappropriate concomitant use of eletriptan and sumatriptan may have contributed to a fatal myocardial infarction in a patient with known cardiovascular risk factors; however, causality was not definitively determined. In addition, patients with cardiac arrhythmias should not receive sumatriptan as rhythm disturbances have been reported with the use of 5-HT1 agonists. Sumatriptan is contraindicated in patients with Wolff-Parkinson-White syndrome or cardiac arrhythmias associated with other cardiac accessory conduction pathway disorders.

    Hypertension

    Sumatriptan is contraindicated in patients with uncontrolled hypertension. Sumatriptan can produce a significant 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

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

    Basilar/hemiplegic migraine

    Sumatriptan is contraindicated in basilar/hemiplegic migraine because safety and efficacy have not been established. Safety and efficacy have not been established in cluster headaches. Sumatriptan should not be administered if the headache is atypical for the patient. Sumatriptan is not recommended for long-term prophylaxis of migraine headaches.

    Intravenous administration

    Intravenous administration of sumatriptan should be avoided because of the potential to cause coronary vasospasm.

    Pregnancy

    A consistent pattern of birth defects among pregnant women exposed to sumatriptan has not been observed. The sumatriptan prospective pregnancy registry collected pregnancy outcomes of 528 infants and fetuses with earliest sumatriptan exposure during the first trimester, 78 during the second trimester, and 16 during the third trimester. The incidence of major birth defects during first trimester exposure was 4.2% (20/478 [95% CI 2.6% to 6.5%]) and during any trimester exposure was 4.2% (24/576 [95% CI 2.7% to 6.2%]). Birth defects reported for more than 2 infants after first trimester exposure included ventricular septal defects (n = 4) and pyloric stenosis (n = 3). Fetal deaths, spontaneous abortions, and elective abortions without reported defects were excluded from analysis. An analysis of data from the Swedish Medical Birth Register reported a relative risk of malformations of 0.99 (107/2,257 [95% CI 0.91 to 1.21]) among live births with first trimester exposure to sumatriptan. A study of the Norwegian birth registry and prescription data reported congenital malformations in 15 infants of 415 women who redeemed prescriptions for sumatriptan during the first trimester of pregnancy, and in 20 infants of 364 women who redeemed prescriptions for sumatriptan before, but not during, pregnancy. Compared to a general population group, the odds ratio for congenital malformation was 1.16 (95% CI 0.69 to 1.94) among women who redeemed prescriptions for sumatriptan during the first trimester and 1.83 (95% CI 1.17 to 2.88) for those who redeemed prescriptions for sumatriptan before pregnancy. During animal reproductive studies, intravenous administration of sumatriptan to rabbits during organogenesis resulted in an increased incidence of embryolethality with a no-effect dose of 0.75 mg/kg/day, which is approximately one tenth of the maximum single oral dose of 100 mg based on body surface area. In rats and rabbits, oral treatment with sumatriptan was associated with fetal abnormalities and pup mortality at doses higher than the maximum single recommended human oral dose based on body surface area.

    Breast-feeding

    Sumatriptan is excreted into the breast milk of humans. Previous American Academy of Pediatrics recommendations considered sumatriptan to be compatible with breast-feeding. Infant exposure to sumatriptan can be minimized by avoiding breast-feeding for 12 hours after treatment. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for sumatriptan and any potential adverse effects on the breast-fed infant from sumatriptan or the underlying maternal condition. In 1 trial, 5 women who had been lactating for an average of 22 weeks received a single 6 mg subcutaneous dose of sumatriptan. Drug concentrations were measured in milk and plasma over an 8 hour period after drug administration. The mean milk:plasma ratio of sumatriptan was 4.9 (95% CI 4.1 to 5.7), indicating a significant transfer of sumatriptan into the milk compartment. However, only 0.24% (14 mcg; CI 6.1 to 22.7 mcg) of the 6 mg sumatriptan dose was recovered in the milk, which corresponds to a weight-adjusted mean exposure of 3.5% (95% CI 0.3% to 6.7%) of the maternal dose. Assuming oral bioavailability of sumatriptan in infants is similar to adults (mean 14%), the weight-adjusted infant dose is roughly 0.49%. Allowance for reduced clearance in the infant predicts an infant exposure varying from 4.9% in the very premature neonate to 0.7% in a 30 week old infant (mean 3.5%). The authors of this study concluded that expressing breast milk and discarding it up to 8 hours after a dose would help to avoid any potential infant exposure to sumatriptan.

