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  • CLASSES

    Ergot Alkaloids

    DEA CLASS

    Rx

    DESCRIPTION

    Parenteral and nasally administered ergotamine derivative
    Used for the treatment of acute migraine with or without aura and cluster headache
    Associated with serious adverse cardiac and cerebrovascular events; cardiovascular evaluation recommended prior to starting therapy

    COMMON BRAND NAMES

    DHE 45, Migranal

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

    For the acute treatment of migraine with or without aura.
    Intravenous dosage
    Adults

    1 mg IV once. May repeat dose every 1 hour as needed. Max: 2 mg/day and 6 mg/week. Guidelines classify parenteral dihydroergotamine as having probable efficacy for the treatment of acute migraine. 

    Adolescents†

    Select low or high dose protocol based on patient tolerability. If no improvement seen after 5 doses, discontinue therapy. If improvement is seen, continue until headache ceases and give 1 additional dose, up to the maximum number of doses. HIGH DOSE: 1 mg IV every 8 hours. Max: 20 doses. Some experts recommend an initial test dose (one-half of the appropriate dose); if tolerated give the remainder of the dose 30 minutes later. LOW DOSE: 0.2 mg IV every 6 hours. May increase by 0.05 mg/dose until the patient has mild abdominal discomfort. Max: 8 to 16 doses.

    Children 10 to 12 years weighing 25 kg or more†

    Select low or high dose protocol based on patient tolerability. If no improvement seen after 5 doses, discontinue therapy. If improvement is seen, continue until headache ceases and give 1 additional dose, up to the maximum number of doses. HIGH DOSE: 1 mg IV every 8 hours. Max: 20 doses. Some experts recommend an initial test dose (one-half of the appropriate dose); if tolerated give the remainder of the dose 30 minutes later. LOW DOSE: 0.15 mg IV every 6 hours. May increase by 0.05 mg/dose until the patient has mild abdominal discomfort. Max: 8 to 16 doses.

    Children 10 to 12 years weighing less than 25 kg†

    Select low or high dose protocol based on patient tolerability. If no improvement seen after 5 doses, discontinue therapy. If improvement is seen, continue until headache ceases and give 1 additional dose, up to the maximum number of doses. HIGH DOSE: 0.5 mg IV every 8 hours. Max: 20 doses. Some experts recommend an initial test dose (one-half of the appropriate dose); if tolerated give the remainder of the dose 30 minutes later. LOW DOSE: 0.15 mg IV every 6 hours. May increase by 0.05 mg/dose until the patient has mild abdominal discomfort. Max: 8 to 16 doses.

    Children 6 to 9 years†

    Select low or high dose protocol based on patient tolerability. If no improvement seen after 5 doses, discontinue therapy. If improvement is seen, continue until headache ceases and give 1 additional dose, up to the maximum number of doses. HIGH DOSE: 0.5 mg IV every 8 hours. Max: 20 doses. Some experts recommend an initial test dose (one-half of the appropriate dose); if tolerated give the remainder of the dose 30 minutes later. LOW DOSE: 0.1 mg IV every 6 hours. May increase by 0.05 mg/dose until the patient has mild abdominal discomfort. Max: 8 to 16 doses.

    Intramuscular or Subcutaneous dosage
    Adults

    1 mg IM or subcutaneously once. May repeat dose every 1 hour as needed. Max: 3 mg/day and 6 mg/week. Guidelines classify parenteral dihydroergotamine as having probable efficacy for the treatment of acute migraine. 

    Intranasal dosage (Migranal nasal spray and generic equivalents)
    Adults

    0.5 mg in each nostril, followed by 0.5 mg in each nostril 15 minutes later for a total dose of 2 mg. Studies have shown no additional benefit from acute doses more than 2 mg for a single migraine episode. The safety of doses more than 3 mg/day and 4 mg/week have not been established. Guidelines classify intranasal dihydroergotamine as having established efficacy for the treatment of acute migraine.

    Intranasal dosage (Trudhesa nasal spray)
    Adults

    0.725 mg in each nostril once. May repeat dose after at least 1 hour after the first dose if needed. Max: 2.9 mg/day and 4.35 mg/week. Guidelines classify intranasal dihydroergotamine as having established efficacy for the treatment of acute migraine.

    For the treatment of cluster headache.
    Intravenous dosage
    Adults

    1 mg IV once. May repeat dose every 1 hour as needed. Max: 2 mg/day and 6 mg/week.

    Intramuscular or Subcutaneous dosage
    Adults

    1 mg IM or subcutaneously once. May repeat dose every 1 hour as needed. Max: 3 mg/day and 6 mg/week.

    MAXIMUM DOSAGE

    Adults

    3 mg/day IM or subcutaneous or 2 mg/day IV and 6 mg/week IV/IM/subcutaneous; 3 mg/day and 4 mg/week intranasal (Migranal and generic equivalents) or 2.9 mg/day and 4.35 mg/week intranasal (Trudhesa).

    Geriatric

    3 mg/day IM or subcutaneous or 2 mg/day IV and 6 mg/week IV/IM/subcutaneous; 3 mg/day and 4 mg/week intranasal (Migranal and generic equivalents) or 2.9 mg/day and 4.35 mg/week intranasal (Trudhesa).

    Adolescents

    Safety and efficacy have not been established; however, doses up to 1 mg/dose IV or 3 mg/day IV have been used off-label.

