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Olaparib
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300 mg PO twice daily 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. 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) compared with placebo 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).[63696] [58662]
300 mg PO twice daily until disease progression, unacceptable toxicity, or completion of 2 years of treatment, in combination with bevacizumab (15 mg/kg IV every 3 weeks for 15 months total, including the period given with chemotherapy and given with maintenance). Patients with a complete response (no radiological evidence of disease) at 2 years should stop treatment with olaparib. 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. Maintenance therapy with olaparib plus bevacizumab significantly improved the primary outcome of median progression-free survival compared with patients receiving bevacizumab plus placebo in HRD-positive patients with advanced high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer following first-line platinum-based chemotherapy and bevacizumab in a multicenter, randomized, double-blind clinical trial (PAOLA-1) (37.2 months vs. 17.7 months); the median overall survival rate was also significantly improved in the olaparib/bevacizumab arm (75.2 months vs. 57.3 months).[58662] [69881]
300 mg PO 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. 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) (SOLO2 trial). Approximately 44% of olaparib patients and 37% of placebo patients in this trial had received 3 or more lines of platinum-based treatment. 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 (51.7 months vs. 38.8 months) irrespective of BRCA 1/2 mutation status but did not meet the predefined threshold for statistical significance.[58662] [65864] [66532]
Dosage not available.
300 mg orally twice daily for a total of 1 year, or until disease progression or unacceptable toxicity if occurring before 1 year. Patients with hormone receptor-positive breast cancer should continue to receive concurrent endocrine therapy according to current clinical practice guidelines. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, double-blind, phase 3 clinical trial (OlympiA), patients with gBRCAm HER2-negative high risk early breast cancer who had completed definitive local treatment and neoadjuvant or adjuvant chemotherapy were randomized to receive 1 year of olaparib or placebo. Treatment with olaparib significantly improved 3-year invasive disease-free survival (85.9% vs. 77.1%) and 3-year distant disease-free survival (87.5% vs. 804%) compared with placebo. Olaparib was also associated with fewer deaths than placebo, although at the interim analysis this difference was not statistically significant.[58662] [67934]
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. Olaparib monotherapy significantly improved the primary endpoint of 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] [67934]
NOTE: Olaparib has been designated by the FDA as an orphan drug for the treatment of pancreatic cancer.
300 mg PO 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 a multicenter, randomized clinical trial, maintenance therapy with olaparib after a lack of disease progression on at least 16 weeks of first-line platinum-based chemotherapy significantly improved median progression-free survival compared with placebo (7.4 months vs. 3.8 months) in patients with deleterious or suspected deleterious gBRCA-mutated metastatic pancreatic cancer. The objective response rate was 23% (complete response [CR], 2.6%) in the olaparib arm compared with 12% (CR, 0%) in patients who received placebo, for a median duration of 25 months versus 4 months, respectively.[58662] [64904] In the final analysis, median overall survival was 19 months in patients who received olaparib and 19.2 months in patients who received placebo.[58662] [67346]
300 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. In a multicenter, randomized, open-label clinical trial (the PROfound study), treatment of HRR-mutated mCRPC with olaparib significantly improved the median radiological progression-free survival (rPFS) compared with enzalutamide or abiraterone in patients with mutations in BRCA1, BRCA2, or ATM (7.4 months vs. 3.6 months); when patients with mutations in other genes involved in the HRR pathway (BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L) were included in the analysis, rPFS was still significantly improved (5.8 months vs. 3.5 months). The confirmed objective response rate (33% vs. 2%) and median overall survival (19.1 months vs. 14.7 months) were also significantly improved in patients with BRCA1, BRCA2, or ATM mutations. Prior taxane therapy did not affect the results compared to patients who had not previously received a taxane. Olaparib is not indicated for patients with PPP2R2A mutations due to an unfavorable risk-benefit.[58662] [65472] [65930]
300 mg PO twice daily in combination with abiraterone (1,000 mg PO once daily) and either prednisone or prednisolone (5 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. In a multicenter, randomized, double-blind clinical trial (PROpel), treatment with olaparib in combination with abiraterone and prednisone or prednisolone significantly improved median radiological progression-free survival (not reached vs. 8 months) and median overall survival (not reached vs. 23 months) compared with placebo plus abiraterone and prednisone/prednisolone in patients with metastatic castration-resistant prostate cancer. Prior treatment with docetaxel for localized or metastatic hormone-sensitive prostate cancer was allowed; patients with prior treatment with abiraterone were excluded.[69052] [58662]
Dosage Adjustments for Treatment-Related Toxicity:
General
Hematologic
300 mg PO twice daily.
