Chemical formula: C₂₄H₂₃FN₄O₃ Molecular mass: 434.463 g/mol
Olaparib interacts in the following cases:
Olaparib inhibits CYP3A4 in vitro and is predicted to be a mild CYP3A inhibitor in vivo. Therefore, caution should be exercised when sensitive CYP3A substrates or substrates with a narrow therapeutic margin (e.g. simvastatin, cisapride, cyclosporine, ergot alkaloids, fentanyl, pimozide, sirolimus, tacrolimus and quetiapine) are combined with olaparib. Appropriate clinical monitoring is recommended for patients receiving CYP3A substrates with a narrow therapeutic margin concomitantly with olaparib.
In vitro, olaparib has been shown to be an inhibitor of BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K. It cannot be excluded that olaparib may increase the exposure to substrates of BCRP (e.g. methotrexate, rosuvastatin), OATP1B1 (e.g. bosentan, glibenclamide, repaglinide, statins and valsartan), OCT1 (e.g. metformin), OCT2 (e.g. serum creatinine), OAT3 (e.g. furosemide and methotrexate), MATE1 (e.g. metformin) and MATE2K (e.g. metformin). In particular, caution should be exercised if olaparib is administered in combination with any statin.
CYP3A4/5 are the isozymes predominantly responsible for the metabolic clearance of olaparib.
A clinical study to evaluate the impact of rifampicin, a known CYP3A inducer, has shown that co-administration with olaparib decreased olaparib mean Cmax by 71% (90% CI: 76-67%) and mean AUC by 87% (90% CI: 89-84%). Therefore, known strong inducers of this isozyme (e.g. phenytoin, rifampicin, rifapentine, carbamazepine, nevirapine, phenobarbital and St John’s Wort) are not recommended with olaparib, as it is possible that the efficacy of olaparib could be substantially reduced. The magnitude of the effect of moderate to strong inducers (e.g. efavirenz, rifabutin) on olaparib exposure is not established, therefore the co-administration of olaparib with these medicinal products is also not recommended.
Induction of CYP1A2, 2B6 and 3A4 has been shown in vitro with CYP2B6 being most likely to be induced to a clinically relevant extent. The potential for olaparib to induce CYP2C9, CYP2C19 and P-gp can also not be excluded. Therefore, olaparib upon co-administration may reduce the exposure to substrates of these metabolic enzymes and transport protein. The efficacy of some hormonal contraceptives may be reduced if co-administered with olaparib.
In vitro, olaparib inhibits the efflux transporter P-gp (IC50=76 μM), therefore it cannot be excluded that olaparib may cause clinically relevant drug interactions with substrates of P-gp (e.g. simvastatin, pravastatin, dabigatran, digoxin and colchicine). Appropriate clinical monitoring is recommended for patients receiving this type of medicinal product concomitantly.
CYP3A4/5 are the isozymes predominantly responsible for the metabolic clearance of olaparib.
A clinical study to evaluate the impact of itraconazole, a known CYP3A inhibitor, has shown that co-administration with olaparib increased mean olaparib Cmax by 42% (90% CI: 33-52%) and mean AUC by 170% (90% CI: 144-197%). Therefore, known strong (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, boceprevir, telaprevir) or moderate (e.g. erythromycin, diltiazem, fluconazole, verapamil) inhibitors of this isozyme are not recommended with olaparib.
If strong or moderate CYP3A inhibitors must be co-administered, the dose of olaparib should be reduced. The recommended olaparib dose reduction is to 100 mg taken twice daily (equivalent to a total daily dose of 200 mg) with a strong CYP3A inhibitor or 150 mg taken twice daily (equivalent to a total daily dose of 300 mg) with a moderate CYP3A inhibitor. It is also not recommended to consume grapefruit juice while on olaparib therapy as it is a CYP3A inhibitor.
For patients with moderate renal impairment (creatinine clearance 31 to 50 ml/min) the recommended dose of olaparib is 200 mg twice daily (equivalent to a total daily dose of 400 mg).
Olaparib is not recommended for use in patients with severe renal impairment or end-stage renal disease (creatinine clearance ≤30 ml/min), as safety and pharmacokinetics have not been studied in these patients. Olaparib may only be used in patients with severe renal impairment if the benefit outweighs the potential risk, and the patient should be carefully monitored for renal function and adverse events.
