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    Ergot Alkaloids

    BOXED WARNING

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

    Ergotamine is contraindicated in patients with peripheral vascular disease (including thromboangiitis obliterans (Buerger's disease), luetic arteritis, severe arteriosclerosis, thrombophlebitis, and Raynaud's phenomenon), coronary artery disease (including unstable or vasospastic angina, or predisposition to vasospastic reactions), sepsis, malnutrition, or uncontrolled hypertension. It is recommended that ergotamine not be given to patients with a history of myocardial infarction or 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, 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 ergotamine 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 ergotamine 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 elevates serum ergotamine concentrations, the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities is increased.

    DEA CLASS

    Rx

    DESCRIPTION

    Ergot alkaloid; roughly 70% effective for relief of migraine. Prolonged use/excessive dose can lead to ergotism, dependence, or rebound HA; do not exceed daily and weekly dose limits.

    COMMON BRAND NAMES

    Ergomar

    HOW SUPPLIED

    Ergomar Sublingual Tablet, SL: 2mg

    DOSAGE & INDICATIONS

    For the treatment of acute migraine or vascular headache.
    NOTE: Titrate doses to determine the minimal effective dose; do not exceed maximum dose guidelines. Titration may be helpful in determining the initial dose needed and tolerated for subsequent migraine attacks.
    Sublingual dosage
    Adults

    2 mg ergotamine (1 tablet) SL at the first sign of an attack. Then, 2 mg SL after 30 minutes if needed. If the additional dose is well tolerated, the initial dose may be increased at the next attack, up to a maximum initial dose of 4 mg ergotamine. Do not exceed 3 tablets (6 mg ergotamine)/24 hours per any 1 attack. Limit of 5 tablets (10 mg ergotamine) per week.

    Adolescents† and older Children† >= 10 years

    Not generally recommended; limited controlled data suggest minimal benefit in aborting pediatric migraine. 1 mg SL as a single dose, repeated after 30 minutes if needed, has been used. Maximum dose 3 mg ergotamine/24 hours PO or per attack. The weekly dose limit is expected to be lower than for adults.

    MAXIMUM DOSAGE

    Adults

    6 mg/24 hours or per attack SL; not to exceed 10 mg/week SL.

    Elderly

    6 mg/24 hours or per attack SL; not to exceed 10 mg/week SL.

    Adolescents

    3 mg/24 hours or per attack SL. The weekly dose limit for ergotamine is expected to be lower than for adults.

    Children

     >= 10 years: 3 mg/24 hours or per attack SL. The pediatric weekly dose limit for ergotamine is expected to be lower than for adults.
     < 10 years: Not recommended.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Use contraindicated. Those with hepatic disease may be at increased risk for developing ergot toxicity due to systemic accumulation of ergotamine.

    Renal Impairment

    Use contraindicated. Patients with severe renal impairment may develop symptoms of ergot toxicity because of impaired ergot elimination.
     
    Intermittent hemodialysis:
    Contraindication to use. However, ergotamine is hemodialyzable.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    NOTE: Ergotamine is more effective if taken early in the migraine attack.
    Place tablet under the tongue and allow to dissolve; do not chew.
    Instruct patient not to swallow saliva until the tablet is completely absorbed.
    Do not to exceed maximum daily or weekly dosage limits.

    STORAGE

    Ergomar:
    - Protect from extreme heat
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Ergot alkaloid hypersensitivity

    Ergotamine is contraindicated in patients with known ergot alkaloid hypersensitivity because they may develop an allergic or otherwise adverse reaction. Patients should be advised not to exceed the recommended dosage of ergotamine 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

    Ergotamine should be avoided in patients with basilar/hemiplegic migraine because safety and efficacy have not been established. 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. Ergotamine should not be used for migraine prophylaxis.

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

    Ergotamine is contraindicated in patients with peripheral vascular disease (including thromboangiitis obliterans (Buerger's disease), luetic arteritis, severe arteriosclerosis, thrombophlebitis, and Raynaud's phenomenon), coronary artery disease (including unstable or vasospastic angina, or predisposition to vasospastic reactions), sepsis, malnutrition, or uncontrolled hypertension. It is recommended that ergotamine not be given to patients with a history of myocardial infarction or 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, 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 ergotamine 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 ergotamine 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 elevates serum ergotamine concentrations, the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities is increased.