    Hepatic disease

    All formulations of sumatriptan are contraindicated in patients with severe hepatic disease or impairment. Sumatriptan is metabolized significantly by the liver. The bioavailability and peak serum concentrations can increase markedly in patients with hepatic disease. The oral formulation should be used cautiously in those with mild to moderate hepatic impairment; dosage adjustments are recommended if treatment with the oral formulation is deemed necessary.

    Renal disease, renal failure, renal impairment

    Sumatriptan is renally excreted; therefore, renal impairment may contribute to an increase in bioavailability. Sumatriptan should be used with caution in patients with renal impairment, including renal disease or renal failure.

    Children

    Sumatriptan is not approved in children under 18 years for the treatment of migraine and the manufacturer does not recommend its use. However, there are studies of sumatriptan for the treatment of migraine in children. Serious post-marketing adverse events have been reported in the pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan.

    Geriatric

    A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD). Generally, dose selection should be cautious, starting at the lower end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiovascular function and of concomitant disease or drug therapy.

    Driving or operating machinery

    Patients should be warned about the possibility of sedation while taking sumatriptan and to use caution when driving or operating machinery.

    Colitis, peripheral vascular disease, Raynaud's phenomenon

    Sumatriptan is contraindicated in patients with peripheral vascular disease including ischemic bowel disease (ischemic colitis) and Raynaud's phenomenon. Sumatriptan may cause vasospastic reactions leading to vascular and colonic ischemia with abdominal pain and bloody diarrhea.

    Seizure disorder, seizures

    There have been rare reports of seizure following administration of sumatriptan. Sumatriptan should be used with caution in patients with a history of seizures (seizure disorder) or structural brain lesions that lower their seizure threshold.

    Visual disturbance

    Rare reports of transient and permanent blindness, including significant partial vision loss have been reported with the use of sumatriptan. Visual disturbance may be a part of any type of migraine headache; therefore, causality cannot be determined.

    MAOI therapy

    Sumatriptan is contraindicated in patients concurrently or recently (i.e., within 2 weeks) receiving MAOI therapy (i.e., MAO-A inhibitors).

    Magnetic resonance imaging (MRI)

    The sumatriptan iontophoretic transdermal system (TDS) contains metal parts. The TDS must be removed before a magnetic resonance imaging (MRI) procedure to prevent injury during the procedure.

    ADVERSE REACTIONS

    Severe

    hypertensive crisis / Early / 0-1.0
    bronchospasm / Rapid / 0-1.0
    bradycardia / Rapid / 0-0.1
    cyanosis / Early / 0-0.1
    AV block / Early / 0-0.1
    thrombosis / Delayed / 0-0.1
    suicidal ideation / Delayed / 0-0.1
    keratitis / Delayed / 0-0.1
    ocular hemorrhage / Delayed / 0-0.1
    GI obstruction / Delayed / 0-0.1
    pancreatitis / Delayed / 0-0.1
    GI bleeding / Delayed / 0-0.1
    peptic ulcer / Delayed / 0-0.1
    hematemesis / Delayed / 0-0.1
    spontaneous fetal abortion / Delayed / 0-0.1
    hearing loss / Delayed / 1.0
    cardiac arrest / Early / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    stroke / Early / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    coronary vasospasm / Early / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    seizures / Delayed / Incidence not known
    bowel ischemia / Delayed / Incidence not known
    atrial fibrillation / Early / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    vasculitis / Delayed / Incidence not known
    serotonin syndrome / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    retinal thrombosis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known

