Ubrelvy (ubrogepant)

Dosage adjustments of ubrogepant are recommended in patients concomitantly receiving moderate or weak cytochrome P-450 (CYP) 3A4 inhibitors or inducers as well as in patients receiving breast cancer resistance protein (BCRP) and/or P-glycoprotein (P-gp) only inhibitors.

Concomitant use of potent CYP3A4 inhibitors or potent CYP3A4 inducers should be avoided during ubrogepant therapy.

Ubrogepant tablets are administered orally without regard to food.

No dosing information is available for this tab.

Ubrogepant is metabolized principally by cytochrome P-450 (CYP) 3A4. In vitro, the drug is a weak inhibitor of CYP isoenzymes 2C8, 2C9, 2D6, and 2C19; monoamine oxidase-A (MAO-A); and UDP-glucuronosyltransferase (UGT) 1A1. This inhibition potential is not expected to be clinically important. Ubrogepant does not inhibit CYP isoenzymes 1A2, 2B6, or 3A4. The drug also does not induce CYP isoenzymes 1A2, 2B6, or 3A4 at clinically relevant concentrations.

In vitro studies indicate that ubrogepant is a substrate of breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp). The drug is a weak substrate of organic anion transporting polypeptide (OATP) 1B1 and 1B3 and organic anion transporter (OAT) 1, but not a substrate of OAT3. Ubrogepant is a weak inhibitor of OATP1B1, OATP1B3, and organic cation transporter (OCT) 2, but does not inhibit P-gp, BCRP, bile salt export pump (BSEP), multidrug resistance-associated protein (MRP) 3 or MRP4, OAT1, OAT3, or sodium taurocholate cotransporting polypeptide (NTCP).

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

Ubrogepant (> 50 Mg)/Moderate 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: Moderate inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in elevated levels of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with moderate CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg. A second dose should be avoided within 24 hours of the first dose when used concurrently with moderate CYP3A4 inhibitors.(1)

DISCUSSION: Co-administration with verapamil, a moderate CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2-4)

Ubrogepant (> 50 Mg)/P-Gp Or Bcrp 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: Inhibitors of P-glycoprotein (P-gp) or BCRP may increase the absorption of ubrogepant.(1)

CLINICAL EFFECTS: The concurrent administration of ubrogepant with an inhibitor of P-glycoprotein or BCRP may result in elevated levels of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when coadministered with P-gp or BCRP inhibitors. The dose of ubrogepant should not exceed 50 mg for initial dose. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(1) For patients on concurrent therapy with vimseltinib and ubrogepant: the manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to ubrogepant.(3) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(4)

DISCUSSION: Ubrogepant is a substrate of P-gp and BCRP transporters. Use of P-gp or BCRP inhibitors may increase the exposure of ubrogepant. Clinical drug interaction studies with inhibitors of these transporters were not conducted. The US manufacturer of ubrogepant recommends dose adjustment if ubrogepant is coadministered with P-gp or BCRP inhibitors.(1) BCRP inhibitors linked to this monograph include: belumosudil, clopidogrel, curcumin, eltrombopag, febuxostat, fostemsavir, leniolisib, momelotinib, oteseconazole, regorafenib, resmetirom, ritonavir, rolapitant, roxadustat, tafamidis, oral tedizolid, turmeric, vadadustat, and zongertinib.(2,3,5) P-glycoprotein inhibitors linked to this monograph include: asunaprevir, belumosudil, capmatinib, carvedilol, danicopan, daraxonrasib, daridorexant, imlunestrant, neratinib, osimertinib, propafenone, quinidine, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, valbenazine, vimseltinib, and voclosporin.(2,3,5)

Ubrogepant (> 50 Mg)/Weak 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: Weak inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of ubrogepant with weak CYP3A4 inhibitors may result in an increase in exposure of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with weak CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg when used concomitantly with weak inhibitors of CYP3A4. A second dose may be given within 24 hours but should not exceed 50 mg when used concurrently with weak CYP3A4 inhibitors.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Coadministration of ubrogepant with verapamil, a moderate CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively. No dedicated drug interaction study was conducted to assess concomitant use with weak CYP3A4 inhibitors. The conservative prediction of the maximal potential increase in ubrogepant exposure with weak CYP3A4 inhibitors is not expected to be more than 2-fold.(1) Weak inhibitors of CYP3A4 include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, delavirdine, deutivacaftor, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, pirtobrutinib, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib. (3,4)