Olaparib is not recommended for use in patients with severe hepatic impairment (Child-Pugh classification C), as safety and pharmacokinetics have not been studied in these patients.
Combination of olaparib with vaccines or immunosuppressant agents has not been studied. Therefore, caution should be taken if these medicinal products are co-administered with olaparib and patients should be closely monitored.
Studies in animals have shown reproductive toxicity including serious teratogenic effects and effects on embryofoetal survival in the rat at maternal systemic exposures lower than those in humans at therapeutic doses. There are no data from the use of olaparib in pregnant women, however, based on the mode of action of olaparib, olaparib should not be used during pregnancy and in women of childbearing potential not using reliable contraception during therapy and for 6 months after receiving the last dose of olaparib.
There are no animal studies on the excretion of olaparib in breast milk. It is unknown whether olaparib or its metabolites are excreted in human milk. Olaparib is contraindicated during breast-feeding and for 1 month after receiving the last dose, given the pharmacologic property of the product.
Women of childbearing potential should not become pregnant while on olaparib and not be pregnant at the beginning of treatment. A pregnancy test should be performed on all women of childbearing potential prior to treatment and considered regularly throughout treatment.
Women of childbearing potential must use two forms of reliable contraception before starting olaparib therapy, during therapy and for 6 months after receiving the last dose of olaparib, unless abstinence is the chosen method of contraception. Two highly effective and complementary forms of contraception are recommended.
11 Since it cannot be excluded that olaparib may reduce exposure to substrates of CYP2C9 through enzyme induction, the efficacy of some hormonal contraceptives may be reduced if co-administered with olaparib. Therefore, an additional non-hormonal contraceptive method should be considered during treatment. For women with hormone dependent cancer, two non-hormonal contraceptive methods should be considered.
It is not known whether olaparib or its metabolites are found in seminal fluid. Male patients must use a condom during therapy and for 3 months after receiving the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients must also use highly effective contraception if they are of childbearing potential. Male patients should not donate sperm during therapy and for 3 months after receiving the last dose of olaparib.
There are no clinical data on fertility. In animal studies, no effect on conception was observed but there are adverse effects on embryofoetal survival.
Olaparib has moderate influence on the ability to drive and use machines. Patients who take olaparib may experience fatigue, asthenia or dizziness. Patients who experience these symptoms should observe caution when driving or using machines.
Olaparib has been associated with adverse reactions generally of mild or moderate severity (CTCAE grade 1 or 2) and generally not requiring treatment discontinuation. The most frequently observed adverse reactions across clinical trials in patients receiving olaparib monotherapy (≥10%) were nausea, fatigue/asthenia, anaemia, vomiting, diarrhoea, decreased appetite, headache, neutropenia, dysgeusia, cough, leukopenia, dizziness, dyspnoea and dyspepsia.
The Grade ≥3 adverse reactions occurring in >2% of patients were anaemia (14%), neutropenia (5%), fatigue/asthenia (4%), leukopenia (2%) and thrombocytopenia (2%).
Adverse reactions that most commonly led to dose interruptions and/or reductions in monotherapy were anaemia (16%), nausea (7%), fatigue/asthenia (6%), neutropenia (6%) and vomiting (6%).
Adverse reactions that most commonly led to permanent discontinuation were anaemia (1.7%), nausea (0.9%), fatigue/asthenia (0.8%), thrombocytopenia (0.7%), neutropenia (0.6%) and vomiting (0.5%).
When olaparib is used in combination with bevacizumab for ovarian cancer, in combination with abiraterone and prednisone or prednisolone for prostate cancer, or in combination with durvalumab following treatment with durvalumab in combination with platinum-based chemotherapy for endometrial cancer, the safety profile is generally consistent with that of the individual therapies.
When used in combination with bevacizumab, adverse events led to dose interruption and/ or reduction of olaparib in 57% of patients and led to permanent discontinuation of treatment with olaparib and placebo in 21% and 6% of patients, respectively. The adverse reactions that most commonly led to dose interruption and/or reduction of olaparib were anaemia (21.7%), nausea (9.5%), fatigue/asthenia (5.4%), vomiting (3.7%), neutropenia (3.6%), thrombocytopenia (3.0%) and diarrhoea (2.6%). The adverse reactions that most commonly led to permanent discontinuation were anaemia (3.7%), nausea (3.6%) and fatigue/asthenia (1.5%).