300 mg PO twice daily.
Safety and effectiveness have not been established.
Safety and effectiveness have not been established.
Not indicated.
Not indicated.
Baseline Hepatic Impairment:
Baseline Renal Impairment:
Olaparib is an oral poly (ADP-ribose) polymerase (PARP) inhibitor. PARP enzymes are involved in normal cellular homeostasis, including DNA transcription, cell cycle regulation, and DNA repair. Increased cytotoxicity and anti-tumor activity has been noted in cell lines and mouse tumor models with deficiencies in BRCA. It is approved by the FDA as monotherapy for the maintenance treatment of platinum-sensitive BRCA-mutated recurrent ovarian cancer, advanced ovarian cancer, and pancreatic cancer; it is approved in combination with bevacizumab for maintenance therapy for platinum-sensitive, homologous recombination deficiency-positive ovarian cancer. It is approved as monotherapy for the adjuvant treatment of BRCA-mutated, HER2-negative high risk early breast cancer in patients who have received neoadjuvant or adjuvant chemotherapy, for previously treated BRCA-mutated, HER2-negative metastatic breast cancer, and for homologous recombination repair gene-mutated metastatic castration-resistant prostate cancer (mCRPC) in patients who progressed after enzalutamide or abiraterone treatment. It is also approved for BRCA-mutated mCRPC in combination with abiraterone and prednisone or prednisolone. The most common adverse reactions include anemia, nausea, fatigue, vomiting, upper respiratory infection, diarrhea, and arthralgia/myalgia.[58662]
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Hazardous Drugs Classification
Emetic Risk
New primary malignancy, specifically myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), has been reported in 1.2% of patients treated with olaparib as monotherapy or as part of a combination regimen in clinical trials and long-term follow-up (n = 2,219); 54% of these cases had a fatal outcome. All patients who developed MDS/AML had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiation therapy. Monitor complete blood counts at baseline and monthly thereafter; do not start olaparib until hematologic toxicity from previous chemotherapy has recovered to grade 1 or less. Hold olaparib therapy for prolonged hematologic toxicity and monitor blood counts weekly until recovery. 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. Discontinue olaparib therapy if a diagnosis of MDS or AML is confirmed.[58662]
Infection was reported in up to 36% of patients treated with olaparib in clinical trials. Upper respiratory tract infections occurred most often, including influenza, naso-pharyngitis, bronchitis, sinusitis, rhinitis (17% to 36%; grade 3 or 4, 1% or less); nasopharyngitis (12%) and pneumonia (5%) were reported individually in separate clinical trials. A urinary tract infection was reported in 13% (grade 3 or 4, 1%) of olaparib-treated patients in one clinical trial.[58662]
Neutropenia (9% to 27%; grade 3 or 4, 9% or less) and leukopenia (5% to 25%; grade 3 or 4, 5% or less) of patients who received olaparib as monotherapy or in combination with bevacizumab across clinical trials; neutropenic fever has occurred in patients treated with olaparib. Lymphopenia occurred in 1% to 8% of patients who received olaparib monotherapy, in 14% (grade 3 or 4, 5%) of patients who received olaparib plus abiraterone, and in 24% (grade 3 or 4, 7%) of patients who received olaparib plus bevacizumab. Decreases from baseline in leukocytes (50% to 71%; grade 3 or 4, 3% to 8%), lymphocytes (61% to 77%; grade 3 or 4, 9% to 23%) and neutrophils (23% to 51%; grade 3 or 4, 3% to 11%) were additionally reported across clinical trials in patients receiving olaparib as monotherapy or in combination with bevacizumab or abiraterone.[58662]