    Biliary tract disease, cholestasis, hepatic disease

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

    Renal disease, renal failure, renal impairment

    Renal impairment, including renal failure, is considered a contraindication to ergotamine use by the manufacturer. Patients with severe renal impairment who receive ergotamine may develop symptoms of ergot poisoning because of impaired elimination. Use with caution in any patient with renal disease due to the vasoconstrictive effects of the drug.

    Children, infants

    Ergotamine should be used with caution in children, including adolescents; safe and effective use has not been established. Older children (>= 10 years) have been treated for severe migraine headaches with ergotamine. However, clinical data reveal poor efficacy rates. Ergotamine use in older children has been recommended to be reserved for cases where less toxic medications have failed to provide relief. Do not give ergotamine to young children or infants.

    Eclampsia, labor, obstetric delivery, preeclampsia, pregnancy

    Ergotamine is classified as FDA pregnancy risk category X. Ergotamine and other ergot alkaloids 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 also contraindicated in labor and obstetric delivery due to its oxytocic effect which is maximal in the third trimester. Although ergotamine is not an established human teratogen, limited data indicate that in utero exposure to ergotamine or ergotamine-containing products during pregnancy may be associated with fetal malformations, primarily consistent with ischemic injury. Until further information becomes available, the possibility of teratogenic potential 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. Animal studies indicate that ergotamine inhibits fetal growth, and increases intrauterine deaths and resorption. 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 ergotamine.

    Breast-feeding

    Ergot derivatives should generally be avoided during breast-feeding. According to the manufacturer of a combination product containing ergotamine, a decision should be made to discontinue nursing or discontinue the drug due to the potential for serious adverse reactions in the nursing infant. Ergotamine is excreted in breast milk and may cause symptoms indicative of ergot toxicity including vomiting, diarrhea, seizures, weak pulse, and unstable blood pressure in the nursing infant. Ergotamine is classified by the American Academy of Pediatrics (AAP) as a drug that has been associated with significant effects on some nursing infants 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 ergotamine 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.

    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. Ergotamine preparations should be used cautiously in those with pulmonary disease or valvular heart disease.

    Surgery

    Because ergotamine may cause vasoconstriction, patients should be advised to inform their health care provider of ergotamine usage prior to any surgeries or related procedures. Ergotamine may cause problems with plastic, cosmetic, or reconstructive surgery in particular; cyanosis, ischemia, or vasoconstriction in the skin or other tissues may occur if ergotamine has been ingested within 48 hours of the surgical procedure.

    ADVERSE REACTIONS

    Severe

    bowel ischemia / Delayed / Incidence not known
    cyanosis / Early / Incidence not known
    bradycardia / Rapid / Incidence not known
    tissue necrosis / Early / Incidence not known
    coronary vasospasm / Early / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    fetal death / Delayed / Incidence not known
    spontaneous fetal abortion / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    cardiac valvulopathy / Delayed / Incidence not known
    retroperitoneal fibrosis / Delayed / Incidence not known

    Moderate

    colitis / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    peripheral vasoconstriction / Rapid / Incidence not known
    hypertension / Early / Incidence not known
    angina / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    physiological dependence / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    uterine contractions / Early / Incidence not known
    edema / Delayed / Incidence not known

