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    Ergot Alkaloids

    BOXED WARNING

    Angina, arteriosclerosis, cardiac disease, coronary artery disease, diabetes mellitus, geriatric, hypercholesterolemia, hypertension, myocardial infarction, obesity, peripheral vascular disease, peripheral vasoconstriction or ischemia, Raynaud's phenomenon, sepsis, thromboangiitis obliterans (Buerger's disease), thrombophlebitis, tobacco smoking

    Due to its potent alpha-adrenergic stimulation, dihydroergotamine is contraindicated in patients with conditions that predispose them to vasospastic reactions. Dihydroergotamine is contraindicated in peripheral vascular disease (including thromboangiitis obliterans (Buerger's disease), luetic arteritis, severe arteriosclerosis, thrombophlebitis, and Raynaud's phenomenon), ischemic heart disease (including unstable or vasospastic angina, or predisposition to vasospastic reactions), sepsis, history of myocardial infarction, or uncontrolled hypertension. It is recommended that dihydroergotamine not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of cardiac disease risk factors (e.g., hypertension, hypercholesterolemia, current tobacco smoking, obesity, diabetes mellitus, strong family history of CAD, postmenopausal females, or males over 40 years of age), unless a cardiovascular evaluation provides sufficient evidence that the patient is reasonably free of ischemic heart disease. Geriatric patients may be more susceptible to vasoconstrictive effects of ergot alkaloids. In general, dihydroergotamine dosing should be more cautious in the elderly, starting at the lower end of the dose range to account for differences in renal, hepatic, or cardiac systems as well as concomitant disease states and medications. Coadministration of dihydroergotamine with potent inhibitors of CYP3A4 is contraindicated due to the risk of acute ergot toxicity. Serious and/or life-threatening peripheral vasoconstriction or ischemia has been associated with the coadministration of dihydroergotamine with potent CYP3A4 inhibitors including protease inhibitors and macrolide antibiotics, with some cases resulting in limb amputation. Cerebral ischemia has occurred rarely in patients taking ergotamine with protease inhibitors (one case fatal). Because CYP3A4 inhibition can elevate serum dihydroergotamine concentrations, the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities is increased.

    DEA CLASS

    Rx

    DESCRIPTION

    A semisynthetic ergot alkaloid used parenterally or intranasally to treat migraine; to avoid ergot toxicity, do not exceed daily or weekly dosing limits.

    COMMON BRAND NAMES

    DHE 45, Migranal

    HOW SUPPLIED

    DHE 45/Dihydroergotamine/Dihydroergotamine Mesylate Intramuscular Inj Sol: 1mg, 1mL
    DHE 45/Dihydroergotamine/Dihydroergotamine Mesylate Intravenous Inj Sol: 1mg, 1mL
    DHE 45/Dihydroergotamine/Dihydroergotamine Mesylate Subcutaneous Inj Sol: 1mg, 1mL
    Dihydroergotamine/Dihydroergotamine Mesylate/Migranal Nasal Spray Met: 1mL, 4mg

    DOSAGE & INDICATIONS

    For the acute treatment of migraine with or without aura and the acute treatment of cluster headache episodes.
    Intramuscular, Intravenous, and Subcutaneous dosage
    Adults

    1 mg IM, subcutaneously, or IV at the first sign of headache, repeat every 1 hour until symptoms resolve. Maximum total dose per 24 hours: 3 mg IM or subcutaneously, or 2 mg IV. Maximum weekly total dose: 6 mg. Do not exceed recommended dose limits.

    Adolescents† and Children† 6 years of age and older

    DHE parenteral therapy is usually reserved for children who are unresponsive to analgesics and to treatment in an emergency room (E.R.) or inpatient environment. Admitted patients receive antiemetics half an hour prior to the first DHE dose with repreated antiemetic dosing as clinically appropriate. In one study (n = 32), the test dose of DHE was first tried (half of the initial dose appropriate for age and weight). If the test dose was tolerated, the remainder of the initial dose was given 30 minutes later. The dose of DHE was 1 mg IV over 3 minutes every 8 hours, the dose was decreased to 0.5 mg IV every 8 hours for patients who weighed less than 25 kg or who were 9 years old or younger. All the patients were offered a minimum of 5 doses before deciding on unresponsiveness. Dosing was repeated every 8 hours in hospitalized responders until headache freedom plus one additional dose, or until the maximum of 20 doses were given. In an E.R. setting, a first dose is given, then a second dose is often given an hour after the first if needed, with a maximum of 2 doses per treatment episode.

    Intranasal dosage
    Adults

    Administer 1 spray (0.5 mg per spray) in each nostril. Fifteen minutes later, administer 1 additional spray (0.5 mg per spray) in each nostril, for a total dosage of 4 sprays (2 mg). Studies have shown no additional benefit from acute doses greater than 2 mg intranasally for a single migraine episode. Dosage should not exceed 3 mg in a 24-hour period and 4 mg/week intranasally.

    For orthostatic hypotension†.
    For the treatment of orthostatic hypotension†.
    Intramuscular or Subcutaneous dosage
    Adults

    1 mg IM once daily or 0.0065—0.013 mg/kg SC once daily in the morning. Maximum dosage 3 mg IM or SC in a 24-hour period. Maximum weekly dose: 6 mg.

    For prevention of orthostatic hypotension (i.e., orthostatic hypotension prophylaxis†) associated with spinal or epidural anesthesia.
    Intravenous dosage
    Adults

    0.5 mg IV as a single dose given a few minutes prior to anesthesia.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    1 mg/dose IM or IV, do not exceed 3 mg/24 hours IM or 2 mg/24 hours IV; not to exceed 6 mg/week.

    Elderly

    1 mg/dose IM or IV, do not exceed 3 mg/24 hours IM or 2 mg/24 hours IV; not to exceed 6 mg/week.

    Adolescents

    0.5 mg/dose IM or 0.25 mg/dose IV, do not exceed 2 doses/24 hours; not to exceed 1 mg/week.

    Children

    >= 6 years: 0.5 mg/dose IM or 0.25 mg/dose IV, do not exceed 2 doses/24 hours; not to exceed 1 mg/week.
    < 6 years: Do not use.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Use generally not recommended. Those with hepatic disease may be at increased risk for developing ergot toxicity.

    Renal Impairment

    Dihydroergotamine is contraindicated in patients with renal impairment.

    ADMINISTRATION

    Oral Administration

    The parenteral solution has been administered via the oral route.

