Adverse reactions : תופעות לוואי

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 or in combination with abiraterone and prednisone or prednisolone for prostate cancer, the safety profile is generally consistent with that of the individual therapies.
Adverse events led to dose interruption and/ or reduction of olaparib in 57% of patients when used in combination with bevacizumab and led to permanent discontinuation of treatment with olaparib/bevacizumab and placebo/bevacizumab in 21% and 6% of patients, respectively. The adverse reactions that most commonly led to dose interruption and/or reduction 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%).
Adverse events led to dose interruption and/or reduction of olaparib in 50.7% of patients when used in combination with abiraterone and led to permanent discontinuation of treatment with olaparib/abiraterone and placebo/abiraterone in 19.0% and 8.8% of patients, respectively. The adverse reactions that most commonly led to dose interruption and/or reduction 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%).
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             Frequency of All CTCAE grades        Frequency of CTCAE System Organ                                            grade 3 and above Class
Neoplasms           Uncommon                                 Uncommon benign,            Myelodysplastic syndrome/ Acute          Myelodysplastic syndrome/ malignant and      myeloid leukaemiaa                       Acute myeloid leukaemia unspecified
(including cysts and polyps)
Blood and          Very common                              Very common lymphatic          Anaemiaa                                 Anaemiaa system             Neutropeniaa, Leukopeniaa                Common disordersb         Common                                   Neutropeniaa, Lymphopeniaa, Thrombocytopeniaa          Thrombocytopeniaa,
Leukopeniaa,

Lymphopeniaa
Immune             Uncommon                                  Rare system             Hypersensitivitya                        Hypersensitivitya disorders          Rare
Angioedema*
Hepatobiliary      Common disorders          Transaminases increaseda
Not known
Drug-induced liver injury*


Metabolism         Very common                              Uncommon and nutrition      Decreased appetite                       Decreased appetite disorders
Nervous            Very common                              Uncommon system             Dizziness, Headache, Dysgeusiaa          Dizziness, Headache disorders
Respiratory,       Very common                              Common thoracic and       Cougha, Dyspnoeaa
Dyspnoeaa mediastinal
Uncommon disorders
Cougha
Adverse reactions
MedDRA            Frequency of All CTCAE grades        Frequency of CTCAE System Organ                                           grade 3 and above Class
Gastrointestina   Very common                                      Common l disorders       Vomiting, Diarrhoea, Nausea,                     Vomiting, Nausea Dyspepsia                                        Uncommon
Common                                           Stomatitisa, Diarrhoea, Stomatitisa, Upper abdominal pain                 Rare
Dyspepsia, Upper abdominal pain
Skin and           Common                                           Uncommon subcutaneous      Rasha                                            Rasha tissue
Uncommon disorders                                                          Rare Dermatitisa
Dermatitisa
Rare
Erythema nodosum
General           Very common                                      Common disorders and     Fatigue (including asthenia)                     Fatigue (including asthenia) administration site conditions
Investigationsb   Common                                           Rare Blood creatinine increased                       Blood creatinine increased Uncommon
Mean cell volume increased
Vascular          Common                                           Common disorders         Venous thromboembolisma                          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.
Hypersensitivityincludes 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 generalised, 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
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).

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 authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il