4.1. Therapeutic indications

Ovarian cancer

Lynparza is indicated as monotherapy for the:

• maintenance treatment of adult patients with advanced (FIGO stages III and IV) BRCA1/2-mutated (germline and/or somatic) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy.

• maintenance treatment of adult patients with platinum‑sensitive relapsed high‑grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum‑based chemotherapy.

Lynparza in combination with bevacizumab is indicated for the:

• maintenance treatment of adult patients with advanced (FIGO stages III and IV) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy in combination with bevacizumab and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either a BRCA1/2 mutation and/or genomic instability (see section 5.1).

Breast cancer

Lynparza is indicated as:

• monotherapy or in combination with endocrine therapy for the adjuvant treatment of adult patients with germline BRCA1/2-mutations who have HER2-negative, high risk early breast cancer previously treated with neoadjuvant or adjuvant chemotherapy (see sections 4.2 and 5.1).

• monotherapy for the treatment of adult patients with germline BRCA1/2-mutations, who have HER2 negative locally advanced or metastatic breast cancer. Patients should have previously been treated with an anthracycline and a taxane in the (neo)adjuvant or metastatic setting unless patients were not suitable for these treatments (see section 5.1). Patients with hormone receptor (HR)-positive breast cancer should also have progressed on or after prior endocrine therapy, or be considered unsuitable for endocrine therapy.

Adenocarcinoma of the pancreas

Lynparza is indicated as monotherapy for the maintenance treatment of adult patients with germline BRCA1/2-mutations who have metastatic adenocarcinoma of the pancreas and have not progressed after a minimum of 16 weeks of platinum treatment within a first-line chemotherapy regimen.

Prostate cancer

Lynparza is indicated:

• as monotherapy for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA1/2-mutations (germline and/or somatic) who have progressed following prior therapy that included a new hormonal agent.

• in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with mCRPC in whom chemotherapy is not clinically indicated (see section 5.1).

Endometrial cancer

Lynparza in combination with durvalumab is indicated for the maintenance treatment of adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair proficient (pMMR) whose disease has not progressed on first-line treatment with durvalumab in combination with carboplatin and paclitaxel.

4.2. Posology and method of administration

Treatment with Lynparza should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Patient selection

First-line maintenance treatment of BRCA-mutated advanced ovarian cancer:

Before Lynparza treatment is initiated for first-line maintenance treatment of high-grade epithelial ovarian cancer (EOC), fallopian tube cancer (FTC) or primary peritoneal cancer (PPC), patients must have confirmation of deleterious or suspected deleterious germline and/or somatic mutations in the breast cancer susceptibility genes (BRCA) 1 or 2 using a validated test.

Maintenance treatment of platinum-sensitive relapsed ovarian cancer:

There is no requirement for BRCA1/2 testing prior to using Lynparza for the monotherapy maintenance treatment of relapsed EOC, FTC or PPC who are in a complete or partial response to platinum-based therapy.

First-line maintenance treatment of HRD positive advanced ovarian cancer in combination with bevacizumab:

Before Lynparza with bevacizumab treatment is initiated for the first-line maintenance treatment of EOC, FTC or PPC, patients must have confirmation of either deleterious or suspected deleterious BRCA1/2 mutation and/or genomic instability determined using a validated test (see section 5.1).

Adjuvant treatment of germline BRCA-mutated high risk early breast cancer

Before Lynparza treatment is initiated for adjuvant treatment of HER2 negative high risk early breast cancer, patients must have confirmation of deleterious or suspected deleterious gBRCA1/2 mutation using a validated test (see section 5.1).

Monotherapy treatment of gBRCA1/2-mutated HER2-negative metastatic breast cancer:

For germline breast cancer susceptibility genes (gBRCA1/2) mutated human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer, patients must have confirmation of a deleterious or suspected deleterious gBRCA1/2 mutation before Lynparza treatment is initiated. gBRCA1/2 mutation status should be determined by an experienced laboratory using a validated test method. Data demonstrating clinical validation of tumour BRCA1/2 tests in breast cancer are not currently available.

First-line maintenance treatment of gBRCA-mutated metastatic adenocarcinoma of the pancreas:

For first-line maintenance treatment of germline BRCA1/2-mutated metastatic adenocarcinoma of the pancreas, patients must have confirmation of a deleterious or suspected deleterious gBRCA1/2 mutation before Lynparza treatment is initiated. gBRCA1/2 mutation status should be determined by an experienced laboratory using a validated test method. Data demonstrating clinical validation of tumour BRCA1/2 tests in adenocarcinoma of the pancreas are not currently available.