    Injectable Administration

    Dihydroergotamine is administered intramuscularly, intravenously, or subcutaneously. Do not administer intraarterially.
    Administer at the first sign of attack. Delayed administration results in increased dosage requirements and a longer onset of action.
    Do not exceed 24-hour or weekly dosage limits.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    In order to reduce the risk of severe side effects from intravenous administration of dihydroergotamine (DHE), administer an antiemetic (i.e., metoclopramide or a phenothiazine antiemetic) at least one hour before the first dose or at the time of administration of DHE.
    Inject by direct intravenous injection. No more than 2 mg should be administered IV per day.

    Intramuscular Administration

    Inject deeply into a large muscle. Aspirate prior to injection to avoid injection into a blood vessel.

    Subcutaneous Administration

    Inject subcutaneously taking care not to inject intradermally.

    Inhalation Administration
    Intranasal Inhalation Administration

    Nasal spray assembly (Migranal)
    Each ampule contains one complete dose of Migranal.
    The nasal sprayer should be assembled immediately prior to use.
    To assemble: 
    Tap the top of the ampule until all the medication is in the bottom.
    Place ampule upright and straight in the well of the Assembly Case with the breaker cap pointing up.
    Push down the Assembly Case lid slowly but firmly, until you hear the ampule snap open. 
    Without removing the ampul from the well, push nasal sprayer onto ampule until it clicks.
    Prior to administration, the pump must be primed (i.e., squeeze 4 times).
     
    Nasal spray administration (Migranal)
    One spray should be administered in each nostril. When spraying, do not tilt the patient's head back and do not have patient sniff the spray. Fifteen minutes later, one additional spray should be administered in each nostril if needed (total dosage for adults: 4 sprays).
    Once the nasal spray has been prepared, it should be discarded (along with any remaining drug in opened ampule) after 8 hours.

    STORAGE

    DHE 45:
    - Do not refrigerate
    - Protect from freezing
    - Store below 77 degrees F
    Migranal:
    - Do not freeze
    - Do not refrigerate
    - Store below 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Ergot alkaloid hypersensitivity

    Dihydroergotamine is contraindicated in patients with known ergot alkaloid hypersensitivity because they may develop an allergic or otherwise serious adverse reaction. Patients should be advised not to exceed the recommended dosage of dihydroergotamine during use. Patients should report any of the following symptoms: abdominal pain, anxiety, chest pain, myalgia, severe nausea and vomiting, numbness, tingling, or vision changes. If signs and symptoms of impaired circulation occur, the medication should be discontinued, and affected extremities should be kept warm.

    Basilar/hemiplegic migraine, stroke

    Dihydroergotamine is contraindicated in patients with basilar/hemiplegic migraine headaches. Treatment for migraine-induced stroke has not been formally evaluated and ergot alkaloids for abortive therapy of the migraine should be avoided because they may further reduce cerebral blood flow to the ischemic area. Dihydroergotamine is not recommended for migraine prophylaxis.

    Angina, arteriosclerosis, cardiac disease, coronary artery disease, diabetes mellitus, geriatric, hypercholesterolemia, hypertension, myocardial infarction, obesity, peripheral vascular disease, peripheral vasoconstriction or ischemia, Raynaud's phenomenon, sepsis, thromboangiitis obliterans (Buerger's disease), thrombophlebitis, tobacco smoking

    Due to its potent alpha-adrenergic stimulation, dihydroergotamine is contraindicated in patients with conditions that predispose them to vasospastic reactions. Dihydroergotamine is contraindicated in peripheral vascular disease (including thromboangiitis obliterans (Buerger's disease), luetic arteritis, severe arteriosclerosis, thrombophlebitis, and Raynaud's phenomenon), ischemic heart disease (including unstable or vasospastic angina, or predisposition to vasospastic reactions), sepsis, history of myocardial infarction, or uncontrolled hypertension. It is recommended that dihydroergotamine not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of cardiac disease risk factors (e.g., hypertension, hypercholesterolemia, current tobacco smoking, obesity, diabetes mellitus, strong family history of CAD, postmenopausal females, or males over 40 years of age), unless a cardiovascular evaluation provides sufficient evidence that the patient is reasonably free of ischemic heart disease. Geriatric patients may be more susceptible to vasoconstrictive effects of ergot alkaloids. In general, dihydroergotamine dosing should be more cautious in the elderly, starting at the lower end of the dose range to account for differences in renal, hepatic, or cardiac systems as well as concomitant disease states and medications. Coadministration of dihydroergotamine with potent inhibitors of CYP3A4 is contraindicated due to the risk of acute ergot toxicity. Serious and/or life-threatening peripheral vasoconstriction or ischemia has been associated with the coadministration of dihydroergotamine with potent CYP3A4 inhibitors including protease inhibitors and macrolide antibiotics, with some cases resulting in limb amputation. Cerebral ischemia has occurred rarely in patients taking ergotamine with protease inhibitors (one case fatal). Because CYP3A4 inhibition can elevate serum dihydroergotamine concentrations, the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities is increased.

    Biliary tract disease, cholestasis, hepatic disease

    Dihydroergotamine is extensively metabolized in the liver and excreted in the bile. The manufacturer considers severe hepatic impairment or severe pruritus (i.e., biliary tract disease or cholestasis) a relative contraindication to use. Those with hepatic disease may be at increased risk for developing ergot toxicity due to systemic accumulation of the drug.

    Renal disease, renal failure, renal impairment

    Dihydroergotamine is hepatically metabolized and excreted renally. It should not be used in cases of severe renal impairment or in renal failure. Dihydroergotamine is relatively contraindicated in patients renal disease due to the increased risk of toxic accumulation of the drug and its metabolites.

    Eclampsia, labor, obstetric delivery, preeclampsia, pregnancy

    Dihydroergotamine is classified as FDA pregnancy risk category X. Dihydroergotamine and related ergot alkaloids such as ergotamine are contraindicated during pregnancy because the potent oxytocic and uterine stimulant properties of this drug class will likely cause harm to the fetus. Ergotamine is contraindicated in labor and delivery. Dihydroergotamine should also be avoided in labor and obstetric delivery due to its potent oxytocic effect. One report describes 20 women at term who were given 1 mg of dihydroergotamine IV to induce labor. There were 6 adverse outcomes including 4 stillborns, 1 death shortly after birth, and 1 severely depressed infant who developed seizures 3 days after delivery. Although ergot alkaloids are not established human teratogens, limited data indicate that in utero exposure to ergotamine during pregnancy may be associated with fetal malformations, primarily consistent with ischemic injury. Until further information becomes available, the possibility of teratogenic potential of ergot alkaloids in humans cannot be ruled out, particularly during prolonged administration or use of high doses. Patients with eclampsia or preeclampsia should not receive ergot alkaloids; these conditions may be exacerbated and patients may be more likely to experience ergot-related side effects. In animal studies, administration of intranasal dihydroergotamine resulted in decreased fetal body weights, skeletal ossification, and/or impaired reproductive function in offspring. Prolonged vasoconstriction of the uterine vessels and/or increased myometrial tone leading to reduced myometrial and placental blood flow may contribute to the inhibition of fetal growth observed in animals. Women of child-bearing potential should be counseled on the potential risks to the fetus should pregnancy occur during use of dihydroergotamine.

