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  • CLASSES

    Other Antiemetics and Antinauseants

    DEA CLASS

    Rx

    DESCRIPTION

    Substance P/neurokinin 1 (NK1) receptor antagonist
    Used in combination with dexamethasone and a 5-HT3 receptor antagonist for the prevention of CINV
    Contraindicated with CYP2D6 substrates with a narrow therapeutic index, such as thioridazine and pimozide

    COMMON BRAND NAMES

    Varubi

    HOW SUPPLIED

    Rolapitant/Varubi Oral Tab: 90mg
    Varubi Intravenous Inj Emulsion: 1mL, 1.8mg

    DOSAGE & INDICATIONS

    For delayed chemotherapy-induced nausea/vomiting prophylaxis, in combination with other antiemetic agents.
    For delayed chemotherapy-induced nausea/vomiting prophylaxis associated with highly emetogenic chemotherapy.
    Oral dosage
    Adults

    180 mg orally on day 1, given 1 to 2 hours before chemotherapy. Additionally, 30 minutes prior to chemotherapy on day 1, administer dexamethasone (20 mg orally or intravenously) and a 5-HT3 receptor antagonist; dexamethasone (8 mg orally twice daily) should be continued on days 2, 3, and 4. Repeat rolapitant administration at intervals of at least 2 weeks or more, prior to the start of each chemotherapy cycle. In a multicenter, randomized, double-blind, placebo-controlled clinical trial, 72.7% of patients treated with chemotherapy including cisplatin (mean dose, 77 mg/m2) who were premedicated with rolapitant plus dexamethasone and granisetron (n = 266) had a complete response, defined as no emetic episodes and no rescue medicine in the delayed phase (25 to 120 hours), compared with 58.4% of those who received placebo plus dexamethasone and granisetron (n = 266) (p is less than 0.001). In a similar clinical trial where the mean cisplatin dose was 76 mg/m2, 70.1% patients in the rolapitant group (n = 278) had a complete response as previously defined, compared with 61.9% of those in the placebo group (n = 277) (p is less than 0.043).

    Intravenous dosage
    Adults

    166.5 mg intravenously over 30 minutes on day 1, given 1 to 2 hours before chemotherapy. Additionally, 30 minutes prior to chemotherapy on day 1, administer dexamethasone (20 mg orally or intravenously) and a 5-HT3 receptor antagonist; dexamethasone (8 mg orally twice daily) should be continued on days 2, 3, and 4. Repeat rolapitant administration at intervals of at least 2 weeks or more, prior to the start of each chemotherapy cycle.

    For delayed chemotherapy-induced nausea/vomiting prophylaxis associated with moderately emetogenic chemotherapy and combinations of anthracycline and cyclophosphamide.
    Oral dosage
    Adults

    180 mg orally on day 1, given 1 to 2 hours before chemotherapy. Additionally, 30 minutes prior to chemotherapy on day 1, administer dexamethasone (20 mg orally or intravenously) and a 5-HT3 receptor antagonist. Follow the 5HT-3 antagonist dosing information regarding continued administration on days 2, 3, and 4. Repeat rolapitant administration at intervals of at least 2 weeks or more, prior to the start of each chemotherapy cycle. In a multicenter, randomized, double-blind, placebo-controlled clinical trial of patients treated with moderately emetogenic chemotherapy (including at least 50% of patients treated with the combination of an anthracycline and cyclophosphamide), 71.3% of patients premedicated with rolapitant plus dexamethasone and granisetron (n = 684) had a complete response, defined as no emetic episodes and no rescue medication in the delayed phase (25 to 120 hours), compared with 61.6% of those who received placebo plus dexamethasone and granisetron (n = 685) (p is less than 0.001).

    Intravenous dosage
    Adults

    166.5 mg intravenously over 30 minutes on day 1, given 1 to 2 hours before chemotherapy. Additionally, 30 minutes prior to chemotherapy on day 1, administer dexamethasone (20 mg orally or intravenously) and a 5-HT3 receptor antagonist. Follow the 5HT-3 antagonist dosing information regarding continued administration on days 2, 3, and 4. Repeat rolapitant administration at intervals of at least 2 weeks or more, prior to the start of each chemotherapy cycle.

    MAXIMUM DOSAGE

    Adults

    180 mg orally or 166.5 mg intravenously as a single dose on day 1 of the chemotherapy regimen.

    Geriatric

    180 mg orally or 166.5 mg intravenously as a single dose on day 1 of the chemotherapy regimen.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild or moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment necessary.
    Severe hepatic impairment (Child-Pugh class C): Do not use rolapitant; there are no clinical or pharmacokinetic data in patients with severe hepatic impairment. If use in severe hepatic impairment is necessary, monitor patients for rolapitant-related adverse effects.

    Renal Impairment

    Mild to moderate renal impairment (CrCL 30 to 90 mL/min): No dosage adjustment necessary.
    Severe renal impairment or end-stage renal disease requiring hemodialysis: Insufficient information is available for a dosing recommendation.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    May be administered without regard to meals.

    Injectable Administration
    Intravenous Administration

    Administer by intravenous infusion only.
    Injectable emulsion
    Use aseptic technique to prepare the infusion.
    The emulsion is homogenous (no shaking required) and translucent white in appearance.
    Insert a vented intravenous set through the septum of the vial. Once the stopper is punctured, use immediately. Do not dilute rolapitant injectable emulsion.
    Rolapitant injectable emulsion is compatible with the following other intravenous fluids through a Y-site connection: Sodium Chloride 0.9% Injection, Dextrose 5% Injection, Dextrose 5% in Lactated Ringer’s Injection, and Lactated Ringer’s Injection. Other drugs should not be added to the emulsion vial until compatibility can be further evaluated.
    Administration:
    Administer 92.5 mL as an intravenous infusion over 30 minutes.

    STORAGE

    Varubi:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Children, infants, neonates

    The safety and effectiveness of rolapitant have not been established in pediatric patients (neonates, infants, children).

    Infertility, pregnancy

    Female patients of reproductive potential should be advised of the risk of infertility with rolapitant; in animal fertility studies, rolapitant impaired fertility in a reversible fashion. Although there are no adequate and well-controlled studies in pregnancy, there were no teratogenic or embryo-fetal effects observed with oral administration of rolapitant to rats and rabbits during organogenesis at doses up to 1.3 and 2.9 times the maximum recommended human dose (MRHD), respectively. Pregnant rats experienced decreased weight gain and/or weight loss as well as a decrease in food consumption during the first week of dosing equivalent to 13.5 or 22.5 mg/kg/day of rolapitant free base (0.72 to 1.2 times the MRHD); additional maternal toxicities included total litter loss, prolonged parturition, decreased length of gestation, and increased number of unaccounted for implantation sites at doses equivalent to 1.2 times the MRHD. At this dose, offspring experienced decreased postnatal survival and decreased or increased body weight, which may be related to the maternal toxicity. At a maternal dose equivalent to 0.5 times the MRHD, there was a decrease in memory in female pups in a maze test and a decrease in pup body weight.

    Breast-feeding

    According to the manufacturer, it is not known whether rolapitant is excreted in human milk. Caution should be exercised when administering rolapitant to a breast-feeding woman. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Risk of serious hypersensitivity reactions or anaphylaxis, soya lecithin hypersensitivity

    There is a risk of serious hypersensitivity reactions or anaphylaxis in patients receiving rolapitant injection. Anaphylaxis, anaphylactic shock and other serious hypersensitivity reactions have been reported during postmarketing experience with rolapitant injection, some requiring hospitalization. These reactions have occurred during or soon after the infusion of rolapitant; most reactions have occurred within the first few minutes of administration. Symptoms of anaphylaxis can include wheezing or difficulty breathing, angioedema, urticaria or flushing, pruritis, abdominal cramping, abdominal pain or vomiting, back pain or chest pain, hypotension or shock. Use caution in patients with a hypersensitivity to any component of the product. Rolapitant injection contains soybean oil; use caution in patients with a soya lecithin hypersensitivity and in patients with known allergies to legumes or other related allergens as cross-sensitivity to other allergens is possible. If a serious reaction is suspected, discontinue rolapitant injection and manage the patient appropriately; do not restart rolapitant injection.

