Emend (Fosaprepitant) (fosaprepitant dimeglumine)

Dosage of fosaprepitant dimeglumine is expressed in terms of fosaprepitant.

Aprepitant is administered orally as capsules (40 mg, 80 mg, 125 mg) or as a powder for oral suspension (125 mg). Aprepitant is also available for IV administration as an injectable emulsion in single-dose vials containing 32 mg/4.4 mL (7.2 mg/mL) or 130 mg/18 mL (7.2 mg/mL).

Fosaprepitant dimeglumine, a prodrug of aprepitant, is available for IV administration as a lyophilized powder for reconstitution in single-dose vials containing 150 mg of fosaprepitant. Fosaprepitant dimeglumine is also available as a ready-to-use injection solution in single-dose vials containing 150 mg/50 mL (3 mg/mL) of fosaprepitant.

No dosing information is available for this tab.

No dosing information is available for this tab.

Aprepitant is extensively metabolized in the liver to weakly active metabolites, principally by cytochrome P-450 (CYP) isoenzyme 3A4 and to a lesser extent by CYP1A2 and CYP2C19.

Aprepitant is a substrate, a weak to moderate inhibitor (dose-dependent), and an inducer of CYP3A4. When administered as a 3-day regimen (i.e., 125 mg on day 1 followed by 80 mg on days 2 and 3), aprepitant acts as a moderate inhibitor of CYP3A4. When administered as a single 40-mg dose, aprepitant acts as a weak inhibitor and has not been shown to alter the plasma concentrations of concomitant drugs that are primarily metabolized through CYP3A4. Aprepitant is also an inducer of CYP2C9.

Fosaprepitant, a prodrug of aprepitant, is a weak inhibitor of CYP3A4 when given as a single 150-mg dose, and the weak inhibition of CYP3A4 continues for 2 days after single dose administration. Single-dose fosaprepitant does not induce CYP3A4.

Because fosaprepitant is rapidly metabolized to aprepitant in vivo, interactions reported with aprepitant are expected to occur with fosaprepitant.

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

Aprepitant/Astemizole; Terfenadine

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: Aprepitant may inhibit the metabolism of astemizole and terfenadine by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of aprepitant and either astemizole or terfenadine may result in elevated levels of astemizole or terfenadine, which may result in cardiac arrhythmias, including life-threatening torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of aprepitant states that the concurrent use of aprepitant with either astemizole or terfenadine is contraindicated.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Aprepitant is a moderate inhibitor of CYP3A4. Elevated levels of astemizole and terfenadine have been shown to increase the QTc interval, which may result in life-threatening arrhythmias, including torsades de pointes. Therefore, the manufacturer of aprepitant states that the concurrent use of aprepitant and astemizole or terfenadine is contraindicated.(1)

Aprepitant/Cisapride

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: Aprepitant may inhibit the metabolism of cisapride by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of aprepitant and cisapride may result in elevated levels of cisapride, which may result in cardiac arrhythmias, including life-threatening torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of aprepitant states that the concurrent use of aprepitant and cisapride is contraindicated.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Aprepitant is a moderate inhibitor of CYP3A4. Elevated levels of cisapride have been shown to increase the QTc interval, which may result in life-threatening arrhythmias, including torsades de pointes. Therefore, the manufacturer of aprepitant states that the concurrent use of aprepitant and cisapride is contraindicated.(1)

Aprepitant/Pimozide

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: Aprepitant may inhibit the metabolism of pimozide by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of aprepitant and pimozide may result in elevated levels of pimozide, which may result in cardiac arrhythmias, including life-threatening torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increased systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) 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 manufacturer of aprepitant states that the concurrent use of aprepitant and pimozide is contraindicated.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Aprepitant is a moderate inhibitor of CYP3A4. Elevated levels of pimozide have been shown to increase the QTc interval, which may result in life-threatening arrhythmias, including torsades de pointes. Therefore, the manufacturer of aprepitant states that the concurrent use of aprepitant and pimozide is contraindicated.(1)

Weak Cyp3a4 Inhibitors/Lemborexant (> 5 Mg)

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 CYP3A4 may inhibit the metabolism of lemborexant.(1)

CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP3A4 may result in increased levels of and effects from lemborexant, including somnolence, fatigue, CNS depressant effects, daytime impairment, headache, and nightmare or abnormal dreams.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The maximum recommended dose of lemborexant with concurrent use of a weak CYP3A4 inhibitors should not exceed 5 mg per dose.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Lemborexant is a CYP3A4 substrate. In a PKPB model, concurrent use of lemborexant with itraconazole increased area-under-curve (AUC) and concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively. Concurrent use of lemborexant with fluconazole increased AUC and Cmax by 4.25-fold and 1.75-fold, respectively.(1) Weak inhibitors of CYP3A4 include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib.(1,3)

Weak Cyp3a4 Inhibitors/Ubrogepant (> 50 Mg)

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)

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

Aprepitant/Selected Anticoagulants (Vitamin K Antagonists)

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

MECHANISM OF ACTION: Aprepitant may induce the metabolism of S-warfarin by CYP2C9.(1-3)

CLINICAL EFFECTS: Use of aprepitant in patients maintained on warfarin may result in decreased levels and effectiveness of warfarin 7-10 days after initiation of aprepitant.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of aprepitant recommend careful monitoring of INR values in the 2 week period, particularly at 7-10 days, following initiation of the 3 day course of aprepitant therapy with each chemotherapy cycle.(1-3)

DISCUSSION: In a study in healthy subjects maintained on warfarin, a single 125 mg dose of aprepitant was administered on Day 1, followed by single 80 mg doses on Days 2 and 3. There was no effect on the area-under-curve (AUC) of R-warfarin or S-warfarin on Day 3. However, there was a 34% decrease in S-warfarin AUC and a 14% decrease in INR 5 days after the completion of aprepitant therapy (Day 8).(1-3)

Aprepitant; Fosaprepitant/Steroidal Contraceptives

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

MECHANISM OF ACTION: Aprepitant and fosaprepitant may induce the CYP3A4 mediated metabolism of hormonal contraceptives.(1,2)

CLINICAL EFFECTS: The effectiveness of hormonal contraceptives may be reduced during and for 28 days following aprepitant and fosaprepitant use.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients taking hormonal contraceptives should be instructed to use alternative or back-up methods of contraception while using aprepitant or fosaprepitant and for 1 month after the last dose of aprepitant or fosaprepitant.(1,2) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.

DISCUSSION: The concurrent use of aprepitant (100 mg daily for 14 days) with an oral contraceptive (ethinyl estradiol, 35 mcg and norethindrone, 1 mg) decreased the area-under-curve (AUC) of ethinyl estradiol and norethindrone by 43% and 8%, respectively.(1) In another study, an oral contraceptive (ethinyl estradiol and norethindrone, dosages not stated) was administered on Days 1 through 21. Subjects also received aprepitant (125 mg Day 8, 80 mg daily Days 9 and 10), ondansetron (32 mg Day 8), dexamethasone (12 mg Day 8, 8 mg daily Days 9 through 11). The AUC of ethinyl estradiol decreased by 19% on Day 10 and by as much as 64% on Days 9 through 21. There was no effect on the AUC of norethindrone on Day 10, but there was as much as a 60% decrease in norethindrone minimum concentration (Cmin) during Days 9 through 21.(1) In another study, an oral contraceptive (ethinyl estradiol and norgestimate, dosages not stated) was administered on Days 1 through 21. Subjects also received aprepitant (40 mg Day 8). The AUC of ethinyl estradiol decreased by 4% and 29% on Days 8 and 12, respectively. The AUC of norelgestromin (norgestimate is converted to norelgestromin) increased by 18% on Day 8 and decreased by 10% on Day 12. Trough concentrations of ethinyl estradiol and norelgestromin on Days 8 through 21 were generally lower following aprepitant.(1)

Aprepitant; Netupitant/Carbamazepine

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

MECHANISM OF ACTION: Aprepitant and netupitant are metabolized primarily by CYP3A4. Carbamazepine, a strong inducer of CYP3A4, may increase their metabolism and clearance via CYP3A4.(1,2) Aprepitant and netupitant, inhibitors of CYP3A4, may inhibit the hepatic metabolism of carbamazepine.(3,4)

CLINICAL EFFECTS: Concurrent use with carbamazepine may result in significantly decreased levels and effectiveness of aprepitant and netupitant.(1,2) In addition, serum carbamazepine levels may increase, with subsequent increases in the pharmacological and toxic effects of carbamazepine, including dizziness, ataxia, blurred vision, or SIADH.(3)

PREDISPOSING FACTORS: Simultaneous use of other drugs, i.e. other anticonvulsants, or carbamazepine blood levels already near the toxic range before initiation of a CYP3A4 inhibitor may increase the risk of a severe interaction.