    Breast-feeding

    Use of dihydroergotamine during breast-feeding is contraindicated by the manufacturer. There are no specific studies evaluating the use of dihydroergotamine in nursing mothers; however, other ergot alkaloids such as ergotamine are excreted in breast milk and may cause symptoms indicative of ergot toxicity in the nursing infant including vomiting, diarrhea, seizures, weak pulse, and unstable blood pressure. Ergotamine is classified by the American Academy of Pediatrics (AAP) as a drug that has been associated with significant effects on the nursing infant in some cases and should be given to nursing mothers with caution. Ergot derivatives are known to inhibit prolactin, and thus, interference with proper lactation is possible. Sumatriptan, a serotonin receptor agonist indicated for the treatment of migraines, is classified by the AAP as usually compatible with breast-feeding. Sumatriptan may be considered as an alternative to dihydroergotamine for the acute treatment of migraines in breast-feeding mothers. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Intramuscular administration

    The combination of dihydroergotamine and heparin is not recommended for intramuscular administration. There appears to be an increased risk of injection site reactions with this route of administration.

    Children, infants

    Dihydroergotamine should be used with caution in children and adolescents. Safe and effective use has not been established, but children > 6 years old have been treated for severe migraine headaches with this drug. It is recommended that dihydroergotamine use in older children is reserved for cases where less toxic medications have failed to provide relief. Do not use in very young children or infants.

    Pulmonary disease, pulmonary fibrosis, retroperitoneal fibrosis, valvular heart disease

    Long-term use of ergot alkaloids such as ergotamine has been associated with abnormal heart valve findings including aortic and/or mitral regurgitation, mitral stenosis, severe tricuspid regurgitation, and pulmonary regurgitation. Chronic use of ergotamine preparations has caused fibrotic thickening of the aortic, mitral, tricuspid, and/or pulmonary valves. Retroperitoneal fibrosis and pulmonary fibrosis have occurred in rare instances. Caffeine; ergotamine preparations should be used cautiously in those with pulmonary disease or valvular heart disease.

    Surgery

    Dihydroergotamine may cause vasoconstriction. Patients should be advised to inform their health care provider of usage prior to any surgeries or related procedures. Dihydroergotamine use is contraindicated in patients who have recently undergone vascular surgery. Ergot alkaloids may cause problems with plastic, cosmetic, or reconstructive surgery in particular; cyanosis, ischemia, and vasoconstriction in the skin or other tissues may occur if dihydroergotamine has been used within 48 hours of the surgical procedure.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 0.1-1.0
    bronchospasm / Rapid / 0-0.1
    bowel ischemia / Delayed / Incidence not known
    cyanosis / Early / Incidence not known
    tissue necrosis / Early / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    coronary vasospasm / Early / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    stroke / Early / Incidence not known
    fetal abortion / Delayed / Incidence not known
    fetal death / Delayed / Incidence not known
    retroperitoneal fibrosis / Delayed / Incidence not known
    cardiac valvulopathy / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known

    Moderate

    dysphagia / Delayed / 0.1-1.0
    palpitations / Early / 0.1-1.0
    hypertension / Early / 0-1.0
    euphoria / Early / 0.1-1.0
    confusion / Early / 0.1-1.0
    dystonic reaction / Delayed / 0.1-1.0
    hot flashes / Early / 1.0-1.0
    photophobia / Early / 0.1-1.0
    conjunctivitis / Delayed / 0.1-1.0
    cystitis / Delayed / 0.1-1.0
    dyspnea / Early / 0.1-1.0
    angina / Early / 0-0.1
    hypotension / Rapid / 0-0.1
    depression / Delayed / 0-0.1
    migraine / Early / 0-0.1
    myoclonia / Delayed / 0-0.1
    vaginitis / Delayed / 0-0.1
    colitis / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    peripheral vasoconstriction / Rapid / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    hematoma / Early / Incidence not known
    uterine contractions / Early / Incidence not known
    edema / Delayed / Incidence not known

    Mild

    rhinitis / Early / 26.0-26.0
    nausea / Early / 10.0-10.0
    dysgeusia / Early / 8.0-8.0
    vomiting / Early / 4.0-4.0
    dizziness / Early / 4.0-4.0
    pharyngitis / Delayed / 3.0-3.0
    drowsiness / Early / 3.0-3.0
    diarrhea / Early / 2.0-2.0
    paresthesias / Delayed / 2.0-2.0
    xerostomia / Early / 1.0-1.0
    abdominal pain / Early / 0.1-1.0
    hiccups / Early / 0.1-1.0
    dyspepsia / Early / 0.1-1.0
    sinusitis / Delayed / 1.0-1.0
    tremor / Early / 0.1-1.0
    insomnia / Early / 0.1-1.0
    vertigo / Early / 0.1-1.0
    hypoesthesia / Delayed / 0.1-1.0
    muscle cramps / Delayed / 0.1-1.0
    myalgia / Early / 0.1-1.0
    weakness / Early / 0.1-1.0
    rash (unspecified) / Early / 0.1-1.0
    petechiae / Delayed / 0.1-1.0
    pruritus / Rapid / 0.1-1.0
    diaphoresis / Early / 0.1-1.0
    fever / Early / 0.1-1.0
    malaise / Early / 0.1-1.0
    chills / Rapid / 0.1-1.0
    asthenia / Delayed / 1.0-1.0
    fatigue / Early / 1.0-1.0
    lacrimation / Early / 0.1-1.0
    tinnitus / Delayed / 0.1-1.0
    dysosmia / Delayed / 0.1-1.0
    polyuria / Early / 0.1-1.0
    hypersalivation / Early / 0-0.1
    epistaxis / Delayed / 0-0.1
    hyperkinesis / Delayed / 0-0.1
    anxiety / Delayed / 0-0.1
    anorexia / Delayed / 0-0.1
    arthralgia / Delayed / 0-0.1
    urticaria / Rapid / 0-0.1
    maculopapular rash / Early / 0-0.1
    laryngitis / Delayed / 0-0.1
    yawning / Early / 0-0.1
    ocular pain / Early / 0-0.1
    nasal dryness / Early / Incidence not known
    throat irritation / Early / Incidence not known
    nasal congestion / Early / Incidence not known
    nasal irritation / Early / Incidence not known
    ecchymosis / Delayed / Incidence not known
    injection site reaction / Rapid / Incidence not known
    flushing / Rapid / Incidence not known
    otalgia / Early / Incidence not known