Monotherapy treatment of BRCA1/2-mutated metastatic castration-resistant prostate cancer:

For BRCA1/2-mutated metastatic castration-resistant prostate cancer (mCRPC), patients must have confirmation of a deleterious or suspected deleterious BRCA1/2 mutation (using either tumour or blood sample) before Lynparza treatment is initiated (see section 5.1). BRCA1/2 mutation status should be determined by an experienced laboratory using a validated test method.

Treatment of mCRPC in combination with abiraterone and prednisone or prednisolone:

No genomic testing is required prior to using Lynparza in combination with abiraterone and prednisone or prednisolone for the treatment of patients with mCRPC.

First-line maintenance treatment of MMR-Proficient (pMMR) advanced or recurrent endometrial cancer in combination with durvalumab:

Before treatment is initiated, patients must have confirmation of proficient mismatch repair (pMMR) tumour status using a validated test (see section 5.1).

Genetic counselling for patients tested for mutations in BRCA1/2 genes should be performed according to local regulations.

Posology

Lynparza is available as 100 mg and 150 mg tablets.

The recommended dose of Lynparza in monotherapy or in combination with other agents is 300 mg (two 150 mg tablets) taken twice daily, equivalent to a total daily dose of 600 mg. The 100 mg tablet is available for dose reduction.

Lynparza monotherapy

Patients with platinum-sensitive relapsed (PSR) high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy should start treatment with Lynparza no later than 8 weeks after completion of their final dose of the platinum‑containing regimen.

Lynparza in combination with bevacizumab

When Lynparza is used in combination with bevacizumab for the first-line maintenance treatment of high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer following completion of first-line platinum-based therapy with bevacizumab, the dose of bevacizumab is 15 mg/kg once every 3 weeks. Please refer to the full product information for bevacizumab (see section 5.1).

Lynparza in combination with endocrine therapy

Please refer to the full product information of the endocrine therapy combination partner(s) (aromatase inhibitor/anti-oestrogen agent and/or LHRH) for the recommended posology.

Lynparza in combination with abiraterone and prednisone or prednisolone

When Lynparza is used in combination with abiraterone for the treatment of patients with mCRPC, the dose of abiraterone is 1000 mg orally once daily (see section 5.1). Abiraterone should be given with prednisone or prednisolone 5 mg orally twice daily. Please refer to the full product information for abiraterone.

Lynparza in combination with durvalumab

When Lynparza is used in combination with durvalumab for the maintenance treatment of patients with MMR-Proficient (pMMR) primary advanced or recurrent endometrial cancer whose disease has not progressed on first-line treatment with durvalumab in combination with carboplatin and paclitaxel, the dose of durvalumab is 1500 mg every 4 weeks (see section 5.1). Please refer to the full product information for durvalumab.

Duration of treatment

First-line maintenance treatment of BRCA-mutated advanced ovarian cancer:

Patients can continue treatment until radiological disease progression, unacceptable toxicity or for up to 2 years if there is no radiological evidence of disease after 2 years of treatment. Patients with evidence of disease at 2 years, who in the opinion of the treating physician can derive further benefit from continuous treatment, can be treated beyond 2 years.

Maintenance treatment of platinum-sensitive relapsed ovarian cancer:

For patients with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer, it is recommended that treatment be continued until progression of the underlying disease or unacceptable toxicity.

First-line maintenance treatment of HRD positive advanced ovarian cancer in combination with bevacizumab:

Patients can continue treatment with Lynparza until radiological disease progression, unacceptable toxicity or for up to 2 years if there is no radiological evidence of disease after 2 years of treatment. Patients with evidence of disease at 2 years, who in the opinion of the treating physician can derive further benefit from continuous Lynparza treatment, can be treated beyond 2 years. Please refer to the product information for bevacizumab for the recommended overall duration of treatment of a maximum of 15 months including the periods in combination with chemotherapy and as maintenance (see section 5.1).

Adjuvant treatment of germline BRCA-mutated high risk early breast cancer

It is recommended that patients are treated for up to 1 year, or until disease recurrence, or unacceptable toxicity, whichever occurs first.

Monotherapy treatment of gBRCA1/2-mutated HER2-negative metastatic breast cancer:

It is recommended that treatment be continued until progression of the underlying disease or unacceptable toxicity.

