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    Small Molecule Antineoplastic Poly (ADP-ribose) Polymerase (PARP) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Poly (ADP-ribose) polymerase (PARP) inhibitor
    Used as monotherapy in patients with BRCA-mutated ovarian cancer who have been treated with 2 or more prior chemotherapy regimens and as maintenance therapy for recurrent ovarian cancer after a response to platinum-based chemotherapy
    Most common grade 3 or 4 adverse reactions include anemia, asthenia/fatigue, increased ALT, and neutropenia

    COMMON BRAND NAMES

    Rubraca

    HOW SUPPLIED

    Rubraca Oral Tab: 200mg, 250mg, 300mg

    DOSAGE & INDICATIONS

    For the treatment of ovarian cancer.
    For the treatment of BRCA mutation-positive (germline and/or somatic) epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who have received 2 or more prior chemotherapy regimens, as monotherapy.
    Oral dosage
    Adults

    600 mg orally twice daily until disease progression or unacceptable toxicity. In two multicenter, open-label, single-arm clinical trials (n = 106), patients with advanced, BRCA mutation-positive ovarian cancer were treated with rucaparib after failure of 2 prior chemotherapy regimens. The investigator-assessed objective response rate (ORR) was 54% (95% CI, 44% to 64%), with 9% of patients experiencing a complete response and a partial response in 45%. The median duration of response was 9.2 months (95% CI, 6.6 to 11.6 months).

    For the maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer after a complete or partial response to platinum-based chemotherapy, as monotherapy.
    Oral dosage
    Adults

    600 mg orally twice daily until disease progression or unacceptable toxicity. In an interim analysis of a double-blind clinical trial of patients with platinum sensitive, high-grade serous or endometroid ovarian, primary peritoneal, or fallopian tube carcinoma, maintenance therapy with rucaparib within 8 weeks of completion of platinum therapy significantly improved progression-free survival (PFS) compared with placebo (10.8 months vs. 5.4 months). Patients in this trial had received at least 2 previous platinum-based chemo regimens. Overall survival data were not mature.

    MAXIMUM DOSAGE

    Adults

    600 mg PO twice daily.

    Geriatric

    600 mg PO twice daily.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment:
    Mild hepatic impairment (total bilirubin less than or equal to the upper limit of normal (ULN) and AST greater than ULN, or total bilirubin 1 to 1.5 times ULN and any AST: No dosage adjustment necessary.
    Moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN): No recommendation is available due to a lack of data.

    Renal Impairment

    Baseline Renal Impairment:
    Mild to moderate renal impairment (CrCL 30 to 89 mL/min): No dosage adjustment necessary.
    Severe renal impairment (CrCL less than 30 mL/min) or hemodialysis: No recommendation is available due to lack of data.

    ADMINISTRATION

    Oral Administration

    Take tablets with or without food. Administration with a high-fat meal increases the Cmax and AUC of rucaparib (by 20% and 38%, respectively), and delays clearance by 2.5 hours.
    If a dose is missed, the patient should take the next dose at the regularly scheduled time; do not replace doses if vomiting occurs.

    STORAGE

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

    CONTRAINDICATIONS / PRECAUTIONS

    Leukemia, myelodysplastic syndrome (MDS)

    Myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) has been reported in 12 patients who received rucaparib therapy, including those in long term follow-up, between 1 to 28 months after starting treatment with rucaparib; 5 of these patients developed MDS/AML during treatment or during the 28 day safety follow-up. All patients had received prior treatment with platinum-containing chemotherapy and other DNA damaging agents. Monitor complete blood counts (CBC) prior to starting therapy and monthly thereafter. Rucaparib should not be started until any prior hematologic toxicity resolves to grade 1 or less. For prolonged hematologic toxicity (greater than 4 weeks), hold therapy or reduce the dose and check a CBC every week until recovery. If resolution to grade 1 or less has not occurred after 4 weeks or if MDS/AML is suspected, the patient should be referred to a hematologist for further investigations including a bone marrow analysis and cytogenetics. Rucaparib should be discontinued if a diagnosis of MDS or AML is confirmed.

    Contraception requirements, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during rucaparib treatment. Rucaparib can be cause embryo-fetal death if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 6 months after treatment. Females of reproductive potential should undergo pregnancy testing prior to initiation of rucaparib. Women who become pregnant while receiving rucaparib should be apprised of the potential hazard to the fetus. Fertility studies have not been conducted; however, there were no effects on male or female reproductive organs in rats or dogs at exposures of 0.09 to 0.3 times the exposures expected with recommended dosing in humans.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during rucaparib treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in humans, rucaparib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Administration of rucaparib to pregnant rats during organogenesis resulted in embryo-fetal death in all animals at exposures equal to 0.04 times the AUC expected at recommended human doses.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from rucaparib, advise women to discontinue breast-feeding during treatment and for 2 weeks after the final dose. It is not known whether rucaparib is present in human milk, although many drugs are excreted in human milk.