    ADVERSE REACTIONS

    Severe

    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    neutropenia / Delayed / 7.0-9.0
    stomatitis / Delayed / 4.0-4.0
    anemia / Delayed / 3.0-3.0
    infusion-related reactions / Rapid / 2.6-2.6

    Mild

    anorexia / Delayed / 9.0-9.0
    dizziness / Early / 6.0-6.0
    hiccups / Early / 5.0-5.0
    dyspepsia / Early / 4.0-4.0
    infection / Delayed / 4.0-4.0
    abdominal pain / Early / 3.0-3.0

    DRUG INTERACTIONS

    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with rolapitant may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of rolapitant could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If rolapitant is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Rolapitant is a moderate inhibitor of CYP2D6.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with rolapitant may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of rolapitant could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If rolapitant is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Rolapitant is a moderate inhibitor of CYP2D6.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured. (Major) Use caution if products containing chlorpheniramine and rolapitant are used concurrently, and monitor for chlorpheniramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Chlorpheniramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured. (Major) Use caution if products containing chlorpheniramine and rolapitant are used concurrently, and monitor for chlorpheniramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Chlorpheniramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Major) Use caution if products containing chlorpheniramine and rolapitant are used concurrently, and monitor for chlorpheniramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Chlorpheniramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with rolapitant may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of rolapitant could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If rolapitant is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Rolapitant is a moderate inhibitor of CYP2D6.
    Acetaminophen; Dextromethorphan: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured.
    Acetaminophen; Dextromethorphan; Doxylamine: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured.
    Acetaminophen; Diphenhydramine: (Major) Use caution if diphenhydramine and rolapitant are used concurrently, and monitor for diphenhydramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Diphenhydramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with rolapitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of rolapitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If rolapitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Rolapitant is a moderate inhibitor of CYP2D6. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration.
    Acetaminophen; Oxycodone: (Major) Use caution if oxycodone and rolapitant are used concurrently, and monitor for oxycodone-related adverse effects. Oxycodone is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Acetaminophen; Tramadol: (Major) Use caution if tramadol and rolapitant are used concurrently, and monitor for tramadol-related adverse effects as well as possible changes to the efficacy of tramadol. Rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6; therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 is expected to result in reduced metabolic clearance of tramadol, which in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures; serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Afatinib: (Moderate) If the concomitant use of rolapitant and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of rolapitant. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and rolapitant is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Amitriptyline: (Major) Monitor for increased serum concentrations of amitriptyline and for amitriptyline-related adverse effects, such as nausea, dizziness, hypotension, syncope, and QT prolongation, if coadministered with rolapitant. Lower doses of either drug may be required with coadministration. When rolapitant is withdrawn from co-therapy, an increased dose of amitriptyline may be required. Amitriptyline is a CYP2D6 substrate, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Amitriptyline; Chlordiazepoxide: (Major) Monitor for increased serum concentrations of amitriptyline and for amitriptyline-related adverse effects, such as nausea, dizziness, hypotension, syncope, and QT prolongation, if coadministered with rolapitant. Lower doses of either drug may be required with coadministration. When rolapitant is withdrawn from co-therapy, an increased dose of amitriptyline may be required. Amitriptyline is a CYP2D6 substrate, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Apalutamide: (Major) Avoid coadministration of rolapitant with apalutamide due to decreased plasma concentrations of rolapitant. Rolapitant is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased rolapitant exposure by 85%; the mean half-life of rolapitant decreased from 176 hours to 41 hours.
    Aprepitant, Fosaprepitant: (Major) Rolapitant and aprepitant, fosaprepitant should not be used together, as they are a duplication of therapy. Additionally, rolapitant is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of rolapitant. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aripiprazole: (Moderate) Aripiprazole is a partial CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. If aripiprazole and rolapitant are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions, including QT prolongation and torsade de pointes. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor.
    Asenapine: (Major) Use caution if asenapine and rolapitant are used concurrently, and monitor for asenapine-related adverse effects. Asenapine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with rolapitant may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of rolapitant could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If rolapitant is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Rolapitant is a moderate inhibitor of CYP2D6.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with rolapitant may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of rolapitant could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If rolapitant is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Rolapitant is a moderate inhibitor of CYP2D6.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with rolapitant may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of rolapitant could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If rolapitant is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Rolapitant is a moderate inhibitor of CYP2D6.
    Aspirin, ASA; Oxycodone: (Major) Use caution if oxycodone and rolapitant are used concurrently, and monitor for oxycodone-related adverse effects. Oxycodone is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Atazanavir; Cobicistat: (Major) Use caution if cobicistat and rolapitant are used concurrently, and monitor for cobicistat-related adverse effects. Cobicistat is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Atomoxetine: (Major) Use caution if atomoxetine and rolapitant are used concurrently, and monitor for atomoxetine-related adverse effects. Atomoxetine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid the use of rolapitant with chronic administration of phenobarbital; this also applies to drugs that are metabolized to phenobarbital, such as mephobarbital and primidone. Rolapitant is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. When another strong CYP3A4 inducer, rifampin (600 mg once daily), was administered for 7 days before and 7 days after a single dose of rolapitant (180 mg), the mean Cmax and AUC of rolapitant were decreased by 30% and 85%, respectively; additionally, the mean half-life decreased from 176 hours to 41 hours. Significantly reduced plasma concentrations and decreased half-life can decrease the efficacy of rolapitant.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid the use of rolapitant with chronic administration of phenobarbital; this also applies to drugs that are metabolized to phenobarbital, such as mephobarbital and primidone. Rolapitant is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. When another strong CYP3A4 inducer, rifampin (600 mg once daily), was administered for 7 days before and 7 days after a single dose of rolapitant (180 mg), the mean Cmax and AUC of rolapitant were decreased by 30% and 85%, respectively; additionally, the mean half-life decreased from 176 hours to 41 hours. Significantly reduced plasma concentrations and decreased half-life can decrease the efficacy of rolapitant.
    Brexpiprazole: (Moderate) Use caution if brexpiprazole and rolapitant are used concurrently, and monitor for increased brexpiprazole-related adverse effects. Brexpiprazole is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor. The inhibitory effect of rolapitant lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration. In addition, the manufacturer of brexpiprazole recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Therefore, if rolapitant is used in combination with brexpiprazole and a moderate to strong CYP3A4 inhibitor, the brexpiprazole dose should be adjusted and the patient should be carefully monitored for brexpiprazole-related adverse reactions.
    Brimonidine; Timolol: (Major) Use caution if timolol and rolapitant are used concurrently, and monitor for timolol-related adverse effects. Timolol is a substrate of CYP2D6 and rolapitant is an inhibitor of CYP2D6 ; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with rolapitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of rolapitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If rolapitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Rolapitant is a moderate inhibitor of CYP2D6. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with rolapitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of rolapitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If rolapitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Rolapitant is a moderate inhibitor of CYP2D6. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration.
    Carbamazepine: (Major) Avoid the use of rolapitant with chronic administration of carbamazepine. Rolapitant is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. When another strong CYP3A4 inducer, rifampin (600 mg once daily), was administered for 7 days before and 7 days after a single dose of rolapitant (180 mg), the mean Cmax and AUC of rolapitant were decreased by 30% and 85%, respectively; additionally, the mean half-life decreased from 176 hours to 41 hours. Significantly reduced plasma concentrations and decreased half-life can decrease the efficacy of rolapitant.
    Carbetapentane; Chlorpheniramine: (Major) Use caution if products containing chlorpheniramine and rolapitant are used concurrently, and monitor for chlorpheniramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Chlorpheniramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Major) Use caution if products containing chlorpheniramine and rolapitant are used concurrently, and monitor for chlorpheniramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Chlorpheniramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Major) Use caution if diphenhydramine and rolapitant are used concurrently, and monitor for diphenhydramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Diphenhydramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with rolapitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of rolapitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If rolapitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Rolapitant is a moderate inhibitor of CYP2D6. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with rolapitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of rolapitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If rolapitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Rolapitant is a moderate inhibitor of CYP2D6. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration.