The efficacy and safety of maintenance retreatment with Lynparza following first or subsequent relapse in ovarian cancer patients has not been established. There are no efficacy or safety data on retreatment of breast cancer patients (see section 5.1).

First-line maintenance treatment of gBRCA-mutated metastatic adenocarcinoma of the pancreas:

It is recommended that treatment be continued until progression of the underlying disease or unacceptable toxicity.

Monotherapy treatment of BRCA1/2-mutated metastatic castration-resistant prostate cancer:

It is recommended that treatment be continued until progression of the underlying disease or unacceptable toxicity. Medical castration with luteinising hormone releasing hormone (LHRH) analogue should be continued during treatment in patients not surgically castrated.

Treatment of mCRPC in combination with abiraterone and prednisone or prednisolone:

It is recommended that treatment be continued until progression of the underlying disease or unacceptable toxicity when Lynparza is used in combination with abiraterone and prednisone or prednisolone. Treatment with a gonadotropin-releasing hormone (GnRH) analogue should be continued during treatment in all patients, or patients should have had prior bilateral orchiectomy. Please refer to the product information for abiraterone.

There are no efficacy or safety data on retreatment with Lynparza in prostate cancer patients (see section 5.1).

First-line maintenance treatment of MMR-Proficient (pMMR) advanced or recurrent endometrial cancer in combination with durvalumab:

It is recommended that treatment be continued until progression of the underlying disease or unacceptable toxicity. Please refer to the product information for durvalumab.

Missing dose

If a patient misses a dose of Lynparza, they should take their next normal dose at its scheduled time.

Dose adjustments for adverse reactions

Treatment may be interrupted to manage adverse reactions such as nausea, vomiting, diarrhoea, and anaemia and dose reduction can be considered (see section 4.8).

The recommended dose reduction is to 250 mg (one 150 mg tablet and one 100 mg tablet) twice daily (equivalent to a total daily dose of 500 mg).

If a further dose reduction is required, then reduction to 200 mg (two 100 mg tablets) twice daily (equivalent to a total daily dose of 400 mg) is recommended.

Dose adjustments for co-administration with CYP3A inhibitors

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 Lynparza dose reduction is to 100 mg (one 100 mg tablet) taken twice daily (equivalent to a total daily dose of 200 mg). If a moderate CYP3A inhibitor must be co‑administered, the recommended Lynparza dose reduction is to 150 mg (one 150 mg tablet) taken twice daily (equivalent to a total daily dose of 300 mg) (see sections 4.4 and 4.5).

Special populations

Elderly

No adjustment in starting dose is required for elderly patients.

Renal impairment

For patients with moderate renal impairment (creatinine clearance 31 to 50 ml/min) the recommended dose of Lynparza is 200 mg (two 100 mg tablets) twice daily (equivalent to a total daily dose of 400 mg) (see section 5.2).

Lynparza can be administered in patients with mild renal impairment (creatinine clearance 51 to 80 ml/min) with no dose adjustment.

Lynparza 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. Lynparza 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.

Hepatic impairment

Lynparza can be administered to patients with mild or moderate hepatic impairment (Child‑Pugh classification A or B) with no dose adjustment (see section 5.2). Lynparza 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.

Non‑Caucasian patients

There are limited clinical data available in non‑Caucasian patients. However, no dose adjustment is required on the basis of ethnicity (see section 5.2).

Paediatric population

The safety and efficacy of Lynparza in children and adolescents (< 18 years) have not been established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on posology can be made.

Method of administration

Lynparza is for oral use.

Lynparza tablets should be swallowed whole and not chewed, crushed, dissolved or divided. Lynparza tablets may be taken without regard to meals.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Breast‑feeding during treatment and for 1 month after the last dose (see section 4.6).

4.4. Special warnings and precautions for use

Haematological toxicity

Haematological toxicity has been reported in patients treated with Lynparza, including clinical diagnoses and/or laboratory findings of generally mild or moderate (CTCAE grade 1 or 2) anaemia, neutropenia, thrombocytopenia and lymphopenia. Pure red cell aplasia (PRCA) (see Section 4.8) and/or autoimmune haemolytic anaemia (AIHA) have been reported when Lynparza has been used in combination with durvalumab.

Patients should not start treatment with Lynparza 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 (see section 4.8).