    DRUG INTERACTIONS

    Acebutolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Acetaminophen; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Acrivastine; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Aliskiren; Amlodipine: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Almotriptan: (Severe) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.
    Amiodarone: (Major) Coadministration of dihydroergotamine with inhibitors of CYP3A4, such as amiodarone, may potentially increase the risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Coadministration should be done cautiously, and avoided when possible.
    Amlodipine: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Amlodipine; Atorvastatin: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Amlodipine; Benazepril: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Amlodipine; Olmesartan: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Amlodipine; Telmisartan: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Amlodipine; Valsartan: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Amoxicillin; Clarithromycin; Lansoprazole: (Severe) Coadministration of clarithromycin with dihydroergotamine is contraindicated due to the risk of ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, cyanosis, and numbness). Clarithromycin inhibits dihydroergotamine metabolism via inhibition of the CYP3A4 enzyme.
    Amoxicillin; Clarithromycin; Omeprazole: (Severe) Coadministration of clarithromycin with dihydroergotamine is contraindicated due to the risk of ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, cyanosis, and numbness). Clarithromycin inhibits dihydroergotamine metabolism via inhibition of the CYP3A4 enzyme.
    Amphetamine; Dextroamphetamine Salts: (Major) Amphetamines, which increase catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with amphetamines may be advisable.
    Aprepitant, Fosaprepitant: (Major) Use caution if ergot alkaloids and aprepitant, fosaprepitant are used concurrently and monitor for an increase in ergot alkaloid-related adverse effects (e.g., severe peripheral vasospasm with possible ischemia, potentially leading to gangrene, cyanosis, stroke, numbness of the extremities and/or other serious effects) for several days after administration of a multi-day aprepitant regimen. Ergot alkaloids are CYP3A4 substrates. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of ergot alkaloids. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Articaine; Epinephrine: (Severe) Ergot alkaloids should not be administered with vasoconstrictors such as epinephrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene.
    Atazanavir; Cobicistat: (Severe) Coadministration of dihydroergotamine with cobicistat is contraindicated. Cobicistat is an inhibitor of CYP3A, and plasma concentrations of drugs extensively metabolized by this enzyme, such as ergot alkaloids, are expected to increase with concurrent use. Elevated plasma concentrations of ergot alkaloids are associated with risk of acute ergot toxicity which is characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
    Atenolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Atenolol; Chlorthalidone: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Theoretically, concurrent use of methylene blue and ergot alkaloids 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 ergot alkaloids 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 psychiatric 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.
    Azithromycin: (Minor) Until more data are available, the manufacturer of azithromycin recommends caution and careful monitoring of patients who receive azithromycin and either ergotamine or dihydroergotamine concurrently. The simultaneous use of certain ergot alkaloids with certain macrolides may produce ergot toxicity.
    Bendroflumethiazide; Nadolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Theoretically, concurrent use of methylene blue and ergot alkaloids 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 ergot alkaloids 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 psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
    Benzphetamine: (Major) Amphetamines, which increase catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with amphetamines may be advisable.
    Beta-blockers: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Betaxolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Bisoprolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Boceprevir: (Severe) Concurrent use of ergot alkaloids and boceprevir is contraindicated due to the potential for serious/life-threatening ergot toxicities, such as peripheral vasospasm and ischemia of the extremities and other tissues. Boceprevir is a potent inhibitor of CYP3A4, which is responsible for the metabolism of ergot alkaloids. Coadministration may result in large increases in ergot alkaloid serum concentrations, which could cause fatal ergot toxicities.
    Bosentan: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Brigatinib: (Moderate) Monitor for decreased efficacy of dihydroergotamine if coadministration with brigatinib is necessary. Dihydroergotamine is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of dihydroergotamine may decrease.
    Brimonidine; Timolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Bromocriptine: (Severe) The concomitant use of bromocriptine, an ergot derivative, with ergot alkaloids may potentially lead to ergot toxicity; therefore the combination should be avoided. Symptoms of ergotism include angina, asthenia, chest pain (unspecified), coronary vasospasm, muscle cramps (claudication), myalgia, paresthesias, and palpitations or changes in heart rate (e.g., sinus bradycardia or sinus tachycardia). Peripheral vasoconstriction of the arteries may result in hypothermia or tissue necrosis, which may lead to gangrene. Other serious complications include hypertension (portal), mesenteric artery thrombosis, myocardial infarction, and renal tubular necrosis. Symptoms such as confusion, depression, drowsiness, and seizures rarely occur.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Brompheniramine; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Bupivacaine Liposomal: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Bupivacaine: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Bupivacaine; Lidocaine: (Major) If epinephrine is added to bupivacaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Cabergoline: (Major) Although cabergoline is an ergot alkaloid derivative, no evidence of changes in efficacy or safety of cabergoline have been noted when given concomitantly with ergot alkaloids; however, it is prudent to avoid concurrent use to minimize the potential risk of ergot toxicity, cardiac valvulopathy, or extracardiac fibrotic complications.
    Calcium-channel blockers: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Carbetapentane; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Carbinoxamine; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Carteolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Carvedilol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Ceritinib: (Major) Avoid coadministration of ceritinib with dihydroergotamine due to increased dihydroergotamine exposure, which may increase the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities. If coadministration is unavoidable, monitor for dihydroergotamine-related adverse reactions. Ceritinib is a CYP3A4 inhibitor and dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic index.
    Cetirizine; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Chloroprocaine: (Major) If epinephrine is added to chloroprocaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Chlorpheniramine; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Cimetidine: (Major) Monitor for increased dihydroergotamine-related adverse effects with coadministration of cimetidine. The serum concentration of dihydroergotamine may increase during concurrent use. Cimetidine is a weak CYP3A4 inhibitor; dihydroergotamine is a CYP3A4 substrate.
    Clarithromycin: (Severe) Coadministration of clarithromycin with dihydroergotamine is contraindicated due to the risk of ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, cyanosis, and numbness). Clarithromycin inhibits dihydroergotamine metabolism via inhibition of the CYP3A4 enzyme.
    Clevidipine: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Cobicistat: (Severe) Coadministration of dihydroergotamine with cobicistat is contraindicated. Cobicistat is an inhibitor of CYP3A, and plasma concentrations of drugs extensively metabolized by this enzyme, such as ergot alkaloids, are expected to increase with concurrent use. Elevated plasma concentrations of ergot alkaloids are associated with risk of acute ergot toxicity which is characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Severe) Coadministration of dihydroergotamine with cobicistat is contraindicated. Cobicistat is an inhibitor of CYP3A, and plasma concentrations of drugs extensively metabolized by this enzyme, such as ergot alkaloids, are expected to increase with concurrent use. Elevated plasma concentrations of ergot alkaloids are associated with risk of acute ergot toxicity which is characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Severe) Coadministration of dihydroergotamine with cobicistat is contraindicated. Cobicistat is an inhibitor of CYP3A, and plasma concentrations of drugs extensively metabolized by this enzyme, such as ergot alkaloids, are expected to increase with concurrent use. Elevated plasma concentrations of ergot alkaloids are associated with risk of acute ergot toxicity which is characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