Ubrogepant/Strong Cyp3a4 Inducers

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 inducers of CYP3A4 may induce the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inducer may result in decreased levels and effectiveness of ubrogepant.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of ubrogepant states that concurrent use with strong CYP3A4 inducers should be avoided.(1)

DISCUSSION: Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-3)

Ubrogepant/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 metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of ubrogepant with strong CYP3A4 inhibitors may result in a significant increase in exposure of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of ubrogepant states coadministration with strong CYP3A4 inhibitors is contraindicated.(1)

DISCUSSION: Coadministration of ubrogepant with ketoconazole, a strong CYP3A4 inhibitor, resulted in a 9.7-fold and 5.3-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)

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

Selected P-Glycoprotein (P-Gp) Substrates/Venetoclax

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

MECHANISM OF ACTION: Venetoclax is an inhibitor of the P-glycoprotein (P-gp) system and may increase the absorption of P-gp substrates.(1)

CLINICAL EFFECTS: Concurrent use of venetoclax with P-gp substrates may result in elevated levels and toxicities of the substrate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of venetoclax states that the concurrent use of P-gp substrates should be avoided. If concurrent therapy cannot be avoided, the P-gp substrate should be taken at least 6 hours before venetoclax.(1) If concurrent therapy with afatinib is unavoidable and not tolerated, the US manufacturer of afatinib states that the afatinib dose should be reduced by 10 mg. Resume the previous dose of afatinib if venetoclax is discontinued.(2) The manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant when coadministered with P-gp inhibitors. The initial dose of ubrogepant should not exceed 50 mg. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(8)

DISCUSSION: In vitro data suggests venetoclax is a P-gp inhibitor at therapeutic doses in the gut.(1) Administration of a single venetoclax 100 mg dose with digoxin increased the maximum concentration (Cmax) and area-under-the-curve of digoxin by 35% and 9%, respectively.(1) Selected P-gp substrates linked to this monograph include: afatinib, aliskiren, betrixaban, bilastine, cyclosporine, dabigatran, digoxin, edoxaban, everolimus, loperamide, sirolimus, talazoparib, topotecan, and ubrogepant.(1-9)

Ubrogepant/Aumolertinib

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

MECHANISM OF ACTION: Aumolertinib is a weak CYP3A4 inducer and a BCRP inhibitor.(1) Ubrogepant is a CYP3A4 and BCRP substrate.(2,3) Aumolertinib may induce the metabolism and increase the absorption of ubrogepant.(1,2)

CLINICAL EFFECTS: The net effect of this interaction is unknown. Concurrent use of weak CYP3A4 inducers with ubrogepant may result in decreased levels and effectiveness of ubrogepant while concurrent use of agents that inhibit BCRP may result in elevated levels and side effects from ubrogepant.(1,2)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of aumolertinib states avoid coadministration with drugs that are sensitive substrates of CYP3A4 such as ubrogepant. It also states that coadministration with drugs that are sensitive BCRP substrates should be avoided. If coadministration cannot be avoided, dose adjustment of ubrogepant should be considered.(1,3) The manufacturer of ubrogepant does not have recommendations for concurrent use with agents that are both weak CYP3A4 inducers and BCRP inhibitors.(2) If coadministration with weak CYP3A4 inducers cannot be avoided, the manufacturer of ubrogepant recommends a dose adjustment of ubrogepant.(1) The dose of ubrogepant should not exceed 100 mg for initial dose. A second dose of ubrogepant should not exceed 100 mg and may be taken at least 2 hours after the initial dose if needed.(1) If coadministration with BCRP inhibitors cannot be avoided, the manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant. The dose of ubrogepant should not exceed 50 mg for initial dose. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(1)

DISCUSSION: Ubrogepant is a substrate of CYP3A4 and the BCRP transporter.(2,3) The impact of weak CYP3A4 inducers on the pharmacokinetics of ubrogepant has not been investigated in clinical studies. Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure.(2) Coadministration of aumolertinib with midazolam (a sensitive CYP3A4 substrate) decreased the area-under-the-curve (AUC) by 27% in a clinical study.(1) Use of BCRP inhibitors may increase the exposure of ubrogepant. Clinical drug interaction studies with inhibitors of this transporter were not conducted.(2)