    Children

    10 to 12 years weighing 25 kg or more: Safety and efficacy have not been established; however, doses up to 1 mg/dose IV or 3 mg/day IV have been used off-label.
    10 to 12 years weighing less than 25 kg: Safety and efficacy have not been established; however, doses up to 0.5 mg/dose IV or 1.5 mg/day IV have been used off-label.
    6 to 9 years: Safety and efficacy have not been established; however, doses up to 0.5 mg/dose IV or 1.5 mg/day IV have been used off-label.
    1 to 5 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Use is contraindicated in patients with severe hepatic impairment.

    Renal Impairment

    Use is contraindicated in patients with severe renal impairment.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Administer IV hydration and premedication with an antiemetic prior to administration.
    Administer via slow IV push; in pediatric patients, give dose over 3 minutes.

    Inhalation Administration
    Intranasal Inhalation Administration

    Nasal spray assembly
    Each vial contains 1 complete dose.
    Assemble the nasal spray applicator immediately prior to use.
    Storage: Use within 8 hours after the vial is opened or the product has been assembled.
     
    Nasal spray administration (Migranal and generic equivalents)
    Prime the nasal spray device before administration by releasing 4 sprays. Use the spray immediately after priming.
    Do not have patient tilt head back or sniff while spraying or immediately after.
    Spray once in each nostril. Wait 15 minutes, spray once again in each nostril.
    Storage: Discard the nasal spray pump with the vial after use.
     
    Nasal spray administration (Trudhesa)
    Prime the nasal spray device before administration by releasing 4 sprays. Use the spray immediately after priming.
    Make sure the patient's head is straight and the nasal spray device is upright. Sniffing while or after dosing is not necessary; however, it will not cause harm or make the medicine less effective.
    Spray once in each nostril.
    Prepare a new nasal spray device for a second dose, if needed.
    Storage: Discard the assembled nasal spray device immediately after use.

    STORAGE

    DHE 45:
    - Avoid exposure to heat
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Do not refrigerate
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in carton until contents are used
    Migranal:
    - Do not freeze
    - Do not refrigerate
    - Store below 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Ergot alkaloid hypersensitivity

    Dihydroergotamine is contraindicated in patients with known ergot alkaloid hypersensitivity.

    Basilar/hemiplegic migraine

    Dihydroergotamine is contraindicated in patients with basilar/hemiplegic migraine.

    Angina, cardiac disease, coronary artery disease, diabetes mellitus, hypercholesterolemia, hypertension, myocardial infarction, obesity, peripheral vascular disease, postmenopausal females, tobacco smoking, vasospastic angina

    Dihydroergotamine is contraindicated in patients with uncontrolled hypertension, peripheral vascular disease, ischemic cardiac disease (angina pectoris, history of myocardial infarction, or documented silent ischemia) or patients who have clinical symptoms or findings consistent with coronary artery vasospasm, including Prinzmetal's variant angina (i.e., vasospastic angina). Serious adverse cardiac events, including some that have been fatal, have occurred after dihydroergotamine use. Prior to initiation of dihydroergotamine, a cardiovascular evaluation is recommended to determine if the patient is free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. If, during the cardiovascular evaluation, the patient's medical history (including risk factors), or electrocardiographic investigation, findings are consistent with coronary artery vasospasm or myocardial ischemia, do not administer dihydroergotamine. For patients with risk factors predictive of coronary artery disease (e.g., hypertension, hypercholesterolemia, tobacco smoking, obesity, diabetes mellitus, strong family history of coronary artery disease, postmenopausal females, or males who are older than 40 years) who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of dihydroergotamine take place in the setting of an equipped health care facility, unless the patient has previously received dihydroergotamine. During the interval immediately after the first use of dihydroergotamine, an electrocardiogram is recommended in those patients with risk factors because ischemia can occur in the absence of clinical symptoms. It is recommended that patients who are intermittent long-term users of dihydroergotamine and who have or acquire risk factors predictive of coronary artery disease undergo periodic interval cardiovascular evaluation as they continue to use dihydroergotamine.

    Hepatic disease

    Dihydroergotamine is contraindicated in patients with severe hepatic disease.

    Renal failure, renal impairment

    Dihydroergotamine is contraindicated in patients with severe renal impairment or renal failure.

    Sepsis, surgery

    Dihydroergotamine is contraindicated after vascular surgery and in patients with sepsis.

    Pregnancy

    Avoid dihydroergotamine use during pregnancy. Dihydroergotamine possesses oxytocic properties. Available data indicate an increased risk of preterm delivery with dihydroergotamine use during pregnancy. Data collected over decades have shown no increased risk of major birth defects or miscarriage with use of dihydroergotamine during pregnancy. In animal studies, adverse effects on embryofetal development were observed after administration of dihydroergotamine during pregnancy (decreased fetal body weight and/or skeletal ossification) in rats and rabbits or during pregnancy and lactation (decreased body weight and impaired reproductive function in the offspring) in rats at doses less than those used clinically and which were not associated with maternal toxicity. [52524]

    Breast-feeding

    Because of the potential for reduced milk supply and serious adverse events in the breast-fed infant, advise patients against breast-feeding during treatment with dihydroergotamine and for 3 days after the last dose. Breast milk supply during this time should be pumped and discarded. There are no data on the presence of dihydroergotamine in human milk; however, ergotamine, a related drug, is present in human milk. There are reports of diarrhea, vomiting, weak pulse, and unstable blood pressure in breast-fed infants exposed to ergotamine. Dihydroergotamine may reduce milk supply because it may decrease prolactin concentrations. [52524] As a possible alternative, previous American Academy of Pediatrics (AAP) recommendations considered sumatriptan, a serotonin receptor agonist indicated for the treatment of migraines, as usually compatible with breast-feeding.[27500]