    Mild

    vomiting / Early / Incidence not known
    diarrhea / Early / Incidence not known
    nausea / Early / Incidence not known
    myalgia / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    muscle cramps / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    weakness / Early / Incidence not known
    headache / Early / Incidence not known
    vertigo / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / 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: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and amlodipine together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of amlodipine, a weak CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and amlodipine together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of amlodipine, a weak CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    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.
    Alprazolam: (Moderate) Drugs that may inhibit CYP3A4, such as ergotamine, may reduce the metabolism of alprazolam. Use alprazolam and ergotamine with caution and consider alprazolam dose reduction of up to 50%.
    Amiodarone: (Major) Coadministration of ergotamine 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: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and amlodipine together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of amlodipine, a weak CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Amlodipine; Atorvastatin: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and amlodipine together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of amlodipine, a weak CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Amlodipine; Benazepril: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and amlodipine together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of amlodipine, a weak CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Amlodipine; Celecoxib: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and amlodipine together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of amlodipine, a weak CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and amlodipine together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of amlodipine, a weak CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and amlodipine together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of amlodipine, a weak CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Amlodipine; Olmesartan: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and amlodipine together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of amlodipine, a weak CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Amlodipine; Telmisartan: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and amlodipine together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of amlodipine, a weak CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Amlodipine; Valsartan: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and amlodipine together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of amlodipine, a weak CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Amoxicillin; Clarithromycin; Lansoprazole: (Severe) The concurrent use of clarithromycin and ergotamine is contraindicated due to the risk for ergot toxicity; severe vasospastic adverse events, including extremity ischemia that may require amputation, can occur. Ergotamine is primarily metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4. Rare cases of cerebral ischemia, which may result in death, have also been reported when ergotamine was administered with other strong CYP3A4 inhibitors.
    Amoxicillin; Clarithromycin; Omeprazole: (Severe) The concurrent use of clarithromycin and ergotamine is contraindicated due to the risk for ergot toxicity; severe vasospastic adverse events, including extremity ischemia that may require amputation, can occur. Ergotamine is primarily metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4. Rare cases of cerebral ischemia, which may result in death, have also been reported when ergotamine was administered with other strong CYP3A4 inhibitors.
    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 ergotamine with cobicistat is contraindicated. Cobicistat is a strong 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) The manufacturer of azithromycin recommends caution and careful monitoring of patients who receive azithromycin and ergotamine, because simultaneous use of ergotamine with other 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.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Coadministration of ergotamine with inhibitors of CYP3A4, such as metronidazole, may potentially increase the risk of ergot toxicity.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Coadministration of ergotamine with inhibitors of CYP3A4, such as metronidazole, may potentially increase the risk of ergot toxicity.
    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) Use of vasodilators and ergot alkaloids may result in antagonism of the vasoconstrictive effects of the ergot derivative. This interaction is used to clinical benefit, i.e., nitroprusside used for supportive care of ergot alkaloid toxicity.
    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.
    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: (Severe) Coadministration of ergotamine and ceritinib is contraindicated due to the potential for increased ergotamine exposure resulting in ergotism and other serious vasospastic adverse events. Ergotamine is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. When administered with strong CYP3A4 inhibitors, acute ergot toxicity (ergotism) characterized by vasospasm and ischemia of the extremities has occurred, with some cases resulting in amputation. There have also been rare reports of cerebral ischemia, with at least one fatality, in patients receiving concomitant strong CYP3A4 inhibitors.
    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) Coadministration of ergotamine with inhibitors of CYP3A4, such as cimetidine, may potentially increase the risk of ergot toxicity. Coadministration should be done cautiously, and avoided when possible.
    Citalopram: (Moderate) Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., citalopram), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Clarithromycin: (Severe) The concurrent use of clarithromycin and ergotamine is contraindicated due to the risk for ergot toxicity; severe vasospastic adverse events, including extremity ischemia that may require amputation, can occur. Ergotamine is primarily metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4. Rare cases of cerebral ischemia, which may result in death, have also been reported when ergotamine was administered with other strong CYP3A4 inhibitors.
    Clofazimine: (Moderate) Monitor for increased toxicity of ergotamine if used concomitantly with clofazimine. Concomitant use may increase the concentration of ergotamine, increasing the risk of adverse effects. Ergotamine is a CYP3A4 substrate that has a narrow therapeutic range; in vitro data suggest clofazimine inhibits CYP3A4.