PATIENT MANAGEMENT: The manufacturers of aprepitant and netupitant recommend avoiding strong CYP3A4 inducers.(1,2) Patients treated concurrently with carbamazepine should be monitored for decreased antiemetic efficacy. When possible and clinically appropriate, consider use of an alternative antiemetic or alternatives to carbamazepine. The manufacturer of carbamazepine states CYP3A4 inhibitors may increase plasma carbamazepine levels. If concurrent use is warranted, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.(3) In patients receiving concurrent therapy with carbamazepine and a CYP3A4 inhibitor, carbamazepine levels should be monitored closely and the patient observed for signs of toxicity (dizziness, ataxia, blurred vision, or SIADH). The dosage of carbamazepine may need to be adjusted or carbamazepine may need to be discontinued.(3)

DISCUSSION: Rifampin (600 mg daily) decreased the area-under-curve (AUC) and half-life of aprepitant (375 mg single dose) by 11-fold and 3-fold, respectively.(1) Rifampin (600 mg daily for 17 days) decreased the mean maximum concentration (Cmax) and AUC of netupitant by 62% and 82% respectively.(2) Carbamazepine is almost completely metabolized to carbamazepine-10,11-epoxide, with only 5% of the drug excreted unchanged. Pharmacokinetics studies have indicated the major pathway for carbamazepine metabolism is catalyzed by CYP3A4, with minor contributions from CYP2C8 and CYP3A5.(3,4)

Aprepitant; Netupitant/Selected Strong Cyp3a4 Inducers

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

MECHANISM OF ACTION: Aprepitant and netupitant are metabolized primarily by CYP3A4. Strong inducers of CYP3A4 may increase their metabolism and clearance via CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use with strong inducers of CYP3A4 may result in significantly decreased levels and effectiveness of aprepitant and netupitant.(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 aprepitant recommends avoiding concurrent use with strong CYP3A4 inducers.(1) The manufacturer of netupitant recommends avoiding use of netupitant in patients who are chronically using strong CYP3A4 inducers.(2) Patients treated concurrently with a strong CYP3A4 inducer should be monitored for decreased antiemetic efficacy. When possible and clinically appropriate, consider use of an alternative antiemetic or alternatives to the strong CYP3A4 inducer.

DISCUSSION: Rifampin (600 mg daily) decreased the area-under-curve (AUC) and half-life of aprepitant (375 mg single dose) by 11-fold and 3-fold, respectively.(1) Rifampin (600 mg daily for 17 days) decreased the mean maximum concentration (Cmax) and AUC of netupitant by 62% and 82% respectively.(2) Strong CYP3A4 inducers linked to this monograph are: apalutamide, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's Wort.(3,4) FDA defines a Strong CYP inducer as an agent which decreases the area-under-curve (AUC) of a Sensitive Substrate by > or = 80 per cent.(3)

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

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

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

Selected Moderate Cyp2c9 Inducers/Siponimod

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

MECHANISM OF ACTION: Drugs that are moderate inducers of CYP2C9 may increase the metabolism of siponimod.(1)

CLINICAL EFFECTS: Concurrent use of a siponimod with a moderate CYP2C9 inducer may result in decreased levels and effectiveness of siponimod.(1)

PREDISPOSING FACTORS: Concurrent use of a strong inducer of CYP3A4 may magnify the effect of the CYP2C9 inducer on siponimod and further decrease the levels of siponimod. Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of siponimod says that the combination of siponimod with a moderate CYP2C9 inducer and a strong CYP3A4 inducer is not recommended.(1)

DISCUSSION: In a study, rifampin (600 mg daily) decreased siponimod area-under-curve (AUC) and maximum concentration (Cmax) by 57 % and 45 %, respectively in CYP2C9 normal metabolizers. Across all CYP2C9 genotypes, rifampin decreased the AUC of siponimod by 78 % in an in silico evaluation.(1) Drugs that are both moderate CYP2C9 inducers linked to this monograph include: aprepitant and ritonavir.(2-3)

Selected Myelosuppressive Agents/Clozapine

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

MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2)

CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal.

PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia.

PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(1-2) Australia, Canada, and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2)

DISCUSSION: Concurrent use of clozapine and selected myelosuppressive agents may require more frequent ANC monitoring or consideration of treatment alternatives secondary to neutropenic episodes. Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26)

Selected Myelosuppressive Agents/Deferiprone

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

MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1)

CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal.

PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2)

PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1)

DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3)

Selected Myelosuppressive Agents/Dipyrone

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

MECHANISM OF ACTION: Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1-29)

CLINICAL EFFECTS: Concurrent use of dipyrone with agents that cause bone marrow depression, including myelosuppressives, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding. Undetected severe neutropenia or agranulocytosis may be fatal.(1-29)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of dipyrone and myelosuppressive agents should be avoided. The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(3) International labeling for dipyrone and methotrexate state that co-administration may increase the hematotoxicity of methotrexate, especially in elderly patients, and therefore should be avoided.(1-2) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(1-3)

DISCUSSION: A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(4) In a review of 1,448 reports of agranulocytosis attributed to dipyrone, patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78).(5) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(2,6-26)

Weak Cyp3a4 Inhibitors/Eliglustat

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

MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of eliglustat. If the patient is also taking an inhibitor of CYP2D6, eliglustat metabolism can be further inhibited.(1)

CLINICAL EFFECTS: Concurrent use of an agent that is a weak inhibitor of CYP3A4 may result in elevated levels of and clinical effects of eliglustat, including prolongation of the PR, QTc, and/or QRS intervals, which may result in life-threatening cardiac arrhythmias.(1)

PREDISPOSING FACTORS: If the patient is also taking an inhibitor of CYP2D6, is a poor metabolizer of CYP2D6, and/or has hepatic impairment, eliglustat metabolism can be further inhibited.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The concurrent use of eliglustat with weak inhibitors of CYP3A4 in poor metabolizers of CYP2D6 should be avoided.(1) The dosage of eliglustat with weak inhibitors of CYP3A4 in extensive metabolizers of CYP2D6 with mild (Child-Pugh Class A) hepatic impairment should be limited to 84 mg daily.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(3)

DISCUSSION: Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4, increased eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve (AUC) by 4-fold and 4.4-fold, respectively, in extensive metabolizers. Physiologically-based pharmacokinetic (PKPB) models suggested ketoconazole would increase eliglustat Cmax and AUC by 4.4-fold and 5.4-fold, respectively, in intermediate metabolizers. PKPB models suggested ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily) by 4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1) PKPB models suggested fluconazole, a moderate inhibitor of CYP3A4, would increase eliglustat Cmax and AUC by 2.8-fold and 3.2-fold, respectively, in extensive metabolizers and by 2.5-fold and 2.9-fold, respectively in intermediate metabolizers. PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 7.5-fold and 9.8-fold, respectively.(1) PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine (a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 4.2-fold and 5-fold, respectively.(1) Weak inhibitors of CYP3A4 include: amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, vonoprazan, and ziftomenib.(4,5)

Weak Cyp3a4 Inhibitors/Lomitapide

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

MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of lomitapide.(1) Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Thus even weak CYP3A4 inhibitors may affect lomitapide exposure (AUC, area-under-curve).

CLINICAL EFFECTS: Concurrent use of a weak inhibitor of CYP3A4 may result in 2-fold increases in lomitapide levels and toxicity from lomitapide.(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment or with end-stage renal disease.(1)

PATIENT MANAGEMENT: When initiating lomitapide in patients taking a stable dose of a weak CYP3A4 inhibitor, follow the recommended dose and titration schedule per labeling. When initiating a weak CYP3A4 inhibitor in patients taking lomitapide, decrease the dose of lomitapide by 50%. The maximum recommended lomitapide dose with concurrent weak CYP3A4 inhibitors should be: -Adults (age 18 years and older): 30 mg daily, -Age group 11 to 17 years: 20 mg daily, -Age group 2 to 10 years: 10 mg daily. Due to lomitapide's long half-life, it may take 1 to 2 weeks to see the full effect of this interaction.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Based upon interactions with stronger inhibitors, weak inhibitors of CYP3A4 are predicted to increase lomitapide area-under-curve(AUC) 2-fold.(1) Weak CYP3A4 inhibitors linked to this interaction include: amiodarone, amlodipine, anamorelin, asciminib, atorvastatin, avapritinib, azithromycin, Baikal skullcap, belumosudil, bicalutamide, blueberry juice, brodalumab, camizestrant, cannabidiol, capivasertib, cilostazol, cimetidine, ciprofloxacin, chlorzoxazone, clotrimazole, cranberry juice, cyclosporine, daridorexant, delavirdine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, sevabertinib, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, ziftomenib, and zileuton.(1-3)

