TRUDHESA (dihydroergotamine mesylate)

There are 8 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
5-HT1D Agonists/Ergot Alkaloids SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: The 5-HT1D agonists and ergot alkaloids can produce vasospastic reactions. CLINICAL EFFECTS: Concurrent therapy may produce additive vasospastic effects. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer states that sumatriptan should not be used within 24 hours of an ergotamine-containing or ergotamine-like medication (such as dihydroergotamine or methysergide).(1,2) The Australian(3) and UK(4,5) manufacturers state that 24 hours should elapse before sumatriptan is administered following an ergotamine-containing preparation and 6 hours should elapse before an ergotamine-containing preparation is administered following sumatriptan. The US manufacturer states that zolmitriptan should not be used within 24 hours of an ergotamine-containing or ergotamine-like medication.(6) The UK manufacturer states that zolmitriptan should not be used within 6 hours of an ergotamine-containing or ergotamine-like medication.(7) The The Australian manufacturer states that 24 hours should elapse before zolmitriptan is administered following an ergotamine-containing preparation and 6 hours should elapse before an ergotamine-containing medication is administered following zolmitriptan.(8) The US manufacturer states that the use of rizatriptan within 24 hours of an ergotamine-containing or ergot-type medication is contraindicated.(9) The US manufacturer states that the use of naratriptan within 24 hours of an ergotamine-containing or ergot-type medication is contraindicated.(10) The Australian manufacturer states that concurrent use of naratriptan and ergotamine or ergotamine derivatives is not recommended.(11) The US manufacturer states that the use of eletriptan within 24 hours of an ergotamine-containing or ergot-type medication is contraindicated.(12) The UK manufacturer states that the use of eletriptan within 24 hours of an ergotamine-containing or ergot-type medication is not recommended.(13) DISCUSSION: Because of the theoretical risk of additive vasospastic effects, the US manufacturer states that the use of sumatriptan within 24 hours of an ergotamine-containing or ergotamine-like medication is contraindicated.(1,2) The Australian(3) and UK(4,5) manufacturer states that 24 hours should elapse before sumatriptan is administered following an ergotamine-containing preparation and 6 hours should elapse before an ergotamine-containing medication is administered following sumatriptan. Although the pharmacokinetics of zolmitriptan were not affected by ergotamine, the UK manufacturer of zolmitriptan recommends that 6 hours should elapse between the administration of zolmitriptan and an ergotamine preparation.(7) The US manufacturer of zolmitriptan states under contraindications that zolmitriptan should not be used within 24 hours of an ergotamine-containing or ergot-type medication.(6) The Australian manufacturer states that 24 hours should elapse before zolmitriptan is administered following an ergotamine-containing preparation and 6 hours should elapse before an ergotamine-containing medication is administered following zolmitriptan.(8) Because of the additive risk of prolonged vasospastic reactions, the manufacturers of rizatriptan(9) and naratriptan(10) in the US state that the use of ergotamine-containing or ergot-type medications and these agents is contraindicated. The Australian manufacturer states that concurrent use of naratriptan and ergotamine or ergotamine derivatives is not recommended.(11) Administration of oral ergotamine one and two hours after eletriptan resulted in additive increases in blood pressure.(13)	ALMOTRIPTAN MALATE, ELETRIPTAN HBR, FROVA, FROVATRIPTAN SUCCINATE, IMITREX, MAXALT, MAXALT MLT, MIGRANOW, NARATRIPTAN HCL, ONZETRA XSAIL, RELPAX, RIZATRIPTAN, SUMATRIPTAN, SUMATRIPTAN SUCC-NAPROXEN SOD, SUMATRIPTAN SUCCINATE, SYMBRAVO, TOSYMRA, TREXIMET, ZEMBRACE SYMTOUCH, ZOLMITRIPTAN, ZOLMITRIPTAN ODT, ZOMIG
Ergot Alkaloids/Selected Macrolide Antibiotics SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: The macrolides may inhibit the hepatic metabolism of ergot alkaloids by inhibition of CYP3A4.(1) CLINICAL EFFECTS: Concurrent use may result in increased levels of ergot alkaloids, which may result in clinical signs of ergotism, including vasospasm, dysesthesia, renal ischemia, and peripheral ischemia. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of ergotamine(2) and dihydroergotamine (3) state that the concurrent use of these agents with clarithromycin, erythromycin, or troleandomycin is contraindicated. The US manufacturer of methylergonovine states that methylergonovine should not be administered with potent CYP3A4 inhibitors such as the macrolide antibiotics clarithromycin, erythromycin, and troleandomycin.