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  • CLASSES

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

    DEA CLASS

    Rx

    DESCRIPTION

    Oral PARP inhibitor
    Used for previously treated BRCA-positive or suspected BRCA-positive germline BRCA-mutated (gBRCAm) advanced ovarian cancer, for maintenance treatment of recurrent epithelial ovarian, fallopian tube, or peritoneal cancer after response to platinum-based chemotherapy, and for previously treated HER2-negative, gBRCAm metastatic breast cancer
    Most common adverse events include anemia, nausea, fatigue, vomiting, upper respiratory tract infection, diarrhea, and arthralgia/myalgia

    COMMON BRAND NAMES

    Lynparza

    HOW SUPPLIED

    Lynparza Oral Cap: 50mg
    Olaparib Oral Tab: 100mg, 150mg

    DOSAGE & INDICATIONS

    For the treatment of ovarian cancer.
    For the treatment of deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer in patients who have failed 3 or more prior courses of chemotherapy, as monotherapy.
    NOTE: Patients should be selected based on the presence of deleterious or suspected deleterious gBRCA-mutation. Information on FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at http://www.fda.gov/CompanionDiagnostics.
    Oral dosage (capsules)
    Adults

    400 mg PO twice daily (total daily dose, 800 mg) until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Do not substitute olaparib capsules with olaparib tablets. In a single-arm clinical trial, patients with deleterious or suspected deleterious gBRCAm advanced ovarian cancer and progression on 3 or more prior lines of chemotherapy (n = 137) had an objective response rate to olaparib of 34% (complete response, 2%; partial response, 32%), with a median duration of 7.9 months.

    Oral dosage (tablets)
    Adults

    300 mg PO twice daily (total daily dose, 600 mg) until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Do not substitute olaparib tablets with olaparib capsules. In a single-arm clinical trial, patients with deleterious or suspected deleterious gBRCAm advanced ovarian cancer and progression on 3 or more prior lines of chemotherapy (n = 137) had an objective response rate to olaparib of 34% (complete response, 2%; partial response, 32%), with a median duration of 7.9 months.

    For the maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in a complete or partial response to platinum-based chemotherapy, as monotherapy.
    Oral dosage (tablets)
    Adults

    300 mg PO twice daily (total daily dose, 600 mg) until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Do not substitute olaparib tablets with olaparib capsules. Maintenance treatment with olaparib (n = 196) significantly improved the primary endpoint of median progression-free survival (PFS) compared with placebo (n = 99) in a randomized, double-blind clinical trial of patients with gBRCAm ovarian, fallopian tube, or primary peritoneal cancer who had obtained either a complete or partial response to platinum-based chemotherapy (19.1 months vs. 5.5 months). Approximately 44% of olaparib patients and 37% of placebo patients in this trial had received 3 or more lines of platinum-based treatment.[58662] In long-term follow-up, 24% of patients were treated with olaparib for 2 years and 11% received treatment for over 6 years. Olaparib improved overall survival compared with placebo (HR 0.73) irrespective of BCRA 1/2 mutation status but did not meet the predefined threshold for statistical significance.[62692] Olaparib (n = 136) also significantly improved PFS (8.4 months vs. 4.8 months) and median overall survival (29.8 months vs. 27.8 months) compared with placebo (n = 129) in another randomized, double-blind clinical trial of patients with platinum-sensitive ovarian cancer who had received 2 or more previous platinum-based chemotherapy regimens.[58662]

    For the first-line maintenance treatment of newly diagnosed deleterious or suspected deleterious germline or somatic BRCA mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in a complete or partial response to first-line platinum-based chemotherapy, as monotherapy.
    NOTE: Patients should be selected based on the presence of deleterious or suspected deleterious gBRCAm or sBRCAm. An FDA-approved test for the detection of tumor BRCA gene mutation for the first-line maintenance treatment of advanced ovarian cancer is not currently available. Information on FDA-approved tests for the detection of BRCA mutations is available at http://www.fda.gov/CompanionDiagnostics.[58662]
    Oral dosage (tablets)
    Adults