    ADVERSE REACTIONS

    Severe

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

    Moderate

    sinus tachycardia / Rapid / 0.1-1.0
    palpitations / Early / 0.1-1.0
    edema / Delayed / 0.1-1.0
    confusion / Early / 0.1-1.0
    euphoria / Early / 0.1-1.0
    dyspnea / Early / 0.1-1.0
    dysphagia / Delayed / 0.1-1.0
    dystonic reaction / Delayed / 0.1-1.0
    hot flashes / Early / 1.0-1.0
    conjunctivitis / Delayed / 0.1-1.0
    photophobia / Early / 0.1-1.0
    cystitis / Delayed / 0.1-1.0
    peripheral vasoconstriction / Rapid / 0-0.1
    angina / Early / 0-0.1
    hypotension / Rapid / 0-0.1
    migraine / Early / 0-0.1
    depression / Delayed / 0-0.1
    vaginitis / Delayed / 0-0.1
    hypertension / Early / Incidence not known
    withdrawal / Early / Incidence not known
    medication overuse headache / Delayed / Incidence not known

    Mild

    rhinitis / Early / 19.0-26.0
    pharyngitis / Delayed / 3.0-21.0
    nausea / Early / 10.0-10.0
    dysgeusia / Early / 6.0-8.0
    sinusitis / Delayed / 1.0-5.0
    dizziness / Early / 4.0-4.0
    vomiting / Early / 4.0-4.0
    drowsiness / Early / 3.0-3.0
    epistaxis / Delayed / 0-3.0
    paresthesias / Delayed / 2.0-2.0
    diarrhea / Early / 2.0-2.0
    hypoesthesia / Delayed / 0.1-1.0
    tremor / Early / 0.1-1.0
    vertigo / Early / 0.1-1.0
    insomnia / Early / 0.1-1.0
    infection / Delayed / 0.1-1.0
    rhinorrhea / Early / 1.0-1.0
    hiccups / Early / 0.1-1.0
    xerostomia / Early / 1.0-1.0
    dyspepsia / Early / 0.1-1.0
    abdominal pain / Early / 0.1-1.0
    myalgia / Early / 0.1-1.0
    muscle cramps / Delayed / 0.1-1.0
    weakness / Early / 0.1-1.0
    petechiae / Delayed / 0.1-1.0
    pruritus / Rapid / 0.1-1.0
    rash / Early / 0.1-1.0
    malaise / Early / 0.1-1.0
    chills / Rapid / 0.1-1.0
    fever / Early / 0.1-1.0
    asthenia / Delayed / 1.0-1.0
    fatigue / Early / 1.0-1.0
    tinnitus / Delayed / 0.1-1.0
    lacrimation / Early / 0.1-1.0
    dysosmia / Delayed / 0.1-1.0
    otalgia / Early / 0.1-1.0
    increased urinary frequency / Early / 0.1-1.0
    gait disturbance / Delayed / 0-0.1
    hyperkinesis / Delayed / 0-0.1
    anxiety / Delayed / 0-0.1
    anorexia / Delayed / 0-0.1
    hypersalivation / Early / 0-0.1
    arthralgia / Delayed / 0-0.1
    urticaria / Rapid / 0-0.1
    maculopapular rash / Early / 0-0.1
    yawning / Early / 0-0.1
    ocular pain / Early / 0-0.1
    pallor / Early / Incidence not known
    flushing / Rapid / Incidence not known
    headache / Early / Incidence not known
    throat irritation / Early / Incidence not known
    nasal irritation / Early / Incidence not known
    nasal congestion / Early / Incidence not known
    nasal dryness / Early / Incidence not known
    hyperhidrosis / Delayed / 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: (Contraindicated) 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; Guaifenesin; Pseudoephedrine: (Contraindicated) 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: (Contraindicated) 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: (Contraindicated) 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: (Contraindicated) 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 dihydroergotamine 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 CYP3A4 inhibitor, and dihydroergotamine, 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 dihydroergotamine 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 CYP3A4 inhibitor, and dihydroergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Almotriptan: (Contraindicated) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.
    Amiodarone: (Major) Coadministration of dihydroergotamine with inhibitors of CYP3A4, such as amiodarone, may potentially increase the risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Coadministration should be done cautiously, and avoided when possible.
    Amlodipine: (Moderate) Be alert for symptoms of ergot toxicity if using dihydroergotamine 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 CYP3A4 inhibitor, and dihydroergotamine, 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 dihydroergotamine 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 CYP3A4 inhibitor, and dihydroergotamine, 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 dihydroergotamine 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 CYP3A4 inhibitor, and dihydroergotamine, 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 dihydroergotamine 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 CYP3A4 inhibitor, and dihydroergotamine, 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 dihydroergotamine 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 CYP3A4 inhibitor, and dihydroergotamine, 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 dihydroergotamine 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 CYP3A4 inhibitor, and dihydroergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Be alert for symptoms of ergot toxicity if using dihydroergotamine 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 CYP3A4 inhibitor, and dihydroergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Amoxicillin; Clarithromycin; Omeprazole: (Contraindicated) Coadministration of clarithromycin with dihydroergotamine is contraindicated due to the risk of ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, cyanosis, and numbness). Clarithromycin inhibits dihydroergotamine metabolism via inhibition of the CYP3A4 enzyme.
    Amphetamine; Dextroamphetamine Salts: (Major) Amphetamines, which increase catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with amphetamines may be advisable.
    Aprepitant, Fosaprepitant: (Major) Use caution if ergot alkaloids and aprepitant, fosaprepitant are used concurrently and monitor for an increase in ergot alkaloid-related adverse effects (e.g., severe peripheral vasospasm with possible ischemia, potentially leading to gangrene, cyanosis, stroke, numbness of the extremities and/or other serious effects) for several days after administration of a multi-day aprepitant regimen. Ergot alkaloids are CYP3A4 substrates. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of ergot alkaloids. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Atazanavir; Cobicistat: (Contraindicated) Coadministration of dihydroergotamine 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) Carefully monitor patients when azithromycin and dihydroergotamine are used concomitantly. Pharmacokinetic and/or pharmacodynamic interactions with dihydroergotamine have been observed with other macrolides.
    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.
    Berotralstat: (Moderate) Monitor for dihydroergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with berotralstat is necessary. Dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic range and berotralstat is a moderate CYP3A inhibitor.
    Beta-blockers: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Betaxolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Bisoprolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Boceprevir: (Contraindicated) Concurrent use of ergot alkaloids and boceprevir is contraindicated due to the potential for serious/life-threatening ergot toxicities, such as peripheral vasospasm and ischemia of the extremities and other tissues. Boceprevir is a potent inhibitor of CYP3A4, which is responsible for the metabolism of ergot alkaloids. Coadministration may result in large increases in ergot alkaloid serum concentrations, which could cause fatal ergot toxicities.