    Moderate

    myasthenia / Delayed / 0-5.0
    contact dermatitis / Delayed / 4.0-4.0
    chest pressure syndrome / Rapid / 0-2.0
    hypotension / Rapid / 0-1.0
    hypertension / Early / 0.1-1.0
    sinus tachycardia / Rapid / 0.1-1.0
    erythema / Early / 0.1-1.0
    dysarthria / Delayed / 0-1.0
    euphoria / Early / 0-1.0
    confusion / Early / 0.1-1.0
    depression / Delayed / 0-1.0
    constipation / Delayed / 0-1.0
    dysphagia / Delayed / 0.1-1.0
    dysuria / Early / 0-1.0
    elevated hepatic enzymes / Delayed / 0.1-1.0
    edema / Delayed / 0-1.0
    fluid retention / Delayed / 0.1-1.0
    angina / Early / 0-0.1
    peripheral vasodilation / Rapid / 0-0.1
    phlebitis / Rapid / 0-0.1
    lymphadenopathy / Delayed / 0-0.1
    atopic dermatitis / Delayed / 0-0.1
    dystonic reaction / Delayed / 0-0.1
    hallucinations / Early / 0-0.1
    memory impairment / Delayed / 0-0.1
    hyperesthesia / Delayed / 0-0.1
    myoclonia / Delayed / 0-0.1
    conjunctivitis / Delayed / 0-0.1
    tetany / Early / 0-0.1
    colitis / Delayed / 0-0.1
    gastritis / Delayed / 0-0.1
    melena / Delayed / 0-0.1
    hypothyroidism / Delayed / 0-0.1
    hyperglycemia / Delayed / 0-0.1
    dehydration / Delayed / 0-0.1
    galactorrhea / Delayed / 0-0.1
    hypoglycemia / Early / 0-0.1
    cystitis / Delayed / 0-0.1
    hematuria / Delayed / 0-0.1
    nephrolithiasis / Delayed / 0-0.1
    anemia / Delayed / 0-0.1
    endometrial hyperplasia / Delayed / 0-0.1
    palpitations / Early / 0.1
    photophobia / Early / 1.0
    hyperacusis / Delayed / 1.0
    bleeding / Early / 1.0
    dyspnea / Early / 0.1
    ST-T wave changes / Rapid / Incidence not known
    premature ventricular contractions (PVCs) / Early / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    QT prolongation / Rapid / Incidence not known
    withdrawal / Early / Incidence not known
    hyperthermia / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    peripheral vasoconstriction / Rapid / Incidence not known
    thrombocytopenia / Delayed / Incidence not known