Increased creatinine was reported as an adverse reaction in 2% to 11% of patients treated with olaparib monotherapy across clinical trials; however, a mild (grade 1 or 2) increase in creatinine from baseline in laboratory parameters was reported more commonly (34% to 99%). Grade 3 or 4 increases in creatinine from baseline (renal failure (unspecified)) occurred in 2% or fewer patients. In general, treatment with olaparib generally increased creatinine from baseline approximately 15% to 31% more often than placebo.[58662]
Nausea was reported in 41% to 77% of patients treated with olaparib monotherapy across clinical trials (grade 3 or 4, 3% or less); vomiting occurred in 18% to 40% of patients (grade 3 or 4, 3% or less). The incidence of nausea (53%; grade 3 or 4, 2.4%) and vomiting (22%; grade 3 or 4, 1.7%) were similar in ovarian cancer patients receiving maintenance therapy with olaparib plus bevacizumab. Nausea was reported in 30% (grade 3 or 4, 0.3%) of patients with metastatic prostate cancer treated with olaparib plus abiraterone compared with 14% (grade 3 or 4, 0.3%) of those receiving abiraterone plus placebo; vomiting was not reported in this trial.[58662]
Abdominal pain (45% or less; grade 3 or 4, 2% or less), diarrhea (including colitis and gastroenteritis) (18% to 37%; grade 3 or 4, 3% or less), and constipation (28% or less) occurred in patients treated with olaparib monotherapy across clinical trials; upper abdominal pain was separately reported in 4.9% to 7% of patients in 2 clinical trials. The incidence of diarrhea (18%) was similar in ovarian cancer patients receiving maintenance therapy with olaparib plus bevacizumab. Abdominal pain (13%) and diarrhea (19%; grade 3 or 4, 1%) were also reported in metastatic prostate cancer patients treated with olaparib plus abiraterone.[58662]
Stomatitis (including aphthous ulcer, oral ulceration, oral abscess, oral herpes, and oral infection) occurred in 2.5% to 20%; grade 3 or 4, 1% or less) of patients treated with olaparib as monotherapy or in combination with bevacizumab or abiraterone across clinical trials.[58662]
Anorexia was reported in 13% to 30% of patients treated with olaparib as monotherapy or in combination with bevacizumab or abiraterone across clinical trials (grade 3 or 4, 3% or less); dysgeusia (7% to 27%) and dyspepsia (4.3% to 17%) were also reported in olaparib-treated patients.[58662]
One patient receiving olaparib salvage treatment for advanced ovarian cancer after at least 3 prior chemotherapy regimens died due to GI perforation in pooled data of 6 clinical trials.[58662]
Mild (grade 1 or 2) arthralgia/myalgia was reported in 30% of patients receiving olaparib maintenance therapy for advanced ovarian cancer (n = 195) compared with 28% of those who received placebo (n = 99) in a randomized, double-blind clinical trial. Arthralgia was reported in 15% (grade 3 or 4, 1%) of patients with metastatic pancreatic cancer receiving olaparib maintenance therapy (n = 91) compared with 10% of those receiving placebo (n = 60) in one randomized clinical trial; back pain occurred in 19% of olaparib-treated patients in this trial.[58662]
Fatigue (including asthenia, lethargy, and malaise) was reported in 37% to 67% (grade 3 or 4, 1.8% to 5%) of olaparib-treated patients in clinical trials of patients receiving olaparib maintenance therapy. Fatigue was less common in 3 clinical trials of patients receiving treatment for metastatic breast cancer or metastatic prostate cancer (37% to 41%; grade 3 or 4, 2.3% to 4%). The incidence of fatigue (53%; grade 3 or 4, 5%) was similar in ovarian cancer patients receiving maintenance therapy with olaparib plus bevacizumab.[58662]
Hypomagnesemia was reported in 14% of patients receiving olaparib maintenance therapy for advanced ovarian cancer (n = 195) in a randomized, double-blind clinical trial.[58662]
Rash (up to 15%) and dermatitis (up to 1%) have been reported in patients receiving olaparib as treatment or maintenance therapy in clinical trials; the term rash included erythematous rash and maculopapular rash. Rash, dermatitis, and erythema nodosum have also been reported in postmarketing experience with olaparib.[58662]