    300 mg PO twice daily (total daily dose, 600 mg) until disease progression, unacceptable toxicity, or completion of 2 years of treatment. Patients with a complete response (no radiological evidence of disease) at 2 years should stop treatment. Patients with evidence of disease at 2 years can continue treatment with olaparib if the treating healthcare provider feels the patient can derive further benefit. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Do not substitute olaparib tablets with olaparib capsules. In a multicenter, randomized, double-blind, phase 3 clinical trial, maintenance therapy with olaparib significantly improved PFS (not reached vs.13.8 months) and time to first subsequent treatment (51.8 months vs. 15.1 months) in patients with newly diagnosed gBRCAm advanced or high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer in patients who were in a complete or partial response to platinum-based chemotherapy (SOLO1 trial).

    For the treatment of HER2-negative, deleterious or suspected deleterious germline BRCA mutated (gBRCAm) metastatic breast cancer in patients who have been previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting.
    NOTE: Hormone receptor-positive patients should have been treated with prior endocrine therapy or be considered inappropriate for endocrine therapy prior to treatment with olaparib.
    NOTE: Patients should be selected based on the presence of deleterious or suspected deleterious gBRCA mutation. Information on FDA-approved tests for the detection of BRCA mutations is available at http://www.fda.gov/CompanionDiagnostics.
    Oral dosage (tablets)
    Adults

    300 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. Do not substitute olaparib capsules for olaparib tablets. Olaparib monotherapy significantly improved progression-free survival (PFS) compared with physician's choice of single-agent chemotherapy in patients with HER2-negative, gBRCAm metastatic breast cancer in a phase 3 clinical trial; subgroup analysis indicates patients with triple-negative breast cancer or BRCA1 mutations confer significant benefit.[62322] [58662]

    MAXIMUM DOSAGE

    Adults

    Capsules: 400 mg PO twice daily (800 mg per day).
    Tablets: 300 mg PO twice daily (600 mg per day).

    Geriatric

    Capsules: 400 mg PO twice daily (800 mg per day).
    Tablets: 300 mg PO twice daily (600 mg per day).

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Not indicated.

    Neonates

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment:
    Mild to moderate hepatic impairment (Child-Pugh class A and B): No dosage adjustment necessary.
    Severe hepatic impairment (Child-Pugh class C): No data are available.
    Treatment-Related Hepatotoxicity:
    Consider an interruption of treatment or a dose reduction of olaparib. The recommended dose of olaparib capsules for treatment-related hepatotoxicity is 200 mg PO twice daily (total daily dose, 400 mg); the dose may be further reduced to 100 mg PO twice daily (total daily dose, 200 mg) for additional toxicities. The recommended dose of olaparib tablets is 250 mg PO twice daily (total daily dose, 500 mg); the dose may be further reduced to 200 mg PO twice daily (total daily dose, 400 mg) for additional toxicities.

    Renal Impairment

    Dosage Adjustment for Baseline Renal Impairment:
    CrCL greater than 50 mL/min: No dosage adjustment needed.
    CrCL 31 to 50 mL/min: Reduce the dose of olaparib capsules to 300 mg PO twice daily. Reduce the dose of olaparib tablets to 200 mg PO twice daily.
    CrCL 30 mL/min or less, or dialysis: No data are available.
    Treatment-Related Nephrotoxicity:
    Consider an interruption of treatment or a dose reduction of olaparib. The recommended dose of olaparib capsules for treatment-related nephrotoxicity is 200 mg PO twice daily (total daily dose, 400 mg); the dose may be further reduced to 100 mg PO twice daily (total daily dose, 200 mg) for additional toxicities. The recommended dose of olaparib tablets is 250 mg PO twice daily (total daily dose, 500 mg); the dose may be further reduced to 200 mg PO twice daily (total daily dose, 400 mg) for additional toxicities.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Select patients based on the presence of deleterious or suspected deleterious BRCA-mutations. Information on FDA-approved tests for the detection of BRCA-mutations is available at http://www.fda.gov/companiondiagnostics.
    Do not substitute olaparib capsules for olaparib tablets on a milligram-to-milligram basis due to differences in dosing and bioavailability.
    Store olaparib tablets in the original bottle to protect from moisture.
    Swallow the capsules or tablets whole; do not crush or dissolve. Do not divide tablets. Do not take capsules that appear deformed or show evidence of leakage; wash hands thoroughly with soap and water if a leaky capsule is touched.
    Olaparib may be administered with or without food. The patient should avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during treatment since these fruits and juices will raise blood levels of the drug, increasing toxicity risk.
    If a dose is missed, the patient should take the next dose at the regularly scheduled time; instruct the patient not to take 2 doses at the same time.