    Carvedilol: (Major) Use caution if carvedilol and rolapitant are used concurrently, and monitor for carvedilol-related adverse effects. Carvedilol is a substrate of CYP2D6 and P-glycoprotein (P-gp) that is individually dose-titrated, and rolapitant is an inhibitor of CYP2D6 and P-gp. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. When oral rolapitant was administered with another P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied. When the P-gp substrate was administered with a single dose of intravenous rolapitant, no effect on AUC and a 21% increase in the Cmax of P-gp substrate was observed.
    Cevimeline: (Major) Use caution if cevimeline and rolapitant are used concurrently, and monitor for cevimeline-related adverse effects. Cevimeline is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Chlorpheniramine: (Major) Use caution if products containing chlorpheniramine and rolapitant are used concurrently, and monitor for chlorpheniramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Chlorpheniramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Chlorpheniramine; Codeine: (Major) Use caution if products containing chlorpheniramine and rolapitant are used concurrently, and monitor for chlorpheniramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Chlorpheniramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. (Moderate) Concomitant use of codeine with rolapitant may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of rolapitant could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If rolapitant is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Rolapitant is a moderate inhibitor of CYP2D6.
    Chlorpheniramine; Dextromethorphan: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured. (Major) Use caution if products containing chlorpheniramine and rolapitant are used concurrently, and monitor for chlorpheniramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Chlorpheniramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured. (Major) Use caution if products containing chlorpheniramine and rolapitant are used concurrently, and monitor for chlorpheniramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Chlorpheniramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Use caution if products containing chlorpheniramine and rolapitant are used concurrently, and monitor for chlorpheniramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Chlorpheniramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. (Moderate) Concomitant use of dihydrocodeine with rolapitant may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of rolapitant could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If rolapitant is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Rolapitant is a moderate inhibitor of CYP2D6.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Use caution if products containing chlorpheniramine and rolapitant are used concurrently, and monitor for chlorpheniramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Chlorpheniramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. (Moderate) Concomitant use of dihydrocodeine with rolapitant may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of rolapitant could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If rolapitant is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Rolapitant is a moderate inhibitor of CYP2D6.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Use caution if products containing chlorpheniramine and rolapitant are used concurrently, and monitor for chlorpheniramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Chlorpheniramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. (Moderate) Concomitant use of hydrocodone with rolapitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of rolapitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If rolapitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Rolapitant is a moderate inhibitor of CYP2D6. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration.
    Chlorpheniramine; Hydrocodone: (Major) Use caution if products containing chlorpheniramine and rolapitant are used concurrently, and monitor for chlorpheniramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Chlorpheniramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. (Moderate) Concomitant use of hydrocodone with rolapitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of rolapitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If rolapitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Rolapitant is a moderate inhibitor of CYP2D6. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Use caution if products containing chlorpheniramine and rolapitant are used concurrently, and monitor for chlorpheniramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Chlorpheniramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. (Moderate) Concomitant use of hydrocodone with rolapitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of rolapitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If rolapitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Rolapitant is a moderate inhibitor of CYP2D6. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Use caution if products containing chlorpheniramine and rolapitant are used concurrently, and monitor for chlorpheniramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Chlorpheniramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. (Moderate) Concomitant use of hydrocodone with rolapitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of rolapitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If rolapitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Rolapitant is a moderate inhibitor of CYP2D6. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration.
    Chlorpheniramine; Phenylephrine: (Major) Use caution if products containing chlorpheniramine and rolapitant are used concurrently, and monitor for chlorpheniramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Chlorpheniramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Chlorpheniramine; Pseudoephedrine: (Major) Use caution if products containing chlorpheniramine and rolapitant are used concurrently, and monitor for chlorpheniramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Chlorpheniramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Chlorpromazine: (Major) Monitor for chlorpromazine-related adverse effects, including QT prolongation and torsade de pointes (TdP), if coadministered with rolapitant. Increased exposure to chlorpromazine may occur. Chlorpromazine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Cinacalcet: (Major) Use caution if cinacalcet and rolapitant are used concurrently, and monitor for cinacalcet-related adverse effects. Cinacalcet is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Clomipramine: (Major) Monitor for increased serum concentrations of clomipramine and for clomipramine-related adverse effects, such as nausea, dizziness, hypotension, syncope, and QT prolongation, if coadministered with rolapitant. Lower doses of either drug may be required with coadministration. When rolapitant is withdrawn from co-therapy, an increased dose of clomipramine may be required. Clomipramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Clozapine: (Moderate) Use caution if clozapine and rolapitant are used concurrently, and monitor for clozapine-related adverse effects, including QT prolongation. Clozapine is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration. Elevated plasma concentrations of clozapine may increase the risk for QT prolongation, torsade de pointes (TdP), sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP2D6 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cobicistat: (Major) Use caution if cobicistat and rolapitant are used concurrently, and monitor for cobicistat-related adverse effects. Cobicistat is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Use caution if cobicistat and rolapitant are used concurrently, and monitor for cobicistat-related adverse effects. Cobicistat is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Use caution if cobicistat and rolapitant are used concurrently, and monitor for cobicistat-related adverse effects. Cobicistat is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. (Moderate) Use caution if tenofovir, PMPA and rolapitant are used concurrently, and monitor for tenofovir-related adverse effects. Tenofovir is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Cobimetinib: (Minor) If concurrent use of cobimetinib and rolapitant is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and rolapitant is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
    Codeine: (Moderate) Concomitant use of codeine with rolapitant may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of rolapitant could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If rolapitant is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Rolapitant is a moderate inhibitor of CYP2D6.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with rolapitant may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of rolapitant could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If rolapitant is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Rolapitant is a moderate inhibitor of CYP2D6.
    Codeine; Phenylephrine; Promethazine: (Major) Use caution if promethazine and rolapitant are used concurrently, and monitor for promethazine-related adverse effects. Promethazine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. (Moderate) Concomitant use of codeine with rolapitant may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of rolapitant could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If rolapitant is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Rolapitant is a moderate inhibitor of CYP2D6.
    Codeine; Promethazine: (Major) Use caution if promethazine and rolapitant are used concurrently, and monitor for promethazine-related adverse effects. Promethazine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. (Moderate) Concomitant use of codeine with rolapitant may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of rolapitant could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If rolapitant is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Rolapitant is a moderate inhibitor of CYP2D6.