(4) The US manufacturer of clarithromycin states that concurrent administration of ergotamine or dihydroergotamine is contraindicated.(5) It would be prudent to avoid the concurrent use of all ergot alkaloids and macrolide antibiotics that inhibit CYP3A4. Patients receiving concurrent therapy with macrolides and ergot alkaloids should be monitored for clinical signs of ergotism. One or both agents may need to be discontinued. Patients should be treated symptomatically for ergotism. DISCUSSION: Three case reports have documented clinical signs of ergotism following concomitant therapy with erythromycin and ergotamine. Symptoms included vasospasm, dysesthesia, renal ischemia, and peripheral ischemia. Symptoms occurred within one to seven days of concurrent therapy and with small doses of ergotamine.(6-8) Five case reports have documented peripheral vasospasm following the concurrent administration of ergotamine and troleandomycin. Ergotamine dosages ranged from single dose to long term therapy.(9-12) A similar interaction was reported for ergotamine and troleandomycin(13) and ergotamine and clarithromycin.(14) Other case reports document similar interactions between dihydroergotamine and erythromycin(15-19), troleandomycin(16-19), and ponsinomycin(20). One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.	CLARITHROMYCIN, CLARITHROMYCIN ER, E.E.S. 200, E.E.S. 400, ERY-TAB, ERYPED 200, ERYPED 400, ERYTHROCIN LACTOBIONATE, ERYTHROCIN STEARATE, ERYTHROMYCIN, ERYTHROMYCIN ESTOLATE, ERYTHROMYCIN ETHYLSUCCINATE, ERYTHROMYCIN LACTOBIONATE, LANSOPRAZOL-AMOXICIL-CLARITHRO, OMECLAMOX-PAK, VOQUEZNA TRIPLE PAK
Protease Inhibitors/Ergot Alkaloids SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: The protease inhibitors may inhibit the metabolism of the ergot alkaloids by CYP3A4, including dihydroergotamine, ergotamine, ergonovine, and methylergonovine. (1-13) CLINICAL EFFECTS: The concurrent administration of a protease inhibitor with an ergot alkaloid may result in elevated levels, clinical effects, and adverse effects of the ergot alkaloids.(1-13) Signs of ergotism may include peripheral vasospasm and ischemia. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The concurrent administration of ergot alkaloids with amprenavir,(1) atazanavir,(2,3) darunavir,(4) fosamprenavir,(5) indinavir, (6) the combination of lopinavir and ritonavir,(7) nelfinavir,(8) nirmatrelvir coadministered with ritonavir,(25) ritonavir, (12) saquinavir,(9,10) and tipranavir coadministered with ritonavir(11) is contraindicated. The US manufacturer of methylergonovine states that methylergonovine should not be administered with potent CYP3A4 inhibitors such as protease inhibitors.(13) Protease inhibitors linked include: amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, nirmatrelvir, ritonavir, saquinavir, and tipranavir. DISCUSSION: There have been several case reports of ergotism developing in patients receiving concurrent ergotamine derivatives with indinavir,(14) nelfinavir,(15) or ritonavir.(16-23) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.	APTIVUS, ATAZANAVIR SULFATE, DARUNAVIR, EVOTAZ, FOSAMPRENAVIR CALCIUM, KALETRA, LOPINAVIR-RITONAVIR, PAXLOVID, PREZCOBIX, PREZISTA, REYATAZ, SYMTUZA, VIRACEPT
Ergot Alkaloids/Posaconazole; Voriconazole SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Posaconazole(1,2) and voriconazole(3,4) may inhibit the metabolism of the ergot alkaloids by CYP3A4. CLINICAL EFFECTS: The concurrent use of posaconazole(1,2) or voriconazole (3,4) and ergot alkaloids may result in elevated levels of the ergot alkaloids and ergotism. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The UK(1) and US(2) manufacturers of posaconazole state that the concurrent use of ergot alkaloids is contraindicated. The manufacturer of voriconazole states that the concurrent use of voriconazole and ergot alkaloids is contraindicated.(3) The US manufacturer of methylergonovine states that methylergonovine should not be administered with potent CYP3A4 inhibitors such as voriconazole.(4) DISCUSSION: Posaconazole has been shown to inhibit the CYP3A4 mediated metabolism of midazolam by 83%.(1) Voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 8 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of sirolimus (2 mg) by 7-fold and 11-fold, respectively. Ergot alkaloids are metabolized by the same isoenzyme system.(3) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.	NOXAFIL, POSACONAZOLE, VFEND, VFEND IV, VORICONAZOLE