When used in combination with abiraterone, adverse events led to dose interruption and/or reduction of olaparib in 50.7% of patients and led to permanent discontinuation of treatment with olaparib and placebo in 19.0% and 8.8% of patients, respectively. The adverse reactions that most commonly led to dose interruption and/or reduction of olaparib were anaemia (17.1%), fatigue/asthenia (5.5%), nausea (4.1%), neutropenia (3.4%), vomiting (2.3%), diarrhoea (2.1%) and venous thrombotic events (2.1%). The adverse reactions that most commonly led to permanent discontinuation were anaemia (4.5%) and fatigue/asthenia (1.3%).
When used in combination with durvalumab following treatment with durvalumab in combination with platinum-based chemotherapy, adverse events led to dose interruption and/or reduction of olaparib in 59.9% of patients and led to permanent discontinuation of treatment with olaparib in 10.9% of patients. The adverse reactions that most commonly led to dose interruption and/or reduction of olaparib were anaemia (20.8%), nausea (8.3%), neutropenia (7.3%), fatigue/asthenia (5.7%), thrombocytopenia (4.2%), vomiting (4.2%), blood creatinine increased (3.1%), leukopenia (3.1%), and decreased appetitive (2.6%), diarrhoea (2.1%). The adverse reactions that most commonly led to permanent discontinuation of olaparib were anaemia (3.6%) and neutropenia (1%).
The safety profile is based on pooled data from 4499 patients with solid tumours treated with olaparib monotherapy in clinical trials at the recommended dose.
The following adverse reactions have been identified in clinical trials with patients receiving olaparib monotherapy where patient exposure is known. Adverse drug reactions are listed by MedDRA System Organ Class (SOC) and then by MedDRA preferred term in Table 1. Within each SOC, preferred terms are arranged by decreasing frequency and then by decreasing seriousness. Frequencies of occurrence of adverse reactions are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from available data).
Table 1. Tabulated list of adverse reactions:
| Adverse reactions | ||
|---|---|---|
| MedDRA System Organ Class | Frequency of All CTCAE grades | Frequency of CTCAE grade 3 and above |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | Uncommon Myelodysplastic syndrome/Acute myeloid leukaemiaa | Uncommon Myelodysplastic syndrome/ Acute myeloid leukaemia |
| Blood and lymphatic system disordersb | Very common Anaemiaa, Neutropeniaa, Leukopeniaa Common Lymphopeniaa, Thrombocytopeniaa | Very common Anaemiaa Common Neutropeniaa, Thrombocytopeniaa, Leukopeniaa, Lymphopeniaa |
| Immune system disorders | Uncommon Hypersensitivitya Rare Angioedema* | Rare Hypersensitivitya |
| Hepatobiliary disorders | Common Transaminases increaseda Not known Drug-induced liver injury* | |
| Metabolism and nutrition disorders | Very common Decreased appetite | Uncommon Decreased appetite |
| Nervous system disorders | Very common Dizziness, Headache, Dysgeusiaa | Uncommon Dizziness, Headache |
| Respiratory, thoracic and mediastinal disorders | Very common Cougha, Dyspnoeaa | Common Dyspnoeaa Uncommon Cougha |
| Gastrointestinal disorders | Very common Vomiting, Diarrhoea, Nausea, Dyspepsia Common Stomatitisa, Upper abdominal pain | Common Vomiting, Nausea Uncommon Stomatitisa, Diarrhoea Rare Dyspepsia, Upper abdominal pain |
| Skin and subcutaneous tissue disorders | Common Rasha Uncommon Dermatitisa Rare Erythema nodosum | Uncommon Rasha Rare Dermatitisa |
| General disorders and administration site conditions | Very common Fatigue (including asthenia) | Common Fatigue (including asthenia) |
| Investigationsb | Common Blood creatinine increased Uncommon Mean cell volume increased | Rare Blood creatinine increased |
| Vascular disorders | Common Venous thromboembolisma | Common Venous thromboembolisma |
a MDS/AML includes preferred terms (PTs) of acute myeloid leukaemia, myelodysplastic syndrome and myeloid leukaemia.