    Cobicistat: (Severe) Coadministration of ergotamine with cobicistat is contraindicated. Cobicistat is a strong 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.
    Cocaine: (Severe) Ergot alkaloids should not be administered with vasoconstrictors such as cocaine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene.
    Conivaptan: (Severe) Ergotamine is a CYP3A4 substrate. Conivaptan is a potent inhibitor of CYP3A4 and may increase concentrations of ergotamine. The risk of ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, potentially leading to gangrene, cyanosis, stroke, numbness of the extremities, or other serious effects) is potentially increased by the concomitant use of CYP3A4 inhibitors. Coadministration of ergotamine and conivaptan should be avoided to minimize the risk of ergot toxicity. According to the manufacturer of conivaptan, treatment with CYP3A4 substrates (i.e., ergotamine) may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Crizotinib: (Moderate) Closely monitor for ergotamine-related adverse reactions, including vasospasm leading to cerebral ischemia and/or ischemia of the extremities, if coadministration with crizotinib is necessary. Ergotamine is a CYP3A4 substrate with a narrow therapeutic index and crizotinib is a moderate CYP3A inhibitor. While ergot toxicity has not been reported with moderate CYP3A inhibition, there is a potential risk for serious toxicity including vasospasm when these drugs are used with ergotamine.
    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 ergotamine with cobicistat is contraindicated. Cobicistat is a strong 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.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Severe) Coadministration of ergotamine with cobicistat is contraindicated. Cobicistat is a strong 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.
    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) Use of vasodilators and ergot alkaloids may result in antagonism of the vasoconstrictive effects of the ergot derivative. This interaction is used to clinical benefit, i.e., nitroprusside used for supportive care of ergot alkaloid toxicity.
    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: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and diltiazem together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of diltiazem, a CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Dirithromycin: (Moderate) Use caution in combining dirithromycin with ergotamin. Although not reported with dirithromycin, concomitant use of ergotamine with other macrolides has produced ergot toxicity. The mechanism is related to inhibition of ergot metabolism via CYP3A4.
    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. Ergotamine 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.
    Elexacaftor; tezacaftor; ivacaftor: (Moderate) Use caution when administering ivacaftor and ergotamine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as ergotamine, can increase ergotamine exposure leading to increased or prolonged therapeutic effects and adverse events, including the risk for ergot toxicity.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Severe) Coadministration of ergotamine with cobicistat is contraindicated. Cobicistat is a strong 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.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Severe) Coadministration of ergotamine with cobicistat is contraindicated. Cobicistat is a strong 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.
    Emapalumab: (Moderate) Monitor for decreased efficacy of ergotamine and adjust the dose as needed during coadministration with emapalumab. Ergotamine is a CYP3A4 substrate with a narrow therapeutic range. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
    Enzalutamide: (Major) Avoid coadministration of ergotamine with enzalutamide due to decreased plasma concentrations of ergotamine. Ergotamine 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.
    Erythromycin: (Severe) The concurrent use of erythromycin and ergotamine is contraindicated due to the risk for ergot toxicity; severe vasospastic adverse events, including extremity ischemia that may require amputation, can occur. Erythromycin inhibits the hepatic clearance of ergotamine via inhibition of the CYP3A4 isoenzyme. Rare cases of cerebral ischemia, which may result in death, have also been reported when ergotamine was administered with strong CYP3A4 inhibitors.
    Erythromycin; Sulfisoxazole: (Severe) The concurrent use of erythromycin and ergotamine is contraindicated due to the risk for ergot toxicity; severe vasospastic adverse events, including extremity ischemia that may require amputation, can occur. Erythromycin inhibits the hepatic clearance of ergotamine via inhibition of the CYP3A4 isoenzyme. Rare cases of cerebral ischemia, which may result in death, have also been reported when ergotamine was administered with strong CYP3A4 inhibitors.
    Escitalopram: (Moderate) Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., escitalopram), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    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 ergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with everolimus is necessary. Ergotamine is a CYP3A4 substrate with a narrow therapeutic range and everolimus is a weak CYP3A4 inhibitor.
    Fedratinib: (Moderate) Use caution if coadministration of fedratinib, a moderate CYP3A4 inhibitor, with ergotamine, a CYP3A4 substrate, is necessary, as the systemic exposure of ergotamine may be increased resulting in an increase in ergotamine-related adverse reactions including the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities; adjust the dose of ergotamine if necessary.
    Fenoldopam: (Minor) Use of vasodilators and ergot alkaloids may result in antagonism of the vasoconstrictive effects of the ergot derivative. This interaction is used to clinical benefit, i.e., nitroprusside used for supportive care of ergot alkaloid toxicity.
    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.