Ergot Alkaloids/Itraconazole; Ketoconazole SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Itraconazole(1,2) and ketoconazole(3-5) may inhibit the metabolism of ergot alkaloids by CYP3A4. CLINICAL EFFECTS: Concurrent use may result in increased levels of ergot alkaloids, which may result in clinical signs of ergotism, including vasospasm, dysesthesia, renal ischemia, and peripheral ischemia. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturers of itraconazole(1) and ketoconazole(5) state that concurrent administration with ergot alkaloids metabolized by CYP3A4 is contraindicated. The US manufacturer of itraconazole also states that concurrent administration of ergot alkaloids is contraindicated during and two weeks after itraconazole treatment.(1) The manufacturers of dihydroergotamine(3) and ergotamine(4) state that the concurrent use of these agents with strong inhibitors of CYP3A4 such as itraconazole, ketoconazole, or levoketoconazole is contraindicated. The US manufacturer of methylergonovine states that methylergonovine should not be administered with potent CYP3A4 inhibitors such as itraconazole, ketoconazole, or levoketoconazole.(2) DISCUSSION: Coadministration of dihydroergotamine(3) and ergotamine(4) with potent inhibitors of CYP3A4 such as clarithromycin, erythromycin, indinavir, nelfinavir, ritonavir, and troleandomycin has resulted in ergotism, characterized by vasospasm and ischemia of the extremities. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.	ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KETOCONAZOLE, SPORANOX, TOLSURA
Selected CYP3A4 Substrates/Mifepristone SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Mifepristone is an inhibitor of CYP3A4 and may increase levels and effects of drugs metabolized by this enzyme.(1) CLINICAL EFFECTS: Lovastatin, simvastatin and CYP3A4 substrates with a narrow therapeutic window such as alprazolam, cyclosporine, dihydroergotamine, ergotamine, pimozide, quinidine, sirolimus, and tacrolimus or CYP3A4 substrates with a high first pass effect such as oral midazolam, sildenafil, and triazolam are particularly susceptible to significant toxicity.(1,2) PREDISPOSING FACTORS: Due to the need for continuous therapy and mifepristone's long half-life of 85 hours(1) which leads to accumulation, patients with endogenous Cushing's syndrome may be at an increased risk for toxicity. With pimozide, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3) PATIENT MANAGEMENT: The US manufacturer of mifepristone for hypercortisolism due to endogenous Cushing's syndrome states use with lovastatin, simvastatin, CYP3A4 substrates with a narrow therapeutic range, or CYP3A4 substrates with a high first pass effect is contraindicated.(1) DISCUSSION: Administration of mifepristone 1200 mg daily for 10 days followed by a single dose of simvastatin 80 mg led to an increase of simvastatin and simvastatin acid (active metabolite) area-under-curve (AUC) of 10.4-fold and 15.7-fold, respectively.	KORLYM, MIFEPREX, MIFEPRISTONE
Ergot Alkaloids/Selected Strong CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the hepatic metabolism of ergot alkaloids.(1-4) CLINICAL EFFECTS: Concurrent use may result in increased levels of ergot alkaloids, which may result in clinical signs of ergotism, including vasospasm, dysesthesia, renal ischemia, and peripheral ischemia. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The concurrent use of dihydroergotamine,(1,2) ergotamine,(2,3) or methylergonovine(2,4) and strong inhibitors of CYP3A4 is contraindicated. It would be prudent to avoid the concurrent use of all ergot alkaloids and strong inhibitors of CYP3A4. Patients receiving concurrent therapy should be monitored for clinical signs of ergotism. One or both agents may need to be discontinued. Patients should be treated symptomatically for ergotism. DISCUSSION: Case reports have documented clinical signs of ergotism following concomitant therapy with various ergot alkaloids and strong inhibitors of CYP3A4 such as clarithromycin, erythromycin, indinavir, nelfinavir, ritonavir, and troleandomycin. Selected strong CYP3A4 inhibitors linked include: adagrasib, ceritinib, cobicistat, grapefruit, idelalisib, josamycin, levoketoconazole, lonafarnib, mibefradil, nefazodone, ribociclib, and tucatinib.	GENVOYA, KISQALI, KRAZATI, NEFAZODONE HCL, RECORLEV, STRIBILD, TUKYSA, TYBOST, ZOKINVY, ZYDELIG, ZYKADIA
Ergot Alkaloids/Letermovir SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Letermovir, a moderate inhibitor of CYP3A4, may inhibit the hepatic metabolism of ergot alkaloids.(1) CLINICAL EFFECTS: Concurrent use may result in increased levels of the ergot alkaloid, which may result in clinical signs of ergotism, including vasospasm, dysesthesia, renal ischemia, and peripheral ischemia. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The concurrent use of ergotamine derivatives and letermovir is contraindicated.(1) It would be prudent to avoid the concurrent use of all ergot alkaloids and letermovir. Patients receiving concurrent therapy should be monitored for clinical signs of ergotism. One or both agents may need to be discontinued. Patients should be treated symptomatically for ergotism. DISCUSSION: Letermovir is a moderate inhibitor of CYP3A4. In a study, concurrent administration of letermovir (240 mg once daily) increased the area-under-the curve (AUC), and C24hr of midazolam (1 mg single dose intravenous, a CYP3A4 substrate) by 1.47-fold and 2.74-fold.(1)	PREVYMIS