    ADVERSE REACTIONS

    Severe

    anemia / Delayed / 21.0-25.0
    elevated hepatic enzymes / Delayed / 0.3-13.0
    asthenia / Delayed / 7.0-11.0
    fatigue / Early / 7.0-11.0
    neutropenia / Delayed / 0-8.0
    thrombocytopenia / Delayed / 5.0-5.0
    nausea / Early / 4.0-5.0
    vomiting / Early / 4.0-4.0
    hypercholesterolemia / Delayed / 2.0-4.0
    abdominal pain / Early / 3.0-3.0
    anorexia / Delayed / 1.0-3.0
    diarrhea / Early / 0.5-2.0
    constipation / Delayed / 2.0-2.0
    new primary malignancy / Delayed / 0-1.1
    stomatitis / Delayed / 0-1.0
    rash / Early / 0-1.0
    renal failure (unspecified) / Delayed / 0.3-1.0
    dyspnea / Early / 0-0.5
    dysgeusia / Early / 0-0.3
    pharyngitis / Delayed / 0.3-0.3
    infection / Delayed / 0.3-0.3

    Moderate

    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 0-2.0
    lymphopenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known

    Mild

    dyspepsia / Early / 0-19.0
    dizziness / Early / 17.0-19.0
    headache / Early / 0-18.0
    fever / Early / 11.0-13.0
    photosensitivity / Delayed / 0-10.0
    pruritus / Rapid / 0-9.0
    maculopapular rash / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions if coadministration with rucaparib is necessary. Some patients may need to reduce or limit their caffeine intake. Caffeine is a sensitive CYP1A2 substrate and rucaparib is a weak CYP1A2 inhibitor. Concomitant use increased the AUC of caffeine by 2.55-fold.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions if coadministration with rucaparib is necessary. Some patients may need to reduce or limit their caffeine intake. Caffeine is a sensitive CYP1A2 substrate and rucaparib is a weak CYP1A2 inhibitor. Concomitant use increased the AUC of caffeine by 2.55-fold.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions if coadministration with rucaparib is necessary. Some patients may need to reduce or limit their caffeine intake. Caffeine is a sensitive CYP1A2 substrate and rucaparib is a weak CYP1A2 inhibitor. Concomitant use increased the AUC of caffeine by 2.55-fold. (Moderate) Monitor for an increase in codeine-related adverse reactions, including sedation and respiratory depression, if coadministration with rucaparib is necessary; consider reducing the dose of codeine if clinically appropriate. If rucaparib is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the codeine dose if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Rucaparib is a weak CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with rucaparib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of rucaparib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If rucaparib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Rucaparib is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Monitor for an increase in caffeine-related adverse reactions if coadministration with rucaparib is necessary. Some patients may need to reduce or limit their caffeine intake. Caffeine is a sensitive CYP1A2 substrate and rucaparib is a weak CYP1A2 inhibitor. Concomitant use increased the AUC of caffeine by 2.55-fold.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Monitor for an increase in caffeine-related adverse reactions if coadministration with rucaparib is necessary. Some patients may need to reduce or limit their caffeine intake. Caffeine is a sensitive CYP1A2 substrate and rucaparib is a weak CYP1A2 inhibitor. Concomitant use increased the AUC of caffeine by 2.55-fold.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Monitor for an increase in caffeine-related adverse reactions if coadministration with rucaparib is necessary. Some patients may need to reduce or limit their caffeine intake. Caffeine is a sensitive CYP1A2 substrate and rucaparib is a weak CYP1A2 inhibitor. Concomitant use increased the AUC of caffeine by 2.55-fold.
    Acetaminophen; Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions, including sedation and respiratory depression, if coadministration with rucaparib is necessary; consider reducing the dose of codeine if clinically appropriate. If rucaparib is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the codeine dose if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Rucaparib is a weak CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the hydrocodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Hydrocodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If rucaparib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If rucaparib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Acetaminophen; Tramadol: (Moderate) Monitor for an increase in tramadol-related adverse reactions, including serotonin syndrome, seizures, sedation, and respiratory depression, if coadministration with rucaparib is necessary; the risk is greatest if rucaparib is added to a stable dose of tramadol. Consider decreasing the dose of tramadol if necessary. Rucaparib is a weak CYP3A4 inhibitor and tramadol is metabolized by both CYP3A4 and CYP2D6. Coadministration with a CYP3A4 inhibitor may result in a greater amount of tramadol metabolism via CYP2D6, and greater levels of the active metabolite, M1.
    Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If rucaparib is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
    Alosetron: (Major) Avoid coadministration of alosetron and rucaparib unless clinically necessary due to the risk of increased plasma concentrations of alosetron. Alosetron is a CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor. Coadministration with a strong CYP1A2 inhibitor increased alosetron exposure by approximately 6-fold and prolonged the half-life by approximately 3-fold. Concomitant use with moderate CYP1A2 inhibitors has not been evaluated, but is expected to have similar potential drug interactions.
    Anagrelide: (Moderate) Monitor for cardiovascular events and titrate anagrelide doses accordingly if coadministration with rucaparib is necessary. Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide; dose-related increases in mean QTc and heart rate were also observed in healthy subjects. Anagrelide is a CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor. Drugs that inhibit CYP1A2 could increase anagrelide exposure.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions if coadministration with rucaparib is necessary. Some patients may need to reduce or limit their caffeine intake. Caffeine is a sensitive CYP1A2 substrate and rucaparib is a weak CYP1A2 inhibitor. Concomitant use increased the AUC of caffeine by 2.55-fold.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions if coadministration with rucaparib is necessary. Some patients may need to reduce or limit their caffeine intake. Caffeine is a sensitive CYP1A2 substrate and rucaparib is a weak CYP1A2 inhibitor. Concomitant use increased the AUC of caffeine by 2.55-fold. (Moderate) Monitor for an increase in codeine-related adverse reactions, including sedation and respiratory depression, if coadministration with rucaparib is necessary; consider reducing the dose of codeine if clinically appropriate. If rucaparib is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the codeine dose if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Rucaparib is a weak CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with rucaparib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of rucaparib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If rucaparib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Rucaparib is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Monitor for an increase in caffeine-related adverse reactions if coadministration with rucaparib is necessary. Some patients may need to reduce or limit their caffeine intake. Caffeine is a sensitive CYP1A2 substrate and rucaparib is a weak CYP1A2 inhibitor. Concomitant use increased the AUC of caffeine by 2.55-fold.
