Olaparib

Concomitant use of strong or moderate CYP3A inhibitors is not recommended and alternative agents should be considered. If a strong CYP3A inhibitor must be co-administered, the recommended olaparib dose reduction is to 150 mg taken twice daily (equivalent to a total daily dose of 300 mg). If a moderate CYP3A inhibitor must be co-administered, the recommended olaparib dose reduction is to 200 mg taken twice daily (equivalent to a total daily dose of 400 mg).

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 C_max 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 150 mg taken twice daily (equivalent to a total daily dose of 300 mg) with a strong CYP3A inhibitor or 200 mg taken twice daily (equivalent to a total daily dose of 400 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.

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.

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 = 76μM), 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.

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.

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 C_max 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.

For patients with moderate renal impairment (creatinine clearance 31 to 50 ml/min) the recommended dose of olaparib is 300 mg twice daily (equivalent to a total daily dose of 600 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.

A clinical study has been performed to assess the combination of olaparib with anastrozole, letrozole or tamoxifen. No significant interaction was observed with anastrozole or letrozole whereas tamoxifen decreased exposure to olaparib by 27%. The clinical relevance of this effect is unknown. Olaparib does not affect the pharmacokinetics of tamoxifen.

Pneumonitis, including events with a fatal outcome, has been reported in <1.0% of patients treated with olaparib in clinical studies. Reports of pneumonitis had no consistent clinical pattern and were confounded by a number of pre-disposing factors (cancer and/or metastases in lungs, underlying pulmonary disease, smoking history, and/or previous chemotherapy and radiotherapy). If patients present with new or worsening respiratory symptoms such as dyspnoea, cough and fever, or an abnormal chest radiologic finding is observed, olaparib treatment should be interrupted and prompt investigation initiated. If pneumonitis is confirmed, olaparib treatment should be discontinued and the patient treated appropriately.

Haematological toxicity has been reported in patients treated with olaparib, including clinical diagnoses and/or laboratory findings of generally mild or moderate (CTCAE grade 1 or 2) anaemia, neutropenia, thrombocytopenia and lymphopenia. Patients should not start treatment with olaparib until they have recovered from haematological toxicity caused by previous anticancer therapy (haemoglobin, platelet and neutrophil levels should be ≤CTCAE grade 1). 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.

If a patient develops severe haematological toxicity or blood transfusion dependence, treatment with olaparib should be interrupted and appropriate haematological testing should be initiated. If the blood parameters remain clinically abnormal after 4 weeks of olaparib dose interruption, bone marrow analysis and/or blood cytogenetic analysis are recommended.

The overall incidence of myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) in patients treated in clinical trials with olaparib monotherapy, including long-term survival follow-up, was <1.5% and the majority of events had a fatal outcome. The duration of therapy with olaparib in patients who developed MDS/AML varied from <6 months to >2 years. 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 (1.7% and 1.4%, respectively). Some of the patients had a history of previous cancer or of bone marrow dysplasia. If MDS and/or AML are confirmed while on treatment with olaparib, it is recommended that olaparib should be discontinued and the patient be treated appropriately.

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, olaparib should not be used during pregnancy and in women of childbearing potential not using reliable contraception during therapy and for 1 month 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/contraception in females

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 1 month 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.

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.

Fertility

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.

Summary of the safety profile

Olaparib monotherapy 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, vomiting, diarrhoea, dyspepsia, fatigue, headache, dysgeusia, decreased appetite, dizziness, upper abdominal pain, cough, dyspnoea, anaemia, neutropenia, thrombocytopenia and leukopenia.

The Grade ≥3 adverse reactions occurring in >2% of patients were anaemia (16%), neutropenia (6%), fatigue/asthenia (6%), leukopenia (3%), thrombocytopenia (2%) and vomiting (2%).

Adverse reactions that most commonly led to dose interruptions and/ or reductions were anaemia (13.9%), vomiting (7.1%), nausea (6.6%), fatigue/asthenia (6.1%) and neutropenia (5.8%). Adverse reactions that most commonly led to permanent discontinuation were anaemia (1.3%), nausea (0.8%) and thrombocytopenia (0.5%).

List of adverse reactions

The safety profile is based on pooled data from 1,826 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 the following list. 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).

Frequency of All CTCAE grades:

Blood and lymphatic system disorders

Very common: Anaemia^a, Neutropenia^a, Thrombocytopenia^a, Leukopenia^a

Common: Lymphopenia^a

Immune system disorders

Common: Rash^a

Uncommon: Hypersensitivity^a, Dermatitis^a

Metabolism and nutrition disorders

Very common: Decreased appetite

Nervous system disorders

Very common: Dizziness, Headache, Dysgeusia

Respiratory, thoracic and mediastinal disorders

Very common: Cough^a, Dyspnoea^a

Gastrointestinal disorders

Very common: Vomiting, Diarrhoea, Nausea, Dyspepsia, Upper abdominal pain

Common: Stomatitis^a

General disorders and administration site conditions

Very common: Fatigue (including asthenia)

Investigations

Common: Increase in blood creatinine

Uncommon: Mean corpuscular volume elevation

Frequency of CTCAE grade 3 and above:

Blood and lymphatic system disorders

Very common: Anaemia^a

Common: Neutropenia^a, Thrombocytopenia^a, Leukopenia^a

Uncommon: Lymphopenia^a

Metabolism and nutrition disorders

Uncommon: Decreased appetite

Nervous system disorders

Uncommon: Dizziness, Headache

Respiratory, thoracic and mediastinal disorders

Common: Dyspnoea^a

Uncommon: Cough^a

Gastrointestinal disorders

Common: Vomiting, Diarrhoea, Nausea

Uncommon: Stomatitis^a, Upper abdominal pain

General disorders and administration site conditions

Common: Fatigue (including asthenia)

Investigations

Uncommon: Increase in blood creatinine

Description of selected adverse reactions

Haematological toxicity

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 Study 19, the incidence of anaemia was 22.8% (CTCAE grade ≥3 7.4%) and the incidences of dose interruptions, reductions and discontinuations for anaemia were 2.9%, 5.1% and 0%, respectively; 16.2% of patients treated with olaparib needed one or more blood transfusions during the treatment. 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 20%, absolute neutrophils 20%, platelets 5%, lymphocytes 30% and leucocytes 20% (all % approximate).

The incidence of elevations in mean corpuscular volume from low or normal at baseline to above the ULN was approximately 55%. 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.

Other laboratory findings

In clinical studies with olaparib the incidence of CTCAE grade ≥2 shifts (elevations) from baseline in blood creatinine was approximately 10%. 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.

Gastrointestinal toxicities

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.

Paediatric population

No studies have been conducted in paediatric patients.

Other special populations

Limited safety data are available in elderly (age ≥75 years) and non-Caucasian patients.