    Bosentan: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    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: (Contraindicated) 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: (Contraindicated) 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: (Contraindicated) 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; Dextromethorphan: (Contraindicated) 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.
    Bupivacaine; Meloxicam: (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: (Moderate) Cabergoline is an ergot derivative that has been associated with valvulopathy and fibrosis; the risk may increase with chronic. prolonged use. Cabergoline should be used with caution in patients exposed to other medications associated with valvulopathy and fibrosis, such as ergot alkaloids. Monitor patients taking these drugs for possible signs and symptoms, which may include dyspnea, persistent cough, chest pain, heart failure, renal insufficiency, or urethral/abdominal obstruction.
    Canakinumab: (Moderate) Monitor for an altered patient response to dihydroergotamine if coadministration with canakinumab is necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as dihydroergotamine, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Dihydroergotamine is a CYP3A4 substrate and a narrow therapeutic index drug.
    Carbetapentane; Pseudoephedrine: (Contraindicated) 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: (Contraindicated) 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: (Contraindicated) 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: (Contraindicated) 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: (Contraindicated) Coadministration of dihydroergotamine with ceritinib is contraindicated due to the potential for elevated dihydroergotamine exposure. 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. Ceritinib is a strong inhibitor of CYP3A4; dihydroergotamine is a CYP3A4 substrate.
    Cetirizine; Pseudoephedrine: (Contraindicated) 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: (Contraindicated) 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; Dextromethorphan; Pseudoephedrine: (Contraindicated) 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; Dihydrocodeine; Pseudoephedrine: (Contraindicated) 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: (Contraindicated) 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: (Contraindicated) 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; Ibuprofen; Pseudoephedrine: (Contraindicated) 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: (Contraindicated) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Cimetidine: (Major) Monitor for increased dihydroergotamine-related adverse effects with coadministration of cimetidine. The serum concentration of dihydroergotamine may increase during concurrent use. Cimetidine is a weak CYP3A4 inhibitor; dihydroergotamine is a CYP3A4 substrate.
    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: (Contraindicated) Coadministration of clarithromycin with dihydroergotamine is contraindicated due to the risk of ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, cyanosis, and numbness). Clarithromycin inhibits dihydroergotamine metabolism via inhibition of the CYP3A4 enzyme.
    Clofazimine: (Moderate) Monitor for increased toxicity of dihydroergotamine if used concomitantly with clofazimine. Concomitant use may increase the concentration of dihydroergotamine, increasing the risk of adverse effects. Dihydroergotamine is a CYP3A4 substrate that has a narrow therapeutic range; in vitro data suggest clofazimine inhibits CYP3A4.
    Cobicistat: (Contraindicated) Coadministration of dihydroergotamine 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: (Contraindicated) 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. Ergoloid mesylates preparations are not expected to interact with sympathomimetics because this compound does not possess the vasoconstrictor properties of other ergot alkaoloids.
    Codeine; Guaifenesin; Pseudoephedrine: (Contraindicated) 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.
    Conivaptan: (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of conivaptan is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and conivaptan is a moderate CYP3A inhibitor.
    Crizotinib: (Moderate) Monitor for dihydroergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with crizotinib is necessary. Dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic range and crizotinib is a moderate CYP3A inhibitor.
    Danazol: (Major) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of some drugs, such as ergot alkaloids, and lead to ergot toxicity.
    Darunavir; Cobicistat: (Contraindicated) Coadministration of dihydroergotamine 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: (Contraindicated) Coadministration of dihydroergotamine 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: (Contraindicated) 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: (Contraindicated) 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.
    Dexbrompheniramine; Pseudoephedrine: (Contraindicated) 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.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Contraindicated) 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: (Contraindicated) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Diazoxide: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Contraindicated) 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 dihydroergotamine 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 dihydroergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Dobutamine: (Major) The concomitant administration of ergot alkaloids and sympathomimetics has resulted in dangerous hypertension.
    Dorzolamide; Timolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Dihydroergotamine is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Duloxetine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as ergot alkaloids. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Elbasvir; Grazoprevir: (Moderate) Administering ergot alkaloids with elbasvir; grazoprevir may result in elevated plasma concentrations of the ergot alkaloids. Ergot alkaloids are substrates of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eletriptan: (Contraindicated) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.
    Elexacaftor; tezacaftor; ivacaftor: (Moderate) Use caution when administering ivacaftor and dihydroergotamine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dihydroergotamine, can increase dihydroergotamine exposure leading to increased or prolonged therapeutic effects and adverse events, including the risk for ergot toxicity.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Contraindicated) Coadministration of dihydroergotamine 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: (Contraindicated) Coadministration of dihydroergotamine 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 dihydroergotamine and adjust the dose as needed during coadministration with emapalumab. Dihydroergotamine 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 dihydroergotamine with enzalutamide due to decreased plasma concentrations of dihydroergotamine. Dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic index and enzalutamide is a strong CYP3A4 inducer.
    Epoprostenol: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Erythromycin: (Contraindicated) Coadministration is contraindicated as ergot toxicity can occur, resulting in ischemic reactions and peripheral vasospasm. Erythromycin inhibits the hepatic clearance of dihydroergotamine via inhibition of the CYP3A4 isoenzyme.