    STORAGE

    Lynparza:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    New primary malignancy, radiation therapy

    New primary malignancy, specifically myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), has been reported in patients treated with olaparib monotherapy; the majority of these cases were fatal. The duration of olaparib therapy in patients who developed MDS/AML varied from less than 6 months to greater than 2 years. All patients who developed MDS/AML had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiation therapy; some also had a history of more than one primary malignancy or of bone marrow dysplasia. Monitor complete blood counts at baseline and monthly thereafter. Refer patients to a hematologist for bone marrow analysis and cytogenetics if blood counts do not recover to grade 1 or less within 4 weeks. If MDS/AML is confirmed, discontinue olaparib.

    Bone marrow suppression, chemotherapy

    Bone marrow suppression may be increased or prolonged if olaparib is administered in combination with other myelosuppressive chemotherapy. Do not administer olaparib until hematologic toxicity from previous treatment is grade 1 or better; monitor blood counts weekly until recovery in patients with prolonged hematologic toxicity.

    Chronic lung disease (CLD), pneumonitis, pulmonary disease

    Use olaparib with caution in patients with pre-existing pulmonary disease or chronic lung disease (CLD). Pneumonitis/interstitial lung disease, with some cases including fatalities, have been reported in patients treated with olaparib. Hold olaparib therapy for new or worsening respiratory or pulmonary disease symptoms, including dyspnea, fever, cough, or radiological abnormalities; discontinue olaparib if a diagnosis of pneumonitis is confirmed.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during olaparib treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, olaparib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving olaparib should be apprised of the potential hazard to the fetus. Olaparib caused teratogenicity and embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose when administered during the period of organogenesis. When given orally for 14 days before mating through day 6 of pregnancy, olaparib resulted in increased postimplantation loss at maternal exposures of approximately 7% the AUC at the recommended human dose. At exposures approximately 0.18% the exposure of the recommended dose, pregnant rats experienced increased postimplantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital), and diaphragm (hernia). Additional abnormalities included incomplete or absent ossification of the vertebrae/sternebrae, ribs, and limbs, as well as other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter, and umbilical artery.

    Contraception requirements, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during olaparib treatment. Olaparib can be teratogenic and embryotoxic if the mother is exposed during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during treatment and for at least 6 months after the last dose of olaparib. Male patients with female partners of reproductive potential should use effective contraception during treatment and for at least 3 months after the last dose of olaparib. Male patients should also not donate sperm during therapy and for 3 months after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of olaparib. Women who become pregnant while receiving olaparib should be apprised of the potential hazard to the fetus. Olaparib does not appear to cause infertility in males or females based on animal studies.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from olaparib, advise women to discontinue breast-feeding during treatment and for 1 month after the final dose. It is not known whether olaparib is present in human milk, although many drugs are excreted in human milk.

    ADVERSE REACTIONS

    Severe

    anemia / Delayed / 7.0-21.0
    thromboembolism / Delayed / 1.0-10.0
    leukopenia / Delayed / 0-9.0
    neutropenia / Delayed / 0-9.0
    fatigue / Early / 4.0-9.0
    vomiting / Early / 0-4.0
    nausea / Early / 1.0-3.0
    diarrhea / Early / 1.0-3.0
    infection / Delayed / 0-2.0
    renal failure (unspecified) / Delayed / 0-2.0
    abdominal pain / Early / 0-2.0
    new primary malignancy / Delayed / 0-1.5
    thrombocytopenia / Delayed / 0-1.0
    stomatitis / Delayed / 0-1.0
    anorexia / Delayed / 0-1.0
    constipation / Delayed / 0-1.0
    headache / Early / 0-1.0
    GI perforation / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    stroke / Early / Incidence not known