    Aspirin, ASA; Carisoprodol: (Minor) Monitor for changes in clinical response to carisoprodol or for an increase in carisoprodol-related adverse reactions if coadministration with rucaparib is necessary. Carisoprodol is a CYP2C19 substrate and rucaparib is a weak CYP2C19 inhibitor. Concomitant use could increase carisoprodol exposure and decrease exposure to the metabolite meprobamate. The full pharmacological impact of these potential alterations is unknown.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions, including sedation and respiratory depression, if coadministration with rucaparib is necessary; consider reducing the dose of codeine if clinically appropriate. If rucaparib is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the codeine dose if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Rucaparib is a weak CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations. (Minor) Monitor for changes in clinical response to carisoprodol or for an increase in carisoprodol-related adverse reactions if coadministration with rucaparib is necessary. Carisoprodol is a CYP2C19 substrate and rucaparib is a weak CYP2C19 inhibitor. Concomitant use could increase carisoprodol exposure and decrease exposure to the metabolite meprobamate. The full pharmacological impact of these potential alterations is unknown.
    Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If rucaparib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Monitor for an increase in phenobarbital-related adverse reactions if coadministration with rucaparib is necessary. Phenobarbital is a CYP2C9 and CYP2C19 substrate. Rucaparib is a weak inhibitor of both of these isoenzymes. Concomitant use may increase plasma concentrations of phenobarbital.
    Avatrombopag: (Moderate) A dosage adjustment of avatrombopag may be necessary if administered with rucaparib. Concomitant use may increase avatrombopag exposure, which may increase the risk of adverse reactions. Avatrombopag is metabolized by CYP2C9 and CYP3A4; rucaparib is a dual inhibitor of CYP3A4 and CYP2C9. Coadministration of another dual inhibitor of CYP2C9 and CYP3A4 increased exposure to avatrombopag by 2-fold.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Monitor for an increase in phenobarbital-related adverse reactions if coadministration with rucaparib is necessary. Phenobarbital is a CYP2C9 and CYP2C19 substrate. Rucaparib is a weak inhibitor of both of these isoenzymes. Concomitant use may increase plasma concentrations of phenobarbital. (Moderate) Monitor for ergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with rucaparib is necessary. Ergotamine is a CYP3A4 substrate with a narrow therapeutic range and rucaparib is a weak CYP3A4 inhibitor.
    Bendamustine: (Moderate) Monitor for an increase in bendamustine-related adverse reactions if coadministration with rucaparib is necessary; consider alternative treatments if clinically appropriate. The active metabolites of bendamustine, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4), are formed via cytochrome P450 CYP1A2. Rucaparib is a moderate CYP1A2 inhibitor. Formal clinical assessments of drug interactions between bendamustine and other drugs have not been conducted.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the hydrocodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Hydrocodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If rucaparib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the hydrocodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Hydrocodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If rucaparib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Bupivacaine; Lidocaine: (Moderate) Monitor for an increase in lidocaine-related adverse reactions if coadministration with rucaparib is necessary. Lidocaine is a CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor. Coadministration may increase lidocaine plasma concentrations.
    Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions if coadministration with rucaparib is necessary. Some patients may need to reduce or limit their caffeine intake. Caffeine is a sensitive CYP1A2 substrate and rucaparib is a weak CYP1A2 inhibitor. Concomitant use increased the AUC of caffeine by 2.55-fold.
    Caffeine; Ergotamine: (Moderate) Monitor for an increase in caffeine-related adverse reactions if coadministration with rucaparib is necessary. Some patients may need to reduce or limit their caffeine intake. Caffeine is a sensitive CYP1A2 substrate and rucaparib is a weak CYP1A2 inhibitor. Concomitant use increased the AUC of caffeine by 2.55-fold. (Moderate) Monitor for ergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with rucaparib is necessary. Ergotamine is a CYP3A4 substrate with a narrow therapeutic range and rucaparib is a weak CYP3A4 inhibitor.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the hydrocodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Hydrocodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If rucaparib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the hydrocodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Hydrocodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If rucaparib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Carisoprodol: (Minor) Monitor for changes in clinical response to carisoprodol or for an increase in carisoprodol-related adverse reactions if coadministration with rucaparib is necessary. Carisoprodol is a CYP2C19 substrate and rucaparib is a weak CYP2C19 inhibitor. Concomitant use could increase carisoprodol exposure and decrease exposure to the metabolite meprobamate. The full pharmacological impact of these potential alterations is unknown.
    Carvedilol: (Moderate) Monitor for signs of bradycardia or heart block if coadministration of carvedilol with rucaparib is necessary. Carvedilol is a CYP2C9 substrate and rucaparib is a weak CYP2C9 inhibitor. Concomitant use may enhance the beta-blocking properties of carvedilol resulting in further slowing of the heart rate or cardiac conduction.
    Celecoxib: (Moderate) Monitor for an increase in celecoxib-related adverse reactions if coadministration with rucaparib is necessary. Celecoxib is a CYP2C9 substrate and rucaparib is a weak CYP2C9 inhibitor.