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

Aprepitant(>40Mg);Fosaprep/Dexamethasone;Methylprednisolone

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

MECHANISM OF ACTION: Aprepitant and fosaprepitant may inhibit the metabolism of dexamethasone and methylprednisolone by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use with multiple dose of aprepitant or fosaprepitant without dosage adjustments of the corticosteroid may result in elevated levels of the corticosteroids and adverse effects.(1,2)

PREDISPOSING FACTORS: The effects of the interaction are greater when the corticosteroids are administered orally versus intravenously.(1)

PATIENT MANAGEMENT: The US manufacturer states that the dosage of oral dexamethasone should be reduced by 50% when administered with the 125/80 mg regimen of aprepitant(1) or with fosaprepitant.(2) No dosage adjustment is required with single 40 mg doses of aprepitant.(1) The US manufacturer states that the dosage of oral methylprednisolone should be reduced by 50% and that the dosage of intravenous methylprednisolone should be reduced by 25% when methylprednisolone is administered with the 125/80 mg regimen of aprepitant(1) or with fosaprepitant.(2) No dosage adjustment is required with single 40 mg doses of aprepitant.(1)

DISCUSSION: In a clinical trial, the administration of oral dexamethasone (20 mg on Day 1, then 8 mg Days 2-5) and aprepitant (125 mg on Day 1, then 80 mg Days 2-5) increased the dexamethasone area-under-curve (AUC) by 2.2-fold on Days 1 and 5. A single dose of aprepitant (40 mg) increased the AUC of a single dose of dexamethasone (20 mg) by 1.45-fold.(1) In another clinical trial, the administration of methylprednisolone (125 mg intravenously on Day 1, then 40 mg orally Days 2-3) and aprepitant (125 mg on Day 1, then 80 mg Days 2-3) increased methylprednisolone AUC by 1.34-fold on Day 1 and by 2.5-fold on Day 3.(1) In a study in 440 subjects receiving aprepitant (40 mg or 125 mg), the clearance of single dose intravenous dexamethasone was decreased by 24.7% and 47.5% when coadministered with aprepitant 40 mg or 125 mg, respectively, compared to dexamethasone alone.(3)

Selected Sensitive Cyp3a4 Substrates/Schisandra

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

MECHANISM OF ACTION: Schisandra is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,2)

CLINICAL EFFECTS: Concurrent use of Schisandra may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(3-7)

PREDISPOSING FACTORS: With darifenacin, 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.(8)

PATIENT MANAGEMENT: If Schisandra must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor the CYP3A4 substrate and adjust its dose as appropriate.(3-7) The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(8)

DISCUSSION: A study in 12 healthy volunteers found that Schisandra led to an increase in midazolam area-under-curve (AUC) and maximum concentration (Cmax) of 2.05- and 1.65-fold, respectively, compared to midazolam administered alone.(3) In a study of 18 healthy volunteers, sirolimus AUC and Cmax increased by 2.07-fold and 1.96-fold, respectively when given with Schisandra compared to sirolimus administered alone.(4) The effect of Schisandra on tacrolimus has been examined in several small pharmacokinetic studies in healthy volunteers as well as liver and kidney transplant patients. Compared to tacrolimus given alone, tacrolimus AUC when administered with Schisandra was consistently increased by 2.1-fold, while the increase in Cmax varied between 1.83- and 2.11-fold in the transplant studies(5-6) and 3-fold in the study on healthy subjects.(7) In the study with kidney transplant patients, a decrease in tacrolimus dose of 40.9 % was required to bring tacrolimus levels into the therapeutic range.(5)

Slt Moderate And Weak Cyp3a4 Inhibit/Sirolimus Protein-Bound

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

MECHANISM OF ACTION: Moderate and weak CYP3A4 inhibitors may inhibit the metabolism of sirolimus by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of moderate or weak CYP3A4 inhibitors may result in elevated levels of and side effects from sirolimus.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(1)