    Moderate

    hypomagnesemia / Delayed / 0-20.0
    peripheral edema / Delayed / 0-20.0
    edema / Delayed / 0-20.0
    dyspnea / Early / 13.0-15.0
    cystitis / Delayed / 0-15.0
    peripheral neuropathy / Delayed / 1.0-10.0
    pneumonitis / Delayed / 0-1.0
    wheezing / Rapid / Incidence not known
    colitis / Delayed / Incidence not known
    oral ulceration / Delayed / Incidence not known

    Mild

    dysgeusia / Early / 9.0-27.0
    dyspepsia / Early / 8.0-25.0
    dizziness / Early / 7.0-20.0
    cough / Delayed / 16.0-18.0
    fever / Early / 0-10.0
    rash / Early / 0-6.0
    pharyngitis / Delayed / Incidence not known
    rhinitis / Early / Incidence not known
    sinusitis / Delayed / Incidence not known
    influenza / Delayed / Incidence not known
    lethargy / Early / Incidence not known
    malaise / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Major) Avoid the coadministration of olaparib with butalbital due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Acetaminophen; Butalbital; Caffeine: (Major) Avoid the coadministration of olaparib with butalbital due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Avoid the coadministration of olaparib with butalbital due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Amiodarone: (Major) Avoid coadministration of olaparib with amiodarone and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and amiodarone is a moderate CYP3A4 inhibitor.
    Amobarbital: (Major) Avoid the coadministration of olaparib with amobarbital due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and amobarbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of olaparib with clarithromycin and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and clarithromycin is a strong CYP3A4 inhibitor.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of olaparib with clarithromycin and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and clarithromycin is a strong CYP3A4 inhibitor.
    Amprenavir: (Major) Avoid coadministration of olaparib with amprenavir and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate. Amprenavir is a strong CYP3A4 inhibitor.
    Apalutamide: (Major) Avoid the coadministration of olaparib with apalutamide due to the risk of decreased olaparib efficacy. Olaparib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC of olaparib by 87%.
    Aprepitant, Fosaprepitant: (Major) Avoid coadministration of olaparib for several days after a multi-day regimen of oral aprepitant and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate. Aprepitant is a moderate CYP3A4 inhibitor when administered as a 3-day oral regimen. When administered as a single oral or single intravenous dose (fosaprepitant), the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid the coadministration of olaparib with butalbital due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid the coadministration of olaparib with butalbital due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Atazanavir: (Major) Avoid coadministration of olaparib with atazanavir and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and atazanavir is a strong CYP3A4 inhibitor.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of olaparib with atazanavir and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and atazanavir is a strong CYP3A4 inhibitor. (Major) Avoid coadministration of olaparib with cobicistat and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid the coadministration of olaparib with phenobarbital due to the risk of decreased olaparib efficacy. Olaparib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC of olaparib by 87%.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid the coadministration of olaparib with phenobarbital due to the risk of decreased olaparib efficacy. Olaparib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC of olaparib by 87%.
    Bexarotene: (Major) Avoid the coadministration of olaparib with bexarotene due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Bosentan: (Major) Avoid the coadministration of olaparib with bosentan due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Butabarbital: (Major) Avoid the coadministration of olaparib with butabarbital due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and butabarbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Carbamazepine: (Major) Avoid the coadministration of olaparib with carbamazepine due to the risk of decreased olaparib efficacy. Olaparib is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC of olaparib by 87%.
    Ceritinib: (Major) Coadministration of olaparib and ceritinib is not advised. Olaparib is a CYP3A4 substrate that has different dosing requirements dependent on whether a coadministered drug is a moderate or strong CYP3A4 inhibitor. The AUC of olaparib was increased 170% in the presence of a strong CYP3A4 inhibitor and 121% in the presence of a moderate CYP3A4 inhibitor. Ceritinib inhibits CYP3A4; however, the strength of inhibition is unknown. Therefore, dosage adjustments for the safe use of ceritinib and olaparib cannot be provided.
    Chloramphenicol: (Major) Avoid coadministration of olaparib with chloramphenicol and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and chloramphenicol is a strong CYP3A4 inhibitor.
    Ciprofloxacin: (Major) Avoid coadministration of olaparib with ciprofloxacin and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and ciprofloxacin is a moderate CYP3A4 inhibitor.
    Clarithromycin: (Major) Avoid coadministration of olaparib with clarithromycin and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and clarithromycin is a strong CYP3A4 inhibitor.