    Chlorpheniramine; Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions, including sedation and respiratory depression, if coadministration with rucaparib is necessary; consider reducing the dose of codeine if clinically appropriate. If rucaparib is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the codeine dose if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Rucaparib is a weak CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with rucaparib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of rucaparib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If rucaparib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Rucaparib is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with rucaparib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of rucaparib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If rucaparib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Rucaparib is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the hydrocodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Hydrocodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If rucaparib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the hydrocodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Hydrocodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If rucaparib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the hydrocodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Hydrocodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If rucaparib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the hydrocodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Hydrocodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If rucaparib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Citalopram: (Moderate) The maximum daily dose of citalopram in patients receiving concomitant treatment with rucaparib is 20 mg. Monitor for an increase in citalopram-related adverse reactions, including QT prolongation. Citalopram is a CYP2C19 substrate and rucaparib is a weak CYP2C19 inhibitor.
    Clomipramine: (Moderate) Therapeutic monitoring is recommended if coadministration of clomipramine with rucaparib is necessary. Rucaparib is a moderate CYP1A2 inhibitor. Clomipramine is primarily metabolized by CYP2D6, however CYP1A2 is also involved.
    Clopidogrel: (Moderate) Monitor for decreased efficacy of clopidogrel if coadministration with rucaparib is necessary. Clopidogrel is a prodrug that is metabolized to its active metabolite by CYP2C19. Rucaparib is a weak CYP2C19 inhibitor. Concomitant use may reduce concentrations of the active metabolite, therefore decreasing the antiplatelet activity of clopidogrel.
    Clozapine: (Moderate) Monitor for an increase in clozapine-related adverse reactions (e.g., sedation, orthostasis, seizures, and QT prolongation) if coadministration with rucaparib is necessary; consider reducing the dose of clozapine if needed. If rucaparib is discontinued, monitor for a lack of efficacy, increasing the clozapine dose if necessary. Clozapine is a CYP1A2 and CYP3A4 substrate. Rucaparib is a moderate CYP1A2 inhibitor as well as a weak CYP3A4 inhibitor. Coadministration may increase plasma concentrations of clozapine.
    Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions, including sedation and respiratory depression, if coadministration with rucaparib is necessary; consider reducing the dose of codeine if clinically appropriate. If rucaparib is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the codeine dose if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Rucaparib is a weak CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Codeine; Guaifenesin: (Moderate) Monitor for an increase in codeine-related adverse reactions, including sedation and respiratory depression, if coadministration with rucaparib is necessary; consider reducing the dose of codeine if clinically appropriate. If rucaparib is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the codeine dose if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Rucaparib is a weak CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Codeine; Phenylephrine; Promethazine: (Moderate) Monitor for an increase in codeine-related adverse reactions, including sedation and respiratory depression, if coadministration with rucaparib is necessary; consider reducing the dose of codeine if clinically appropriate. If rucaparib is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the codeine dose if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Rucaparib is a weak CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Codeine; Promethazine: (Moderate) Monitor for an increase in codeine-related adverse reactions, including sedation and respiratory depression, if coadministration with rucaparib is necessary; consider reducing the dose of codeine if clinically appropriate. If rucaparib is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the codeine dose if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Rucaparib is a weak CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Colchicine: (Moderate) Closely monitor for evidence of colchicine toxicity if coadministration with rucaparib is necessary. Consider adjusting the colchicine dose by either reducing the daily dose or reducing the dose frequency. Concurrent use may increase colchicine exposure resulting in serious colchicine toxicity including multi-organ failure and death. Colchicine is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor.
    Cyclosporine: (Moderate) Monitor cyclosporine levels and watch for cyclosporine-related adverse reactions if coadministration with rucaparib is necessary. Cyclosporine is a CYP3A4 substrate with a narrow therapeutic index and rucaparib is a weak CYP3A4 inhibitor. Concomitant use may increase plasma concentrations of cyclosporine.
    Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions including sedation and respiratory depression if coadministration with rucaparib is necessary. Diazepam is a CYP2C19 substrate and rucaparib is a weak CYP2C19 inhibitor. Concomitant use may increase plasma concentrations of diazepam.
    Diclofenac: (Moderate) Monitor for an increase in diclofenac-related adverse reactions if coadministration with rucaparib is necessary. Diclofenac is a CYP2C9 substrate and rucaparib is a weak CYP2C9 inhibitor.
    Diclofenac; Misoprostol: (Moderate) Monitor for an increase in diclofenac-related adverse reactions if coadministration with rucaparib is necessary. Diclofenac is a CYP2C9 substrate and rucaparib is a weak CYP2C9 inhibitor.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with rucaparib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of rucaparib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If rucaparib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Rucaparib is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Dihydroergotamine: (Moderate) Monitor for dihydroergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with rucaparib is necessary. Dihydroergotamine is a CYP3A4 substrate with a narrow therapeutic range and rucaparib is a weak CYP3A4 inhibitor.
