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

    DEA CLASS

    Rx

    DESCRIPTION

    Poly (ADP-ribose) polymerase (PARP) inhibitor
    Used for certain types of ovarian cancer and prostate cancer
    Most common serious adverse reactions include anemia, increased ALT, and neutropenia

    COMMON BRAND NAMES

    Rubraca

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

    For the treatment of ovarian cancer.
    NOTE: Rucaparib is designated by the FDA as an orphan drug for this indication.
    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.
    NOTE: Patients should be selected based on the presence of a deleterious BRCA mutation (germline and/or somatic). Information on FDA-approved tests for the detection of a tumor BRCA mutation in patients with ovarian cancer is available at www.fda.gov/CompanionDiagnostics.
    Oral dosage
    Adults

    600 mg orally twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. 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. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. 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.

    For the treatment of prostate cancer.
    For the treatment of BRCA-mutated (germline and/or somatic) metastatic castration-resistant prostate cancer (CRPC) in patients who have previously been treated with androgen receptor-directed therapy and a taxane-based chemotherapy.
    NOTE: Patients should be selected based on the presence of a deleterious BRCA mutation (germline and/or somatic) in plasma specimens. A negative result from a plasma specimen does not mean that the patient's tumor is negative for BRCA mutations; if the plasma specimen is negative, consider performing further genomic testing using tumor specimens as clinically indicated. Information on FDA-approved tests for the detection of a tumor BRCA mutation in patients with prostate cancer is available at www.fda.gov/CompanionDiagnostics.
    Oral dosage
    Adults

    600 mg PO twice daily until disease progression or unacceptable toxicity. Patients should concurrently receive treatment with a gonadotropin-releasing hormone (GnRH) analog or have had a bilateral orchiectomy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with rucaparib resulted in a confirmed objective response rate of 44% in patients with BRCA-mutated metastatic CRPC who had been treated with androgen receptor-directed therapy and taxane-based chemotherapy in an ongoing multicenter, noncomparative trial. The median duration of response was not evaluable.

    MAXIMUM DOSAGE

    Adults

    600 mg PO twice daily.

    Geriatric

    600 mg PO twice daily.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment:
    Mild to moderate hepatic impairment (total bilirubin less than or equal to 3 times the upper limit of normal [ULN] and AST greater than ULN): No dosage adjustment necessary.
    Severe hepatic impairment (total bilirubin greater than 3 times ULN and any AST): Rucaparib has not been studied in this population.

    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: Rucaparib has not been studied in this population.

    ADMINISTRATION

    Emetic Risk
    Moderate/High
    Administer routine antiemetic prophylaxis prior to treatment.

    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 20 patients who received rucaparib therapy, including those in long term follow-up, between 1 to 53 months after starting treatment with rucaparib (n = 1,146); 8 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. MDS and/or AML was not observed in patients with metastatic castration-resistant prostate cancer, regardless of homologous recombination deficiency (HRD) mutation. 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.

    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.

    Contraception requirements, male-mediated teratogenicity, 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. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should not donate sperm and should use effective contraception during treatment and for 3 months after the last dose. 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.

    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
    renal failure (unspecified) / Delayed / 0.3-20.0
    thromboembolism / Delayed / 0-20.0
    elevated hepatic enzymes / Delayed / 0.3-13.0
    asthenia / Delayed / 7.0-11.0
    fatigue / Early / 7.0-11.0
    thrombocytopenia / Delayed / 5.0-10.0
    neutropenia / Delayed / 0-8.0
    nausea / Early / 3.0-5.0
    hypercholesterolemia / Delayed / 2.0-4.0
    vomiting / Early / 1.0-4.0
    anorexia / Delayed / 1.0-3.0
    abdominal pain / Early / 0-3.0
    diarrhea / Early / 0.5-2.0
    constipation / Delayed / 1.0-2.0
    rash / Early / 0-2.0
    new primary malignancy / Delayed / 0-1.7
    stomatitis / Delayed / 0-1.0
    dyspnea / Early / 0-0.5
    dysgeusia / Early / 0-0.3
    pharyngitis / Delayed / 0-0.3
    infection / Delayed / 0-0.3
    exfoliative dermatitis / Delayed / Incidence not known

    Moderate

    bleeding / Early / 0-20.0
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 0-2.0
    lymphopenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    psoriasis / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    wheezing / Rapid / Incidence not known
    hyponatremia / Delayed / Incidence not known
    hypophosphatemia / Delayed / Incidence not known