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

Myelodysplastic syndrome/Acute myeloid leukaemia

Myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) has occurred in patients treated with Lynparza (see section 4.8). The majority of events had a fatal outcome. Patients with BRCAm platinum-sensitive relapsed ovarian cancer who had received at least two prior lines of platinum chemotherapy were at higher risk to experience MDS/AML. The duration of therapy with olaparib in patients who developed MDS/AML varied from <6 months to >4 years.

If MDS/AML is suspected, the patient should be referred to a haematologist for further investigations, including bone marrow analysis and blood sampling for cytogenetics. If, following investigation for prolonged haematological toxicity, MDS/AML is confirmed, Lynparza should be discontinued and the patient treated appropriately.

Venous Thromboembolic Events

Venous thromboembolic events, predominantly events of pulmonary embolism, have occurred in patients treated with Lynparza and had no consistent clinical pattern. A higher incidence was observed in patients with metastatic castration-resistant prostate cancer, who also received androgen deprivation therapy, compared with other approved indications (see section 4.8). Monitor patients for clinical signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate. Patients with a prior history of VTE may be more at risk of a further occurrence and should be monitored appropriately.

Pneumonitis

Pneumonitis, including events with a fatal outcome, has been reported in patients treated with Lynparza in clinical studies (see section 4.8). If patients present with new or worsening respiratory symptoms such as dyspnoea, cough and fever, or an abnormal chest radiologic finding is observed, Lynparza treatment should be interrupted and prompt investigation initiated. If pneumonitis is confirmed, Lynparza treatment should be discontinued and the patient treated appropriately.

Hepatotoxicity

Cases of hepatotoxicity have been reported in patients treated with olaparib (see section 4.8). If clinical symptoms or signs suggestive of hepatotoxicity develop, prompt clinical evaluation of the patient and measurement of liver function tests should be performed. In case of suspected drug-induced liver injury (DILI), treatment should be interrupted. In case of severe DILI treatment discontinuation should be considered as clinically appropriate.

Embryofoetal toxicity

Based on its mechanism of action (PARP inhibition), Lynparza could cause foetal harm when administered to a pregnant woman. Nonclinical studies in rats have shown that olaparib causes adverse effects on embryofoetal survival and induces major foetal malformations at exposures below those expected at the recommended human dose of 300 mg twice daily.

Pregnancy/contraception

Lynparza should not be used during pregnancy. Women of childbearing potential must use two forms of reliable contraception before starting Lynparza treatment, during therapy and for 6 months after receiving the last dose of Lynparza. Two highly effective and complementary forms of contraception are recommended. Male patients and their female partners of childbearing potential should use reliable contraception during therapy and for 3 months after receiving the last dose of Lynparza (see section 4.6).

Interactions

Lynparza co‑administration with strong or moderate CYP3A inhibitors is not recommended (see section 4.5). If a strong or moderate CYP3A inhibitor must be co‑administered, the dose of Lynparza should be reduced (see sections 4.2 and 4.5).

Lynparza co‑administration with strong or moderate CYP3A inducers is not recommended. In the event that a patient already receiving Lynparza requires treatment with a strong or moderate CYP3A inducer, the prescriber should be aware that the efficacy of Lynparza may be substantially reduced (see section 4.5).

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per 100 mg or 150 mg tablet, that is to say essentially “sodium-free”.

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Clinical studies of olaparib in combination with other anticancer medicinal products, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. The recommended Lynparza monotherapy dose is not suitable for combination with myelosuppressive anticancer medicinal products.

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 Lynparza and patients should be closely monitored.

Pharmacokinetic interactions

Effect of other medicinal products on olaparib

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 Lynparza (see section 4.4). If strong or moderate CYP3A inhibitors must be co‑administered, the dose of Lynparza should be reduced. The recommended Lynparza 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 (see sections 4.2 and 4.4). It is also not recommended to consume grapefruit juice while on Lynparza therapy as it is a CYP3A inhibitor.

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 Lynparza, as it is possible that the efficacy of Lynparza 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 Lynparza with these medicinal products is also not recommended (see section 4.4).

Effect of olaparib on other medicinal products

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.

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 (see sections 4.4 and 4.6).

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.

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.

Combination with anastrozole, letrozole and tamoxifen

A clinical study has been performed to assess the combination of olaparib with anastrozole, letrozole or tamoxifen. No clinically relevant interactions were observed.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/contraception in females

Women of childbearing potential should not become pregnant while on Lynparza 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 Lynparza therapy, during therapy and for 6 months after receiving the last dose of Lynparza, unless abstinence is the chosen method of contraception (see section 4.4). 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 (see section 4.5). For women with hormone dependent cancer, two non‑hormonal contraceptive methods should be considered.