    Diltiazem: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with rucaparib is necessary. Diltiazem is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the hydrocodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Hydrocodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If rucaparib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Disopyramide: (Moderate) Monitor for an increase in disopyramide-related adverse reactions if coadministration with rucaparib is necessary. Disopyramide is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of disopyramide. Specific drug interaction studies have not been done for disopyramide; however, cases of life-threatening interactions have been reported when coadministered with moderate and strong CYP3A4 inhibitors. Coadministration of disopyramide with CYP3A4 inhibitors could result in a potentially fatal interaction.
    Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with rucaparib is necessary. Rucaparib is a weak CYP3A4 inhibitor and dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Doxorubicin: (Major) Avoid coadministration of rucaparib with doxorubicin due to the risk of increased doxorubicin exposure. Rucaparib is a CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4; clinically significant interactions have been reported with other CYP3A4 inhibitors, resulting in increased concentration and clinical effect of doxorubicin.
    Dronabinol: (Moderate) Monitor for an increase in dronabinol-related adverse reactions if coadministration with rucaparib is necessary. Dronabinol is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor.
    Efavirenz: (Moderate) Monitor for an increase in efavirenz-related adverse reactions if coadministration with rucaparib is necessary. Efavirenz is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Monitor for an increase in efavirenz-related adverse reactions if coadministration with rucaparib is necessary. Efavirenz is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in efavirenz-related adverse reactions if coadministration with rucaparib is necessary. Efavirenz is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor.
    Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of rucaparib and eliglustat is not recommended. Rucaparib is a weak CYP3A inhibitor; eliglustat is a CYP3A substrate. In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration of eliglustat with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias) in these patients.
    Enalapril; Felodipine: (Moderate) Monitor blood pressure if coadministration of felodipine and rucaparib is necessary. Felodipine is a sensitive substrate of CYP3A4 and rucaparib is a weak CYP3A4 inhibitor. Concomitant use may increase felodipine exposure.
    Ergotamine: (Moderate) Monitor for ergotamine-related adverse reactions including vasospasm leading to cerebral ischemia and/or ischemia of the extremities if coadministration with rucaparib is necessary. Ergotamine is a CYP3A4 substrate with a narrow therapeutic range and rucaparib is a weak CYP3A4 inhibitor.
    Ethosuximide: (Moderate) Monitor for an increase in ethosuximide-related adverse reactions if coadministration with rucaparib is necessary. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic index and rucaparib is a weak CYP3A4 inhibitor.
    Felodipine: (Moderate) Monitor blood pressure if coadministration of felodipine and rucaparib is necessary. Felodipine is a sensitive substrate of CYP3A4 and rucaparib is a weak CYP3A4 inhibitor. Concomitant use may increase felodipine exposure.
    Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If rucaparib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
    Flibanserin: (Moderate) Monitor for hypotension, syncope, somnolence, or other flibanserin-related adverse reactions if coadministration with multiple weak CYP3A4 inhibitors, including rucaparib, is necessary. Flibanserin is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Concomitant use of flibanserin and multiple weak CYP3A4 inhibitors may increase flibanserin plasma concentrations.
    Fluvastatin: (Moderate) Monitor for an increase in fluvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with rucaparib is necessary. Fluvastatin is a CYP2C9 substrate and rucaparib is a weak CYP2C9 inhibitor.
    Fosphenytoin: (Moderate) Monitor for an increase in fosphenytoin-related adverse reactions if coadministration with rucaparib is necessary. Fosphenytoin is a CYP2C9 and CYP2C19 substrate. Rucaparib is a weak inhibitor of both of these isoenzymes. Concomitant use may increase plasma concentrations of fosphenytoin.
    Glyburide: (Moderate) Closely monitor blood sugars if coadministration of glyburide with rucaparib is necessary. Glyburide is a CYP2C9 substrate and rucaparib is a weak CYP2C9 inhibitor.
    Glyburide; Metformin: (Moderate) Closely monitor blood sugars if coadministration of glyburide with rucaparib is necessary. Glyburide is a CYP2C9 substrate and rucaparib is a weak CYP2C9 inhibitor.
    Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the hydrocodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Hydrocodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If rucaparib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the hydrocodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Hydrocodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If rucaparib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Haloperidol: (Moderate) Monitor for an increase in haloperidol-related adverse reactions if coadministration with rucaparib is necessary. Haloperidol is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. In clinical trials, mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with CYP3A4 inhibitors.
    Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the hydrocodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Hydrocodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If rucaparib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Monitor patients for hypotension and bradycardia if coadministration of propranolol with rucaparib is necessary. Propranolol is a CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor. Concomitant use of CYP1A2 inhibitors may increase exposure to propranolol.
    Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the hydrocodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Hydrocodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If rucaparib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the hydrocodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Hydrocodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If rucaparib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the hydrocodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Hydrocodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If rucaparib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the hydrocodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Hydrocodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If rucaparib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the hydrocodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Hydrocodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If rucaparib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the hydrocodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Hydrocodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If rucaparib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If rucaparib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Indinavir: (Moderate) Monitor for an increase in indinavir-related adverse reactions if coadministration with rucaparib is necessary. Indinavir is a sensitive substrate of CYP3A4 and rucaparib is a weak CYP3A4 inhibitor.