DISCUSSION: In an open, randomized, cross-over trial in 18 healthy subjects, concurrent single doses of diltiazem (120 mg) and sirolimus (10 mg) increased sirolimus area-under-curve (AUC) and maximum concentration (Cmax) by 60% and by 43%, respectively. Sirolimus apparent oral clearance and volume of distribution decreased by 38% and 45%, respectively. There were no effects on diltiazem pharmacokinetics or pharmacodynamics.(2) In a study in 26 healthy subjects, concurrent sirolimus (2 mg daily) with verapamil (180 mg twice daily) increased sirolimus AUC and Cmax by 2.2-fold and 2.3-fold, respectively. The AUC and Cmax of the active S-enantiomer of verapamil each increased by 1.5-fold. Verapamil time to Cmax (Tmax) was increased by 1.2 hours.(2) Moderate and weak CYP3A4 inhibitors linked to this monograph include: amlodipine, anamorelin, aprepitant, avacopan, azithromycin, berberine, berotralstat, bicalutamide, blueberry, brodalumab, camizestrant, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clofazimine, conivaptan, crizotinib, daclatasvir, daridorexant, delavirdine, diltiazem, diosmin, elinzanetant, estrogen, flibanserin, fluvoxamine, fosaprepitant, fosnetupitant, fostamatinib, ginkgo, givinostat, glecaprevir/pibrentasvir, gepotidacin, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib, oral lefamulin, lenacapavir, levamlodipine, linagliptin, lomitapide, lumateperone, lurasidone, mavorixafor, netupitant, nicardipine, omeprazole, osilodrostat, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, rimegepant, roxithromycin, scutellarin, sevabertinib, simeprevir, sitaxsentan, stiripentol, ticagrelor, tofisopam, tolvaptan, trofinetide, vonoprazan, and voxelotor.(3,4)

Weak Cyp3a4 Inhibitors/Lemborexant (<= 5 Mg)

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

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of lemborexant.(1)

CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP3A4 may result in increased levels of and effects from lemborexant, including somnolence, fatigue, CNS depressant effects, daytime impairment, headache, and nightmare or abnormal dreams.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The maximum recommended dose of lemborexant with concurrent use of a weak CYP3A4 inhibitors should not exceed 5 mg per dose.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Lemborexant is a CYP3A4 substrate. In a PKPB model, concurrent use of lemborexant with itraconazole increased area-under-curve (AUC) and concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively. Concurrent use of lemborexant with fluconazole increased AUC and Cmax by 4.25-fold and 1.75-fold, respectively.(1) Weak inhibitors of CYP3A4 include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib.(1,3)

Weak Cyp3a4 Inhibitors/Mavacamten

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

MECHANISM OF ACTION: Weak CYP3A4 inhibitors may decrease the metabolism of mavacamten.(1)

CLINICAL EFFECTS: Concurrent use of weak CYP3A4 inhibitors may increase the plasma levels and the incidence and severity of adverse reactions of mavacamten.(1)

PREDISPOSING FACTORS: CYP2C19 poor metabolizers may experience an increased incidence or severity of adverse effects.(1)

PATIENT MANAGEMENT: The UK manufacturer of mavacamten states no dose adjustment is necessary when starting mavacamten in patients on weak CYP3A4 inhibitors or in intermediate, normal, rapid, or ultra-rapid CYP2C19 metabolizers already on mavacamten and starting a weak CYP3A4 inhibitor. In poor CYP2C19 metabolizers already on mavacamten and starting a weak CYP3A4 inhibitor, reduce mavacamten 5 mg to 2.5 mg or if on 2.5 mg pause treatment for 4 weeks. If CYP2C19 phenotype is unknown, consider a mavacamten starting dose of 2.5 mg daily.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: In a PBPK model, concomitant use of mavacamten (15 mg daily) with cimetidine 400 mg twice daily, a weak CYP3A4 inhibitor, was predicted to increase mavacamten area-under-curve (AUC) by 6% and maximum concentration (Cmax) by 4% in poor CYP2C19 metabolizers and by 3% and 2%, respectively, in both intermediate and normal CYP2C19 metabolizers.(3) Weak CYP3A4 inhibitors include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, chlorzoxazone, cilostazol, clotrimazole, cranberry, cyclosporine, delavirdine, dihydroberberine, diosmin, everolimus, flibanserin, fosaprepitant, fostamatinib, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, istradefylline, ivacaftor, lacidipine, lapatinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, pazopanib, peppermint oil, propiverine, propofol, ranitidine, resveratrol, roxithromycin, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, and viloxazine. (4,5)

Weak Cyp3a4 Inhibitors/Ubrogepant (<= 50 Mg)

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)

*Concomitant use with pimozide.