    Fluoxetine: (Major) Avoid use of ergot alkaloids with fluoxetine if possible due to decreased ergot alkaloid metabolism via CYP3A4. There is a potential risk for serious ergot-related toxicity including vasospasm when these drugs are used with ergotamine. Fluoxetine is a weak inhibitor of CYP3A4, and ergot alkaloids are metabolized via CYP3A4. This interaction has not been studied specifically. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., fluoxetine), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Fluoxetine; Olanzapine: (Major) Avoid use of ergot alkaloids with fluoxetine if possible due to decreased ergot alkaloid metabolism via CYP3A4. There is a potential risk for serious ergot-related toxicity including vasospasm when these drugs are used with ergotamine. Fluoxetine is a weak inhibitor of CYP3A4, and ergot alkaloids are metabolized via CYP3A4. This interaction has not been studied specifically. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., fluoxetine), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Fluvoxamine: (Major) Avoid use of ergot alkaloids with fluvoxamine if possible due to decreased ergot alkaloid metabolism via CYP3A4. There is a potential risk for serious ergot-related toxicity including vasospasm when these drugs are used with ergotamine. Fluvoxamine is an inhibitor of CYP3A4, and ergot alkaloids are metabolized via CYP3A4. This interaction has not been studied specifically. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., fluvoxamine), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Fostamatinib: (Moderate) Monitor for ergotamine toxicities that may require ergotamine dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a CYP3A4 substrate may increase the concentration of the CYP3A4 substrate. The active metabolite of fostamatinib, R406, is a CYP3A4 inhibitor; ergotamine is a substrate for CYP3A4. Coadministration of fostamatinib with a sensitive CYP3A4 substrate increased the substrate AUC by 64% and Cmax by 113%.
    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 ergotamine may result in decreased exposure of ergotamine. Ergotamine is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of ergotamine during coadministration.
    Grapefruit juice: (Major) The risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects) from ergotamine is potentially increased by the use of CYP3A4 inhibitors. 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. Therefore grapefruit juice may decrease ergotamine metabolism via CYP3A4. According to the manufacturers, the prescriber should consider the effects of other agents on CYP3A4 before concomitant use with ergotamine.
    Green Tea: (Minor) Some green tea products contain caffeine. Administration of caffeine with ergotamine increases the absorption rate and peak plasma levels of ergotamine. This interaction is used to therapeutic advantage, although, excessive caffeine ingestion is probably best avoided.
    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.
    Hydralazine: (Minor) Use of vasodilators and ergot alkaloids may result in antagonism of the vasoconstrictive effects of the ergot derivative. This interaction is used to clinical benefit, i.e., nitroprusside used for supportive care of ergot alkaloid toxicity.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Minor) Use of vasodilators and ergot alkaloids may result in antagonism of the vasoconstrictive effects of the ergot derivative. This interaction is used to clinical benefit, i.e., nitroprusside used for supportive care of ergot alkaloid toxicity.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Minor) Use of vasodilators and ergot alkaloids may result in antagonism of the vasoconstrictive effects of the ergot derivative. This interaction is used to clinical benefit, i.e., nitroprusside used for supportive care of ergot alkaloid toxicity.
    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 ergotamine, a CYP3A substrate, as ergotamine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    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 ergotamine may result in increased serum concentrations of ergotamine. Ergotamine 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) The concomitant administration of ergot alkaloids and sympathomimetics has resulted in dangerous hypertension. Ergot alkaloids exacerbate the effect of isoproterenol on increased cardiac output while producing peripheral vasoconstriction, resulting in increased blood pressure.
    Istradefylline: (Moderate) Monitor for ergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with istradefylline is necessary. Ergotamine is a CYP3A4 substrate with a narrow therapeutic range and istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
    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 ergotamine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as ergotamine, can increase ergotamine 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 ergotamine due to increased ergotamine exposure, which may increase the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities. If coadministration is unavoidable, monitor for ergotamine -related adverse reactions. Ergotamine 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.
    Lapatinib: (Moderate) Use caution if coadministration of lapatinib, a weak CYP3A4 inhibitor, with ergotamine, a CYP3A4 substrate, is necessary, as the systemic exposure of ergotamine may be increased resulting in an increase in ergotamine-related adverse reactions including the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities; adjust the dose of ergotamine if necessary.
    Larotrectinib: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and larotrectinib together is medically necessary. An ergotamine dose reduction may be necessary if these drugs are used together. Concomitant use of larotrectinib, a weak CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate, may result in increased ergot alkaloid levels.
    Lefamulin: (Moderate) Use caution if coadministration of oral lefamulin, a moderate CYP3A4 inhibitor, with ergotamine, a CYP3A4 substrate, is necessary, as the systemic exposure of ergotamine may be increased resulting in an increase in ergotamine-related adverse reactions including the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities; adjust the dose of ergotamine if necessary. An interaction is not expected with intravenous lefamulin.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of ergotamine; monitor for potential reduction in efficacy. Ergotamine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of ergotamine; monitor for potential reduction in efficacy. Ergotamine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Letermovir: (Severe) Concurrent administration of ergot alkaloids and letermovir is contraindicated due to the risk of ergotism. Taking these drugs together may result in increased concentrations of ergot alkaloids due to inhibition of CYP3A4 by letermovir.
    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 ergotamine by decreasing its systemic exposure; if used together, monitor patients closely for clinical efficacy. Ergotamine is a substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and ergotamine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as ergotamine, can increase ergotamine 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.
    Metronidazole: (Major) Coadministration of ergotamine with inhibitors of CYP3A4, such as metronidazole, may potentially increase the risk of ergot toxicity.
