Dihydroergotamine Mesylate (dihydroergotamine mesylate)

Available as dihydroergotamine mesylate; dosage expressed in terms of the salt.

Administer dihydroergotamine intranasally or by IM, IV, or subcutaneous injection for acute treatment of migraine. Administer by direct IV injection or continuous IV infusion+ for the acute treatment of intractable migraines in an inpatient setting.

Administer dihydroergotamine by IM, IV, or subcutaneous injection for acute treatment of cluster headaches.

If the drug is being self-administered, the patient should be counseled on proper use and administration technique.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Dihydroergotamine/Sympathomimetics

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: Concurrent use of dihydroergotamine and sympathomimetics may result in additive or synergistic effect on peripheral blood vessels.(1)

CLINICAL EFFECTS: Concurrent use of dihydroergotamine and sympathomimetics may result in increased blood pressure due to peripheral vasoconstriction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Dihydroergotamine is contraindicated with sympathomimetics because the combination may result in additive or synergistic elevation of blood pressure.(1)

DISCUSSION: Significant elevation in blood pressure has been reported in patients treated with dihydroergotamine.(1) Sympathomimetics can be expected to have additional effects on blood pressure.

Ergot Alkaloids/5-Ht1d Agonists

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)

Ergot Alkaloids/Boceprevir; Telaprevir

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: Boceprevir(1) and telaprevir(2) may inhibit the metabolism of ergot alkaloids by CYP3A4.

CLINICAL EFFECTS: Concurrent use of boceprevir(1) or telaprevir(2) may result in elevated levels of and effects from ergot alkaloids, including peripheral vasospasm and ischemia.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of boceprevir(1) and telaprevir(2) state that concurrent use of ergot alkaloids, including dihydroergotamine, ergonovine, ergotamine, and methylergonovine, is contraindicated.

DISCUSSION: Boceprevir has been shown to be a strong inhibitor of CYP3A4.(1) Telaprevir has also been shown to inhibit CYP3A4.(2) Therefore, concurrent use of boceprevir(1) or telaprevir(2) with agents that are highly dependent on CYP3A4 for clearance and for which elevated plasma levels are associated with serious and/or life-threatening events is contraindicated.

Ergot Alkaloids/Delavirdine

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: Delavirdine may inhibit the metabolism of the ergot alkaloids by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent administration with delavirdine may result in increased levels, clinical effects, and possible toxicity of the ergot alkaloids.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of delavirdine states that the concurrent use of ergot alkaloids is contraindicated.(1) The US manufacturer of methylergonovine states that methylergonovine should not be administered with potent CYP3A4 inhibitors such as delavirdine.(2)

DISCUSSION: Delavirdine has been shown to inhibit CYP3A4. Concurrent use of delavirdine with agents that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events, such as the ergot alkaloids, is contraindicated.(1)

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.

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)

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.

Ergot Alkaloids/Protease 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: 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, ensitrelvir, 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.

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.

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, relacorilant, ribociclib, and tucatinib.

Ergot Alkaloids/Telithromycin

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: Telithromycin may inhibit the metabolism of the ergot alkaloids at CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use of telithromycin and an ergot alkaloid may result in ergotism (severe vasoconstriction) with possible necrosis of the extremities.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK manufacturer of telithromycin states that the concurrent use of telithromycin and ergot alkaloids is contraindicated.(1) The US manufacturer of telithromycin states that concurrent use is not recommended.(2)

DISCUSSION: Concurrent administration of macrolides such as erythromycin and josamycin with ergot alkaloids has resulted in severe vasoconstriction and necrosis of the extremities. Telithromycin is a potent inhibitor of CYP3A4.(1,2) 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.(3)

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.

Serotonergic Agents/Sibutramine

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: Concurrent administration may result in additive effects on serotonin, resulting in serotonin syndrome.