    Erythromycin; Sulfisoxazole: (Contraindicated) Coadministration is contraindicated as ergot toxicity can occur, resulting in ischemic reactions and peripheral vasospasm. Erythromycin inhibits the hepatic clearance of dihydroergotamine via inhibition of the CYP3A4 isoenzyme.
    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.
    Fedratinib: (Moderate) Monitor for dihydroergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with fedratinib is necessary. Dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic range and fedratinib is a moderate CYP3A inhibitor.
    Fenoldopam: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Fexofenadine; Pseudoephedrine: (Contraindicated) 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.
    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 dihydroergotamine toxicities that may require dihydroergotamine 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; dihydroergotamine is a substrate for CYP3A4. Coadministration of fostamatinib with a sensitive CYP3A4 substrate increased the substrate AUC by 64% and Cmax by 113%.
    Frovatriptan: (Contraindicated) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.
    Glycerol Phenylbutyrate: (Moderate) Concomitant use of glycerol phenylbutyrate and dihydroergotamine may result in decreased exposure of dihydroergotamine. Dihydroergotamine is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of dihydroergotamine during coadministration.
    Grapefruit juice: (Major) The risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects) is potentially increased by the use of CYP3A4 inhibitors. Grapefruit juice may decrease dihydroergotamine metabolism via CYP3A4. Patients should probably use caution with grapefruit juice by not modifying their usual grapefruit juice intake while taking dihydroergotamine. Elderly patients have the greatest possibility of ingesting grapefruit and interacting medications and are the most vulnerable to the adverse clinical consequences. Grapefruit juice inhibits the cytochrome P-450 3A4 isozyme in the gut wall. Grapefruit juice contains furanocoumarins that are metabolized by CYP3A4 to reactive intermediates. These intermediates form a covalent bond to the active site of the CYP3A4 enzyme, causing irreversible inactivation (mechanism-based inhibition). Consequently, CYP3A4 activity in the gut wall is inhibited until de novo synthesis returns the enzyme to its previous level.
    Green Tea: (Moderate) Some, but not all, green tea products contain caffeine. Excessive caffeine ingestion is probably best avoided including ingestion of foods or beverages that contain caffeine, such as green tea, in patients taking dihydroergotamine.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Contraindicated) 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: (Contraindicated) 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) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Contraindicated) 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: (Contraindicated) 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: (Contraindicated) 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: (Contraindicated) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with dihydroergotamine, a CYP3A substrate, as dihydroergotamine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloprost: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Imatinib: (Contraindicated) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme Coadministration of ergotamine with potent inhibitors of CYP3A4 is considered contraindicated due to the risk of acute ergot toxicity.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with dihydroergotamine may result in increased serum concentrations of dihydroergotamine. Dihydroergotamine is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoproterenol: (Contraindicated) Dihydroergotamine should not be administered with other vasoconstrictors, such as isoproterenol. Dihydroergotamine inhibits the uptake of norepinephrine and stimulates alpha-adrenergic receptors, causing prolonged vasoconstriction.
    Istradefylline: (Moderate) Monitor for dihydroergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with istradefylline is necessary. Dihydroergotamine 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: (Contraindicated) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as itraconazole, or administration for 2 weeks after discontinuation of itraconazole treatment is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and dihydroergotamine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dihydroergotamine, can increase dihydroergotamine exposure leading to increased or prolonged therapeutic effects and adverse events, including the risk for ergot toxicity.
    Ketoconazole: (Contraindicated) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as ketoconazole, is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
    Labetalol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Lanreotide: (Major) Avoid coadministration of lanreotide with dihydroergotamine due to increased dihydroergotamine exposure, which may increase the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities. If coadministration is unavoidable, monitor for dihydroergotamine-related adverse reactions. Dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic index. Limited published data available indicate that somatostatin analogs may decrease the metabolic clearance of CYP3A4 substrates, which may be due to the suppression of growth hormone; it cannot be excluded that lanreotide has this effect.
    Lansoprazole; Amoxicillin; Clarithromycin: (Contraindicated) Coadministration of clarithromycin with dihydroergotamine is contraindicated due to the risk of ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, cyanosis, and numbness). Clarithromycin inhibits dihydroergotamine metabolism via inhibition of the CYP3A4 enzyme.
    Lapatinib: (Moderate) Use caution if coadministration of lapatinib, a weak CYP3A4 inhibitor, with dihydroergotamine, a CYP3A4 substrate, is necessary, as the systemic exposure of dihydroergotamine may be increased resulting in an increase in dihydroergotamine-related adverse reactions including the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities; adjust the dose of dihydroergotamine if necessary.
    Larotrectinib: (Moderate) Be alert for symptoms of ergot toxicity if using dihydroergotamine and larotrectinib together is medically necessary. A dihydroergotamine dose reduction may be necessary if these drugs are used together. Concomitant use of larotrectinib, a weak CYP3A4 inhibitor, and dihydroergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Lefamulin: (Moderate) Monitor for dihydroergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with oral lefamulin is necessary. Dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic range and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of dihydroergotamine; monitor for potential reduction in efficacy. Dihydroergotamine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of dihydroergotamine; monitor for potential reduction in efficacy. Dihydroergotamine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Letermovir: (Contraindicated) 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.
    Levamlodipine: (Moderate) Be alert for symptoms of ergot toxicity if using dihydroergotamine 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 CYP3A4 inhibitor, and dihydroergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    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.
    Lidocaine; 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.