    Mild

    injection site reaction / Rapid / 30.0-59.0
    dysgeusia / Early / 13.5-24.5
    vertigo / Early / 1.0-12.0
    dizziness / Early / 1.0-12.0
    flushing / Rapid / 7.0-7.0
    paresthesias / Delayed / 0.1-5.0
    rhinorrhea / Early / 5.0-5.0
    nausea / Early / 1.0-4.0
    vomiting / Early / 1.0-4.0
    rhinalgia / Early / 2.5-3.8
    fatigue / Early / 0-3.0
    malaise / Early / 0-3.0
    drowsiness / Early / 0.1-3.0
    hyperhidrosis / Delayed / 0-2.0
    headache / Early / 2.0-2.0
    myalgia / Early / 0-2.0
    pallor / Early / 0-1.0
    fever / Early / 0-1.0
    rash / Early / 0.1-1.0
    agitation / Early / 0-1.0
    anxiety / Delayed / 0-1.0
    chills / Rapid / 0.1-1.0
    tremor / Early / 0.1-1.0
    shivering / Rapid / 0.1-1.0
    lacrimation / Early / 0-1.0
    ocular irritation / Rapid / 0-1.0
    muscle cramps / Delayed / 0-1.0
    back pain / Delayed / 0-1.0
    gastroesophageal reflux / Delayed / 0-1.0
    xerostomia / Early / 0.1-1.0
    diarrhea / Early / 0.1-1.0
    parosmia / Delayed / 0-1.0
    otalgia / Early / 0-1.0
    increased urinary frequency / Early / 0-1.0
    cough / Delayed / 0-1.0
    dysmenorrhea / Delayed / 0-1.0
    xerosis / Delayed / 0-0.1
    seborrhea / Delayed / 0-0.1
    phobia / Delayed / 0-0.1
    yawning / Early / 0-0.1
    mydriasis / Early / 0-0.1
    ocular pruritus / Rapid / 0-0.1
    ocular pain / Early / 0-0.1
    arthralgia / Delayed / 0-0.1
    dysesthesia / Delayed / 0-0.1
    dental pain / Delayed / 0-0.1
    flatulence / Early / 0-0.1
    hypersalivation / Early / 0-0.1
    eructation / Early / 0-0.1
    polydipsia / Early / 0-0.1
    weight gain / Delayed / 0-0.1
    weight loss / Delayed / 0-0.1
    hiccups / Early / 0-0.1
    influenza / Delayed / 0-0.1
    menstrual irregularity / Delayed / 0-0.1
    breast discharge / Delayed / 0-0.1
    syncope / Early / 0.1
    sinusitis / Delayed / 1.0
    infection / Delayed / 0.1
    tinnitus / Delayed / 1.0
    rhinitis / Early / 1.0
    epistaxis / Delayed / 1.0
    premature atrial contractions (PACs) / Early / Incidence not known
    skin irritation / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    photosensitivity / Delayed / Incidence not known
    abdominal pain / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dihydrocodeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Hydrocodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Oxycodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering oxycodone with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Tramadol: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tramadol with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Alfentanil: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering alfentanil with sumatriptan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Almotriptan: (Contraindicated) Almotriptan is contraindicated for use within 24 hours of treatment with sumatriptan due to the risk for additive vasospastic reactions. Additive serotonergic effects, including serotonin syndrome, may also occur.
    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.
    Amphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. 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. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Amphetamine; Dextroamphetamine Salts: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. 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. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Amphetamine; Dextroamphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. 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. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dihydrocodeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Aspirin, ASA; Oxycodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering oxycodone with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    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.
    Benzhydrocodone; Acetaminophen: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering benzhydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    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: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Bromocriptine: (Major) There are limited clinical trial data supporting the safety of giving a serotonin-receptor agonist ("triptan") with bromocriptine, an ergot derivative. The concomitant use of these agents with bromocriptine should be avoided. There is concern that prolonged vasospastic reactions, hypertension, tachycardia, or other side effects may occur.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Buprenorphine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with serotonergic-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Buprenorphine; Naloxone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with serotonergic-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    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.
    Butorphanol: (Moderate) The safety of using intranasal butorphanol and sumatriptan nasal spray during the same episode of migraine has not been established; however, it should be noted that both products are capable of producing transient increases in blood pressure. Theoretically, the effect of intranasal butorphanol may be increased by intranasal sumatriptan. To reduce the likelihood of this interaction, allow 30 minutes between the administration of each drug. In healthy volunteers, the pharmacokinetics of butorphanol intranasal (1 mg) were not affected by the coadministration of a single dose of sumatriptan SC 6 mg. However, in another study, the pharmacokinetics of butorphanol were significantly altered (29% decrease in AUC and 38% decrease in Cmax) when butorphanol intranasal (1 mg) was administered 1 minute after a 20-mg dose of sumatriptan nasal spray (in opposite nostrils); however, if patients wait 30 minutes between administrations any interaction effect should be minimal. Butorphanol intranasal administration does not affect the pharmacokinetics of sumatriptan when given intranasally.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Chlorpheniramine; Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Chlorpheniramine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dihydrocodeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dihydrocodeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Chlorpheniramine; Hydrocodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Citalopram: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sumatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and sumatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
    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.
    Cocaine: (Moderate) Concomitant use of cocaine with other drugs that have CNS serotonergic properties, such as serotonin-receptor agonists, could potentiate serotonin neurotransmission, and result in serotonergic side effects or rarely, serotonin syndrome. The actions of cocaine are presumed to include inhibition of presynaptic reuptake of serotonin. In most medical use cases, cocaine would be administered topically, and this interaction would not be of concern, as serotonin-agonists for migraine are used mostly "as needed". Illicit use of cocaine is of potential concern for interactions.
    Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Codeine; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Codeine; Phenylephrine; Promethazine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Codeine; Promethazine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    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: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering desvenlafaxine 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-receptor agonists and serotonin norepinephrine reuptake inhibitors. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextroamphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. 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. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; Promethazine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; Quinidine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dihydrocodeine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Doxepin: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases.
    Droxidopa: (Major) Coadministration of droxidopa with other agents that increase blood pressure, such as serotonin-receptor agonists, would be expected to increase the risk for supine hypertension. Monitor supine blood pressure. Reduce or discontinue droxidopa if supine hypertension persists. If supine hypertension is not well-managed, droxidopa may increase the risk of cardiovascular events.