    Cobicistat: (Major) Avoid coadministration of olaparib with cobicistat and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of olaparib with cobicistat and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of olaparib with cobicistat and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and cobicistat is a strong CYP3A4 inhibitor.
    Conivaptan: (Major) Avoid coadministration of olaparib with conivaptan and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure; subsequent administration of olaparib should be initiated no sooner than 1 week after the conivaptan infusion is completed. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and conivaptan is a strong CYP3A4 inhibitor.
    Crizotinib: (Major) Avoid coadministration of olaparib with crizotinib and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the AUC of olaparib by 121%.
    Cyclosporine: (Major) Avoid coadministration of olaparib with cyclosporine and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and cyclosporine is a moderate CYP3A4 inhibitor.
    Dabrafenib: (Major) Avoid the coadministration of olaparib with dabrafenib due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and dabrafenib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Danazol: (Major) Avoid coadministration of olaparib with danazol and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and danazol is a moderate CYP3A4 inhibitor.
    Darunavir: (Major) Avoid coadministration of olaparib with darunavir and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and darunavir is a strong CYP3A4 inhibitor.
    Darunavir; Cobicistat: (Major) Avoid coadministration of olaparib with cobicistat and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and cobicistat is a strong CYP3A4 inhibitor. (Major) Avoid coadministration of olaparib with darunavir and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and darunavir is a strong CYP3A4 inhibitor.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of olaparib with cobicistat and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and cobicistat is a strong CYP3A4 inhibitor. (Major) Avoid coadministration of olaparib with darunavir and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and darunavir is a strong CYP3A4 inhibitor.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of olaparib with ritonavir and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and ritonavir is a strong CYP3A4 inhibitor.
    Delavirdine: (Major) Avoid coadministration of olaparib with delavirdine and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and delavirdine is a strong CYP3A4 inhibitor.
    Dexamethasone: (Major) Avoid the coadministration of olaparib with dexamethasone due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and dexamethasone is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Diltiazem: (Major) Avoid coadministration of olaparib with diltiazem and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and diltiazem is a moderate CYP3A4 inhibitor.
    Dronedarone: (Major) Avoid coadministration of olaparib with dronedarone and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and dronedarone is a moderate CYP3A4 inhibitor.
    Duvelisib: (Major) Avoid coadministration of olaparib with duvelisib and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and duvelisib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the AUC of olaparib by 121%.
    Efavirenz: (Major) Avoid the coadministration of olaparib with efavirenz due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with efavirenz is predicted to decrease the AUC of olaparib by 60%.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid the coadministration of olaparib with efavirenz due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with efavirenz is predicted to decrease the AUC of olaparib by 60%.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid the coadministration of olaparib with efavirenz due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with efavirenz is predicted to decrease the AUC of olaparib by 60%.
    Elagolix: (Major) Avoid the coadministration of olaparib with elagolix due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and elagolix is a weak to moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Enzalutamide: (Major) Avoid the coadministration of olaparib with enzalutamide due to the risk of decreased olaparib efficacy. Olaparib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC of olaparib by 87%.
    Erythromycin: (Major) Avoid coadministration of olaparib with erythromycin and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and erythromycin is a moderate CYP3A4 inhibitor.
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of olaparib with erythromycin and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and erythromycin is a moderate CYP3A4 inhibitor.
    Eslicarbazepine: (Major) Avoid the coadministration of olaparib with eslicarbazepine due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Etravirine: (Major) Avoid the coadministration of olaparib with etravirine due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and etravirine is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Fluconazole: (Major) Avoid coadministration of olaparib with fluconazole and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and fluconazole is a moderate CYP3A4 inhibitor. Coadministration of olaparib with fluconazole is predicted to increase the AUC of olaparib by 121%.
    Fluvoxamine: (Major) Avoid coadministration of olaparib with fluvoxamine and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the AUC of olaparib by 121%.