    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.
    Lonafarnib: (Contraindicated) Coadministration of dihydroergotamine with lonafarnib is contraindicated due to the potential for elevated dihydroergotamine exposure. 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. Dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic range and lonafarnib is a strong CYP3A inhibitor.
    Loratadine; Pseudoephedrine: (Contraindicated) Ergot alkaloids should not be administered with pseudoephedrine since combining these agents may produce a synergistic increase in blood pressure. There is also an additive risk of peripheral ischemia or gangrene. Of note, at therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids; therefore, ergoloid mesylates are not expected to interact with sympathomimetics.
    Lorcaserin: (Major) Lorcaserin should not be used in combination with serotonergic and dopaminergic drugs that are potent 5-HT2B receptor agonists and are known to increase the risk for cardiac valvulopathy (e.g., cabergoline, ergotamine, dihydroergotamine, and other ergot alkaloids).
    Lumacaftor; Ivacaftor: (Minor) Lumacaftor; ivacaftor may reduce the efficacy of dihydroergotamine by decreasing its systemic exposure; if used together, monitor patients closely for clinical efficacy. Dihydroergotamine is a substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and dihydroergotamine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dihydroergotamine, can increase dihydroergotamine exposure leading to increased or prolonged therapeutic effects and adverse events, including the risk for ergot toxicity.
    Mepivacaine: (Major) If epinephrine is added to mepivacaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Mepivacaine; Levonordefrin: (Major) If epinephrine is added to mepivacaine, do not use the mixture in a patient taking ergot alkaloids. Severe hypertension that may be persistent or a cerebrovascular accident can result from concomitant use of a vasopressor and an ergot type oxytocic drug.
    Methamphetamine: (Major) Amphetamines, which increase catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with amphetamines may be advisable.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Theoretically, concurrent use of methylene blue and ergot alkaloids may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and ergot alkaloids increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
    Methylene Blue: (Moderate) Theoretically, concurrent use of methylene blue and ergot alkaloids may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and ergot alkaloids increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
    Metoprolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Metoprolol; 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.
    Metreleptin: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and dihydroergotamine concomitantly; the precise effect of metreleptin on the metabolism of dihydroergotamine is not known. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, such as dihydroergotamine.
    Miconazole: (Moderate) No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP3A4. Although the systemic absorption of miconazole following buccal miconazole administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously, the potential for interaction with drugs metabolized through CYP3A4 (such as the ergot alkaloids) cannot be ruled out. Be alert for symptoms of a potential interaction, such as ischemia, cyanosis, and numbness of the extremities or other serious ergot-related effects.
    Mifepristone: (Contraindicated) Use of dihydroergotamine 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 dihydroergotamine 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) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Mirtazapine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering mirtazapine with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome. Mirtazapine should be discontinued if a patient develops a combination of symptoms suggestive of serotonin syndrome.
    Mitotane: (Major) Use caution if mitotane and dihydroergotamine are used concomitantly, and monitor for decreased efficacy of dihydroergotamine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and dihydroergotamine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of dihydroergotamine.
    Nadolol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Naproxen; Pseudoephedrine: (Contraindicated) 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.
    Naratriptan: (Contraindicated) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.
    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: (Contraindicated) Nefazodone may reduce the metabolism of dihydroergotamine via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects (e.g., severe peripheral vasospasm with possible ischemia, cyanosis, and numbness of the extremities or other serious effects). In addition, serotonin syndrome has been reported or may be possible with the use of ergot alkaloids like dihydroergotamine. particularly in combination with other serotonin-augmenting drugs. Avoid coadministration with nefazodone when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Nicardipine: (Moderate) Be alert for symptoms of ergot toxicity if using dihydroergotamine 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 dihydroergotamine, 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: (Contraindicated) Ergot alkaloids are contraindicated in patients with hypertension, angina, or coronary artery disease; which are the primary patient populations for which nitroglycerin is utilized. Because of the potential to cause coronary vasospasm, ergot alkaloids can oppose the vasodilatory actions of nitroglycerin and, in doing so, may precipitate angina. In addition, oral administration of nitroglycerin decreases the first-pass metabolism of dihydroergotamine, thereby increasing its oral bioavailability.
    Nitroprusside: (Major) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Norfloxacin: (Major) Coadministration of dihydroergotamine with inhibitors of CYP3A4, such as norfloxacin, may potentially increase the risk of ergot toxicity. Coadministration should be done cautiously, and avoided when possible.
    Olanzapine; 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.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Be alert for symptoms of ergot toxicity if using dihydroergotamine 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 CYP3A4 inhibitor, and dihydroergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Oritavancin: (Minor) Dihydroergotamine is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of dihydroergotamine may be reduced if these drugs are administered concurrently.
    Palbociclib: (Moderate) Monitor for an increase in dihydroergotamine-related adverse reactions if coadministration with palbociclib is necessary. The dose of dihydroergotamine may need to be reduced. Palbociclib is a weak time-dependent inhibitor of CYP3A while dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic index.
    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.
    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 dihydroergotamine 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 CYP3A4 inhibitor, and dihydroergotamine, 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: (Contraindicated) 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: (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.
    Propranolol; 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.
    Protease inhibitors: (Contraindicated) 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: (Contraindicated) 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.