Ubrogepant/Darolutamide

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

MECHANISM OF ACTION: Ubrogepant is a CYP3A4 and BCRP substrate.(1) Darolutamide is a weak CYP3A4 inducer and BCRP inhibitor.(2)

CLINICAL EFFECTS: Concurrent use of ubrogepant with darolutamide may lead to increased or decreased levels and effectiveness of ubrogepant.(1) The net effect of darolutamide on ubrogepant is unknown.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of ubrogepant does not have recommendations for concurrent use with agents that are both weak CYP3A4 inducers and BCRP inhibitors. Concurrent use should be avoided.(1) For concurrent use of ubrogepant with weak CYP3A4 inducers: The manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant. Initial dose of ubrogepant should be 100 mg. If a second dose is needed, the the dose of ubrogepant should be 100 mg.(1) For concurrent use of ubrogepant with BCRP inhibitors: The manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant. The dose of ubrogepant should not exceed 50 mg for initial dose. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(1) For concurrent use of darolutamide with BCRP substrates: The manufacturer of darolutamide states that concurrent use of BCRP substrates should be avoided. If concurrent use cannot be avoided, monitor for adverse events more frequently and consider dose reduction of the BCRP substrate.(2)

DISCUSSION: Ubrogepant is a substrate of CYP3A4 and the BCRP transporter.(1) Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure. No dedicated drug interaction studies were conducted to assess concomitant use with moderate or weak CYP3A4 inducers. Dose adjustment for concomitant use of ubrogepant with moderate or weak CYP3A4 inducers is recommended based on a conservative prediction of 50% reduction in exposure of ubrogepant.(1) Use of P-gp or BCRP inhibitors may increase the exposure of ubrogepant. Clinical drug interaction studies with inhibitors of these transporters were not conducted. The US manufacturer of ubrogepant recommends dose adjustment if ubrogepant is coadministered with P-gp or BCRP inhibitors.(1)

Ubrogepant/Enasidenib

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

MECHANISM OF ACTION: Ubrogepant is a CYP3A4 and BCRP substrate.(1) Enasidenib is a weak CYP3A4 inducer and BCRP inhibitor.(2)

CLINICAL EFFECTS: Concurrent use of ubrogepant with enasidenib may lead to increased or decreased levels and effectiveness of ubrogepant.(1) The net effect of enasidenib on ubrogepant is unknown.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of ubrogepant does not have recommendations for concurrent use with agents that are both weak CYP3A4 inducers and BCRP inhibitors. Concurrent use should be avoided.(1) For concurrent use of ubrogepant with weak CYP3A4 inducers: The manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant. Initial dose of ubrogepant should be 100 mg. If a second dose is needed, the the dose of ubrogepant should be 100 mg.(1) For concurrent use of ubrogepant with BCRP inhibitors: The manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant. The dose of ubrogepant should not exceed 50 mg for initial dose. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(1) For concurrent use of enasidenib with BCRP substrates: The manufacturer of enasidenib states that concurrent use of BCRP substrates should be avoided. If concurrent use cannot be avoided, monitor for adverse events more frequently and consider dose reduction of the BCRP substrate.(2)

DISCUSSION: Ubrogepant is a substrate of CYP3A4 and the BCRP transporter.(1) Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure. No dedicated drug interaction studies were conducted to assess concomitant use with moderate or weak CYP3A4 inducers. Dose adjustment for concomitant use of ubrogepant with moderate or weak CYP3A4 inducers is recommended based on a conservative prediction of 50% reduction in exposure of ubrogepant.(1) Use of P-gp or BCRP inhibitors may increase the exposure of ubrogepant. Clinical drug interaction studies with inhibitors of these transporters were not conducted. The US manufacturer of ubrogepant recommends dose adjustment if ubrogepant is coadministered with P-gp or BCRP inhibitors.(1)

Ubrogepant/Encorafenib

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

MECHANISM OF ACTION: Encorafenib is a strong CYP3A4 inducer and a BCRP inhibitor.(1) Ubrogepant is a CYP3A4 and BCRP substrate.(2) Encorafenib may induce the metabolism and increase the absorption of ubrogepant.(1,2)