Anaemia includes PTs of anaemia, anaemia macrocytic, erythropenia, haematocrit decreased, haemoglobin decreased, normocytic anaemia and red blood cell count decreased.
Neutropenia includes PTs of febrile neutropenia, neutropenia, neutropenic infection, neutropenic sepsis and neutrophil count decreased.
Thrombocytopenia includes PTs of platelet count decreased and thrombocytopenia.
Leukopenia includes PTs of leukopenia and white blood cell count decreased.
Lymphopenia includes PTs of lymphocyte count decreased and lymphopenia.
Hypersensitivity includes PTs of drug hypersensitivity and hypersensitivity.
Transaminases increased includes PTs of alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, and hypertransaminasaemia
Dysgeusia includes PTs of dysgeusia and taste disorder.
Cough includes PTs of cough and productive cough.
Dyspnoea includes PTs of dyspnoea and dyspnoea exertional.
Stomatitis includes PTs of aphthous ulcer, mouth ulceration and stomatitis.
Rash includes PTs of erythema, exfoliative rash, rash, rash erythematous, rash macular, rash maculo-papular, rash papular and rash pruritic.
Dermatitis includes PTs of dermatitis and dermatitis allergic.
Venous thromboembolism includes PTs of embolism, pulmonary embolism, thrombosis, deep vein thrombosis, vena cava thrombosis and venous thrombosis.
b Registered laboratory data are presented below under Haematological toxicity and Other laboratory findings.
* As observed in the post-marketing setting.
For patients receiving olaparib in combination with durvalumab following treatment with durvalumab in combination with platinum-based chemotherapy, most adverse reactions occurred at the same or lower frequency (all grades and CTCAE Grade ≥ 3 AEs) as those shown in the tabulated list of adverse reactions for olaparib monotherapy above. Adverse reactions reported at a higher frequency in patients receiving olaparib in combination with durvalumab were thrombocytopenia and rash (Very Common) and hypersensitivity (Common). The following additional adverse reaction was also identified:
Table 2. Additional adverse drug reaction reported in a clinical trial with olaparib in combination with durvalumab:
| MedDRA SOC | MedDRA Term | CIOMS descriptor/ Overall Frequency (All CTCAE grades) | Frequency of CTCAE grade 3 and above |
|---|---|---|---|
| Blood and lymphatic system disorders | Pure red cell aplasia | Common | Common |
Anaemia and other haematological toxicities were generally low grade (CTCAE grade 1 or 2), however, there were reports of CTCAE grade 3 and higher events. Anaemia was the most common CTCAE grade ≥3 adverse reaction reported in clinical studies. Median time to first onset of anaemia was approximately 4 weeks (approximately 7 weeks for CTCAE grade ≥3 events). Anaemia was managed with dose interruptions and dose reductions, and where appropriate with blood transfusions. In clinical studies with the tablet formulation, the incidence of anaemia adverse reactions was 35.2% (CTCAE grade ≥3 14.8%) and the incidences of dose interruptions, reductions and discontinuations for anaemia were 16.4%, 11.1% and 2.1%, respectively; 15.6% of patients treated with olaparib needed one or more blood transfusions. An exposure-response relationship between olaparib and decreases in haemoglobin has been demonstrated. In clinical studies with olaparib the incidence of CTCAE grade ≥ 2 shifts (decreases) from baseline in haemoglobin was 21%, absolute neutrophils 17%, platelets 5%, lymphocytes 26% and leucocytes 19% (all % approximate).
The incidence of elevations in mean corpuscular volume from low or normal at baseline to above the ULN was approximately 51%. Levels appeared to return to normal after treatment discontinuation and did not appear to have any clinical consequences.
Baseline testing, followed by monthly monitoring of complete blood counts is recommended for the first 12 months of treatment and periodically after this time to monitor for clinically significant changes in any parameter during treatment which may require dose interruption or reduction and/or further treatment.