Drug contraindication overview.

Known or suspected ischemic heart disease (e.g., angina pectoris, history of myocardial infarction, documented silent ischemia), coronary artery vasospasm (e.g., Prinzmetal's variant angina), uncontrolled hypertension, peripheral arterial disease, sepsis, severe renal or hepatic impairment, or following vascular surgery. Basilar or hemiplegic migraine. Concomitant therapy with peripheral and central vasoconstrictors or potent inhibitors of the cytochrome P-450 (CYP) 3A4 isoenzyme or recent (i.e., 24 hours) therapy with a 5-HT1 receptor agonist (e.g., sumatriptan) or an ergot alkaloid (e.g., ergotamine, methysergide).

(See Drug Interactions.) Known or suspected pregnancy and in nursing women. Known hypersensitivity to ergot alkaloids.

Adverse reaction overview.

Vasospasm, paresthesia, hypertension, dizziness, anxiety, dyspnea, headache, flushing, diarrhea, rash, increased sweating, and pleural and retroperitoneal fibrosis after long-term use of the drug have been reported in patients receiving parenteral dihydroergotamine during postmarketing surveillance. Mild-to-moderate nasal or throat irritation (e.g., congestion, burning sensation, dryness, paresthesia, discharge, epistaxis, pain, soreness) and/or taste disturbances have occurred in 30% of patients receiving intranasal dihydroergotamine in clinical studies. Adverse effects occurring in 4-26% of patients receiving intranasal dihydroergotamine and at an incidence greater than with placebo include rhinitis, application site reactions, dizziness, nausea, and vomiting.

Safety and efficacy of dihydroergotamine not established in children.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None