    Fosamprenavir: (Major) Avoid coadministration of olaparib with fosamprenavir and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and fosamprenavir is a strong CYP3A4 inhibitor.
    Fosphenytoin: (Major) Avoid the coadministration of olaparib with fosphenytoin due to the risk of decreased olaparib efficacy. Olaparib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC of olaparib by 87%.
    Grapefruit juice: (Major) Due to the potential for increased olaparib exposure and side effects, patients should be advised to avoid intake of grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during olaparib therapy. Olaparib is a CYP3A4/5 substrate and both grapefruit and Seville oranges are strong CYP3A4 inhibitors. Coadministration with another strong CYP3A inhibitor increased the AUC of olaparib by 170%.
    Idelalisib: (Major) Avoid coadministration of olaparib with idelalisib and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and idelalisib is a strong CYP3A4 inhibitor.
    Imatinib: (Major) Avoid coadministration of olaparib with imatinib and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and imatinib is a moderate CYP3A4 inhibitor.
    Indinavir: (Major) Avoid coadministration of olaparib with indinavir and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and indinavir is a strong CYP3A4 inhibitor.
    Isavuconazonium: (Major) Avoid coadministration of olaparib with isavuconazonium and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and isavuconazonium is a moderate CYP3A4 inhibitor.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the coadministration of olaparib with rifampin due to the risk of decreased olaparib efficacy. Olaparib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the AUC of olaparib by 87%.
    Isoniazid, INH; Rifampin: (Major) Avoid the coadministration of olaparib with rifampin due to the risk of decreased olaparib efficacy. Olaparib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the AUC of olaparib by 87%.
    Itraconazole: (Major) Avoid olaparib use during and for 2 weeks after discontinuation of itraconazole treatment. Consider use of an alternative antifungal agent with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased the AUC of olaparib by 170%.
    Ketoconazole: (Major) Avoid coadministration of olaparib with ketoconazole and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Letermovir: (Major) Avoid concurrent administration olaparib and letermovir, as use of these drugs together may increase olaparib concentrations. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. If olaparib must be given with letermovir, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. If olaparib must be given with letermovir and cyclosporine, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the AUC of olaparib by 121%, and coadministration with a strong CYP3A inhibitor increased the AUC of olaparib by 170%.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of olaparib with lopinavir and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and lopinavir is a strong CYP3A4 inhibitor. (Major) Avoid coadministration of olaparib with ritonavir and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and ritonavir is a strong CYP3A4 inhibitor.
    Lorlatinib: (Major) Avoid the coadministration of olaparib with lorlatinib due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Lumacaftor; Ivacaftor: (Major) Avoid the coadministration of olaparib with lumacaftor; ivacaftor due to the risk of decreased olaparib efficacy. Olaparib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC of olaparib by 87%.
    Mephobarbital: (Major) Avoid the coadministration of olaparib with mephobarbital due to the risk of decreased olaparib efficacy. Olaparib is a CYP3A4 substrate and mephobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC of olaparib by 87%.
    Methohexital: (Major) Avoid the coadministration of olaparib with methohexital due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and methohexital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Mifepristone: (Major) Avoid coadministration of olaparib with chronic mifepristone administration and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and mifepristone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC of olaparib by 170%. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
    Mitotane: (Major) Avoid the coadministration of olaparib with mitotane due to the risk of decreased olaparib efficacy. Olaparib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC of olaparib by 87%.
    Modafinil: (Major) Avoid the coadministration of olaparib with modafinil due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Nafcillin: (Major) Avoid the coadministration of olaparib with nafcillin due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Nefazodone: (Major) Avoid coadministration of olaparib with nefazodone and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and nefazodone is a strong CYP3A4 inhibitor.
    Nelfinavir: (Major) Avoid coadministration of olaparib with nelfinavir and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and nelfinavir is a strong CYP3A4 inhibitor.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid coadministration of olaparib with netupitant and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and netupitant is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the AUC of olaparib by 121%.
    Nevirapine: (Major) Avoid the coadministration of olaparib with nevirapine due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and nevirapine is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Nicardipine: (Major) Avoid coadministration of olaparib with nicardipine and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and nicardipine is a moderate CYP3A4 inhibitor.