    Mild

    dizziness / Early / 0-20.0
    dyspepsia / Early / 0-20.0
    headache / Early / 0-18.0
    fever / Early / 0-13.0
    photosensitivity / Delayed / 0-10.0
    pruritus / Rapid / 0-9.0
    urticaria / Rapid / Incidence not known
    maculopapular rash / Early / Incidence not known
    flushing / Rapid / 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 2.6-fold.
    Acetaminophen; 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 2.6-fold.
    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 2.6-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 2.6-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 2.6-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 norcodeine; 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. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like rucaparib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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.
    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.
    Alprazolam: (Major) Avoid coadministration of alprazolam and rucaparib due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with rucaparib, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration with another weak CYP3A4 inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
    Amitriptyline: (Moderate) Monitor for an increase in amitryptiline-related adverse reactions if coadministration with rucaparib is necessary; a dose reduction of amitryptiline may be necessary. Concurrent use may increase the plasma concentrations of amitryptiline. Amitryptiline is a CYP2D6 substrate and rucaparib is a CYP2D6 inhibitor.
    Amlodipine; 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.
    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 2.6-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 2.6-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 norcodeine; 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: (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 2.6-fold.
    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 2.6-fold.
    Aspirin, ASA; Caffeine; Orphenadrine: (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 2.6-fold.
    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 norcodeine; 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; 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.
    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.
    Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of rucaparib with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and rucaparib is a CYP2C19 inhibitor.
    Bendamustine: (Major) Consider the use of an alternative therapy if rucaparib treatment is needed in patients receiving bendamustine. Rucaparib may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and rucaparib is a CYP1A2 inhibitor.
    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. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like rucaparib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like rucaparib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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.
    Bupivacaine; Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with rucaparib is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and rucaparib is a weak CYP2C9 inhibitor.
    Buprenorphine: (Moderate) Concomitant use of buprenorphine and rucaparib can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when rucaparib is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping rucaparib, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If rucaparib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and rucaparib is a CYP3A4 inhibitor.
    Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and rucaparib can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when rucaparib is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping rucaparib, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If rucaparib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and rucaparib is a CYP3A4 inhibitor.
    Butalbital; Acetaminophen; 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 2.6-fold.
    Butalbital; Acetaminophen; 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 2.6-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 norcodeine; 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.
    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. (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 2.6-fold.
    Caffeine; Sodium Benzoate: (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 2.6-fold.
    Carbamazepine: (Moderate) Monitor carbamazepine concentrations closely during coadministration of rucaparib; carbamazepine dose adjustments may be needed. Concomitant use may increase carbamazepine concentrations. Carbamazepine is a CYP3A4 substrate and rucaparib is a 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. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like rucaparib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like rucaparib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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.
    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.
    Celecoxib; Tramadol: (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. (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.
    Chlordiazepoxide; Amitriptyline: (Moderate) Monitor for an increase in amitryptiline-related adverse reactions if coadministration with rucaparib is necessary; a dose reduction of amitryptiline may be necessary. Concurrent use may increase the plasma concentrations of amitryptiline. Amitryptiline is a CYP2D6 substrate and rucaparib is a CYP2D6 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 norcodeine; 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. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like rucaparib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like rucaparib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like rucaparib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like rucaparib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Cisapride: (Moderate) Monitor for an increase in cisapride-related adverse reactions if concurrent treatment with rucaparib is necessary, as plasma concentrations of cisapride may increase. Cisapride is a CYP3A4 substrate with a narrow therapeutic index and rucaparib is a weak CYP3A inhibitor.
    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) Monitor for an increase in clomipramine-related adverse reactions if concurrent use of rucaparib is necessary as plasma concentrations of clomipramine may increase; a dose reduction of clomipramine may be necessary. Clomipramine is a CYP2D6 and CYP1A2 substrate; rucaparib is a weak CYP2D6 inhibitor and a moderate CYP1A2 inhibitor.
    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 norcodeine; 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 norcodeine; 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; Pseudoephedrine: (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 norcodeine; 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 norcodeine; 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 norcodeine; 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.
    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.
    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. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like rucaparib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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).
    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; 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 2.6-fold.
    Erlotinib: (Major) Avoid coadministration of erlotinib with rucaparib if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP1A2. rucaparib is a CYP3A4 and CYP1A2 inhibitor. Coadministration with a moderate CYP3A4/CYP1A2 inhibitor increased erlotinib exposure by 39% and increased the erlotinib Cmax by 17%.
    Fedratinib: (Major) Avoid coadministration of fedratinib with rucaparib as concurrent use may increase fedratinib exposure. Fedratinib is a substrate of both CYP3A4 and CYP2C19; rucaparib is an inhibitor of both CYP3A4 and CYP2C19. The coadministration of fedratinib with agents that are both a CYP3A4 and CYP2C19 inhibitor has not been evaluated.
    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.
    Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or rucaparib; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and rucaparib is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
    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.
    Fluoxetine: (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with rucaparib. Concurrent use may result in increased fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and rucaparib is a weak CYP2D6 inhibitor.
    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.
    Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like rucaparib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like rucaparib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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.
    Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like rucaparib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like rucaparib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like rucaparib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like rucaparib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like rucaparib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like rucaparib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like rucaparib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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.
    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.
    Lemborexant: (Major) Limit the dose of lemborexant to a maximum of 5 mg PO once daily if coadministered with rucaparib as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; rucaparib is a weak CYP3A4 inhibitor. Coadministration of lemborexant with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
    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.
    Lidocaine; Epinephrine: (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.
    Lidocaine; Prilocaine: (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.
    Lonafarnib: (Major) Avoid coadministration of lonafarnib and rucaparib; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing rucaparib. Lonafarnib is a sensitive CYP3A4 and CYP2C9 substrate; rucaparib is a weak CYP3A4 and CYP2C9 inhibitor.
    Mefloquine: (Moderate) Use mefloquine with caution if coadministration with rucaparib is necessary as concurrent use may increase mefloquine exposure and mefloquine-related adverse events. Mefloquine is a substrate of CYP3A4 and rucaparib is a weak CYP3A4 inhibitor.
    Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with rucaparib is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and rucaparib is a weak CYP2C9 inhibitor.
    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.
    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 1.4-fold.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with rucaparib is necessary. The dose of sirolimus may also need to be reduced with coadministration of rucaparib. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of rucaparib. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; rucaparib is a weak CYP3A 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.
    Olanzapine; Fluoxetine: (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with rucaparib. Concurrent use may result in increased fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and rucaparib is a weak CYP2D6 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.
    Perphenazine; Amitriptyline: (Moderate) Monitor for an increase in amitryptiline-related adverse reactions if coadministration with rucaparib is necessary; a dose reduction of amitryptiline may be necessary. Concurrent use may increase the plasma concentrations of amitryptiline. Amitryptiline is a CYP2D6 substrate and rucaparib is a CYP2D6 inhibitor.
    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.
    Phenobarbital; Hyoscyamine; Atropine; 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.
    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%.
    Porfimer: (Major) Avoid coadministration of porfimer with rucaparib due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like rucaparib may increase the risk of a photosensitivity reaction.
    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: (Major) Avoid concurrent use of propafenone and rucaparib; concurrent use may increase plasma concentrations of propafenone, which may lead to cardiac arrhythmias and exaggerated beta-blocking activity. Propafenone is a CYP3A4, CYP2D6, and CYP1A2 substrate; rucaparib is a weak CYP3A4 inhibitor, a weak CYP2D6 inhibitor, and a moderate CYP1A2 inhibitor.
    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.
    Propranolol; Hydrochlorothiazide, HCTZ: (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.
    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 when coadministered with rucaparib. Coadministration may result in increased rasagiline concentrations. Rasagiline is primarily metabolized by CYP1A2; rucaparib is a moderate CYP1A2 inhibitor. When rasagiline was administered with a strong CYP1A2 inhibitor, the AUC of rasagiline increased by 83%.
    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.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with rucaparib is necessary. The dose of sirolimus may also need to be reduced with coadministration of rucaparib. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of rucaparib. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; rucaparib is a weak CYP3A 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.
    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.
    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.
    Tramadol; Acetaminophen: (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 signs of triazolam toxicity during coadministration with rucaparib and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and rucaparib is a weak CYP3A inhibitor.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with rucaparib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; rucaparib is a weak CYP3A4 inhibitor.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with rucaparib is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like rucaparib may increase the risk of a photosensitivity reaction.
    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) Closely monitor the INR if coadministration of warfarin with rucaparib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Rucaparib is a weak CYP3A4/CYP2C9/CYP1A2 inhibitor and warfarin is a CYP3A4/CYP2C9/CYP1A2 substrate.