Edema was reported in 8% of patients treated with olaparib maintenance therapy for advanced ovarian cancer in one clinical trial.[58662]
Thromboembolism/venous thromboembolic events (VTE) including severe or fatal pulmonary embolism (PE) have been reported with olaparib therapy. Monitor patients for signs and symptoms of venous thrombosis and PE; treat VTE as medically appropriate which may include the use of long-term anticoagulation. In combined data of 2 randomized, placebo-controlled trials (n = 1,180), VTE (8% vs. 2.5%) and PE (6% vs 1.5%) occurred more often in patients with metastatic castration-resistant prostate cancer treated with olaparib plus androgen deprivation therapy (ADT) or abiraterone compared to control arms. In other randomized controlled trials, VTE occurred in 0.5% to 5% and PE in 3.5% or fewer patients who received olaparib.[58662]
One patient receiving olaparib salvage treatment for advanced ovarian cancer after at least 3 prior chemotherapy regimens died due to stroke in pooled data of 6 clinical trials.[58662]
Headache occurred in 6% to 26% (grade 3 or 4, 1% or less) and dizziness in 2.6% to 20% (grade 3 or 4, 0.3% or less) of olaparib-treated patients across clinical trials; the term dizziness included vertigo in 1 clinical trial.[58662]
Pneumonitis, including some fatalities, was reported in 0.8% of patients treated with olaparib across clinical trials (n = 2,901). Pneumonitis occurred in 2% of patients with metastatic castration-resistant prostate cancer treated with olaparib plus androgen deprivation therapy. Hold olaparib therapy for new or worsening respiratory symptoms, including dyspnea, fever, cough, wheezing, or radiological abnormalities; discontinue olaparib if a diagnosis of pneumonitis is confirmed. Cough (9% to 18%) and dyspnea (4.2% to 15%; grade 3 or 4, 2% or less) have also been reported in patients treated with olaparib monotherapy. The incidence of dyspnea (8%) was similar in ovarian cancer patients receiving maintenance therapy with olaparib plus bevacizumab.[58662]
Erythema was reported in 3% of ovarian cancer patients receiving maintenance therapy with olaparib plus bevacizumab.[58662]
Anemia was the most common hematologic adverse reaction reported with olaparib treatment as monotherapy or in combination with bevacizumab or abiraterone, occurring in 24% to 48% (grade 3 or 4, 9% to 21%) of olaparib-treated patients across clinical trials; a decrease in hemoglobin from baseline was also reported in olaparib treatment arms (up to 98%; grade 3 or 4, 8% to 19%). A mild increase in mean corpuscular volume above normal limits (57% to 89%) was additionally reported across clinical trials. Increased mean cell volume was reported in 0.4% of patients receiving olaparib as first-line maintenance therapy for ovarian cancer.[58662]
Thrombocytopenia occurred in 4.2% to 14% (grade 3 or 4, 4% or less) of patients receiving single-agent olaparib as treatment or maintenance therapy across clinical trials. Decreases from baseline in platelets counts were additionally reported in 23% to 56% of olaparib-treated patients (grade 3 or 4, 1% to 3%).[58662]
Hypersensitivity reactions including angioedema have been reported in postmarketing experience in patients treated with olaparib; hypersensitivity to olaparib has been reported in 0.9% to 2% of patients.[58662]
New primary malignancy, specifically myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), has been reported in patients treated with olaparib monotherapy; approximately half of these cases were fatal. The median duration of olaparib therapy in patients who developed MDS/AML was 2 years. All patients who developed MDS/AML had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiation therapy. Monitor complete blood counts at baseline and monthly thereafter; do not start olaparib until hematologic toxicity from previous chemotherapy has recovered to grade 1 or less. 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.[58662]
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.[58662]
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.[58662]