    Isradipine: (Minor) Monitor blood pressure if coadministration of isradipine with rucaparib is necessary. Isradipine is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor.
    Ixabepilone: (Major) Consider the use of an agent that does not inhibit CYP3A4 if treatment with ixabepilone is necessary. If concomitant use of rucaparib with ixabepilone is unavoidable, monitor for an increase in ixabepilone-related adverse reactions (e.g., frequent monitoring of peripheral blood counts between cycles of ixabepilone). Ixabepilone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. The effect of mild or moderate CYP3A4 inhibitors on ixabepilone exposure has not been studied.
    Lidocaine: (Moderate) Monitor for an increase in lidocaine-related adverse reactions if coadministration with rucaparib is necessary. Lidocaine is a CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor. Coadministration may increase lidocaine plasma concentrations.
    Lomitapide: (Major) The lomitapide dose should not exceed 30 mg per day PO during concurrent use with rucaparib. Lomitapide is a sensitive substrate of CYP3A4 and rucaparib is a weak CYP3A4 inhibitor. The exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
    Loperamide: (Moderate) Monitor for an increase in loperamide-related adverse reactions, including cardiac effects, if coadministration with rucaparib is necessary. Loperamide is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor.
    Loperamide; Simethicone: (Moderate) Monitor for an increase in loperamide-related adverse reactions, including cardiac effects, if coadministration with rucaparib is necessary. Loperamide is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor.
    Melatonin: (Moderate) Monitor for an increase in melatonin-related adverse reactions if coadministration with rucaparib is necessary. Melatonin is a sensitive CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor. Coadministration may increase melatonin plasma concentrations.
    Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the methadone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Methadone is a CYP3A4, CYP2C9, and CYP2C19 substrate; rucaparib is a weak inhibitor of CYP3A4, CYP2C9, and CYP2C19. Coadministration can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If rucaparib is discontinued, methadone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
    Mexiletine: (Moderate) Monitor for an increase in mexiletine-related adverse reactions if coadministration with rucaparib is necessary. Mexiletine is a CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor. Coadministration may increase mexiletine plasma concentrations.
    Midazolam: (Moderate) Monitor for an increase in midazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with rucaparib is necessary. Midazolam is a sensitive CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Concomitant use increased the AUC of midazolam by 1.38-fold.
    Nateglinide: (Moderate) Closely monitor blood sugars if coadministration with nateglinide and rucaparib is necessary. Nateglinide is a CYP2C9 substrate and rucaparib is a weak CYP2C9 inhibitor. Concomitant use may increase plasma concentrations of nateglinide.
    Nelfinavir: (Moderate) Monitor for an increase in nelfinavir-related adverse reactions if coadministration with rucaparib is necessary. Nelfinavir is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor.
    Nimodipine: (Moderate) Monitor blood pressure if coadministration of nimodipine with rucaparib is necessary; a reduction of the nimodipine dose may be necessary. Nimodipine is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration with another weak CYP3A4 inhibitor increased mean peak nimodipine plasma concentrations by 50% and increased the mean AUC by 90%.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with rucaparib due to the risk of increased plasma concentrations of nisoldipine. Nisoldipine is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor.
    Ospemifene: (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with rucaparib is necessary. Ospemifene is a substrate of CYP2C9, CYP2C19, and CYP3A4, while rucaparib is a weak inhibitor of these 3 isoenzymes. Concomitant use may increase ospemifene plasma concentrations.
    Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If rucaparib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Phenobarbital: (Moderate) Monitor for an increase in phenobarbital-related adverse reactions if coadministration with rucaparib is necessary. Phenobarbital is a CYP2C9 and CYP2C19 substrate. Rucaparib is a weak inhibitor of both of these isoenzymes. Concomitant use may increase plasma concentrations of phenobarbital.
    Phenytoin: (Moderate) Monitor for an increase in phenytoin-related adverse reactions if coadministration with rucaparib is necessary. Phenytoin is a CYP2C9 and CYP2C19 substrate. Rucaparib is a weak inhibitor of both of these isoenzymes. Concomitant use may increase plasma concentrations of phenytoin.
    Pimozide: (Major) Avoid coadministration of pimozide with rucaparib due to the increased risk of cardiac effects. Pimozide is a CYP3A4 and CYP1A2 substrate. Rucaparib is a weak CYP3A4 inhibitor and a moderate CYP1A2 inhibitor. Ventricular arrhythmias associated with prolonged QT intervals have occurred with concomitant treatment with both strong and moderate CYP3A4 inhibitors; the manufacturer of pimozide advises that less potent CYP3A4 inhibitors should also be avoided. There is a theoretical potential for additional pimozide-related effects via inhibition of CYP1A2.
    Pirfenidone: (Major) Reduce the dose of pirfenidone to 534 mg three times daily (1,602 mg/day) if coadministration with rucaparib is necessary. Pirfenidone is a CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor. Coadministration with another moderate CYP1A2 inhibitor increased pirfenidone exposure by 81%.
    Primidone: (Moderate) Monitor for an increase in primidone-related adverse reactions if coadministration with rucaparib is necessary. Primidone is a CYP2C9 and CYP2C19 substrate. Rucaparib is a weak inhibitor of both of these isoenzymes. Concomitant use may increase plasma concentrations of primidone.