CLINICAL EFFECTS: The net effect of this interaction is unknown. Concurrent use of strong CYP3A4 inducers with ubrogepant may result in decreased levels and effectiveness of ubrogepant while concurrent use of agents that inhibit BCRP may result in elevated levels and side effects from ubrogepant.(2)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of ubrogepant does not have recommendations for concurrent use with agents that are both strong CYP3A4 inducers and BCRP inhibitors. Concurrent use should be avoided.(2) For concurrent use of ubrogepant with strong CYP3A4 inducers, the manufacturer of ubrogepant states that concurrent use should be avoided.(2) For concurrent use of ubrogepant with BCRP inhibitors, the manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant. The dose of ubrogepant should not exceed 50 mg for initial dose. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(2)

DISCUSSION: Ubrogepant is a substrate of CYP3A4 and the BCRP transporter.(2) Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure.(2) Use of P-gp or BCRP inhibitors may increase the exposure of ubrogepant. Clinical drug interaction studies with inhibitors of these transporters were not conducted. The US manufacturer of ubrogepant recommends dose adjustment if ubrogepant is coadministered with P-gp or BCRP inhibitors.(2)

Ubrogepant/Ginkgo Biloba

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

MECHANISM OF ACTION: Ubrogepant is a CYP3A4 substrate.(1) Ginkgo biloba is both a weak CYP3A4 inhibitor and inducer.(2,3)

CLINICAL EFFECTS: Concurrent use of ubrogepant with ginkgo biloba may lead to increased or decreased levels and effectiveness of ubrogepant.(1) The net effect of ginkgo biloba on ubrogepant is unknown.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of ubrogepant does not have recommendations for concurrent use with agents that are both weak CYP3A4 inducers and inhibitors. Concurrent use should be avoided.(1) For concurrent use with weak CYP3A4 inhibitors: The manufacturer recommends a dosage adjustment of ubrogepant. Initial dose of ubrogepant should not exceed 50 mg when used concomitantly with weak inhibitors of CYP3A4. A second dose may be given within 24 hours but should not exceed 50 mg when used concurrently with weak CYP3A4 inhibitors.(1) For concurrent use with moderate or weak CYP3A4 inducers: The manufacturer recommends a dosage adjustment of ubrogepant. Initial dose of ubrogepant should be 100 mg. If a second dose is needed, the the dose of ubrogepant should be 100 mg.(1)

DISCUSSION: Coadministration of ubrogepant with verapamil, a moderate CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively. No dedicated drug interaction study was conducted to assess concomitant use with weak CYP3A4 inhibitors. The conservative prediction of the maximal potential increase in ubrogepant exposure with weak CYP3A4 inhibitors is not expected to be more than 2-fold.(1) Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure. No dedicated drug interaction studies were conducted to assess concomitant use with moderate or weak CYP3A4 inducers. Dose adjustment for concomitant use of ubrogepant with moderate or weak CYP3A4 inducers is recommended based on a conservative prediction of 50% reduction in exposure of ubrogepant.(1)

Ubrogepant/Sotorasib

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

MECHANISM OF ACTION: Ubrogepant is a CYP3A4 and P-gp substrate.(1) Sotorasib is a moderate CYP3A4 inducer and a P-glycoprotein (P-gp) inhibitor.(2,3)

CLINICAL EFFECTS: Concurrent use of ubrogepant with sotorasib may lead to increased or decreased levels and effectiveness of ubrogepant.(1) The net effect of sotorasib on ubrogepant is unknown.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of ubrogepant does not have recommendations for concurrent use with agents that are both moderate CYP3A4 inducers and P-gp inhibitors. Concurrent use should be avoided.(1) For concurrent use of ubrogepant with moderate CYP3A4 inducers: The manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant. Initial dose of ubrogepant should be 100 mg. If a second dose is needed, the dose of ubrogepant should be 100 mg.(1) For concurrent use of ubrogepant with P-gp inhibitors: The manufacturer recommends a dosage adjustment of ubrogepant. The dose of ubrogepant should not exceed 50 mg for initial dose. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(1) For concurrent use of sotorasib with P-gp substrates: The US manufacturer of sotorasib states that the concurrent use of narrow therapeutic index P-gp substrates should be avoided. If concurrent therapy cannot be avoided, the dosage of the narrow therapeutic index P-gp substrate should be decreased according to the substrate prescribing information.(2)