CLINICAL EFFECTS: Concurrent use of sibutramine and agents which effect serotonin may result in serotonin syndrome, a serious and potentially fatal reaction. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity. (1-5)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Sibutramine has been removed from the market by the European Medicines Agency and by regulatory agencies in a number of countries including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and the United States. The Canadian manufacturer of sibutramine formerly stated that concurrent use with antidepressants or serotonergic agents is contraindicated. At least 14 days should elapse between discontinuation of these agents and initiation of sibutramine. Five weeks is required following the discontinuation of fluoxetine.(1) The Australian(2) and UK(3) manufacturers of sibutramine stated that sibutramine is contraindicated within 2 weeks of antidepressant use and should not be used with other serotonergic agents. The US manufacturer of sibutramine stated that in general, sibutramine should not be administered with other serotonergic agents such as the selective serotonin reuptake inhibitors, sumatriptan or dihydroergotamine. However, if concurrent administration is clinically indicated, the patient should be appropriately observed.(4) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. Patients in whom serotonin syndrome is suspected should receive immediate medical attention.

DISCUSSION: Sibutramine has been removed from the market by the European Medicines Agency and by regulatory agencies in a number of countries including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and the United States. Sibutramine inhibits serotonin reuptake and serotonin syndrome has been reported during concomitant use of selective serotonin reuptake inhibitors and other selective serotonin reuptake inhibitors, sumatriptan, and dihydroergotamine(1-4)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Ergot Alkaloids/Moderate Cyp3a4 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of ergot alkaloids.

CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor 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: Patients receiving the maximum recommended (or higher than recommended) dosages of ergot alkaloids may be at a higher risk of adverse effects from this combination.

PATIENT MANAGEMENT: When possible, avoid the concurrent use of moderate CYP3A4 inhibitors in patients taking ergot alkaloids. If concurrent use is warranted, consider reducing the dose of the ergot alkaloid during concurrent therapy. Patients receiving concurrent therapy should be monitored for and instructed to report any signs of ergotism.

DISCUSSION: Coadministration of dihydroergotamine and ergotamine 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. Inhibition of ergot alkaloid metabolism by moderate inhibitors would also be expected, but to a lesser degree. Moderate CYP3A4 inhibitors linked to this monograph are aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, tofisopam, treosulfan and verapamil.

Ergot Alkaloids/Nitrates

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Decreased first-pass metabolism of ergot alkaloids. Ergot alkaloids may precipitate angina pectoris.

CLINICAL EFFECTS: Increased standing systolic blood pressure and angina attacks may occur.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid administration of ergot alkaloids to patients receiving nitroglycerin for angina. When it is necessary to give this combination, monitor the patient for increased effects of the ergot alkaloid. Reduce the dose of ergot alkaloid as necessary.

DISCUSSION: Dihydroergotamine has been reported to precipitate angina pectoris. Nitroglycerin administration to patients receiving dihydroergotamine increased the plasma dihydroergotamine level and area under the plasma concentration-time curve. An increase in the mean standing systolic blood pressure was measured.

Ergot Alkaloids/Stiripentol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Stiripentol may inhibit the metabolism of ergot alkaloids by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of stiripentol may result in elevated levels of ergot alkaloids, which may result in ergotism with the possibility of necrosis of the extremities.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK manufacturer of stiripentol states that concurrent use of ergot alkaloids should be avoided unless strictly necessary.(1)

DISCUSSION: Stiripentol has been shown to inhibit CYP3A4. In a pediatric study, concurrent administration of stiripentol and clobazam (a CYP3A4 substrate) increased clobazam plasma levels by approximately 2- to 3-fold.(1)

Selected Sensitive Cyp3a4 Substrates/Voxelotor

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Voxelotor is an inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme.

CLINICAL EFFECTS: Concurrent use of voxelotor may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: A greater risk for serious adverse events would be expected from drugs having a narrow therapeutic window.