    Pseudoephedrine; Triprolidine: (Contraindicated) 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: (Contraindicated) Coadministration of dihydroergotamine with ribociclib is contraindicated due to the potential for elevated dihydroergotamine exposure. 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. Ribociclib is a strong inhibitor of CYP3A; dihydroergotamine is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Contraindicated) Coadministration of dihydroergotamine with ribociclib is contraindicated due to the potential for elevated dihydroergotamine exposure. 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. Ribociclib is a strong inhibitor of CYP3A; dihydroergotamine is a CYP3A4 substrate.
    Rizatriptan: (Contraindicated) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.
    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.
    Sarilumab: (Moderate) Monitor for decreased efficacy of dihydroergotamine if coadministration with sarilumab is necessary. Inhibition of IL-6 signaling by sarilumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as dihydroergotamine, may have fluctuations in drug levels and therapeutic effect when sarilumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping sarilumab. In vitro, sarilumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dihydroergotamine is a CYP3A4 substrate and narrow therapeutic index drug.
    Secukinumab: (Moderate) If secukinumab is initiated or discontinued in a patient taking dihydroergotamine, monitor for altered patient response to dihydroergotamine; dihydroergotamine dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during secukinumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as dihydroergotamine.
    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: (Contraindicated) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.
    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.
    Siltuximab: (Moderate) Monitor for decreased efficacy of dihydroergotamine if coadministration with siltuximab is necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as dihydroergotamine, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dihydroergotamine is a CYP3A4 substrate and narrow therapeutic index drug.
    Simeprevir: (Major) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dihydroergotamine, which is a CYP3A4 substrate. Monitor patients for adverse effects of dihydroergotamine, such as ergot toxicity.
    Sotalol: (Moderate) Concurrent use of beta-blockers and ergot alkaloids should be approached with caution. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of certain ergot alkaloids including dihydroergotamine, ergotamine, methylergonovine, and methysergide. The risk of peripheral ischemia, resulting in cold extremities or gangrene, has been reported to be increased when ergotamine or dihydroergotamine is coadministered with selected beta-blockers, including propranolol, a beta-blocker commonly used for migraine prophylaxis. However, the precise mechanism of these interactions remains elusive. Additionally, because of the potential to cause coronary vasospasm, these ergot alkaloids could antagonize the therapeutic effects of anti-anginal agents including beta-blockers; clinicians should keep in mind that ergot alkaloids are contraindicated for use in patients with coronary heart disease or hypertension.
    Streptogramins: (Moderate) Be alert for symptoms of ergot toxicity if using dihydroergotamine and dalfopristin; quinupristin together is medically necessary. A dihydroergotamine dose reduction may be necessary if these drugs are used together. Concomitant use of dalfopristin; quinupristin, a CYP3A4 inhibitor, and dihydroergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Sumatriptan: (Contraindicated) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.
    Sumatriptan; Naproxen: (Contraindicated) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.
    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: (Contraindicated) 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.
    Telmisartan; Amlodipine: (Moderate) Be alert for symptoms of ergot toxicity if using dihydroergotamine 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 CYP3A4 inhibitor, and dihydroergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and dihydroergotamine is necessary, as the systemic exposure of dihydroergotamine may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of dihydroergotamine; consider increasing the dose of dihydroergotamine if necessary. Dihydroergotamine is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Tezacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and dihydroergotamine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dihydroergotamine, can increase dihydroergotamine exposure leading to increased or prolonged therapeutic effects and adverse events, including the risk for ergot toxicity.
    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.
    Tocilizumab: (Moderate) Monitor for decreased efficacy of dihydroergotamine if coadministration with tocilizumab is necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as dihydroergotamine, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dihydroergotamine is a CYP3A4 substrate and narrow therapeutic index drug.
    Trandolapril; Verapamil: (Moderate) Be alert for symptoms of ergot toxicity if using dihydroergotamine 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 dihydroergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Treprostinil: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
    Tucatinib: (Contraindicated) Coadministration of dihydroergotamine with tucatinib is contraindicated due to the potential for elevated dihydroergotamine exposure. 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. Dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic range and tucatinib is a strong CYP3A inhibitor.
    Vasopressors: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
    Vemurafenib: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as dihydroergotamine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of dihydroergotamine when coadministered with vemurafenib.
    Venlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as ergot alkaloids. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Verapamil: (Moderate) Be alert for symptoms of ergot toxicity if using dihydroergotamine 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 dihydroergotamine, 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: (Contraindicated) Concurrent administration of voriconazole with ergot alkaloids is contraindicated. Voriconazole may reduce the metabolism of the ergot alkaloids via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergotism (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, or other serious effects).
    Vortioxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering vortioxetine with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, vortioxetine and concurrent serotonergic agents should be discontinued.
    Zafirlukast: (Major) Coadministration of dihydroergotamine with inhibitors of CYP3A4, such as zafirlukast, may potentially increase the risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects).
    Zileuton: (Major) Coadministration of dihydroergotamine with inhibitors of CYP3A4, such as zileuton, may potentially increase the risk of ergot toxicity. Symptoms of ergot toxicity include: vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects.
    Zolmitriptan: (Contraindicated) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists.