DISCUSSION: Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure. No dedicated drug interaction studies were conducted to assess concomitant use with moderate or weak CYP3A4 inducers. Dose adjustment for concomitant use of ubrogepant with moderate or weak CYP3A4 inducers is recommended based on a conservative prediction of 50% reduction in exposure of ubrogepant.(1) In a study, sotorasib increased digoxin's area-under-curve (AUC) by 21% and maximum concentration (Cmax) by 91%.(2)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Ubrogepant (<= 50 Mg)/Moderate Cyp3a4 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in elevated levels of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with moderate CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg. A second dose should be avoided within 24 hours of the first dose when used concurrently with moderate CYP3A4 inhibitors.(1)

DISCUSSION: Co-administration with verapamil, a moderate CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2-4)

Ubrogepant (<= 50 Mg)/P-Gp Or Bcrp Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of P-glycoprotein (P-gp) or BCRP may increase the absorption of ubrogepant.(1)

CLINICAL EFFECTS: The concurrent administration of ubrogepant with an inhibitor of P-glycoprotein or BCRP may result in elevated levels of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when coadministered with P-gp or BCRP inhibitors. The dose of ubrogepant should not exceed 50 mg for initial dose. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(1) For patients on concurrent therapy with vimseltinib and ubrogepant: The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to ubrogepant.(3) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(4)

DISCUSSION: Ubrogepant is a substrate of P-gp and BCRP transporters. Use of P-gp or BCRP inhibitors may increase the exposure of ubrogepant. Clinical drug interaction studies with inhibitors of these transporters were not conducted. The US manufacturer of ubrogepant recommends dose adjustment if ubrogepant is coadministered with P-gp or BCRP inhibitors.(1) BCRP inhibitors linked to this monograph include: belumosudil, clopidogrel, curcumin, eltrombopag, febuxostat, fostemsavir, leniolisib, momelotinib, oteseconazole, regorafenib, resmetirom, ritonavir, rolapitant, roxadustat, tafamidis, oral tedizolid, turmeric, vadadustat, and zongertinib.(2,3,5,6) P-glycoprotein inhibitors linked to this monograph include: asunaprevir, belumosudil, capmatinib, carvedilol, danicopan, daraxonrasib, daridorexant, imlunestrant, neratinib, osimertinib, propafenone, quinidine, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, valbenazine, vimseltinib, and voclosporin.(2,3,5,6)

Ubrogepant (<= 50 Mg)/Weak Cyp3a4 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of ubrogepant with weak CYP3A4 inhibitors may result in an increase in exposure of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with weak CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg when used concomitantly with weak inhibitors of CYP3A4. A second dose may be given within 24 hours but should not exceed 50 mg when used concurrently with weak CYP3A4 inhibitors.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Coadministration of ubrogepant with verapamil, a moderate CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively. No dedicated drug interaction study was conducted to assess concomitant use with weak CYP3A4 inhibitors. The conservative prediction of the maximal potential increase in ubrogepant exposure with weak CYP3A4 inhibitors is not expected to be more than 2-fold.(1) Weak inhibitors of CYP3A4 include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, delavirdine, deutivacaftor, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, pirtobrutinib, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib.(3,4)

Ubrogepant/Moderate And Weak Cyp3a4 Inducers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate or weak CYP3A4 inducers may induce the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of ubrogepant.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when coadministered with moderate or weak CYP3A4 inducers. Initial dose of ubrogepant should be 100 mg. If a second dose is needed, the dose of ubrogepant should be 100 mg.(1)

DISCUSSION: Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure. No dedicated drug interaction studies were conducted to assess concomitant use with moderate or weak CYP3A4 inducers. Dose adjustment for concomitant use of ubrogepant with moderate or weak CYP3A4 inducers is recommended based on a conservative prediction of 50% reduction in exposure of ubrogepant.(1) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, dexamethasone, dicloxacillin, echinacea, elafibranor, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, relugolix, repotrectinib, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)

Ubrogepant/Pacritinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Pacritinib is a moderate CYP3A4 inducer and a BCRP inhibitor.(1) Ubrogepant is a CYP3A4 and BCRP substrate.(2,3) Pacritinib may induce the metabolism and increase the absorption of ubrogepant.(1,2)