    Duloxetine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering duloxetine 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-receptor agonists and serotonin norepinephrine reuptake inhibitors. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Eletriptan: (Contraindicated) Eletriptan is contraindicated for use within 24 hours of treatment with sumatriptan due to the risk for additive vasospastic reactions. Additive serotonergic effects, including serotonin syndrome, may also occur.
    Ergot alkaloids: (Contraindicated) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.
    Escitalopram: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sumatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and sumatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
    Fenfluramine: (Moderate) Use fenfluramine and serotonin receptor agonists with caution due to an increased risk of serotonin syndrome. Monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Fentanyl: (Moderate) If concomitant use of fentanyl and sumatriptan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Fluoxetine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sumatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and sumatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
    Fluoxetine; Olanzapine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sumatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and sumatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
    Fluvoxamine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sumatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and sumatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
    Frovatriptan: (Contraindicated) Sumatriptan is contraindicated for use within 24 hours of treatment with frovatriptan due to the risk for additive vasospastic reactions. Additive serotonergic effects, including serotonin syndrome, may also occur.
    Guaifenesin; Hydrocodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Homatropine; Hydrocodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Hydrocodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Hydrocodone; Ibuprofen: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Hydrocodone; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Hydrocodone; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Hydromorphone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydromorphone with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    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: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering oxycodone with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Imipramine: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases.
    Isocarboxazid: (Contraindicated) Concurrent administration of MAO-A inhibitors or use of sumatriptan within 2 weeks of discontinuation of MAO-A inhibitor therapy is contraindicated. Sumatriptan appears to metabolized by monoamine oxidase (MAO), predominantly MAO-type A; therefore, plasma concentrations of sumatriptan may be increased by concurrent use of selective MAO-A inhibitors (e.g., meclobemide) or non-selective MAO-A and MAO-B inhibitors (e.g., phenelzine, tranylcypromine, isocarboxazid). Because oral sumatriptan usually undergoes first-pass metabolism, the increase of AUC after coadministration of an MAO-A inhibitor is greater than the interaction with subcutaneous sumatriptan combined with an MAO-A inhibitor. The effects of an MAOI on the AUC after intranasal sumatriptan use would be expected to be greater than the effect after sumatriptan SC but smaller than the effect after sumatriptan PO. In a study of healthy female volunteers (n = 14), pretreatment with an MAO-A inhibitor (moclobemide) decreased the clearance of subcutaneous sumatriptan resulting in a 2-fold increase in sumatriptan AUC and a 40% increase in elimination half-life. In a similar study of oral sumatriptan, pretreatment with an MAO-A inhibitor followed by 25-mg PO of sumatriptan resulted in an approximately 7-fold increase in sumatriptan AUC.
    Lasmiditan: (Moderate) Serotonin syndrome may occur during coadministration of lasmiditan and serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Levomilnacipran: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran 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-receptor agonists and serotonin norepinephrine reuptake inhibitors. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Levorphanol: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levorphanol with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    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: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Lithium: (Major) There is an increased risk of serotonin syndrome during concurrent use of drugs with central serotonergic properties such as lithium and serotonin-receptor agonists. Signs and symptoms of serotonin syndrome include autonomic instability (e.g., labile blood pressure, tachycardia, diaphoresis, dizziness, hyperthermia), mental status changes (e.g., delirium, confusion, coma), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), gastrointestinal effects (e.g., nausea, vomiting, diarrhea), seizures, and in rare cases, death. If concurrent use is necessary, monitor for the emergence of serotonin syndrome and inform patients of the increased risk. If serotonin syndrome is suspected, serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Lorcaserin: (Major) Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, serotonin-receptor agonists. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS) like signs and symptoms.
    Meperidine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering meperidine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Meperidine; Promethazine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering meperidine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Methadone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering methadone with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Methamphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as methamphetamine and serotonin-receptor agonists. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. 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: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering milnacipran 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-receptor agonists and serotonin norepinephrine reuptake inhibitors. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Mirtazapine: (Major) Based on the mechanism of action of mirtazapine and the potential for serotonin syndrome, caution is advised when mirtazapine is coadministered with other drugs that may affect these neurotransmitter systems, including the serotonin-receptor agonists ("triptans"). The co-use of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
    Morphine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering morphine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Morphine; Naltrexone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering morphine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Nalbuphine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering nalbuphine with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Naratriptan: (Contraindicated) Naratriptan is contraindicated for use within 24 hours of treatment with sumatriptan due to the risk for additive vasospastic reactions. Additive serotonergic effects, including serotonin syndrome, may also occur.
    Nefazodone: (Major) Medications that augment release, decrease the metabolism of, or decrease the reuptake of serotonin, like the serotonin-receptor agonists, may interact with nefazodone by causing serotonin-related side effects, including serotonin syndrome. Whenever possible, these drug combinations should be avoided. If serotonin-syndrome is suspected, offending agents should be discontinued.
    Nortriptyline: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases.
    Oliceridine: (Moderate) If concomitant use of oliceridine and serotonin-receptor agonists is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Oxycodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering oxycodone with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Oxymorphone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering oxymorphone with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Ozanimod: (Major) Coadministration of ozanimod with serotonin receptor agonists "triptans" is not recommended due to the potential for hypertensive crisis or serotonin syndrome. If coadministration is necessary, closely monitor patients for hypertension and serotonergic effects. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for hypertensive crisis or serotonin syndrome. Serotonin receptor agonists may increase blood pressure by increasing serotonin concentrations.