    PREGNANCY AND LACTATION

    Pregnancy

    Avoid dihydroergotamine use during pregnancy. Dihydroergotamine possesses oxytocic properties. Available data indicate an increased risk of preterm delivery with dihydroergotamine use during pregnancy. Data collected over decades have shown no increased risk of major birth defects or miscarriage with use of dihydroergotamine during pregnancy. In animal studies, adverse effects on embryofetal development were observed after administration of dihydroergotamine during pregnancy (decreased fetal body weight and/or skeletal ossification) in rats and rabbits or during pregnancy and lactation (decreased body weight and impaired reproductive function in the offspring) in rats at doses less than those used clinically and which were not associated with maternal toxicity. [52524]

    Because of the potential for reduced milk supply and serious adverse events in the breast-fed infant, advise patients against breast-feeding during treatment with dihydroergotamine and for 3 days after the last dose. Breast milk supply during this time should be pumped and discarded. There are no data on the presence of dihydroergotamine in human milk; however, ergotamine, a related drug, is present in human milk. There are reports of diarrhea, vomiting, weak pulse, and unstable blood pressure in breast-fed infants exposed to ergotamine. Dihydroergotamine may reduce milk supply because it may decrease prolactin concentrations. [52524] As a possible alternative, previous American Academy of Pediatrics (AAP) recommendations considered sumatriptan, a serotonin receptor agonist indicated for the treatment of migraines, as usually compatible with breast-feeding.[27500]

    MECHANISM OF ACTION

    Dihydroergotamine binds with high affinity to 5-HT1D receptors. It also binds with high affinity to serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors, alpha1 and alpha2-adrenergic receptors, and dopamine D2L and D3 receptors. The therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effect at 5HT1D receptors. It is hypothesized that activation of 5-HT1D receptors located on intracranial blood vessels, including those on arterio-venous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine headache. An alternative hypothesis suggests that activation of 5-HT1D receptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release.

    PHARMACOKINETICS

    Dihydroergotamine is administered parenterally or intranasally. Dihydroergotamine is 93% bound to plasma protein, and the apparent steady-state Vd is approximately 800 L. The major metabolite, 8'-beta-hydroxy dihydroergotamine, exhibits affinity equivalent to its parent for adrenergic and 5-HT receptors and demonstrates equivalent potency in several venoconstrictor activity models, in vivo and in vitro. The other metabolites, dihydrolysergic acid, dihydrolysergic amide, and a metabolite formed by oxidative opening of the proline ring, are of minor importance. After intranasal administration, total metabolites represent only 20% to 30% of plasma AUC. The major excretory route of dihydroergotamine is via the bile in the feces. The total body clearance is 1.5 L/minute, which reflects mainly hepatic clearance. Only 6% to 7% of unchanged dihydroergotamine is excreted in the urine after intramuscular injection. The renal clearance (0.1 L/minute) is unaffected by the route of dihydroergotamine administration. The decline of plasma dihydroergotamine after intramuscular or intravenous administration is multi-exponential with a terminal half-life of about 9 hours. The decline of plasma dihydroergotamine after nasal administration is biphasic with a half-life of about 10 to 12 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4
    Dihydroergotamine is a substrate for CYP3A4.

    Intravenous Route

    After administration of dihydroergotamine 1 mg IV in healthy adults, Tmax was approximately 1 to 2 minutes and Cmax was less than 10 ng/mL.

    Intramuscular Route

    No difference was observed in dihydroergotamine bioavailability from intramuscular and subcutaneous doses. Bioavailability after intramuscular administration is 100%. After administration of dihydroergotamine 1 mg IM in healthy adults, Tmax was 24 minutes and Cmax was 2.9 ng/mL.

    Subcutaneous Route

    Absolute bioavailability for subcutaneous administration have not been determined. However, no difference was observed in dihydroergotamine bioavailability from intramuscular and subcutaneous doses.

    Other Route(s)

    Intranasal Route
    Absorption of dihydroergotamine is variable after intranasal administration. Mean bioavailability of dihydroergotamine mesylate is 32% to 40% after intranasal administration relative to injectable administration.  Tmax after intranasal administration is approximately 0.5 hours.