    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: (Severe) Use of ergotamine with mifepristone is contraindicated when mifepristone is used chronically for hormonal conditions, such as in the treatment of Cushing's syndrome. Mifepristone, a CYP3A4 inhibitor, is likely to increase ergot alkaloid concentrations and adverse effects, since ergotamine is a CYP3A4 substrate with a narrow therapeutic index. 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) Use of vasodilators and ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. This interaction is used to clinical benefit, i.e., nitroprusside for supportive care of ergot alkaloid toxicity. Care must be taken to avoid aggravating an already existent hypotension occurring with ergot overdose.
    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 ergotamine are used concomitantly, and monitor for decreased efficacy of ergotamine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and ergotamine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ergotamine.
    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: (Major) Nefazodone may reduce the metabolism of ergotamine 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 ergotamine, particularly in combination with other serotonin-augmenting drugs. Avoid coadministration of ergotamine with nefazodone when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Nicardipine: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and nicardipine together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of nicardipine, a CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    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.
    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.
    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) Norfloxacin is a significant CYP3A4 inhibitor. Coadministration of ergotamine with inhibitors of CYP3A4 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.
    Oritavancin: (Minor) Ergotamine is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of ergotamine may be reduced if these drugs are administered concurrently.
    Palbociclib: (Moderate) Monitor for an increase in ergotamine-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A while ergotamine is a CYP3A4 substrate with a narrow therapeutic index.
    Paroxetine: (Moderate) Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., paroxetine), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and ergotamine, a CYP3A4 substrate, may cause an increase in systemic concentrations of ergotamine. Use caution when administering these drugs concomitantly.
    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: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and amlodipine together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of amlodipine, a weak CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    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: (Severe) Coadministration of ergotamine and ribociclib is contraindicated due to the potential for increased ergotamine exposure resulting in ergotism and other serious vasospastic adverse events. Ergotamine is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. When administered with strong CYP3A4 inhibitors, acute ergot toxicity (ergotism) characterized by vasospasm and ischemia of the extremities has occurred, with some cases resulting in amputation. There have also been rare reports of cerebral ischemia, with at least one fatality, in patients receiving concomitant strong CYP3A4 inhibitors.
    Ribociclib; Letrozole: (Severe) Coadministration of ergotamine and ribociclib is contraindicated due to the potential for increased ergotamine exposure resulting in ergotism and other serious vasospastic adverse events. Ergotamine is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. When administered with strong CYP3A4 inhibitors, acute ergot toxicity (ergotism) characterized by vasospasm and ischemia of the extremities has occurred, with some cases resulting in amputation. There have also been rare reports of cerebral ischemia, with at least one fatality, in patients receiving concomitant strong CYP3A4 inhibitors.
    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.
    Rucaparib: (Moderate) Monitor for ergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with rucaparib is necessary. Ergotamine is a CYP3A4 substrate with a narrow therapeutic range and rucaparib is a weak CYP3A4 inhibitor.
    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.
    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.
    Sertraline: (Moderate) Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., sertraline), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    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.
    Simeprevir: (Major) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of ergotamine, which is a CYP3A4 substrate. Monitor patients for adverse effects of ergotamine, 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: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and dalfopristin; quinupristin together is medically necessary. An ergotamine dose reduction may be necessary if these drugs are used together. Concomitant use of dalfopristin; quinupristin, a CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate, may result in increased ergot alkaloid levels.
    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 ergotamine is necessary, as the systemic exposure of ergotamine may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of ergotamine; consider increasing the dose of ergotamine if necessary. Ergotamine 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.
    Tezacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and ergotamine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as ergotamine, can increase ergotamine exposure leading to increased or prolonged therapeutic effects and adverse events, including the risk for ergot toxicity.
    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: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and verapamil together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of verapamil, a CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    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 ergotamine could be expected with concurrent use. Use caution, and monitor therapeutic effects of ergotamine 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: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and verapamil together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of verapamil, a CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    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) Zafirlukast is a significant CYP3A4 inhibitor. Coadministration of ergotamine with inhibitors of CYP3A4 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.
    Zileuton: (Major) Zileuton is a significant CYP3A4 inhibitor. Coadministration of ergotamine with inhibitors of CYP3A4 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.
    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