PATIENT MANAGEMENT: The manufacturer of voxelotor states that co-administration of sensitive CYP3A4 substrates with a narrow therapeutic index should be avoided. If concomitant use is unavoidable, consider dose reduction of the sensitive substrate.(1)

DISCUSSION: In a study, voxelotor increased the AUC of a single dose of midazolam by 1.6-fold. After multiple doses of midazolam, a 2.5-fold increase in AUC is predicted.(1) Sensitive CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: avanafil, conivaptan, cyclosporine, dihydroergotamine, eplerenone, ergotamine, everolimus, felodipine, fentanyl, lomitapide, lovastatin, methylergonovine, midazolam, nisoldipine, sildenafil, simvastatin, ticagrelor, tolvaptan, triazolam, and vardenafil.(2,3)

Selected Sensitive Cyp3a4; Cyp2c19 Substrates/Apalutamide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Apalutamide may induce the metabolism of sensitive CYP3A4 or CYP2C19 substrates.(1)

CLINICAL EFFECTS: Concurrent use of apalutamide with drugs primarily metabolized by CYP3A4 or CYP2C19 can result in lower exposure to these medications.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of apalutamide recommends substitution for medications primarily metabolized by CYP3A4 or CYP2C19 when possible or evaluate for loss of activity.(1)

DISCUSSION: Coadministration of apalutamide with single oral doses of sensitive CYP substrates resulted in a 92% decrease in the area-under-curve (AUC) of midazolam (a CYP3A4 substrate) and an 85% decrease in the AUC of omeprazole (a CYP2C19 substrate).(1) Selected sensitive CYP3A4 substrates linked to this monograph: astemizole, dihydroergotamine, ergonovine, ergotamine, and terfenadine. Selected sensitive CYP2C19 substrates linked to this monograph: fosphenytoin, mephenytoin, and phenytoin.(2,3)

Sensitive Cyp3a4; Cyp2c9; Cyp2c19 Substrates/Enzalutamide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Enzalutamide may induce the metabolism of agents metabolized by CYP3A4, CYP2C9, and CYP2C19.(1)

CLINICAL EFFECTS: Concurrent use of enzalutamide with agents metabolized by CYP3A4, CYP2C9, and CYP2C19 may result in decreased levels and effectiveness of these agents.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent use of agents metabolized by CYP3A4, CYP2C9, or CYP2C19 that have a narrow therapeutic index with enzalutamide. If concurrent use is required, consider increased monitoring of the affected agent.(1) Dosage adjustments may be required.

DISCUSSION: In a clinical trial in healthy subjects, enzalutamide was shown to reduce the area-under-curve (AUC) of midazolam (a sensitive CYP3A4 substrate), warfarin (a sensitive CYP2C9 substrate), and omeprazole (a sensitive CYP2C19 substrate.(1) A case report in a 77-year-old Caucasian male was initiated on 160 mg of enzalutamide after being stable on warfarin with an INR of 3.5. The INR dropped to 1.4 after approximately 20 days on enzalutamide therapy. Due to the drop in INR, the warfarin dose was increased by 50% which lead to a therapeutic INR. When enzalutamide was discontinued, the warfarin dose was decreased by 33% to remain at a therapeutic level. Upon reinitiation, the warfarin dose was increased once by 50% to achieve a therapeutic INR.(2) Sensitive CYP3A4 substrates with narrow therapeutic indexes include: astemizole, cisapride, clarithromycin, cyclosporine, dihydroergotamine, ergonovine, ergotamine, pimozide, sirolimus, tacrolimus, temsirolimus, and terfenadine.(1,3,4) Sensitive CYP2C9 substrates with narrow therapeutic indexes include: warfarin.(1,3) Sensitive CYP2C19 substrates with narrow therapeutic indexes include: S-mephenytoin.(1,3)

There are no moderate interactions for this drug.

*Concomitant therapy with strong inhibitors of the cytochrome P-450 (CYP) 3A4 isoenzyme (e.g., clarithromycin, erythromycin, itraconazole, ketoconazole, nelfinavir, ritonavir).

*Known or suspected ischemic heart disease (e.g., angina pectoris, history of myocardial infarction, documented silent ischemia) or clinical symptoms or findings consistent with coronary artery vasospasm (including Prinzmetal's variant angina).

*Uncontrolled hypertension.

*Recent use (i.e., within 24 hours) of a 5-HT1 receptor agonist (e.g., sumatriptan), ergotamine-containing or ergot-type medication or methysergide.

*Basilar or hemiplegic migraine.

*Known peripheral arterial disease, sepsis, severe renal or hepatic impairment, or following vascular surgery.