    Conivaptan: (Severe) Dihydroergotamine is a CYP3A4 substrate. Conivaptan is a potent inhibitor of CYP3A4 and may increase concentrations of dihydroergotamine. The risk of ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, potentially leading to gangrene, cyanosis, stroke, numbness of the extremities, and/or other serious effects) is potentially increased by the concomitant use of CYP3A4 inhibitors. Coadministration of dihydroergotamine and conivaptan should be avoided to minimize the risk of ergot toxicity. According to the manufacturer of conivaptan, treatment with CYP3A4 substrates (i.e., dihydroergotamine) may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Crizotinib: (Moderate) Monitor for dihydroergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with crizotinib is necessary. Dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic range and crizotinib is a moderate CYP3A4 inhibitor.
    Danazol: (Major) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of some drugs, such as ergot alkaloids, and lead to ergot toxicity.
    Darunavir; Cobicistat: (Severe) Coadministration of dihydroergotamine with cobicistat is contraindicated. Cobicistat is an inhibitor of CYP3A, and plasma concentrations of drugs extensively metabolized by this enzyme, such as ergot alkaloids, are expected to increase with concurrent use. Elevated plasma concentrations of ergot alkaloids are associated with risk of acute ergot toxicity which is characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
    Dasatinib: (Major) Dasatinib may inhibit the CYP3A4 mediated metabolism of ergot alkaloids. Increased adverse reactions from ergot alkaloids may occur.
    Delavirdine: (Severe) The concurrent use of delavirdine is contraindicated with ergot alkaloids. This is because delavirdine is a potent inhibitor of the CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as ergot alkaloids, should be expected with concurrent use of delavirdine. This could cause ergot toxicity.
    Desloratadine; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Desvenlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as ergot alkaloids. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Diazoxide: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Diltiazem: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Dirithromycin: (Moderate) Concomitant use of some ergot alkaloids with certain macrolides has produced ergot toxicity. Use caution in combining dirithromycin with dihydroergotamine until more data are available.
    Dobutamine: (Major) The concomitant administration of ergot alkaloids and sympathomimetics has resulted in dangerous hypertension.
    Dorzolamide; Timolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Dihydroergotamine is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Duloxetine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as ergot alkaloids. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Elbasvir; Grazoprevir: (Moderate) Administering ergot alkaloids with elbasvir; grazoprevir may result in elevated plasma concentrations of the ergot alkaloids. Ergot alkaloids are substrates of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eletriptan: (Severe) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.
    Eluxadoline: (Moderate) Although the CYP3A4 inhibitory effects of eluxadoline have not been definitively established, the manufacturer recommends caution when administering eluxadoline concurrently with CYP3A4 substrates that have a narrow therapeutic index, such as ergot alkaloids (e.g., ergotamine, dihydroergotamine, ergonovine, methylergonovine). Closely monitor for increased ergotamine-related side effects (e.g., severe peripheral vasospasm with possible ischemia, potentially leading to gangrene, cyanosis, stroke, numbness of the extremities) when initiating or discontinuing eluxadoline therapy.
    Enalapril; Felodipine: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Enzalutamide: (Major) Avoid coadministration of dihydroergotamine with enzalutamide due to decreased plasma concentrations of dihydroergotamine. Dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic index and enzalutamide is a strong CYP3A4 inducer.
    Epinephrine: (Severe) Ergot alkaloids should not be administered with vasoconstrictors such as epinephrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene.
    Epoprostenol: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Erythromycin: (Severe) Coadministration is contraindicated as ergot toxicity can occur, resulting in ischemic reactions and peripheral vasospasm. Erythromycin inhibits the hepatic clearance of dihydroergotamine via inhibition of the CYP3A4 isoenzyme.
    Erythromycin; Sulfisoxazole: (Severe) Coadministration is contraindicated as ergot toxicity can occur, resulting in ischemic reactions and peripheral vasospasm. Erythromycin inhibits the hepatic clearance of dihydroergotamine via inhibition of the CYP3A4 isoenzyme.
    Esmolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Everolimus: (Moderate) Monitor for dihydroergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with everolimus is necessary. Dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic range and everolimus is a weak CYP3A4 inhibitor.
    Felodipine: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Fenoldopam: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Fexofenadine; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Fluconazole: (Major) Fluconazole should be used cautiously in patients taking certain ergot alkaloids. Fluconazole may reduce the metabolism of ergot alkaloids via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
    Frovatriptan: (Severe) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.
    Glycerol Phenylbutyrate: (Moderate) Concomitant use of glycerol phenylbutyrate and dihydroergotamine may result in decreased exposure of dihydroergotamine. Dihydroergotamine is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of dihydroergotamine during coadministration.
    Grapefruit juice: (Major) The risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects) is potentially increased by the use of CYP3A4 inhibitors. Grapefruit juice may decrease dihydroergotamine metabolism via CYP3A4. Patients should probably use caution with grapefruit juice by not modifying their usual grapefruit juice intake while taking dihydroergotamine. Elderly patients have the greatest possibility of ingesting grapefruit and interacting medications and are the most vulnerable to the adverse clinical consequences. Grapefruit juice inhibits the cytochrome P-450 3A4 isozyme in the gut wall. Grapefruit juice contains furanocoumarins that are metabolized by CYP3A4 to reactive intermediates. These intermediates form a covalent bond to the active site of the CYP3A4 enzyme, causing irreversible inactivation (mechanism-based inhibition). Consequently, CYP3A4 activity in the gut wall is inhibited until de novo synthesis returns the enzyme to its previous level.
    Green Tea: (Moderate) Some, but not all, green tea products contain caffeine. Excessive caffeine ingestion is probably best avoided including ingestion of foods or beverages that contain caffeine, such as green tea, in patients taking dihydroergotamine.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Guaifenesin; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Guarana: (Minor) Caffeine has been used with ergot drugs to alleviate migraine headaches; data reveal that administration of caffeine with ergotamine increases the absorption rate and peak plasma levels of ergotamine. This interaction may also occur with dihydroergotamine to therapeutic advantage, but no data are available. It is unclear what effect caffeine has on methysergide when used for migraine prophylaxis. Guarana contains a high caffeine content, so patients taking these ergot alkaloids should be aware of the caffeine content in guarana-containing supplements or beverages. Excessive guarana ingestion is probably best avoided in patients prescribed dihydroergotamine, ergotamine or methysergide.
    Hydralazine: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Hydrocodone; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Theoretically, concurrent use of methylene blue and ergot alkaloids 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 ergot alkaloids 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 psychiatric 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; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Idelalisib: (Severe) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with dihydroergotamine, a CYP3A substrate, as dihydroergotamine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloprost: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Imatinib: (Severe) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme Coadministration of ergotamine with potent inhibitors of CYP3A4 is considered contraindicated due to the risk of acute ergot toxicity.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with dihydroergotamine may result in increased serum concentrations of dihydroergotamine. Dihydroergotamine is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoproterenol: (Severe) Dihydroergotamine should not be administered with other vasoconstrictors, such as isoproterenol. Dihydroergotamine inhibits the uptake of norepinephrine and stimulates alpha-adrenergic receptors, causing prolonged vasoconstriction.