    Nilotinib: (Major) Avoid coadministration of olaparib with nilotinib and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and nilotinib is a moderate CYP3A4 inhibitor.
    Octreotide: (Major) Avoid coadministration of olaparib with octreotide and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate. Somatostatin analogs, such as octreotide, decrease growth hormone secretion which in turn may inhibit CYP3A4.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of olaparib with ritonavir and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and ritonavir is a strong CYP3A4 inhibitor.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentobarbital: (Major) Avoid the coadministration of olaparib with pentobarbital due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and pentobarbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Phenobarbital: (Major) Avoid the coadministration of olaparib with phenobarbital due to the risk of decreased olaparib efficacy. Olaparib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC of olaparib by 87%.
    Phenytoin: (Major) Avoid the coadministration of olaparib with phenytoin due to the risk of decreased olaparib efficacy. Olaparib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC of olaparib by 87%.
    Posaconazole: (Major) Avoid coadministration of olaparib with posaconazole and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and posaconazole is a strong CYP3A4 inhibitor.
    Primidone: (Major) Avoid the coadministration of olaparib with primidone due to the risk of decreased olaparib efficacy. Olaparib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC of olaparib by 87%.
    Quinine: (Major) Avoid coadministration of olaparib with quinine and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and quinine is a moderate CYP3A4 inhibitor.
    Ribociclib: (Major) Avoid coadministration of olaparib with ribociclib and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC of olaparib by 170%.
    Ribociclib; Letrozole: (Major) Avoid coadministration of olaparib with ribociclib and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC of olaparib by 170%.
    Rifabutin: (Major) Avoid the coadministration of olaparib with rifabutin due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Rifampin: (Major) Avoid the coadministration of olaparib with rifampin due to the risk of decreased olaparib efficacy. Olaparib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the AUC of olaparib by 87%.
    Rifapentine: (Major) Avoid the coadministration of olaparib with rifapentine due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and rifapentine is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Ritonavir: (Major) Avoid coadministration of olaparib with ritonavir and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and ritonavir is a strong CYP3A4 inhibitor.
    Saquinavir: (Major) Avoid coadministration of olaparib with saquinavir and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and saquinavir is a strong CYP3A4 inhibitor.
    Secobarbital: (Major) Avoid the coadministration of olaparib with secobarbital due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and secobarbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    St. John's Wort, Hypericum perforatum: (Major) Avoid the coadministration of olaparib with St. John's Wort due to the risk of decreased olaparib efficacy. Olaparib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC of olaparib by 87%.
    Telithromycin: (Major) Avoid coadministration of olaparib with telithromycin and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and telithromycin is a strong CYP3A4 inhibitor.
    Thiopental: (Major) Avoid the coadministration of olaparib with thiopental due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and thiopental is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    Tipranavir: (Major) Avoid coadministration of olaparib with tipranavir and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and tipranavir is a strong CYP3A4 inhibitor.
    Trandolapril; Verapamil: (Major) Avoid coadministration of olaparib with verapamil and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and verapamil is a moderate CYP3A4 inhibitor.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Verapamil: (Major) Avoid coadministration of olaparib with verapamil and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and verapamil is a moderate CYP3A4 inhibitor.
    Voriconazole: (Major) Avoid coadministration of olaparib with voriconazole and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC of olaparib by 170%.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during olaparib treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, olaparib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving olaparib should be apprised of the potential hazard to the fetus. Olaparib caused teratogenicity and embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose when administered during the period of organogenesis. When given orally for 14 days before mating through day 6 of pregnancy, olaparib resulted in increased postimplantation loss at maternal exposures of approximately 7% the AUC at the recommended human dose. At exposures approximately 0.18% the exposure of the recommended dose, pregnant rats experienced increased postimplantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital), and diaphragm (hernia). Additional abnormalities included incomplete or absent ossification of the vertebrae/sternebrae, ribs, and limbs, as well as other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter, and umbilical artery.