    Ergotamine is classified as FDA pregnancy risk category X. Ergotamine and other ergot alkaloids 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 also contraindicated in labor and obstetric delivery due to its oxytocic effect which is maximal in the third trimester. Although ergotamine is not an established human teratogen, limited data indicate that in utero exposure to ergotamine or ergotamine-containing products during pregnancy may be associated with fetal malformations, primarily consistent with ischemic injury. Until further information becomes available, the possibility of teratogenic potential 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. Animal studies indicate that ergotamine inhibits fetal growth, and increases intrauterine deaths and resorption. 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 ergotamine.

    MECHANISM OF ACTION

    The pharmacologic properties of ergotamine are complex; some of the pharmacologic actions are unrelated to each other; some actions are even mutually antagonistic. Ergotamine exhibits partial agonist and/or antagonist activity against serotonergic, dopaminergic, and alpha-adrenergic receptors depending on their site. Ergotamine also exhibits potent uterine stimulant and emetic properties. In the treatment of migraine headache, some pharmacologic actions are probably related to the drug's effect on serotonin (5-HT) receptors. Ergotamine reduces extracranial blood flow, decreases the amplitude of pulsations in the cranial arteries and decreases hyperperfusion of the basilar artery territory. Caffeine acts synergistically with ergotamine to treat migraine headaches (see Caffeine; Ergotamine monograph). Caffeine may have additive cerebral vasoconstriction activity to ergotamine, but some studies show the increased effect from the combination is due to the enhanced GI absorption of ergotamine tartrate.
     
    At therapeutic doses, ergotamine inhibits the uptake of norepinephrine and stimulates alpha-adrenergic receptors, causing prolonged vasoconstriction of both arteries and veins and decreased blood flow to the extremities. Inhibition of peripheral alpha-adrenergic receptors may occur with higher doses. In doses used to treat vascular headaches, ergotamine usually only produces small elevations in blood pressure but it does increase peripheral vascular resistance and causes a decrease in blood flow to various organs. Vasoconstrictor properties may last for up to 48 hours after a single dose.
     
    Ergotamine increases the force and frequency of uterine contraction; larger doses increase the resting uterine tone. Constriction of the placental vascular bed also occurs.

    PHARMACOKINETICS

    Ergotamine is administered sublingually. It is extensively metabolized in the liver, primarily via CYP3A4 isoenzymes. About 90% of the metabolites are eliminated in the bile. Unchanged ergotamine is secreted erratically in the saliva; trace amounts appear in the feces and urine. The elimination half-life is roughly 2 hours; however, the drug may be stored in some tissues, which would account for the long-lasting therapeutic and toxic effects of the drug.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4

    Oral Route

    The oral absorption of ergotamine is incomplete and erratic; bioavailability data for sublingual administration are not available. Administration with caffeine increases the absorption rate and peak plasma concentrations of ergotamine when administered orally or rectally. The onset of action varies and is likely related to how quickly the drug is administered once the headache begins. Typically, however, migraine relief is obtained within 0.5—2 hours of administration. Pharmacodynamically, the duration of other properties, like vasoconstriction, may persist for up to 48 hours.