CLINICAL EFFECTS: The net effect of this interaction is unknown. Concurrent use of moderate CYP3A4 inducers with ubrogepant may result in decreased levels and effectiveness of ubrogepant while concurrent use of agents that inhibit BCRP may result in elevated levels and side effects from ubrogepant.(1,2)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The effect of CYP3A4 induction and BCRP inhibition on ubrogepant is unknown. The optimal dose of ubrogepant when used concurrently with pacritinib has not been determined. Without guidance on managing these opposing effects, concurrent use cannot be recommended. Dose modifications mentioned below are informational only. The manufacturer of pacritinib states CYP3A4 and BCRP substrates should be monitored and dose adjusted when used concurrently.(1) The manufacturer of ubrogepant does not have recommendations for concurrent use with agents that are both moderate CYP3A4 inducers and BCRP inhibitors.(2) If coadministration with moderate CYP3A4 inducers cannot be avoided, the manufacturer of ubrogepant recommends a dose adjustment of ubrogepant.(2) The dose of ubrogepant should not exceed 100 mg for initial dose. A second dose of ubrogepant should not exceed 100 mg and may be taken at least 2 hours after the initial dose if needed.(2) If coadministration with BCRP inhibitors cannot be avoided, the manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant. The dose of ubrogepant should not exceed 50 mg for initial dose. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(2)

DISCUSSION: Ubrogepant is a substrate of CYP3A4 and the BCRP transporter.(2,3) Pacritinib is a moderate CYP3A4 inducer and BCRP inhibitor.(1,3) Coadministration of pacritinib (200 mg twice daily at steady state) with a single dose of oral midazolam (2 mg) (a CYP3A4 substrate) decreased the concentration maximum (Cmax) and area-under-curve (AUC) of midazolam by 60% and 60%, respectively.(1) Coadministration of rosuvastatin 5 mg (BCRP substrate) with pacritinib 200 mg twice daily resulted in a 2-fold and 1.8-fold increase in rosuvastatin Cmax and AUC, respectively.(1) The impact of moderate CYP3A4 inducers on the pharmacokinetics of ubrogepant has not been investigated in clinical studies. Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure.(2) Use of P-gp or BCRP inhibitors may increase the exposure of ubrogepant. Clinical drug interaction studies with inhibitors of these transporters were not conducted.(2)

*Concomitant use of potent cytochrome P-450 (CYP) 3A4 inhibitors.

*History of serious hypersensitivity to ubrogepant or any of its components.

There are no contraindication contraindications for this drug.

• Child-pugh class C hepatic impairment
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Disease of liver

• Hypertension
• Raynaud's phenomenon

Adverse reactions reported in 2% or more of patients receiving ubrogepant for acute treatment of migraine in controlled clinical studies and more frequently than with placebo include nausea, somnolence (including sedation and fatigue), and dry mouth.

Rare or Very Rare

• Anaphylaxis

More Frequent

• Drowsy
• Nausea

Less Frequent

• Xerostomia

Rare or Very Rare

• Hypersensitivity drug reaction
• Hypertension
• Raynaud's phenomenon

No enhanced messaging available.

Safety and efficacy of ubrogepant have not been established in pediatric patients.

There are no adequate data to date on the developmental risk associated with the use of ubrogepant in pregnant women. Based on animal studies, ubrogepant may cause fetal harm. In animal studies, adverse effects on embryofetal development were observed following administration of the drug during pregnancy (increased embryofetal mortality in rabbits) or during pregnancy and lactation (decreased body weight in offspring in rats) at dosages that were associated with maternal toxicity in the animals and were higher than those used clinically.

The estimated rates of major birth defects and miscarriage among deliveries to women with migraine (2.2-2.9 and 17%, respectively) are similar to rates reported in women without migraine. Clinicians should be aware that published data suggest that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy.

A registry that monitors outcomes in pregnant women exposed to ubrogepant is available. Patients may enroll in the registry by calling 833-277-0206 or visiting https://empresspregnancyregistry.com.

It is not known whether ubrogepant is distributed into human milk; the drug is distributed into milk in rats in concentrations comparable to peak plasma concentrations. The effects of ubrogepant on the breast-fed infant and on milk production also are unknown.

The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for ubrogepant and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

Although routine dosage adjustment does not appear to be necessary in geriatric patients, the manufacturer states that dosage selection should generally be cautious, usually starting at the lower end of the dosage range.

Clinical studies of ubrogepant did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger adults. In pharmacokinetic studies, no clinically important differences in the pharmacokinetics of ubrogepant were observed between geriatric individuals and younger adults. The manufacturer states that, in general, dosage selection for geriatric patients should be cautious and start at the low end of the dosage range.