    Cyclosporine: (Major) Avoid the concurrent use of cyclosporine and rolapitant if possible; if coadministration is necessary, monitor cyclosporine levels and watch for cyclosporine-related adverse effects. Cyclosporine is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied. Additionally, cyclosporine is an inhibitor of CYP3A4 and rolapitant is a CYP3A4 substrate. Theoretically this could increase rolapitant concentrations, but this effect is not expected to be clinically relevant.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with rolapitant, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like rolapitant in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with rolapitant, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Darifenacin: (Major) Use caution if darifenacin and rolapitant are used concurrently, and monitor for darifenacin-related adverse effects. Darifenacin is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Darunavir; Cobicistat: (Major) Use caution if cobicistat and rolapitant are used concurrently, and monitor for cobicistat-related adverse effects. Cobicistat is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Use caution if cobicistat and rolapitant are used concurrently, and monitor for cobicistat-related adverse effects. Cobicistat is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Delavirdine: (Major) Use caution if delavirdine and rolapitant are used concurrently, and monitor for delavirdine-related adverse effects. Delavirdine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Desipramine: (Major) Monitor for increased serum concentrations of desipramine and for desipramine-related adverse effects, such as nausea, dizziness, hypotension, syncope, and QT prolongation, if coadministered with rolapitant. Lower doses of either drug may be required with coadministration. When rolapitant is withdrawn from co-therapy, an increased dose of desipramine may be required. Desipramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured.
    Dextromethorphan: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured. (Major) Use caution if diphenhydramine and rolapitant are used concurrently, and monitor for diphenhydramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Diphenhydramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Dextromethorphan; Guaifenesin: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured.
    Dextromethorphan; Promethazine: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured. (Major) Use caution if promethazine and rolapitant are used concurrently, and monitor for promethazine-related adverse effects. Promethazine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Dextromethorphan; Quinidine: (Major) Monitor for dextromethorphan-related adverse effects and toxicities if coadministered with rolapitant. Dextromethorphan is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to dextromethorphan following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured. (Moderate) Use caution if quinidine and rolapitant are used concurrently, and monitor for quinidine-related adverse effects, including QT prolongation. Quinidine is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Digoxin: (Moderate) Avoid the concurrent use of digoxin and rolapitant if possible; if coadministration is necessary, monitor digoxin levels and watch for digoxin-related adverse effects. Digoxin is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with rolapitant may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of rolapitant could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If rolapitant is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Rolapitant is a moderate inhibitor of CYP2D6.
    Diphenhydramine: (Major) Use caution if diphenhydramine and rolapitant are used concurrently, and monitor for diphenhydramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Diphenhydramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Use caution if diphenhydramine and rolapitant are used concurrently, and monitor for diphenhydramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Diphenhydramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. (Moderate) Concomitant use of hydrocodone with rolapitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of rolapitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If rolapitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Rolapitant is a moderate inhibitor of CYP2D6. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration.
    Diphenhydramine; Ibuprofen: (Major) Use caution if diphenhydramine and rolapitant are used concurrently, and monitor for diphenhydramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Diphenhydramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Diphenhydramine; Naproxen: (Major) Use caution if diphenhydramine and rolapitant are used concurrently, and monitor for diphenhydramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Diphenhydramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Diphenhydramine; Phenylephrine: (Major) Use caution if diphenhydramine and rolapitant are used concurrently, and monitor for diphenhydramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Diphenhydramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Docetaxel: (Moderate) Use caution if docetaxel and rolapitant are used concurrently, and monitor for docetaxel-related adverse effects. Docetaxel is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Donepezil: (Major) Use caution if donepezil and rolapitant are used concurrently, and monitor for donepezil-related adverse effects. Donepezil is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Donepezil; Memantine: (Major) Use caution if donepezil and rolapitant are used concurrently, and monitor for donepezil-related adverse effects. Donepezil is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Use caution if tenofovir, PMPA and rolapitant are used concurrently, and monitor for tenofovir-related adverse effects. Tenofovir is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Dorzolamide; Timolol: (Major) Use caution if timolol and rolapitant are used concurrently, and monitor for timolol-related adverse effects. Timolol is a substrate of CYP2D6 and rolapitant is an inhibitor of CYP2D6 ; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Doxepin: (Major) Monitor for increased serum concentrations of doxepin and for doxepin-related adverse effects, such as nausea, dizziness, hypotension, syncope, and QT prolongation, if coadministered with rolapitant. Lower doses of either drug may be required with coadministration. When rolapitant is withdrawn from co-therapy, an increased dose of doxepin may be required. Doxepin is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Doxorubicin: (Major) Avoid coadministration of doxorubicin and rolapitant because it can result in doxorubicin-related adverse effects, including cardiac effects. Doxorubicin is a major substrate of CYP2D6, and is also metabolized via P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); rolapitant inhibits CYP2D6, P-gp, and BCRP. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. The Cmax and AUC of another BCRP substrate were increased by 140% and 130%, respectively, on day 1 and 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with another P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied. Of note, in a multicenter, randomized, double-blind, placebo-controlled clinical trial showing efficacy of rolapitant in patients treated with moderately emetogenic chemotherapy (n = 1369), at least 50% of patients received a combination of anthracycline and cyclophosphamide. In a similarly designed study of patients receiving highly emetogenic chemotherapy (n = 532), 6% received doxorubicin. Non-gastrointestinal adverse effects are not reported by the manufacturer; however, an increased incidence of hematologic toxicity is possible, as well as an unknown impact on short- and long-term cardiotoxicity.
    Duloxetine: (Major) Use caution if duloxetine and rolapitant are used concurrently, and monitor for duloxetine-related adverse effects. Duloxetine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Dutasteride; Tamsulosin: (Major) Use caution if tamsulosin and rolapitant are used concurrently, and monitor for tamsulosin-related adverse effects. Tamsulosin is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Use caution if tenofovir, PMPA and rolapitant are used concurrently, and monitor for tenofovir-related adverse effects. Tenofovir is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Use caution if tenofovir, PMPA and rolapitant are used concurrently, and monitor for tenofovir-related adverse effects. Tenofovir is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Elbasvir; Grazoprevir: (Major) Administering rolapitant with grazoprevir may result in elevated rolapitant plasma concentrations. Rolapitant is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Major) Use caution if eliglustat and rolapitant are used concurrently, and monitor for eliglustat-related adverse effects. Eliglustat is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Use caution if tenofovir, PMPA and rolapitant are used concurrently, and monitor for tenofovir-related adverse effects. Tenofovir is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Use caution if tenofovir, PMPA and rolapitant are used concurrently, and monitor for tenofovir-related adverse effects. Tenofovir is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Encainide: (Major) Use caution if encainide and rolapitant are used concurrently, and monitor for encainide-related adverse effects, including cardiac arrhythmias. Encainide is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Enzalutamide: (Major) Avoid coadministration of rolapitant with enzalutamide due to decreased plasma concentrations of rolapitant. Rolapitant is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased rolapitant exposure by 85%; the mean half-life of rolapitant decreased from 176 hours to 41 hours.
    Etoposide, VP-16: (Moderate) Use caution if etoposide, VP-16 and rolapitant are used concurrently, and monitor for etoposide-related adverse effects. Etoposide is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Flecainide: (Major) Avoid the concurrent use of flecainide and rolapitant if possible; if coadministration is necessary, monitor for flecainide-related adverse effects, including QT prolongation. Flecainide is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Fluoxetine: (Major) Use caution if fluoxetine and rolapitant are used concurrently, and monitor for fluoxetine-related adverse effects. Fluoxetine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Fluoxetine; Olanzapine: (Major) Monitor for olanzapine-related adverse effects, including QT prolongation, if coadministered with rolapitant. Increased exposure to olanzapine may occur. Olanzapine is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. (Major) Use caution if fluoxetine and rolapitant are used concurrently, and monitor for fluoxetine-related adverse effects. Fluoxetine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Fluphenazine: (Major) Monitor for fluphenazine-related adverse effects, including QT prolongation, if coadministered with rolapitant. Increased exposure to fluphenazine may occur. Fluphenazine is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Fluticasone; Umeclidinium; Vilanterol: (Major) Use caution if umeclidinium and rolapitant are used concurrently, and monitor for umeclidinium-related adverse effects. Umeclidinium is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration.
    Fluvoxamine: (Major) Use caution if fluvoxamine and rolapitant are used concurrently, and monitor for fluvoxamine-related adverse effects. Fluvoxamine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Fosamprenavir: (Major) Use caution if fosamprenavir and rolapitant are used concurrently, and monitor for fosamprenavir-related adverse effects. Fosamprenavir is a CYP2D6 and P-glycoprotein (P-gp) substrate and rolapitant is a CYP2D6 and P-gp inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. When rolapitant was administered with another P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Fosphenytoin: (Major) Avoid the use of rolapitant with chronic administration of fosphenytoin. Rolapitant is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. When another strong CYP3A4 inducer, rifampin (600 mg once daily), was administered for 7 days before and 7 days after a single dose of rolapitant (180 mg), the mean Cmax and AUC of rolapitant were decreased by 30% and 85%, respectively; additionally, the mean half-life decreased from 176 hours to 41 hours. Significantly reduced plasma concentrations and decreased half-life can decrease the efficacy of rolapitant.
    Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with rolapitant is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and rolapitant is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Glyburide: (Moderate) Use caution if glyburide and rolapitant are used concurrently, and monitor for hypoglycemia and other glyburide-related adverse effects. Glyburide is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Glyburide; Metformin: (Moderate) Use caution if glyburide and rolapitant are used concurrently, and monitor for hypoglycemia and other glyburide-related adverse effects. Glyburide is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with rolapitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of rolapitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If rolapitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Rolapitant is a moderate inhibitor of CYP2D6. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with rolapitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of rolapitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If rolapitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Rolapitant is a moderate inhibitor of CYP2D6. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration.
    Haloperidol: (Major) Monitor for haloperidol-related adverse effects, including QT prolongation, if coadministered with rolapitant. Increased exposure to haloperidol may occur. Haloperidol is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with rolapitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of rolapitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If rolapitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Rolapitant is a moderate inhibitor of CYP2D6. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Monitor for increased metoprolol adverse reactions including bradycardia and hypotension during coadministration. A dosage reduction for metoprolol may be needed based on response. Concurrent use may increase metoprolol exposure. Metoprolol is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. In the presence of another moderate CYP2D6 inhibitor, the AUC of metoprolol was increased by 3.29-fold with no effect on the cardiovascular response to metoprolol.
    Hydrochlorothiazide, HCTZ; Propranolol: (Major) Use caution if propranolol and rolapitant are used concurrently, and monitor for propranolol-related adverse effects, including bradycardia. Propranolol is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with rolapitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of rolapitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If rolapitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Rolapitant is a moderate inhibitor of CYP2D6. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with rolapitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of rolapitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If rolapitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Rolapitant is a moderate inhibitor of CYP2D6. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with rolapitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of rolapitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If rolapitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Rolapitant is a moderate inhibitor of CYP2D6. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with rolapitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of rolapitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If rolapitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Rolapitant is a moderate inhibitor of CYP2D6. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with rolapitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of rolapitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If rolapitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Rolapitant is a moderate inhibitor of CYP2D6. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with rolapitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of rolapitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If rolapitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Rolapitant is a moderate inhibitor of CYP2D6. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration.
    Ibuprofen; Oxycodone: (Major) Use caution if oxycodone and rolapitant are used concurrently, and monitor for oxycodone-related adverse effects. Oxycodone is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Iloperidone: (Major) Use caution if iloperidone and rolapitant are used concurrently, and monitor for iloperidone-related adverse effects, including QT prolongation. Iloperidone is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Imatinib: (Moderate) Monitor for imatinib-related adverse reactions if coadministration of these drugs is required. Imatinib is a substrate of the breast cancer resistance protein (BCRP) transporter; rolapitant is a BCRP inhibitor.
    Imipramine: (Major) Monitor for increased serum concentrations of imipramine and for imipramine-related adverse effects, such as nausea, dizziness, hypotension, syncope, and QT prolongation, if coadministered with rolapitant. Lower doses of either drug may be required with coadministration. When rolapitant is withdrawn from co-therapy, an increased dose of imipramine may be required. Imipramine is a CYP2D6 substrate with a narrow therapeutic index, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the use of rolapitant with chronic administration of rifampin. Rolapitant is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. When rifampin (600 mg once daily) was administered for 7 days before and 7 days after a single dose of rolapitant (180 mg), the mean Cmax and AUC of rolapitant were decreased by 30% and 85%, respectively; additionally, the mean half-life decreased from 176 hours to 41 hours. Significantly reduced plasma concentrations and decreased half-life can decrease the efficacy of rolapitant.
    Isoniazid, INH; Rifampin: (Major) Avoid the use of rolapitant with chronic administration of rifampin. Rolapitant is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. When rifampin (600 mg once daily) was administered for 7 days before and 7 days after a single dose of rolapitant (180 mg), the mean Cmax and AUC of rolapitant were decreased by 30% and 85%, respectively; additionally, the mean half-life decreased from 176 hours to 41 hours. Significantly reduced plasma concentrations and decreased half-life can decrease the efficacy of rolapitant.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Use caution if tenofovir, PMPA and rolapitant are used concurrently, and monitor for tenofovir-related adverse effects. Tenofovir is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Ledipasvir; Sofosbuvir: (Moderate) Use caution if ledipasvir; sofosbuvir and rolapitant are used concurrently, and monitor for ledipasvir- or sofosbuvir-related adverse effects. Ledipasvir and sofosbuvir are both substrates of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied. (Moderate) Use caution if sofosbuvir and rolapitant are used concurrently, and monitor for sofosbuvir-related adverse effects. Sofosbuvir is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of rolapitant; monitor for potential reduction in efficacy. Rolapitant is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of rolapitant; monitor for potential reduction in efficacy. Rolapitant is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lofexidine: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and rolapitant. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; rolapitant is a CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
    Loperamide: (Major) Concurrent administration of loperamide and rolapitant may increase the risk for loperamide-associated adverse reactions, such as CNS events and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest). Loperamide is a CYP2D6 and P-glycoprotein (P-gp) substrate and rolapitant is a CYP2D6 and P-gp inhibitor; the inhibitory effect of rolapitant on CYP2D6 is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. When rolapitant was administered with another P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Loperamide; Simethicone: (Major) Concurrent administration of loperamide and rolapitant may increase the risk for loperamide-associated adverse reactions, such as CNS events and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest). Loperamide is a CYP2D6 and P-glycoprotein (P-gp) substrate and rolapitant is a CYP2D6 and P-gp inhibitor; the inhibitory effect of rolapitant on CYP2D6 is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. When rolapitant was administered with another P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Maprotiline: (Major) Use caution if maprotiline and rolapitant are used concurrently, and monitor for maprotiline-related adverse effects. Maprotiline is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Maraviroc: (Moderate) Use caution and closely monitor for increased adverse effects with the coadministration of maraviroc and rolapitant as increased maraviroc concentrations may occur. Maraviroc is a substrate of P-glycoprotein (P-gp); rolapitant is an inhibitor of P-gp. The effects of P-gp on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
    Meclizine: (Major) Use caution if meclizine and rolapitant are used concurrently, and monitor for meclizine-related adverse effects. Meclizine is a substrate of CYP2D6 and rolapitant is an inhibitor of CYP2D6; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Meperidine; Promethazine: (Major) Use caution if promethazine and rolapitant are used concurrently, and monitor for promethazine-related adverse effects. Promethazine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Mephobarbital: (Major) Avoid the use of rolapitant with chronic administration of phenobarbital; this also applies to drugs that are metabolized to phenobarbital, such as mephobarbital and primidone. Rolapitant is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. When another strong CYP3A4 inducer, rifampin (600 mg once daily), was administered for 7 days before and 7 days after a single dose of rolapitant (180 mg), the mean Cmax and AUC of rolapitant were decreased by 30% and 85%, respectively; additionally, the mean half-life decreased from 176 hours to 41 hours. Significantly reduced plasma concentrations and decreased half-life can decrease the efficacy of rolapitant.
    Methadone: (Major) Use caution if methadone and rolapitant are used concurrently, and monitor for methadone-related adverse effects. Methadone is a substrate of CYP2D6 and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is an inhibitor of CYP2D6 and P-gp. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. When oral rolapitant was administered with another P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied. When the P-gp substrate was administered with a single dose of intravenous rolapitant, no effect on AUC and a 21% increase in the Cmax of P-gp substrate was observed.