    Paroxetine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sumatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and sumatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
    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: (Contraindicated) Concurrent administration of sumatriptan and selective monoamine oxidase A inhibitors (e.g., moclobemide) or non-selective monoamine oxidase inhibitors (MAOIs) or use of sumatriptan within 2 weeks of discontinuation of an MAOI is contraindicated. Sumatriptan appears to be metabolized by monoamine oxidase, predominantly MAO-type A; therefore, plasma concentrations of sumatriptan may be increased by concurrent use of MAO-A inhibitors or non-selective inhibitors (e.g., phenelzine, tranylcypromine, isocarboxazid). Because oral sumatriptan usually undergoes first-pass metabolism, the increase of AUC after coadministration of a non-selective MAOI is greater than the interaction with subcutaneous sumatriptan combined with an MAO-A selective inhibitor. The effects of a selective MAO-A inhibitor on the AUC after intranasal sumatriptan use would be expected to be greater than the effect after SC sumatriptan but smaller than the effect after oral sumatriptan. In a study of healthy female volunteers (n = 14), pretreatment with moclobemide decreased the clearance of subcutaneous sumatriptan resulting in a 2-fold increase in sumatriptan AUC and a 40% increase in elimination half-life. In a similar study of oral sumatriptan, pretreatment with an MAO-A inhibitor followed by 25-mg PO of sumatriptan resulted in an approximately 7-fold increase in sumatriptan AUC.
    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: (Moderate) Use together with caution. Serotonin syndrome has been reported during administration of serotonin-receptor agonists ("triptans") and non-selective monoamine oxidase inhibitors (MAOIs). Since rasagiline selectively inhibits MAO-B at recommended doses, no interaction with sumatriptan would be expected with normal prescription use. However, there is a decline in MAO-B selectivity with increasing rasagiline doses. Monitor for potential serotonin-related side effects. If serotonin syndrome occurs, discontinue all serotonergic agents and institute appropriate treatment.
    Remifentanil: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Rizatriptan: (Contraindicated) Rizatriptan is contraindicated for use within 24 hours of treatment with sumatriptan due to the risk for additive vasospastic reactions. Additive serotonergic effects, including serotonin syndrome, may also occur.
    Safinamide: (Moderate) Safinamide and serotonin-receptor agonists, also known as triptans, should be used together with caution. Serotonin syndrome has been reported during administration of serotonin-receptor agonists and non-selective monoamine oxidase inhibitors (MAOIs). Since safinamide selectively inhibits MAO-B at recommended doses, no interaction with serotonin-receptor agonists would be expected with normal prescription use. However, monitoring for serotonin-related side effects is advisable since the potential for serotonin syndrome exists. If serotonin syndrome occurs, discontinue all serotonergic agents and institute appropriate treatment.
    Selective serotonin reuptake inhibitors: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sumatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and sumatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
    Selegiline: (Contraindicated) Because of the potential risk and severity of serotonin syndrome, use of sumatriptan with or within 2 weeks of discontinuing transdermal selegiline, orally disintegrating selegiline tablets, and high doses of oral selegiline capsules and tablets is contraindicated. Since selegiline oral tablets and capsules selectively inhibit MAO-B at recommended doses, no interaction with sumatriptan would be expected with normal prescription use. However, MAO-B selectivity decreases with increasing doses, therefore, an interaction may occur with high dose treatment.
    Sertraline: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sumatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and sumatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
    Sibutramine: (Major) Sibutramine is a serotonin reuptake inhibitor. Concomitant use of two serotonin-augmenting drugs has been associated with serotonin syndrome, so concurrent use of the serotonin-receptor agonists with sibutramine is not recommended.
    St. John's Wort, Hypericum perforatum: (Major) Although unlikely to occur during monotherapy with 5-HT1 agonists such as sumatriptan, serotonin syndrome may occur from combining medications that potentiate serotonin activity. Serotonin syndrome, while uncommon, can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. St. John's wort, Hypericum perforatum can potentiate the effects of serotonin through inhibiting serotonin reuptake.
    Sufentanil: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sufentanil with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Tapentadol: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tapentadol with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Tedizolid: (Minor) Caution is warranted with the concurrent use of tedizolid and serotonin-receptor agonists such as sumatriptan. Tedizolid is an antibiotic that is also a weak reversible, non-selective inhibitor of MAO. The monoamine oxidase (MAO) type A enzyme metabolizes serotonin. Non-selective traditional MAO inhibitors increase the plasma concentrations of these drugs and some of their active metabolites, thus increasing levels of serotonin. Serious CNS reactions, such as serotonin syndrome, have been reported during the concurrent use of linezolid, which is structurally similar to tedizolid, and psychiatric medications that enhance central serotonergic activity; therefore, caution is warranted with concomitant use of other agents with serotonergic activity. This interaction could lead to 'serotonin syndrome' (presenting as agitation, restlessness, aggressive behavior, insomnia, poor concentration, headache, paresthesia, incoordination, worsening of obsessive thoughts or compulsive behavior, nausea, abdominal cramps, diarrhea, palpitations, or chills). The manufacturers of serotonin agonists contraindicate the administration of their drugs to patients receiving non-selective MAO inhibitors or within 2 weeks of discontinuation of a MAO inhibitor.
    Tramadol: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tramadol with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Tranylcypromine: (Contraindicated) Due to the risk of serotonin syndrome and significantly increased sumatriptan exposure, tranylcypromine is contraindicated for use with sumatriptan. Tranylcypromine should not be used within 4 to 5 half-lives of discontinuing treatment with sumatriptan. Conversely, do not initiate sumatriptan within 2 weeks of discontinuing tranylcypromine.
    Trazodone: (Moderate) Coadministration of trazodone and serotonin-receptor agonists may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue the serotonin-receptor agonist and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    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.
    Tryptophan, 5-Hydroxytryptophan: (Contraindicated) Combining medications that potentiate serotonin neurotransmission, such as serotonin-receptor agonists and tryptophan, could result in serotonin syndrome. Serotonin syndrome, while uncommon, can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever.
    Venlafaxine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering venlafaxine 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-receptor agonists and serotonin norepinephrine reuptake inhibitors. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    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.
    Zolmitriptan: (Contraindicated) Sumatriptan is contraindicated for use within 24 hours of treatment with zolmitriptan due to the risk for additive vasospastic reactions. Additive serotonergic effects, including serotonin syndrome, may also occur.