Contraception in males

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 Lynparza 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 (see section 4.4). Male patients should not donate sperm during therapy and for 3 months after receiving the last dose of Lynparza.

Pregnancy

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 (see section 5.3). There are no data from the use of olaparib in pregnant women, however, based on the mode of action of olaparib, Lynparza 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 Lynparza. (See previous paragraph: “Women of childbearing potential/contraception in females” for further information about birth control and pregnancy testing.)

Breast‑feeding

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. Lynparza is contraindicated during breast‑feeding and for 1 month after receiving the last dose, given the pharmacologic property of the product (see section 4.3).

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 (see section 5.3).

4.7. Effects on ability to drive and use machines

Lynparza has moderate influence on the ability to drive and use machines. Patients who take Lynparza may experience fatigue, asthenia or dizziness. Patients who experience these symptoms should observe caution when driving or using machines.

4.8. Undesirable effects

Summary of the safety profile

Lynparza 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 Lynparza 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 Lynparza 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 appetite (2.6%), diarrhoea (2.1%). The adverse reactions that most commonly led to permanent discontinuation of olaparib were anaemia (3.6%) and neutropenia (1%).

Tabulated list of adverse reactions

The safety profile is based on pooled data from 4499 patients with solid tumours treated with Lynparza monotherapy in clinical trials at the recommended dose.

The following adverse reactions have been identified in clinical trials with patients receiving Lynparza 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 commonAnaemiaa, Neutropeniaa, Leukopeniaa

CommonLymphopeniaa, Thrombocytopeniaa

Very commonAnaemiaa

CommonNeutropeniaa, 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

UncommonDecreased appetite

Nervous system disorders

Very common Dizziness, Headache, Dysgeusiaa

UncommonDizziness, Headache

Respiratory, thoracic and mediastinal disorders

Very common Cougha, Dyspnoeaa

Uncommon

Pneumonitisa

Common

Dyspnoeaa

UncommonCougha, Pneumonitisa

Gastrointestinal disorders

Very commonVomiting, Diarrhoea, Nausea, Dyspepsia

CommonStomatitisa, Upper abdominal pain

CommonVomiting, Nausea

UncommonStomatitisa, Diarrhoea

Rare Dyspepsia, Upper abdominal pain

Skin and subcutaneous tissue disorders

CommonRasha

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

CommonBlood creatinine increased

Uncommon Mean cell volume increased

RareBlood 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.

Pneumonitis includes PTs of pneumonitis, interstitial lung disease, acute interstitial pneumonitis, eosinophilic pneumonia, eosinophilic pneumonia acute and hypersensitivity pneumonitis.

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 Lynparza 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 Lynparza monotherapy above. Adverse reactions reported at a higher frequency in patients receiving Lynparza 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 Lynparza 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

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 (see section 4.2), 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 Lynparza 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 (see sections 4.2 and 4.4).

Myelodysplastic syndrome/Acute myeloid leukaemia

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, (see section 4.4).

Pure Red Cell Aplasia

Pure Red Cell Aplasia (PRCA) has been reported when Lynparza has been used in combination with durvalumab. In a clinical study of patients with endometrial cancer treated with Lynparza 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 Lynparza and durvalumab. The majority of events were managed with blood transfusion and immunosuppression and recovered; there were no fatal events. For risk mitigation and management see section 4.4.

Venous Thromboembolic 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 (section 4.4).

Other laboratory findings

In clinical studies with Lynparza 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.

Gastrointestinal toxicities

Nausea was generally reported very early, with first onset within the first month of Lynparza treatment in the majority of patients. Vomiting was reported early, with first onset within the first two months of Lynparza 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.

Paediatric population

No new safety signals were observed in the study population relative to the known safety profile of Lynparza in adults, based on the limited number of paediatric patients treated with olaparib in study D0816C00025 (see section 5.1).

Other special populations

Limited safety data are available in non‑Caucasian patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is limited experience of overdose with olaparib. No unexpected adverse reactions were reported in a small number of patients who took a daily dose of up to 900 mg of olaparib tablets over two days. Symptoms of overdose are not established and there is no specific treatment in the event of Lynparza overdose. In the event of an overdose, physicians should follow general supportive measures and should treat the patient symptomatically.