    Methamphetamine: (Major) Avoid coadministration of methamphetamine, a CYP2D6 substrate, with rolapitant, a moderate CYP2D6 inhibitor because it may result in methamphetamine-related adverse effects and toxicities, including serotonin syndrome. Consider alternative drug therapy with a drug that does not inhibit CYP2D6. If coadministration is necessary, initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during methamphetamine initiation and after a dosage increase. If serotonin syndrome occurs, discontinue methamphetamine and the CYP2D6 rolapitant. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Methotrexate: (Major) Avoid the concurrent use of methotrexate and rolapitant if possible; if coadministration is necessary, monitor methotrexate levels and watch for methotrexate-related adverse effects. Methotrexate is a substrate of the Breast Cancer Resistance Protein (BCRP), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration.
    Metoclopramide: (Major) Use caution if metoclopramide and rolapitant are used concurrently, and monitor for metoclopramide-related adverse effects. Metoclopramide is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Metoprolol: (Moderate) Monitor for increased metoprolol adverse reactions including bradycardia and hypotension during coadministration. A dosage reduction for metoprolol may be needed based on response. Concurrent use may increase metoprolol exposure. Metoprolol is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. In the presence of another moderate CYP2D6 inhibitor, the AUC of metoprolol was increased by 3.29-fold with no effect on the cardiovascular response to metoprolol.
    Mexiletine: (Major) Use caution if mexiletine and rolapitant are used concurrently, and monitor for mexiletine-related adverse effects and toxicities. Mexiletine is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Mirtazapine: (Major) Use caution if mirtazapine and rolapitant are used concurrently, and monitor for mirtazapine-related adverse effects. Mirtazapine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Mitotane: (Major) Avoid the concomitant use of mitotane with rolapitant; if coadministration cannot be avoided, monitor for decreased efficacy of rolapitant. Mitotane is a strong CYP3A4 inducer and rolapitant is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of rolapitant. When another strong CYP3A4 inducer, rifampin (600 mg once daily), was administered for 7 days before and 7 days after a single dose of rolapitant (180 mg), the mean Cmax and AUC of rolapitant were decreased by 30% and 85%, respectively; additionally, the mean half-life decreased from 176 hours to 41 hours.
    Morphine: (Major) Use caution if morphine and rolapitant are used concurrently, and monitor for morphine-related adverse effects. Morphine is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Morphine; Naltrexone: (Major) Use caution if morphine and rolapitant are used concurrently, and monitor for morphine-related adverse effects. Morphine is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Nebivolol: (Major) Avoid the concomitant use of nebivolol and rolapitant. If these drugs are coadministered, patients should be monitored and the nebivolol dose should be adjusted according to blood pressure response. Nebivolol is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Nebivolol; Valsartan: (Major) Avoid the concomitant use of nebivolol and rolapitant. If these drugs are coadministered, patients should be monitored and the nebivolol dose should be adjusted according to blood pressure response. Nebivolol is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Nortriptyline: (Major) Monitor for increased serum concentrations of nortriptyline and for nortriptyline-related adverse effects, such as nausea, dizziness, hypotension, syncope, and QT prolongation, if coadministered with rolapitant. Lower doses of either drug may be required with coadministration. When rolapitant is withdrawn from co-therapy, an increased dose of nortriptyline may be required. Nortriptyline is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Olanzapine: (Major) Monitor for olanzapine-related adverse effects, including QT prolongation, if coadministered with rolapitant. Increased exposure to olanzapine may occur. Olanzapine is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Ondansetron: (Major) Use caution if ondansetron and rolapitant are used concurrently, and monitor for ondansetron-related adverse effects. Ondansetron is a substrate of CYP2D6 and P-glycoprotein (P-gp) and rolapitant is an inhibitor of CYP2D6 and P-gp. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. When oral rolapitant was administered with another P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied. When the P-gp substrate was administered with a single dose of intravenous rolapitant, no effect on AUC and a 21% increase in the Cmax of P-gp substrate was observed.
    Oxycodone: (Major) Use caution if oxycodone and rolapitant are used concurrently, and monitor for oxycodone-related adverse effects. Oxycodone is a CYP2D6 substrate where an increase in exposure may significantly increase adverse effects, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Paclitaxel: (Moderate) Use caution if paclitaxel and rolapitant are used concurrently, and monitor for paclitaxel-related adverse effects. Paclitaxel is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Paroxetine: (Major) Use caution if paroxetine and rolapitant are used concurrently, and monitor for paroxetine-related adverse effects. Paroxetine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Pazopanib: (Moderate) Use caution if pazopanib and rolapitant are used concurrently, and monitor for pazopanib-related adverse effects. Pazopanib is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied. Additionally, pazopanib is also a weak inhibitor of CYP3A4 and rolapitant is a CYP3A4 substrate. Theoretically this could increase rolapitant concentrations, but this effect is not expected to be clinically relevant.
    Pentamidine: (Major) Use caution if pentamidine and rolapitant are used concurrently, and monitor for pentamidine-related adverse effects. Pentamidine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Perphenazine: (Major) Monitor for perphenazine-related adverse effects, including QT prolongation, if coadministered with rolapitant. Increased exposure to perphenazine may occur. Perphenazine is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Perphenazine; Amitriptyline: (Major) Monitor for increased serum concentrations of amitriptyline and for amitriptyline-related adverse effects, such as nausea, dizziness, hypotension, syncope, and QT prolongation, if coadministered with rolapitant. Lower doses of either drug may be required with coadministration. When rolapitant is withdrawn from co-therapy, an increased dose of amitriptyline may be required. Amitriptyline is a CYP2D6 substrate, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. (Major) Monitor for perphenazine-related adverse effects, including QT prolongation, if coadministered with rolapitant. Increased exposure to perphenazine may occur. Perphenazine is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Phenobarbital: (Major) Avoid the use of rolapitant with chronic administration of phenobarbital; this also applies to drugs that are metabolized to phenobarbital, such as mephobarbital and primidone. Rolapitant is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. When another strong CYP3A4 inducer, rifampin (600 mg once daily), was administered for 7 days before and 7 days after a single dose of rolapitant (180 mg), the mean Cmax and AUC of rolapitant were decreased by 30% and 85%, respectively; additionally, the mean half-life decreased from 176 hours to 41 hours. Significantly reduced plasma concentrations and decreased half-life can decrease the efficacy of rolapitant.
    Phenylephrine; Promethazine: (Major) Use caution if promethazine and rolapitant are used concurrently, and monitor for promethazine-related adverse effects. Promethazine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Phenytoin: (Major) Avoid the use of rolapitant with chronic administration of phenytoin. Rolapitant is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. When another strong CYP3A4 inducer, rifampin (600 mg once daily), was administered for 7 days before and 7 days after a single dose of rolapitant (180 mg), the mean Cmax and AUC of rolapitant were decreased by 30% and 85%, respectively; additionally, the mean half-life decreased from 176 hours to 41 hours. Significantly reduced plasma concentrations and decreased half-life can decrease the efficacy of rolapitant.
    Pimozide: (Severe) Because of the potential for QT prolongation and torsade de pointes (TdP), concurrent use of pimozide and rolapitant is contraindicated. Pimozide is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Pimozide is associated with an established risk of QT prolongation and torsade de pointes (TdP); a significant increase in plasma concentrations may increase this risk.
    Pirfenidone: (Major) Use caution if pirfenidone and rolapitant are used concurrently, and monitor for pirfenidone-related adverse effects. Pirfenidone is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Primidone: (Major) Avoid the use of rolapitant with chronic administration of phenobarbital; this also applies to drugs that are metabolized to phenobarbital, such as mephobarbital and primidone. Rolapitant is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. When another strong CYP3A4 inducer, rifampin (600 mg once daily), was administered for 7 days before and 7 days after a single dose of rolapitant (180 mg), the mean Cmax and AUC of rolapitant were decreased by 30% and 85%, respectively; additionally, the mean half-life decreased from 176 hours to 41 hours. Significantly reduced plasma concentrations and decreased half-life can decrease the efficacy of rolapitant.
    Promethazine: (Major) Use caution if promethazine and rolapitant are used concurrently, and monitor for promethazine-related adverse effects. Promethazine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Propafenone: (Major) Monitor for propafenone-related adverse effects, including QT prolongation, if coadministered with rolapitant. Increased exposure to propafenone may occur . Propafenone is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Propranolol: (Major) Use caution if propranolol and rolapitant are used concurrently, and monitor for propranolol-related adverse effects, including bradycardia. Propranolol is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Protriptyline: (Major) Monitor for increased serum concentrations of protriptyline and protriptyline-related adverse effects, such as nausea, dizziness, hypotension, syncope, and QT prolongation, if coadministered with rolapitant. Lower doses of either drug may be required with coadministration. When rolapitant is withdrawn from co-therapy, an increased dose of protriptyline may be required. Protriptyline is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Quinidine: (Moderate) Use caution if quinidine and rolapitant are used concurrently, and monitor for quinidine-related adverse effects, including QT prolongation. Quinidine is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Ranolazine: (Major) Use caution if ranolazine and rolapitant are used concurrently, and monitor for ranolazine-related adverse effects. Ranolazine is a CYP2D6 and P-glycoprotein (P-gp) substrate and rolapitant is a CYP2D6 and P-gp inhibitor; the inhibitory effect of rolapitant on CYP2D6 lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Rifampin: (Major) Avoid the use of rolapitant with chronic administration of rifampin. Rolapitant is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. When rifampin (600 mg once daily) was administered for 7 days before and 7 days after a single dose of rolapitant (180 mg), the mean Cmax and AUC of rolapitant were decreased by 30% and 85%, respectively; additionally, the mean half-life decreased from 176 hours to 41 hours. Significantly reduced plasma concentrations and decreased half-life can decrease the efficacy of rolapitant.