    PREGNANCY AND LACTATION

    Pregnancy

    A consistent pattern of birth defects among pregnant women exposed to sumatriptan has not been observed. The sumatriptan prospective pregnancy registry collected pregnancy outcomes of 528 infants and fetuses with earliest sumatriptan exposure during the first trimester, 78 during the second trimester, and 16 during the third trimester. The incidence of major birth defects during first trimester exposure was 4.2% (20/478 [95% CI 2.6% to 6.5%]) and during any trimester exposure was 4.2% (24/576 [95% CI 2.7% to 6.2%]). Birth defects reported for more than 2 infants after first trimester exposure included ventricular septal defects (n = 4) and pyloric stenosis (n = 3). Fetal deaths, spontaneous abortions, and elective abortions without reported defects were excluded from analysis. An analysis of data from the Swedish Medical Birth Register reported a relative risk of malformations of 0.99 (107/2,257 [95% CI 0.91 to 1.21]) among live births with first trimester exposure to sumatriptan. A study of the Norwegian birth registry and prescription data reported congenital malformations in 15 infants of 415 women who redeemed prescriptions for sumatriptan during the first trimester of pregnancy, and in 20 infants of 364 women who redeemed prescriptions for sumatriptan before, but not during, pregnancy. Compared to a general population group, the odds ratio for congenital malformation was 1.16 (95% CI 0.69 to 1.94) among women who redeemed prescriptions for sumatriptan during the first trimester and 1.83 (95% CI 1.17 to 2.88) for those who redeemed prescriptions for sumatriptan before pregnancy. During animal reproductive studies, intravenous administration of sumatriptan to rabbits during organogenesis resulted in an increased incidence of embryolethality with a no-effect dose of 0.75 mg/kg/day, which is approximately one tenth of the maximum single oral dose of 100 mg based on body surface area. In rats and rabbits, oral treatment with sumatriptan was associated with fetal abnormalities and pup mortality at doses higher than the maximum single recommended human oral dose based on body surface area.

    Sumatriptan is excreted into the breast milk of humans. Previous American Academy of Pediatrics recommendations considered sumatriptan to be compatible with breast-feeding. Infant exposure to sumatriptan can be minimized by avoiding breast-feeding for 12 hours after treatment. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for sumatriptan and any potential adverse effects on the breast-fed infant from sumatriptan or the underlying maternal condition. In 1 trial, 5 women who had been lactating for an average of 22 weeks received a single 6 mg subcutaneous dose of sumatriptan. Drug concentrations were measured in milk and plasma over an 8 hour period after drug administration. The mean milk:plasma ratio of sumatriptan was 4.9 (95% CI 4.1 to 5.7), indicating a significant transfer of sumatriptan into the milk compartment. However, only 0.24% (14 mcg; CI 6.1 to 22.7 mcg) of the 6 mg sumatriptan dose was recovered in the milk, which corresponds to a weight-adjusted mean exposure of 3.5% (95% CI 0.3% to 6.7%) of the maternal dose. Assuming oral bioavailability of sumatriptan in infants is similar to adults (mean 14%), the weight-adjusted infant dose is roughly 0.49%. Allowance for reduced clearance in the infant predicts an infant exposure varying from 4.9% in the very premature neonate to 0.7% in a 30 week old infant (mean 3.5%). The authors of this study concluded that expressing breast milk and discarding it up to 8 hours after a dose would help to avoid any potential infant exposure to sumatriptan.