    Propafenone: (Moderate) Monitor for an increase in propafenone-related adverse reactions including cardiac arrhythmias and increased beta-blocking activity if coadministration with rucaparib is necessary. Propafenone is a CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor. Concomitant use may increase plasma concentrations of propafenone.
    Propranolol: (Moderate) Monitor patients for hypotension and bradycardia if coadministration of propranolol with rucaparib is necessary. Propranolol is a CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor. Concomitant use of CYP1A2 inhibitors may increase exposure to propranolol.
    Quinine: (Moderate) Monitor for an increase in quinine-related adverse reactions if coadministration with rucaparib is necessary. Quinine is a CYP3A4 substrate and rucaparib is a weak CYP3A inhibitor.
    Ramelteon: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with rucaparib is necessary. Ramelteon is a CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor.
    Rasagiline: (Major) Do not exceed a rasagiline dose of 0.5 mg once daily in patients receiving concomitant treatment with rucaparib. Rasagiline is a CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor. Coadministration with another moderate CYP1A2 inhibitor increased rasagiline plasma concentrations up to 2-fold.
    Riluzole: (Moderate) Coadministration of riluzole with rucaparib may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and elevated hepatic enzymes. In vitro findings suggest an increase in riluzole exposure is likely; riluzole is a CYP1A2 substrate and rucaparib is a CYP1A2 inhibitor.
    Roflumilast: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if coadministration with rucaparib is necessary. A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2. Rucaparib is a moderate CYP1A2 inhibitor and a weak inhibitor of CYP3A4. Dual inhibitors of CYP3A4 and CYP1A2 may increase roflumilast exposure.
    Ropinirole: (Moderate) Monitor for an increase in ropinirole-related adverse reactions if coadministration with rucaparib is necessary. Ropinirole is a CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor. Coadministration with another moderate CYP1A2 inhibitor increased ropinirole exposure by 84%.
    Sirolimus: (Moderate) Monitor sirolimus levels as clinically appropriate and watch for an increase in sirolimus-related adverse reactions if coadministration with rucaparib is necessary. Sirolimus is a sensitive substrate of CYP3A4 and rucaparib is a weak CYP3A4 inhibitor.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if rucaparib must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like rucaparib can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If rucaparib is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
    Tacrolimus: (Moderate) Frequently monitor tacrolimus levels and watch for an increase in tacrolimus-related adverse reactions if coadministration with rucaparib is necessary. Tacrolimus is a sensitive substrate of CYP3A4 and rucaparib is a weak CYP3A4 inhibitor.
    Theophylline, Aminophylline: (Moderate) Monitor theophylline levels and watch for an increase in theophylline-related adverse reactions if coadministration with rucaparib is necessary; a theophylline dose reduction may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and rucaparib is a moderate CYP1A2 inhibitor. (Minor) Monitor theophylline levels and watch for an increase in theophylline-related adverse reactions if coadministration with rucaparib is necessary; a theophylline dose reduction may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and rucaparib is a moderate CYP1A2 inhibitor.
    Tinidazole: (Moderate) Monitor for an increase in tinidazole-related adverse reactions if coadministration with rucaparib is necessary. Tinidazole is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor.
    Tizanidine: (Major) Avoid coadministration of tizanidine with rucaparib if possible due the risk of increased plasma concentrations of tizanidine. If concomitant use is unavoidable, monitor for an increase in tizanidine-related adverse reactions (e.g., hypotension, bradycardia, excessive drowsiness). Tizanidine is a sensitive CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor.
    Tolbutamide: (Moderate) Closely monitor blood sugars if coadministration of tolbutamide with rucaparib is necessary. Tolbutamide is a sensitive substrate of CYP2C9 and rucaparib is a weak CYP2C9 inhibitor. Concomitant use may increase plasma concentrations of tolbutamide.
    Torsemide: (Moderate) Monitor diuretic effect and blood pressure if coadministration of torsemide with rucaparib is necessary; adjust the dose of torsemide if clinically appropriate. Torsemide is a CYP2C9 substrate and rucaparib is a weak CYP2C9 inhibitor. Concomitant use may increase plasma concentrations of torsemide.
    Tramadol: (Moderate) Monitor for an increase in tramadol-related adverse reactions, including serotonin syndrome, seizures, sedation, and respiratory depression, if coadministration with rucaparib is necessary; the risk is greatest if rucaparib is added to a stable dose of tramadol. Consider decreasing the dose of tramadol if necessary. Rucaparib is a weak CYP3A4 inhibitor and tramadol is metabolized by both CYP3A4 and CYP2D6. Coadministration with a CYP3A4 inhibitor may result in a greater amount of tramadol metabolism via CYP2D6, and greater levels of the active metabolite, M1.
    Triazolam: (Moderate) Monitor for an increase in triazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with rucaparib is necessary. Triazolam is a sensitive substrate of CYP3A4 and rucaparib is a weak CYP3A4 inhibitor.
    Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with rucaparib is necessary. Vinorelbine is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor.
    Voriconazole: (Moderate) Monitor for an increase in voriconazole-related adverse reactions if coadministration with rucaparib is necessary. Voriconazole is a CYP2C19 substrate and rucaparib is a weak CYP2C19 inhibitor. Concomitant use may increase plasma concentrations of voriconazole.
    Warfarin: (Moderate) Monitor for an increased PT/INR if coadministration of warfarin with rucaparib is necessary. The more potent warfarin S-enantiomer is metabolized by CYP2C9, while the R-enantiomer which has a longer half-life is a CYP1A2 substrate. Rucaparib is a moderate CYP1A2 inhibitor as well as a weak inhibitor of CYP2C9. Concomitant use increased the AUC of warfarin by 1.49-fold; the INR and risk for bleeding may increase.
    Zolpidem: (Moderate) Monitor for an increase in sedation and other zolpidem-related adverse reactions if coadministration with rucaparib is necessary. Zolpidem is a CYP3A4 and CYP1A2 substrate. Rucaparib is a moderate CYP1A2 inhibitor as well as a weak inhibitor of CYP3A4.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during rucaparib treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in humans, rucaparib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Administration of rucaparib to pregnant rats during organogenesis resulted in embryo-fetal death in all animals at exposures equal to 0.04 times the AUC expected at recommended human doses.