    Risperidone: (Major) Coadministration of risperidone, a CYP2D6 substrate, and rolapitant, a CYP2D6 inhibitor, may increase plasma concentrations of risperidone. The inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. When oral risperidone is given with a CYP2D6 inhibitor, the dose of risperidone should be reduced; do not exceed 8 mg/day PO in adults. When initiating therapy, titrate risperidone slowly. Upon discontinuation of the CYP2D6 inhibitor, the risperidone dose should be re-evaluated and increased if necessary. For the long-acting injection, the current adult dosage should be re-evaluated when a CYP2D6 inhibitor is initiated or discontinued. When initiation of a CYP2D6 inhibitor is considered, patients may be placed on a lower dose of injectable risperidone 2 to 4 weeks prior to initiation to adjust for the expected increase in risperidone plasma concentrations. For patients receiving a 25 mg dose, it is recommended to maintain the 25 mg dose upon initiation of the CYP2D6 inhibitor unless clinical judgment warrants lowering the dose to 12.5 mg or interrupting risperidone therapy. The efficacy of the 12.5 mg dose has not been evaluated in clinical trials. When injectable risperidone is initiated in patients already receiving a CYP2D6 inhibitor, a starting dose of 12.5 mg can be considered. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Rosuvastatin: (Moderate) Avoid the concurrent use of rosuvastatin and rolapitant if possible; if coadministration is necessary, use the lowest effective dose of rosuvastatin and monitor for rosuvastatin-related adverse effects. Rosuvastatin is a substrate of the Breast Cancer Resistance Protein (BCRP), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration.
    Sertraline: (Major) Use caution if sertraline and rolapitant are used concurrently, and monitor for sertraline-related adverse effects. Sertraline is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Sirolimus: (Moderate) Use caution if sirolimus and rolapitant are used concurrently, and monitor sirolimus levels and watch for sirolimus-related adverse effects. Sirolimus is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase concentrations and adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Sofosbuvir: (Moderate) Use caution if sofosbuvir and rolapitant are used concurrently, and monitor for sofosbuvir-related adverse effects. Sofosbuvir is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution if sofosbuvir and rolapitant are used concurrently, and monitor for sofosbuvir-related adverse effects. Sofosbuvir is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied. (Moderate) Use caution when administering velpatasvir with rolapitant. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); rolapitant is an inhibitor of both P-gp and BCRP.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution if sofosbuvir and rolapitant are used concurrently, and monitor for sofosbuvir-related adverse effects. Sofosbuvir is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied. (Moderate) Use caution when administering velpatasvir with rolapitant. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); rolapitant is an inhibitor of both P-gp and BCRP.
    St. John's Wort, Hypericum perforatum: (Severe) Avoid the use of rolapitant with chronic administration of St. John's Wort, Hypericum perforatum. Rolapitant is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. When another strong CYP3A4 inducer, rifampin (600 mg once daily), was administered for 7 days before and 7 days after a single dose of rolapitant (180 mg), the mean Cmax and AUC of rolapitant were decreased by 30% and 85%, respectively; additionally, the mean half-life decreased from 176 hours to 41 hours. Significantly reduced plasma concentrations and decreased half-life can decrease the efficacy of rolapitant.
    Sulfasalazine: (Moderate) Use caution if sulfasalazine and rolapitant are used concurrently, and monitor for sulfasalazine-related adverse effects. Sulfasalazine is a substrate of the Breast Cancer Resistance Protein (BCRP); rolapitant is a BCRP inhibitor. The Cmax and AUC of sulfasalazine were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration.
    Talazoparib: (Major) Avoid coadministration of rolapitant with talazoparib due to increased talazoparib exposure. If concomitant use is unavoidable, monitor for an increase in talazoparib-related adverse reactions. Talazoparib is a BCRP and P-glycoprotein (P-gp) substrate; rolapitant is a BCRP and P-gp inhibitor. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%. The effect of concomitant administration of BCRP inhibitors on the pharmacokinetics of talazoparib has not been studied; however, BCRP inhibitors may increase talazoparib exposure.
    Tamsulosin: (Major) Use caution if tamsulosin and rolapitant are used concurrently, and monitor for tamsulosin-related adverse effects. Tamsulosin is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and rolapitant is necessary, as the systemic exposure of rolapitant may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of rolapitant as well as an increase in adverse reactions related to telotristat ethyl. Rolapitant is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and rolapitant is a P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with rolapitant is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and rolapitant is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Tenofovir Alafenamide: (Moderate) Coadministration of rolapitant and tenofovir alafenamide may result in elevated tenofovir concentrations. Tenofovir is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp); rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140 percent and 130 percent, respectively, on day 1 with rolapitant, and by 17 percent and 32 percent, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70 percent and 30 percent, respectively; the Cmax and AUC on day 8 were not studied.
    Tenofovir, PMPA: (Moderate) Use caution if tenofovir, PMPA and rolapitant are used concurrently, and monitor for tenofovir-related adverse effects. Tenofovir is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Tetrabenazine: (Major) Use caution if tetrabenazine and rolapitant are used concurrently, and monitor for tetrabenazine-related adverse effects. Tetrabenazine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Thioridazine: (Severe) Because of the potential for QT prolongation and torsade de pointes (TdP), concurrent use of thioridazine and rolapitant is contraindicated. Thioridazine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Pimozide is associated with an established risk of QT prolongation and torsade de pointes (TdP); a significant increase in plasma concentrations may increase this risk.
    Timolol: (Major) Use caution if timolol and rolapitant are used concurrently, and monitor for timolol-related adverse effects. Timolol is a substrate of CYP2D6 and rolapitant is an inhibitor of CYP2D6 ; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Tolterodine: (Major) Use caution if tolterodine and rolapitant are used concurrently, and monitor for tolterodine-related adverse effects. Tolterodine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Topotecan: (Major) Avoid coadministration of rolapitant with oral topotecan due to increased topotecan exposure; rolapitant may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); rolapitant is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Tramadol: (Major) Use caution if tramadol and rolapitant are used concurrently, and monitor for tramadol-related adverse effects as well as possible changes to the efficacy of tramadol. Rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6; therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 is expected to result in reduced metabolic clearance of tramadol, which in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures; serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Trimipramine: (Major) Monitor for increased serum concentrations of trimipramine and for trimipramine-related adverse effects, such as nausea, dizziness, hypotension, syncope, and QT prolongation, if coadministered with rolapitant. Lower doses of either drug may be required with coadministration. When rolapitant is withdrawn from co-therapy, an increased dose of trimipramine may be required. Trimipramine is a CYP2D6 substrate, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Umeclidinium: (Major) Use caution if umeclidinium and rolapitant are used concurrently, and monitor for umeclidinium-related adverse effects. Umeclidinium is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration.
    Umeclidinium; Vilanterol: (Major) Use caution if umeclidinium and rolapitant are used concurrently, and monitor for umeclidinium-related adverse effects. Umeclidinium is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration.
    Vemurafenib: (Moderate) Use caution if vemurafenib and rolapitant are used concurrently, and monitor for vemurafenib-related adverse effects. Vemurafenib is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with rolapitant due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of rolapitant. Venetoclax is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); rolapitant is an inhibitor of P-gp and BCRP. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Venlafaxine: (Major) Use caution if venlafaxine and rolapitant are used concurrently, and monitor for venlafaxine-related adverse effects. Venlafaxine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Vinblastine: (Moderate) Use caution if vinblastine and rolapitant are used concurrently, and monitor for vinblastine-related adverse effects. Vinblastine is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Vincristine Liposomal: (Moderate) Use caution if vincristine and rolapitant are used concurrently, and monitor for vincristine-related adverse effects. Vincristine is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Vincristine: (Moderate) Use caution if vincristine and rolapitant are used concurrently, and monitor for vincristine-related adverse effects. Vincristine is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Vortioxetine: (Major) Use caution if vortioxetine and rolapitant are used concurrently, and monitor for vortioxetine-related adverse effects. Vortioxetine is a substrate of CYP2D6 and rolapitant is an inhibitor of CYP2D6 ; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Warfarin: (Major) Avoid the concurrent use of warfarin and rolapitant if possible; if coadministration is necessary, monitor INR and prothrombin time carefully and adjust the dosage of warfarin, as needed to maintain the target INR range. In vitro, warfarin is a CYP2D6 substrate, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Yohimbine: (Major) Use caution if yohimbine and rolapitant are used concurrently, and monitor for yohimbine-related adverse effects. Yohimbine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.