    MECHANISM OF ACTION

    Sumatriptan stimulates presynaptic 5-HT1D receptors, an action that inhibits both dural vasodilation and inflammation. It directly inhibits trigeminal nuclei cell nociceptive neurotransmission via 5-HT1B/D receptor agonism within the trigeminocervical complex of the brainstem and upper spinal cord. Additionally, vascular 5-HT1B receptor agonism results in vasoconstriction of painfully dilated intracranial extracerebral vessels. Sumatriptan has no pharmacologic activity at dopaminergic, muscarinic, or sympathetic receptors and does not possess intrinsic analgesic properties.[27025]

    PHARMACOKINETICS

    Sumatriptan is administered orally, subcutaneously, or intranasally. Sumatriptan is widely distributed throughout the body. Protein binding ranges from 14% to 21%. Approximately 80% of a dose is hepatically metabolized. Metabolism produces an inactive metabolite and its glucuronide conjugate. Renal clearance is believed to be by tubular secretion as well as glomerular filtration. The elimination half-life of sumatriptan is approximately 2 hours.[28583] [29523] [60543] [63912]
     
    Affected cytochrome P450 isoenzymes and drug transporters: none

    Oral Route

    Oral absorption of sumatriptan, though influenced by variable gastric emptying and small-bowel transit, is rapid. The onset of relief of migraine-associated symptoms is approximately 60 minutes. Peak concentration is achieved within 2 hours; in clinical study, peak relief occurred in about 2 hours for 54% of patients and 4 hours for an additional 17%. Bioavailability is about 15% with oral administration. Poor bioavailability after oral administration results from incomplete absorption and first-pass hepatic metabolism. After oral administration, about 60% is excreted renally primarily as the IAA metabolite with approximately 3% as unchanged drug; the remaining 40% is excreted in the feces.

    Subcutaneous Route

    Subcutaneous absorption of sumatriptan has been shown to give more consistent blood plasma peak concentrations than are achieved from administration by other routes. Peak concentration is achieved within 5 to 20 minutes via the subcutaneous route. Onset of pain relief after subcutaneous injection can occur within 10 minutes, and as many as 80% of patients experience relief within 60 minutes. The onset of relief of migraine-associated symptoms is approximately 20 minutes. The time to peak relief for subcutaneous injection is 1 hour in 68% of patients and 2 hours in an additional 13% of patients. Bioavailability after subcutaneous injection is about 97%; distribution half-life is about 13 minutes. After subcutaneous administration, about 22% of a sumatriptan dose is excreted unchanged in the urine and 38% as the indole acetic acid (IAA) metabolite, with a small amount of excretion occurring in the feces. A single 3 mg subcutaneous dose of Zembrace SymTouch is bioequivalent to Imitrex subcutaneous injection.

    Other Route(s)

    Intranasal Route
    Imitrex and Generic Equivalents Nasal Spray
    Intranasal absorption of Imitrex nasal spray and generic equivalents is rapid with a peak concentration of sumatriptan achieved within 1 to 1.75 hours. Only 3% of the dose is renally eliminated as unchanged drug, with 42% eliminated as the major metabolite. Administration of two 5 mg doses, 1 in each nostril, is equivalent to administration of a single 10 mg dose in 1 nostril.[29523] [60574]
     
    Tosymra Nasal Spray
    A median Tmax of 10 minutes (range 5 to 23 minutes) occurred after a single 10 mg dose in 73 healthy subjects; mean Cmax was 51.8 ng/mL, and the mean AUC was 60.7 ng x hour/mL. Relative bioavailabilities after the single dose were approximately 87% (90% CI, 82% to 94%) and 58% (90% CI, 55% to 62%) of those obtained after subcutaneous injections of 4 and 6 mg, respectively.[63912]
     
    Nasal Powder
    Peak plasma concentration occurred on average at 45 minutes after administration. The relative bioavailability compared to subcutaneous injection is approximately 19%.[60543]