    Isradipine: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Itraconazole: (Severe) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as itraconazole, or administration for 2 weeks after discontinuation of itraconazole treatment is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and dihydroergotamine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dihydroergotamine, can increase dihydroergotamine exposure leading to increased or prolonged therapeutic effects and adverse events, including the risk for ergot toxicity.
    Ketoconazole: (Severe) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as ketoconazole, is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
    Labetalol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Lanreotide: (Major) Avoid coadministration of lanreotide with dihydroergotamine due to increased dihydroergotamine exposure, which may increase the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities. If coadministration is unavoidable, monitor for dihydroergotamine-related adverse reactions. Dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic index. Limited published data available indicate that somatostatin analogs may decrease the metabolic clearance of CYP3A4 substrates, which may be due to the suppression of growth hormone; it cannot be excluded that lanreotide has this effect.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of dihydroergotamine; monitor for potential reduction in efficacy. Dihydroergotamine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of dihydroergotamine; monitor for potential reduction in efficacy. Dihydroergotamine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Levobetaxolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Levobunolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Levomilnacipran: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as ergot alkaloids. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Linezolid: (Moderate) Serious CNS reactions, such as serotonin syndrome, have been reported during the concurrent use of linezolid and psychiatric medications that enhance central serotonergic activity; therefore, caution is warranted with concomitant use of other agents with serotonergic activity, including ergot alkaloids.
    Lisdexamfetamine: (Major) Amphetamines, which increase catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with amphetamines may be advisable.
    Loratadine; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Lorcaserin: (Major) Lorcaserin should not be used in combination with serotonergic and dopaminergic drugs that are potent 5-HT2B receptor agonists and are known to increase the risk for cardiac valvulopathy (e.g., cabergoline, ergotamine, dihydroergotamine, and other ergot alkaloids).
    Lumacaftor; Ivacaftor: (Minor) Lumacaftor; ivacaftor may reduce the efficacy of dihydroergotamine by decreasing its systemic exposure; if used together, monitor patients closely for clinical efficacy. Dihydroergotamine is a substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and dihydroergotamine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dihydroergotamine, can increase dihydroergotamine exposure leading to increased or prolonged therapeutic effects and adverse events, including the risk for ergot toxicity.
    Mepivacaine: (Major) If epinephrine is added to mepivacaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Mepivacaine; Levonordefrin: (Major) If epinephrine is added to mepivacaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Methamphetamine: (Major) Amphetamines, which increase catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with amphetamines may be advisable.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Theoretically, concurrent use of methylene blue and ergot alkaloids 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 ergot alkaloids 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 psychiatric 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: (Moderate) Theoretically, concurrent use of methylene blue and ergot alkaloids 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 ergot alkaloids 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 psychiatric 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.
    Metoprolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Metreleptin: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and dihydroergotamine concomitantly; the precise effect of metreleptin on the metabolism of dihydroergotamine is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, such as dihydroergotamine.
    Miconazole: (Moderate) No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP3A4. Although the systemic absorption of miconazole following buccal miconazole administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously, the potential for interaction with drugs metabolized through CYP3A4 (such as the ergot alkaloids) cannot be ruled out. Be alert for symptoms of a potential interaction, such as ischemia, cyanosis, and numbness of the extremities or other serious ergot-related effects.
    Mifepristone, RU-486: (Severe) Mifepristone, RU-486 inhibits CYP3A4 in vitro. Coadministration of mifepristone may lead to an increase in serum concentrations of drugs that are CYP3A4 substrates and that have a narrow therapeutic index, such as dihydroergotamine. Coadministration is contraindicated when the drug is used chronically, such as in the treatment of Cushing's syndrome. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
    Milnacipran: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as ergot alkaloids. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Minoxidil: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Mirtazapine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering mirtazapine with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome. Mirtazapine should be discontinued if a patient develops a combination of symptoms suggestive of serotonin syndrome.
    Mitotane: (Major) Use caution if mitotane and dihydroergotamine are used concomitantly, and monitor for decreased efficacy of dihydroergotamine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and dihydroergotamine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of dihydroergotamine.
    Nadolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Naproxen; Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Naproxen; Sumatriptan: (Severe) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.
    Naratriptan: (Severe) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.
    Nebivolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Nebivolol; Valsartan: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Nefazodone: (Severe) Nefazodone may reduce the metabolism of dihydroergotamine via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects (e.g., severe peripheral vasospasm with possible ischemia, cyanosis, and numbness of the extremities or other serious effects). In addition, serotonin syndrome has been reported or may be possible with the use of ergot alkaloids like dihydroergotamine. particularly in combination with other serotonin-augmenting drugs. Avoid coadministration with nefazodone when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Nicardipine: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Nicotine: (Major) Concurrent use of vasoconstrictors, such as nicotine, with ergot alkaloids may result in enhanced vasoconstriction. Nicotine acts indirectly as a sympathomimetic agent by releasing catecholamines, potentially resulting in effects such as hypertension, coronary spasm, coronary ischemia, or cardiac arrhythmias, which may be additive with ergot alkaloids. Patients should avoid smoking tobacco or using other nicotine-containing products while taking ergot compounds if possible.
    Nifedipine: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Nilotinib: (Moderate) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and ergot alkaloids (e.g., ergotamine, dihydroergotamine), CYP3A4 substrates with a narrow therapeutic range, may result in increased ergot alkaloid levels. Avoid co-use when possible; consider alternative therapy to the ergot medication. Be alert for symptoms of ergot toxicity if these drugs together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together.
    Nimodipine: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Nisoldipine: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Nitrates: (Severe) Ergot alkaloids are contraindicated in patients with hypertension, angina, or coronary artery disease; which are the primary patient populations for which nitroglycerin is utilized. Because of the potential to cause coronary vasospasm, ergot alkaloids can oppose the vasodilatory actions of nitroglycerin and, in doing so, may precipitate angina. In addition, oral administration of nitroglycerin decreases the first-pass metabolism of dihydroergotamine, thereby increasing its oral bioavailability.
    Nitroprusside: (Major) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Norfloxacin: (Major) Coadministration of dihydroergotamine with inhibitors of CYP3A4, such as norfloxacin, may potentially increase the risk of ergot toxicity. Coadministration should be done cautiously, and avoided when possible.