    Counsel patients about the reproductive risk and contraception requirements during rucaparib treatment. Rucaparib can be cause embryo-fetal death if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 6 months after treatment. Females of reproductive potential should undergo pregnancy testing prior to initiation of rucaparib. Women who become pregnant while receiving rucaparib should be apprised of the potential hazard to the fetus. Fertility studies have not been conducted; however, there were no effects on male or female reproductive organs in rats or dogs at exposures of 0.09 to 0.3 times the exposures expected with recommended dosing in humans.

    MECHANISM OF ACTION

    Rucaparib inhibits poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular homeostasis, such as DNA transcription, cell cycle regulation, and DNA repair. In vitro, inhibition of PARP enzyme activity by rucaparib results in increased PARP-DNA complexes, causing DNA damage, apoptosis, and cell death. Increased cytotoxicity has been observed with rucaparib exposure in tumor cell lines with deficiencies in BRCA 1/2 and other DNA repair genes. In mouse xenograft models of human cancer with or without BRCA deficiencies, rucaparib has been shown to decrease tumor growth.

    PHARMACOKINETICS

    Rucaparib is administered orally. In vitro, rucaparib is 70% protein bound in human plasma at therapeutic concentrations. It is preferentially distributed to red blood cells with a blood-to-plasma concentration ratio of 1.83. In vitro, rucaparib had a low metabolic turnover rate and was metabolized primarily by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4. The mean terminal half-life of rucaparib after a single oral dose is 17 to 19 hours. The apparent clearance after twice daily dosing ranged from 15.3 to 79.2 L/hour; clearance ranged from 13.9 to 18.4 L/hour after a single IV dose. The pharmacokinetics of rucaparib were linear in cancer patients over a dose range of 240 mg to 840 mg twice daily, demonstrating time-independence and dose-proportionality.
     
    Affected cytochrome P450 isoenzymes (CYP450) or drug transporters: CYP1A2, CYP2C9, CYP2C19, CYP3A4
    In vitro, rucaparib is primarily metabolized by CYP2D6, and to a lesser extent by CYP1A2 and CYP3A4. Based on population pharmacokinetics, steady-state concentrations of rucaparib did not significantly differ across CYP2D6 or CYP1A2 genotype subgroups. In clinical studies, rucaparib is a moderate CYP1A2 inhibitor as well as a weak inhibitor of CYP2C9, CYP2C19, and CYP3A4. Rucaparib my increase the toxicity of substrates of these CYP enzymes. In vitro, rucaparib inhibited CYP2C8, CYP2D6, UGT1A1, P-glycoprotein (P-gp), BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, MATE2K, OCT1, OCT2, and MRP4; it induced CYP1A2 and down-regulated CYP3A4 and CYP2B6.

    Oral Route

    The mean steady-state Cmax of rucaparib at the approved recommended dosing was 1,940 ng/mL (coefficient of variation (CV), 54%), reached at a Tmax of 1.9 hours. The AUC was 16,900 ng x hour/mL (CV, 54%), and accumulation was 3.5-fold to 6.2-fold. Mean absolute bioavailability is 36% (range, 30% to 45%). A high-fat meal increased the Cmax by 20% and the AUC by 38%, while the Tmax was delayed by 2.5 hours as compared to dosing under fasting conditions.

    Intravenous Route

    The steady-state volume of distribution (Vd) was 113 L to 262 L after a single IV dose of rucaparib 12 mg to 40 mg.