    PREGNANCY AND LACTATION

    Pregnancy

    Female patients of reproductive potential should be advised of the risk of infertility with rolapitant; in animal fertility studies, rolapitant impaired fertility in a reversible fashion. Although there are no adequate and well-controlled studies in pregnancy, there were no teratogenic or embryo-fetal effects observed with oral administration of rolapitant to rats and rabbits during organogenesis at doses up to 1.3 and 2.9 times the maximum recommended human dose (MRHD), respectively. Pregnant rats experienced decreased weight gain and/or weight loss as well as a decrease in food consumption during the first week of dosing equivalent to 13.5 or 22.5 mg/kg/day of rolapitant free base (0.72 to 1.2 times the MRHD); additional maternal toxicities included total litter loss, prolonged parturition, decreased length of gestation, and increased number of unaccounted for implantation sites at doses equivalent to 1.2 times the MRHD. At this dose, offspring experienced decreased postnatal survival and decreased or increased body weight, which may be related to the maternal toxicity. At a maternal dose equivalent to 0.5 times the MRHD, there was a decrease in memory in female pups in a maze test and a decrease in pup body weight.

    MECHANISM OF ACTION

    Rolapitant is a selective, competitive antagonist of substance P/neurokinin-1 (NK1) receptors. Substance P and the NK1 receptors are present in the brain stem (medulla) centers that control the emetic reflex. Substance P is a peptide that increases the contractions of smooth GI muscles and leads to vasodilation. Rolapitant has little or no affinity for the NK2 or NK3 receptors.

    PHARMACOKINETICS

    Rolapitant is administered orally and crosses the blood brain barrier to occupy NK1 receptors. After a single 180 mg dose of rolapitant was administered to healthy subjects, the mean NK1 receptor occupancy was 73% in the striatum at 120 hours; the relationship between NK1 receptor occupancy and clinical efficacy has not been established. Rolapitant is highly protein bound to human plasma (99.8%), with an apparent volume of distribution (Vd) of 460 liters in healthy subjects indicating extensive tissue distribution; the Vd in cancer patients is 387 liters, based on a population pharmacokinetic analysis. Following single intravenous doses (18 to 180 mg) and single oral doses (4.5 to 180 mg) of rolapitant, the mean terminal half-life of rolapitant ranged from 138 to 205 hours and 169 to 183 hours (approximately 7 days), respectively, and was independent of dose. The mean half-life of the active metabolite, M19, was 158 hours. The apparent total clearance (CL/F) was 0.96/L/hour in cancer patients, based on a population pharmacokinetic analysis. The total clearance following intravenous administration of 166.5 mg rolapitant in healthy subjects was 1.65 L/hour. Rolapitant is eliminated primarily via the hepatic/biliary route, with 14.2% of a radiolabeled dose (range, 9% to 20%) recovered in the urine and 73% (range, 52% to 89%) recovered in feces over 6 weeks. In pooled samples collected over 2 weeks, 8.3% of the dose was recovered in the urine (primarily as metabolites) and 37.8% was recovered in the feces (primarily as unchanged drug); unchanged rolapitant or M19 were not found in the pooled urine sample.
     
    Affected cytochrome P450 (CYP450) isoenzymes and other drug transporters: CYP2D6, CYP3A4, P-glycoprotein (P-gp), and Breast Cancer Resistance Protein (BCRP)
    Rolapitant is metabolized by CYP3A4 to form a major active metabolite, M19 (C4-pyrrolidine-hydroxylated rolapitant); the exposure ratio of M19: rolapitant was approximately 50% in plasma. Rolapitant is a moderate inhibitor of CYP2D6, and also inhibits P-gp and BCRP. Avoid the use of rolapitant with strong CYP3A4 inducers, and with substrates of CYP2D6, P-gp, and BCRP that have a narrow therapeutic index.

    Oral Route

    After a single dose of rolapitant 180 mg under fasting conditions, rolapitant was measurable in the plasma at 30 minutes, with Tmax at about 4 hours; the median Tmax of the active metabolite, M19, was 120 hours (range, 24 to 168 hours). The mean Cmax for rolapitant was 968 ng/mL (CV, 28%). After multiple daily dosing (9 to 45 mg PO), accumulation of rolapitant was approximately 5-fold. Cmax and AUC increase in a dose proportional manner between 4.5 to 180 mg; with an increase in dose by 4 times from the recommended dose of 180mg, the Cmax and AUC increased by 3.1 and 3.7-fold, respectively. Administration with a high fat meal does not significantly affect the pharmacokinetics of rolapitant.

    Intravenous Route

    Following a 30-minute infusion of a single intravenous dose of 166.5 mg rolapitant injectable emulsion to healthy subjects, the mean Cmax at the end of a 30 minute infusion was 1986 ng/mL. Following multiple intravenous doses of 18 to 54 mg once daily of rolapitant (approximately 10% to 33% of the recommended dose) for 10 days, accumulation of rolapitant (ratio of AUC0-24hr) ranged from 4.3 fold to 5.4 fold. The systemic exposures (Cmax and AUC) to rolapitant increased in a dose-proportional manner when single intravenous doses of rolapitant increased from 18 mg to 180 mg. The Cmax and AUC of rolapitant increased 11.6 fold and 10.1 fold, respectively. At the recommended dose, the absolute bioavailability of rolapitant is 91%.