    Counsel patients about the reproductive risk and contraception requirements during olaparib treatment. Olaparib can be teratogenic and embryotoxic if the mother is exposed during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during treatment and for at least 6 months after the last dose of olaparib. Male patients with female partners of reproductive potential should use effective contraception during treatment and for at least 3 months after the last dose of olaparib. Male patients should also not donate sperm during therapy and for 3 months after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of olaparib. Women who become pregnant while receiving olaparib should be apprised of the potential hazard to the fetus. Olaparib does not appear to cause infertility in males or females based on animal studies.

    MECHANISM OF ACTION

    Olaparib inhibits poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular functions, such as DNA transcription and DNA repair. Olaparib has been shown to inhibit growth of select tumor cell lines in vitro and decrease tumor growth in mouse xenograft models of human cancer, both as monotherapy or following platinum-based chemotherapy. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA and non-BRCA proteins involved in the homologous recombination repair of DNA damage and correlated with platinum response. Olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in DNA damage and cancer cell death.

    PHARMACOKINETICS

    Olaparib is administered orally. It is approximately 82% protein bound in vitro. After a single 300 mg oral dose of olaparib, the mean volume of distribution is 158 +/- 136 L. After oral dosing of radiolabeled olaparib, 86% of the radioactivity was recovered within 7 days: 44% via urine and 42% via feces. The majority (70%) of the material was excreted as metabolites. The mean terminal half-life after a single 300 mg dose of olaparib was 14.9 +/- 8.2 hours, while the apparent plasma clearance was 7.4 +/- 3.9 L/hour.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4
    Olaparib is extensively metabolized by oxidation reactions, with many components undergoing subsequent glucuronide or sulfate conjugation; unchanged drug accounts for only 15% and 6% of radioactivity in urine and feces, respectively. Coadministration with itraconazole, a strong CYP3A inhibitor, increased the AUC and Cmax of olaparib by 170% and 42%, respectively, in a drug interaction trial (n = 57). Simulations suggested that a moderate CYP3A inhibitor (fluconazole) may increase the AUC and Cmax of olaparib by 121% and 14%, respectively. Concomitant use of strong and moderate CYP3A inhibitors should be avoided; if unavoidable, a dose adjustment is recommended. Coadministration with rifampicin, a strong CYP3A inducer, decreased the AUC and Cmax of olaparib by 87% and 71%, respectively, in a drug interaction trial (n = 22). Simulations suggested that a moderate CYP3A inducer (efavirenz) may decrease the AUC and Cmax of olaparib by 60% and 31%, respectively. Concomitant use of strong and moderate CYP3A inducers should be avoided; if moderate inducers are unavoidable, there is a potential for decreased efficacy of olaparib.
     
    Olaparib is also an inducer and (weak) inhibitor of CYP3A, and an inducer of CYP2B6 in vitro. In vitro it is also an inhibitor of UGT1A1, BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K. The clinical relevance of these findings is unknown. In vitro, olaparib is a substrate of and inhibitor of P-glycoprotein (P-gp). The potential for olaparib to induce P-gp has not been evaluated.

    Oral Route

    The oral bioavailability of olaparib tablet formulation is higher than then capsule formulation; the steady state AUC after 300 mg tablet twice daily dosing was 77% higher compared to that following 400 mg capsule twice daily dosing, based on population pharmacokinetic analyses.
     
    Absorption of olaparib is rapid following oral administration, with the median Cmax achieved 1.5 hours after dosing. The AUC mean accumulation ratio at steady state (300 mg tablets twice daily) is 1.8. Systemic exposure to olaparib increases approximately proportionally with doses over the dose range of 25 mg to 450 mg; Cmax increased slightly less than proportionally for the same dose range. Coadministration of a high fat meal slowed the rate of absorption (Tmax delayed by 2.5 hours), but did not significantly alter the extent of olaparib absorption (mean AUC increased by approximately 8%). The geometric mean AUC and Cmax following a single 300 mg tablet dose was 42 mcg*hour/mL and 5.8 mcg/mL, respectively (n = 204), and the steady state geometric mean AUC and Cmax following 300 mg tablet twice daily dosing were 49 mcg*hour/mL and 7.7 mcg/mL, respectively (n=227). Olaparib showed time-dependent pharmacokinetics, with the steady state clearance decreasing by 15% after multiple dosing.