    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.

    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.

    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. It is preferentially distributed to red blood cells with a blood-to-plasma concentration ratio of 1.8. The mean apparent volume of distribution is 2,300 liters (CV, 21%). The mean terminal half-life of rucaparib is 26 hours (CV, 39%). The mean apparent clearance at steady-state is 44.2 L/hour (CV, 45%). After administration of a single radiolabeled dose, unchanged rucaparib accounted for 64% of the radioactivity in plasma. Rucaparib accounted for 45% of radioactivity in the urine and 95% of radioactivity in the feces.
     
    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. Additionally, N-demethylation, N-methylation, and glucuronidation are involved in rucaparib metabolism. In vitro, rucaparib is a substrate of P-glycoprotein (P-gp) and BCRP. In clinical studies, rucaparib is a moderate CYP1A2 inhibitor as well as a weak inhibitor of CYP2C9, CYP2C19, CYP3A4, and P-gp. In vitro, rucaparib inhibited CYP2C8, CYP2D6, UGT1A1, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, MATE2K, OCT1, OCT2, and MRP4; it induced CYP1A2.

    Oral Route

    The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of rucaparib has not been fully characterized. The mean steady-state Cmax of rucaparib at the approved recommended dosing was 1,940 ng/mL (CV, 54%), reached at a Tmax of 1.9 hours (range, 0 to 5.98 hours). The AUC was 16,900 ng x hour/mL (CV, 54%), and the mean AUC accumulation ratio was 3.5-fold to 6.2-fold. Mean absolute bioavailability is 36% (range, 30% to 45%). The pharmacokinetics (AUC and Cmax) of rucaparib were linear from a dose of 240 mg to 840 mg twice daily.
    A high-fat meal (approximately 800 to 1,000 calories; 250 calories from carbohydrates, 500 to 600 calories from fat, and 150 calories from protein) increased the Cmax by 20% and the AUC by 38%, while the Tmax was delayed by 2.5 hours as compared to fasting conditions.