LYNPARZA Film-coated tablet Ref.[8404] Active ingredients: Olaparib

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

The overall incidence of myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) in patients treated in clinical trials with Lynparza monotherapy, including long-term survival follow-up, was <1.5%, with higher incidence in patients with BRCAm platinum-sensitive relapsed ovarian cancer who had received at least two prior lines of platinum chemotherapy and were followed up for 5 years (see section 4.8). 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 >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 <1.0% of patients treated with Lynparza 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, 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”.

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 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 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 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 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.

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.

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 (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).

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.

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 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%).

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:

^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 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:

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 studies have been conducted in paediatric patients.

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 national reporting system listed in Appendix V.

Not applicable.