Thromboembolism/venous thromboembolic events (VTE) including severe or fatal pulmonary embolism (PE) have been reported with olaparib therapy. Monitor patients for signs and symptoms of venous thrombosis and PE; treat VTE as medically appropriate which may include the use of long-term anticoagulation.[58662]
Pregnancy should be avoided by females of reproductive potential during olaparib treatment and for 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.[58662]
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 6 months after the last dose of olaparib. Due to the risk of male-mediated teratogenicity, 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 the initiation of olaparib treatment. 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.[58662]
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.[58662]
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. In prostate cancer models, PARP1 has been shown to contribute to androgen receptor (AR) activity regulation; the combination of olaparib and AR inhibition resulted in cytotoxicity in vitro and anti-tumor activity in mouse xenograft models.[58662]
Revision Date: 11/21/2024, 01:49:00 AMOlaparib is administered orally and shows time-dependent pharmacokinetics. 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 in vitro. 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.[58662]
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 the 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.[58662]
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. 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.[58662]
The mean Cmax of olaparib is 5.4 mcg/mL (CV, 32%) following a single dose and 7.6 mcg/mL (CV, 35%) at steady-state. Absorption of olaparib is rapid following oral administration, with the median time to peak plasma concentrations (Tmax) of 1.5 hours. The mean AUC of olaparib is 39.2 mcg x hour/mL (CV, 44%) following a single dose and 49.2 mcg x hour/mL (CV, 44%) at steady-state; the AUC mean accumulation ratio at steady-state is 1.8. Systemic exposure to olaparib increases approximately proportionally with doses over the dose range of 25 mg to 450 mg (0.08 to 1.5 times the recommended dose); Cmax increased slightly less than proportionally for the same dose range.[58662]
Coadministration of a high-fat meal (800 to 1,000 kcal with 50% fat) delayed the Tmax by 2.5 hours but did not significantly alter the extent of olaparib absorption (mean AUC increased by approximately 8%).[58662]
In a hepatic impairment trial, the mean AUC and Cmax of olaparib increased by 15% and 13%, respectively, in patients with mild hepatic impairment (n = 10; Child-Pugh class A) compared to patients with normal hepatic function (n = 13). The mean AUC of olaparib increased by 8%, and the mean Cmax decreased by 13% when administered to patients with moderate hepatic impairment (n = 8; Child-Pugh class B). Hepatic impairment did not affect olaparib protein binding. Therefore total plasma exposure is representative of free drug. There are no data in patients with severe hepatic impairment (Child-Pugh class C).[58662]
In a renal impairment trial, the mean AUC of olaparib increased by 24% and the Cmax increased by 15% in patients with mild renal impairment (CrCl 50 to 80 mL/min; n = 13) compared to patients with normal renal function (CrCl greater than 80 mL/min; n = 12); the mean AUC and Cmax of olaparib increased by 44% and 26%, respectively, in patients with moderate renal impairment (CrCl 31 to 50 mL/min; n = 13). There was no evidence of a relationship between the extent of plasma protein binding of olaparib and creatinine clearance. No data is available for patients with severe renal impairment or end-stage renal disease.[58662]
Pregnancy should be avoided by females of reproductive potential during olaparib treatment and for 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.[58662]
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.[58662]
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