MDS/AML are serious adverse reactions that occurred uncommonly in monotherapy clinical studies at the therapeutic dose, across all indications (0.9%). The incidence was 0.5% including events reported during the long term safety follow up (rate calculated based on overall safety population of 18576 patients exposed to at least one dose of oral olaparib in clinical studies). All patients had potential contributing factors for the development of MDS/AML, having received previous chemotherapy with platinum agents. Many had also received other DNA damaging agents and radiotherapy. The majority of reports were in germline breast cancer susceptibility gene 1 or 2 (gBRCA1/2) mutation carriers. The incidence of MDS/AML cases was similar among gBRCA1m and gBRCA2m patients (1.6% and 1.2%, respectively). Some of the patients had a history of previous cancer or of bone marrow dysplasia.
In patients with BRCAm platinum-sensitive relapsed ovarian cancer who had received at least two prior lines of platinum chemotherapy and received study treatment until disease progression (SOLO2 study, with olaparib treatment ≥2 years in 45% of patients), the incidence of MDS/AML was 8% in patients receiving olaparib and 4% in patients receiving placebo at a follow-up of 5 years. In the olaparib arm, 9 out of 16 MDS/AML cases occurred after discontinuation of olaparib during the survival follow-up. The incidence of MDS/AML was observed in the context of extended overall survival in the olaparib arm and late onset of MDS/AML. The risk of MDS/AML remains low in the first-line setting when olaparib maintenance treatment is given after one line of platinum chemotherapy for a duration of 2 years (1.5%) in SOLO1 study at 7 year follow up and 1.1% in PAOLA-1 study at 5 year follow up. For risk mitigation and management.
Pure Red Cell Aplasia (PRCA) has been reported when olaparib has been used in combination with durvalumab. In a clinical study of patients with endometrial cancer treated with olaparib in combination with durvalumab, the incidence of PRCA was 1.6%. All events were CTCAE Grade 3 or 4. Events were manageable following discontinuation of both olaparib and durvalumab. The majority of events were managed with blood transfusion and immunosuppression and recovered; there were no fatal events.
In men who received olaparib plus abiraterone as first line therapy for mCRPC (PROpel study), the incidence of venous thromboembolic events was 8% in the olaparib plus abiraterone arm, and 3.3% in the placebo plus abiraterone arm. The median time to onset in this study was 170 days (range: 12 to 906 days). The majority of patients recovered from the event and were able to continue olaparib with standard medical treatment.
Patients with significant cardiovascular disease were excluded. Please refer to the product information for abiraterone for cardiovascular exclusion criteria.
In clinical studies with olaparib the incidence of CTCAE grade ≥2 shifts (elevations) from baseline in blood creatinine was approximately 11%. Data from a double-blind placebo-controlled study showed median increase up to 23% from baseline remaining consistent over time and returning to baseline after treatment discontinuation, with no apparent clinical sequelae. 90% of patients had creatinine values of CTCAE grade 0 at baseline and 10% were CTCAE grade 1 at baseline.
Nausea was generally reported very early, with first onset within the first month of olaparib treatment in the majority of patients. Vomiting was reported early, with first onset within the first two months of olaparib treatment in the majority of patients. Both nausea and vomiting were reported to be intermittent for the majority of patients and can be managed by dose interruption, dose reduction and/or antiemetic therapy. Antiemetic prophylaxis is not required.
In first-line ovarian cancer maintenance treatment, patients experienced nausea events (77% on olaparib, 38% on placebo), vomiting (40% on olaparib, 15% on placebo), diarrhoea (34% on olaparib, 25% on placebo) and dyspepsia (17% on olaparib, 12% on placebo). Nausea events led to discontinuation in 2.3% of olaparib-treated patients (CTCAE Grade 2) and 0.8% of placebo-treated patients (CTCAE Grade 1); 0.8% and 0.4% of olaparib-treated patients discontinued treatment due to low grade (CTCAE Grade 2) vomiting and dyspepsia, respectively. No olaparib or placebo-treated patients discontinued due to diarrhoea. No placebo-treated patients discontinued due to vomiting or dyspepsia. Nausea events led to dose interruption and dose reductions in 14% and 4%, respectively, of olaparib-treated patients. Vomiting events led to interruption in 10% of olaparib-treated patients; no olaparib-treated patients experienced a vomiting event leading to dose reduction.
No studies have been conducted in paediatric patients.
Limited safety data are available in non-Caucasian patients.
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