    Oritavancin: (Minor) Dihydroergotamine is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of dihydroergotamine may be reduced if these drugs are administered concurrently.
    Palbociclib: (Moderate) Monitor for an increase in dihydroergotamine-related adverse reactions if coadministration with palbociclib is necessary. The dose of dihydroergotamine may need to be reduced. Palbociclib is a weak time-dependent inhibitor of CYP3A while dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic index.
    Penbutolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Perindopril; Amlodipine: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Phentermine: (Major) Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.
    Phentermine; Topiramate: (Major) Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.
    Pindolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Posaconazole: (Severe) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as posaconazole, is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
    Prilocaine: (Major) If epinephrine is added to prilocaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Prilocaine; Epinephrine: (Severe) Ergot alkaloids should not be administered with vasoconstrictors such as epinephrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. (Major) If epinephrine is added to prilocaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Procaine: (Major) If epinephrine is added to procaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Propranolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Protease inhibitors: (Severe) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
    Pseudoephedrine: (Severe) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Quinine: (Major) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as quinine, may potentially increase the risk of ergot toxicity including vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects.
    Ranolazine: (Major) In vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, such as ergot alkaloids, potentially leading to adverse reactions.
    Ribociclib: (Major) Use caution if coadministration of ribociclib with dihydroergotamine is necessary, as the systemic exposure of dihydroergotamine may be increased resulting in an increase in dihydroergotamine-related adverse reactions including the risk for vasospasm which can lead to cerebral ischemia and/or ischemia of the extremities; adjust the dose of dihydroergotamine if necessary. Ribociclib is a moderate CYP3A4 inhibitor and dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic window.
    Ribociclib; Letrozole: (Major) Use caution if coadministration of ribociclib with dihydroergotamine is necessary, as the systemic exposure of dihydroergotamine may be increased resulting in an increase in dihydroergotamine-related adverse reactions including the risk for vasospasm which can lead to cerebral ischemia and/or ischemia of the extremities; adjust the dose of dihydroergotamine if necessary. Ribociclib is a moderate CYP3A4 inhibitor and dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic window.
    Rizatriptan: (Severe) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.
    Rufinamide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of ergot alkaloids, which is metabolized by CYP3A4, may occur during concurrent use with rufinamide.
    Selective serotonin reuptake inhibitors: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Serotonin norepinephrine reuptake inhibitors: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as ergot alkaloids. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Serotonin-Receptor Agonists: (Severe) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.
    Sibutramine: (Major) In general, the use of ergot alkaloids for migraine should be avoided in combination with sibutramine, due to the increased risk for serotonin syndrome. Both agents increase the action of serotonin. Consider alternatives. However, if such a combination is clinically indicated, appropriate observation of the patient is warranted. If serotonin syndrome occurs, all serotonergic agents should be discontinued, and appropriate therapy should be initiated.
    Sildenafil: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Simeprevir: (Major) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dihydroergotamine, which is a CYP3A4 substrate. Monitor patients for adverse effects of dihydroergotamine, such as ergot toxicity.
    Sotalol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Streptogramins: (Major) Coadministration of dihydroergotamine with inhibitors of CYP3A4, such as dalfopristin; quinupristin, may potentially increase the risk of ergot toxicity. Coadministration should be done cautiously, and avoided when possible.
    Sumatriptan: (Severe) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.
    Tedizolid: (Minor) Caution is warranted with the concurrent use of tedizolid and the ergot alkaloids. Tedizolid is an antibiotic that is also a weak reversible, non-selective inhibitor of MAO. 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, including ergot alkaloids.
    Telaprevir: (Severe) Concurrent use of ergot alkaloids and telaprevir is contraindicated due to the potential for serious/life-threatening ergot toxicities, such as peripheral vasospasm and ischemia of the extremities and other tissues. Telaprevir is an inhibitor of CYP3A4, which is responsible for the metabolism of ergot alkaloids. Coadministration may result in large increases in ergot alkaloid serum concentrations, which could cause fatal ergot toxicities.
    Telithromycin: (Major) Coadministration of telithromycin and ergot alkaloids is not recommended due to the potential for ergot toxicity. Although no specific drug interaction studies have been performed with telithromycin, drug interactions have been reported with macrolide antibiotics. Concomitant administration of ergot alkaloids with macrolides resulted in acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and dihydroergotamine is necessary, as the systemic exposure of dihydroergotamine may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of dihydroergotamine; consider increasing the dose of dihydroergotamine if necessary. Dihydroergotamine is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Timolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Tobacco: (Major) Concurrent use of vasoconstrictors, such as nicotine, with ergot alkaloids may result in enhanced vasoconstriction. Nicotine acts indirectly as a sympathomimetic agent by releasing catecholamines, potentially resulting in effects such as hypertension, coronary spasm, coronary ischemia, or cardiac arrhythmias, which may be additive with ergot alkaloids. Patients should avoid smoking tobacco or using other nicotine-containing products while taking ergot compounds if possible.
    Trandolapril; Verapamil: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    Treprostinil: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Vasopressors: (Severe) Ergot alkaloids should not be administered with vasoconstrictors such as vasopressors (e.g., norepinephrine, dopamine, phenylephrine) since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Vemurafenib: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as dihydroergotamine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of dihydroergotamine when coadministered with vemurafenib.
    Venlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as ergot alkaloids. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Verapamil: (Major) Because of the potential to cause coronary vasospasm, dihydroergotamine theoretically could antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. Dihydroergotamine is contraindicated for use in patients with coronary heart disease or hypertension. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties (e.g., diltiazem, nicardipine, verapamil) may also reduce the hepatic metabolism of dihydroergotamine and increase the risk of ergot toxicity.
    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 ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving vilazodone and an ergot alkaloid should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. Vilazodone and the ergot alkaloid should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Voriconazole: (Severe) Concurrent administration of voriconazole with ergot alkaloids is contraindicated. Voriconazole may reduce the metabolism of the ergot alkaloids via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergotism (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, or other serious effects).
    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 ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, vortioxetine and concurrent serotonergic agents should be discontinued.
    Zafirlukast: (Major) Coadministration of dihydroergotamine with inhibitors of CYP3A4, such as zafirlukast, may potentially increase the risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects).
    Zileuton: (Major) Coadministration of dihydroergotamine with inhibitors of CYP3A4, such as zileuton, may potentially increase the risk of ergot toxicity. Symptoms of ergot toxicity include: vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects.
    Zolmitriptan: (Severe) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.