*Known hypersensitivity to aprepitant, fosaprepitant dimeglumine, or any component of the formulations.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

• No disease contraindications

The most common adverse effects (>=3%) with oral aprepitant in adults, when used for the prevention of chemotherapy-induced nausea and vomiting, include fatigue, diarrhea, asthenia, dyspepsia, abdominal pain, hiccups, decreased white blood cell count, dehydration, and increased alanine aminotransferase.

The most common adverse effects (>=3%) with oral aprepitant in pediatric patients, when used for the prevention of chemotherapy-induced nausea and vomiting, include neutropenia, headache, diarrhea, decreased appetite, cough, fatigue, decreased hemoglobin, dizziness, and hiccups.

The most common adverse effects (>=3%) with oral aprepitant in adults, when used for postoperative nausea and vomiting, include constipation and hypotension.

The most common adverse effects (>=2%) with fosaprepitant dimeglumine in adults are fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infection, and pain in the extremity. Adverse effects in pediatric patients are similar to adults.

The most common adverse effects (>=3%) with single-dose aprepitant for injection (32 mg/4.4 mL) include constipation, fatigue, and headache; and constipation and hypotension with single-dose oral aprepitant.

The most common adverse effects with single-dose fosaprepitant with moderately emetogenic chemotherapy (>=2%) include fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infection, and pain in the extremity. The most common adverse effects with 3-day oral aprepitant with moderately emetogenic chemotherapy (>=1% and greater than standard therapy) include fatigue and eructation. Adverse effects with single-dose fosaprepitant with highly emetogenic chemotherapy is generally similar to 3-day oral aprepitant; additionally, infusion site reactions (3%) are reported. The most common adverse effects (>=3%) with single-dose aprepitant for injection (130 mg/18 mL) include headache and fatigue.

More Frequent

• Anemia
• Leukopenia
• Neutropenic disorder
• Peripheral neuropathy

Rare or Very Rare

• Anaphylaxis
• Dyspnea
• Erythema
• Hypersensitivity angiitis
• Hypersensitivity drug reaction
• Hypotension
• Muscle weakness
• Skin rash
• Stevens-johnson syndrome
• Toxic epidermal necrolysis
• Urticaria

More Frequent

• Diarrhea
• Dyspepsia
• Fatigue
• General weakness
• Pain
• Urinary tract infection

Less Frequent

• Injection site sequelae

Rare or Very Rare

• Dizziness
• Flushing
• Localized edema
• Pruritus of skin
• Thrombophlebitis

No enhanced messaging available.

Safety and efficacy of oral aprepitant or parenteral fosaprepitant dimeglumine for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) have not been established in pediatric patients <6 months of age.

The safety and efficacy of parenteral aprepitant have not been established in pediatric patients.

The safety and effectiveness of aprepitant capsules have not been established for the prevention of postoperative nausea and vomiting in pediatric patients.

There are insufficient data on the use of aprepitant or fosaprepitant in pregnant women to inform a drug-associated risk. Animal reproduction studies have not demonstrated adverse developmental effects in rats or rabbits exposed during the period of organogenesis. Aprepitant crosses the placenta in animals.

Avoid use of aprepitant injectable emulsions in pregnancy due to the alcohol content.

Aprepitant is distributed into milk in rats; it is not known whether the drug is distributed into milk in humans. The effects of aprepitant on the breast-fed infant or on milk production are also unknown.

Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for aprepitant or fosaprepitant and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

In general, use caution when dosing geriatric patients, considering the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.

Clinical experience has not identified differences in efficacy of aprepitant or fosaprepitant in geriatric patients relative to younger patients. No clinically important differences in the pharmacokinetics of oral aprepitant were observed in healthy geriatric patients compared to younger adults.

In general, use caution when dosing geriatric patients, considering the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.