*Known hypersensitivity to ergot alkaloids. For the dihydroergotamine subcutaneous autoinjector, known hypersensitivity to dihydroergotamine, ergot alkaloids, latex, or any excipients in the formulation.

*Concomitant use of peripheral and central vasoconstrictors.

• Coronary artery disease
• Lactation
• Peripheral vascular disease
• Pregnancy
• Prinzmetal angina
• Sepsis
• Severe uncontrolled hypertension
• Vascular surgery

• Hypertension
• Porphyria

There are no moderate contraindications for this drug.

Adverse effects of dihydroergotamine injection include vasospasm, paresthesia, hypertension, dizziness, anxiety, dyspnea, headache, flushing, diarrhea, rash, increased sweating, and pleural and retroperitoneal fibrosis after long-term use.

The most common adverse effects of dihydroergotamine nasal spray and powder (>1% of patients) include rhinitis, nausea, altered sense of taste, application site reactions, dizziness, vomiting, somnolence, pharyngitis, and diarrhea.

Rare or Very Rare

• Acquired dystonia
• Acute myocardial infarction
• Angina
• Cardiac arrhythmia
• Coronary artery spasm
• Herpes simplex infection
• Hypersensitivity drug reaction
• Myocardial ischemia
• Peripheral ischemia
• Pleural fibrosis
• Pulmonary fibrosis
• Retroperitoneal fibrosis
• Valvular sclerosis

More Frequent

• Diarrhea
• Dizziness
• Drowsy
• Drug-induced hot flash
• Dysgeusia
• Fatigue
• General weakness
• Hyperhidrosis
• Muscle rigidity
• Nasal passage irritation
• Nausea
• Paresthesia
• Pharyngitis
• Rhinitis
• Sinusitis
• Vomiting
• Xerostomia

Rare or Very Rare

• Acute abdominal pain
• Acute cognitive impairment
• Anorexia
• Bronchitis
• Chills
• Clammy skin
• Conjunctivitis
• Cramps
• Depression
• Dyspepsia
• Dysphagia
• Dyspnea
• Earache
• Edema
• Eye tearing
• Fever
• Hypotension
• Insomnia
• Malaise
• Medication overuse headache
• Muscle weakness
• Myalgia
• Nervousness
• Ocular pain
• Orthostatic hypotension
• Palpitations
• Parosmia
• Periorbital edema
• Petechiae
• Photophobia
• Pruritus of skin
• Sensation of cold
• Sialorrhea
• Skin rash
• Symptoms of anxiety
• Tinnitus
• Tremor
• Upper respiratory infection
• Urticaria
• Vaginitis
• Vertigo
• Visual changes
• Yawning

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Safety and efficacy of dihydroergotamine not established in children.

Available data from published literature indicate an increased risk of preterm delivery associated with dihydroergotamine use during pregnancy. Data collected over decades have found no increased risk of major birth defects or miscarriage. In animal reproduction studies, adverse developmental effects were observed in rats and rabbits following intranasal administration of dihydroergotamine during pregnancy (decreased fetal body weight and/or skeletal ossification) and lactation (decreased body weight and impaired reproductive function in offspring) at doses not associated with maternal toxicity. Dihydroergotamine-induced intrauterine growth retardation has been attributed to reduced uteroplacental blood flow resulting from prolonged vasoconstriction of the uterine vessels and/or increased myometrial tone.

Avoid use of dihydroergotamine during pregnancy.

There are no data on the presence of dihydroergotamine in human milk; however, ergotamine is present in human milk. Vomiting, diarrhea, weak pulse, and unstable blood pressure have been reported in breast-fed infants exposed to ergotamine. Ergot alkaloids inhibit prolactin secretion, which may reduce milk supply. Because of the potential for reduced milk supply and serious adverse effects in the breast-fed infant, advise patients not to breast-feed during treatment with dihydroergotamine and for 3 days after the last dose. Breast milk supply during this time should be pumped and discarded.

The manufacturers make no specific dosage recommendations for geriatric patients. In general, dose selection should be cautious, starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Experience with intranasal dihydroergotamine in patients 65 years of age and older is insufficient to determine whether they respond differently than younger adults. In general, dose selection should be cautious, starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.