    PREGNANCY AND LACTATION

    Pregnancy

    Use of dihydroergotamine during breast-feeding is contraindicated by the manufacturer. There are no specific studies evaluating the use of dihydroergotamine in nursing mothers; however, other ergot alkaloids such as ergotamine are excreted in breast milk and may cause symptoms indicative of ergot toxicity in the nursing infant including vomiting, diarrhea, seizures, weak pulse, and unstable blood pressure. Ergotamine is classified by the American Academy of Pediatrics (AAP) as a drug that has been associated with significant effects on the nursing infant in some cases and should be given to nursing mothers with caution. Ergot derivatives are known to inhibit prolactin, and thus, interference with proper lactation is possible. Sumatriptan, a serotonin receptor agonist indicated for the treatment of migraines, is classified by the AAP as usually compatible with breast-feeding. Sumatriptan may be considered as an alternative to dihydroergotamine for the acute treatment of migraines in breast-feeding mothers. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    The pharmacologic actions of ergot alkaloids are complex. Dihydroergotamine (DHE) binds with high affinity to all known 5-HT1 receptors as well as a number of other biogenic amine receptors, such as 5-HT2 (subtypes A and C), alpha1 and alpha2-adrenergic receptors, and DA2 dopaminergic receptors. The therapeutic effect of DHE in the treatment of migraine is thought to be due primarily to agonist activity at 5-HT1 subtype D receptors. The efficacy of sumatriptan, a selective serotonin agonist, in the treatment of migraine is attributed to agonist activity at 5-HT1 receptor subtypes B and D. It is hypothesized that activation of 5-HT1 receptors (subtypes B and D) located on intracranial blood vessels may cause vasoconstriction of large intracranial conductance arteries and closure of arterio-venous anastomoses which correlates with the relief of migraine headache. Another hypothesis is that activation of 5-HT1 receptors on sensory nerve endings of the trigeminal system may inhibit the release of pro-inflammatory neuropeptides (e.g., substance P and calcitonin gene-related peptide (CGRP) from the trigeminal nerve). Substance P and CGRP may be involved in the generation of pain during a migraine episode.
     
    In the periphery, DHE causes vasoconstriction by stimulating alpha-adrenergic receptors. Although it is also a competitive alpha-adrenergic blocker at higher doses, this effect is somewhat masked by the drug's alpha-adrenergic agonist activity. With therapeutic doses, DHE also inhibits reuptake of norepinephrine, thereby increasing vasoconstriction. Effects of DHE on blood pressure are unpredictable, but the drug vasoconstricts capacitance vessels more than resistance vessels. Therefore, it increases venous return and decreases venous stasis and pooling. Dihydroergotamine has less vasoconstrictor activity than ergotamine. Although DHE possesses oxytocic properties; its oxytocic activity is less than that of ergotamine and much less than that of ergonovine or methylergonovine.

    PHARMACOKINETICS

    Dihydroergotamine (DHE) is administered parenterally or intranasally. Onset of relief from a migraine headache depends on route of administration and how soon the drug is given after the onset of symptoms. The drug is 90—93% bound to plasma proteins.
     
    Extensive metabolism of DHE occurs in the liver. Three active metabolites and two inactive metabolites have been identified. The metabolites include 8'-beta-hydroxydihydroergotamine and dihydrolysergic acid amide, which are further oxidized to the carboxylic acid derivative and to dihydrolysergic acid, respectively. Only 10% of a dose is excreted renally, and the rest is excreted through the biliary-fecal route.
     
    Affected cytochrome P450 isoenzymes: none

    Oral Route

    Dihydroergotamine (DHE) is incompletely and irregularly absorbed from the GI tract.

    Intravenous Route

    Pain relief is usually observed within 5 minutes after intravenous administration.

    Intramuscular Route

    After IM administration, onset of action is usually 15—30 minutes, and the duration is 3—4 hours.

    Subcutaneous Route

    Peak plasma concentrations after subcutaneous administration occur about 45 minutes after the dose (range 30—60 minutes).

    Other Route(s)

    Intranasal Administration
     
    Following intranasal administration, the bioavailability of DHE is roughly 32% relative to injectable administration. Absorption after intranasal administration is variable, probably reflecting intersubject differences in absorption and the technique used for self-administration. The intranasal dosage form exhibits linear pharmacokinetics between doses of 1—4 mg. Peak plasma concentrations after intranasal administration occur about 45 minutes after the dose (range 30—60 minutes). Onset of migraine pain relief after intranasal administration usually begins within 30 minutes. 
     
    Following intranasal administration, urinary recovery of the parent compound is roughly 2% of the dose.