Lynparza

Lynparza

Manufacturer:

AstraZeneca

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Olaparib.
Description
Hard capsule: Each capsule contains 50 mg of olaparib.
FC tablet: Each 100 mg film-coated tablet contains 100 mg of olaparib.
Each 150 mg film-coated tablet contains 150 mg of olaparib.
Excipients/Inactive Ingredients: Hard capsule: Capsule Content: Lauroyl macrogol-32 glycerides.
Capsule Shell: Hypromellose; Titanium dioxide (E171), Gellan gum (E418), Potassium acetate.
Printing Ink: Shellac, Iron oxide black (E172).
FC tablet: Core: Copovidone, Colloidal silicon dioxide, Mannitol, Sodium stearyl fumarate.
Tablet coating: Hypromellose, Macrogol 400, Titanium dioxide (E171), Iron oxide yellow (E172), Iron oxide black (E172) (150 mg FC tablet only).
Action
ATC Code: L01X X46 (FC tablet).
Pharmacology:
Pharmacodynamics: Olaparib is a potent inhibitor of human poly (ADP ribose) polymerase enzymes (PARP 1, PARP 2, and PARP 3), and has been shown to inhibit the growth of selected tumour cell lines in vitro and tumour growth in vivo either as a standalone treatment or in combination with established chemotherapies.
PARPs are required for the efficient repair of DNA single strand breaks and an important aspect of PARP-induced repair requires that after chromatin modification, PARP auto-modifies itself and dissociates from the DNA to facilitate access for base excision repair (BER) enzymes. When olaparib is bound to the active site of DNA-associated PARP it prevents the dissociation of PARP and traps it on the DNA, thus blocking repair. In replicating cells, this also leads to the formation of DNA double-strand breaks (DSBs) when replication forks meet the PARP DNA adducts. In normal cells, homologous recombination repair (HRR) pathway is effective at repairing these DNA DSBs. In cancers that lack functional components of HRR, such as BRCA1 or 2, DNA DSBs cannot be repaired accurately or effectively. Instead, alternative and error-prone pathways are activated, such as the classical non-homologous end joining (NHEJ) pathway, leading to increased genomic instability. After a number of rounds of replication, genomic instability can reach insupportable levels and result in cancer cell death, as cancer cells already have a high DNA damage load relative to normal cells.
In BRCA-deficient in vivo models, olaparib given after platinum treatment resulted in a delay in tumour progression and an increase in overall survival compared to platinum treatment alone that correlated with the period of olaparib maintenance treatment.
FC tablet: In the absence of BRCA1 or BRCA2 mutations, HRR pathway may be compromised by other mechanisms, although the causative aberrancy and penetrance are not fully elucidated. Absence of fully functional HRR pathway is one of the key determinants of platinum sensitivity in ovarian and other cancers.
Clinical data: Hard capsule: Platinum Sensitive Relapsed (PSR) Ovarian Cancer: The safety and efficacy of Lynparza as a maintenance therapy in the treatment of PSR ovarian, fallopian tube or primary peritoneal cancer patients, following treatment with two or more platinum containing regimens, were studied in a Phase II randomised, double blind placebo controlled trial (Study 19). The study compared the efficacy of olaparib maintenance treatment taken to progression with no maintenance treatment in 265 (136 olaparib and 129 placebo) PSR patients who were in response (CR [complete response] or PR [partial response]) following completion of platinum containing chemotherapy. The primary endpoint was PFS based on investigator assessment using RECIST 1.0. Secondary efficacy endpoints included OS (overall survival), DCR (disease control rate) defined as confirmed CR/PR + SD (stable disease), HRQoL (health related quality of life), and disease related symptoms. Exploratory analyses of time to first subsequent therapy or death (TFST) and time to second subsequent therapy or death (TSST) were also performed.
Only PSR patients who were in response following completion of platinum based chemotherapy and whose disease had recurred >6 months after completion of prior penultimate platinum based chemotherapy were enrolled. Patients could not have received prior olaparib or other PARP inhibitor treatment. Patients could have received prior bevacizumab, except in the regimen immediately prior to randomisation.
The study met its primary objective of demonstrating a statistically significant and clinically relevant improvement in PFS for olaparib maintenance monotherapy compared with placebo in the overall population (hazard ratio [HR] 0.35; 95% CI 0.25-0.49; p<0.00001); median 8.4 months olaparib vs 4.8 months placebo). At the final analysis (data cut off [DCO] 9 May 2016) for OS at 79% maturity, the HR comparing olaparib with placebo was 0.73 (95% CI 0.55-0.95; p=0.02138 [did not meet pre-specified significance level of <0.0095]; median 29.8 months olaparib versus 27.8 months placebo).
Preplanned subgroup analysis identified patients with BRCA-mutated ovarian cancer (n=136, 51.3%) as the subgroup that derived the greatest clinical benefit from olaparib maintenance monotherapy. There were no multiplicity strategies in place for the sub-group analyses.
In BRCA-mutated patients (n=136) there was a statistically significant improvement in PFS, TFST, and TSST. The median PFS improvement was 6.9 months over placebo (HR 0.18; 95% CI 0.10-0.31; p<0.00001; median 11.2 months vs 4.3 months). At the final analysis (data cut off [DCO] 9 May 2016) the time from randomisation to start of first subsequent therapy or death (TFST) was 9.4 months longer for olaparib treated patients (HR 0.33; 95% CI 0.22-0.49; p<0.00001; median 15.6 months versus 6.2 months). The time from randomisation to start of second subsequent therapy or death (TSST) was 6.1 months longer for olaparib treated patients (HR 0.43; 95% CI 0.29-0.64; p=0.00003; median 21.4 months versus 15.3 months. For the secondary endpoint of OS, the HR for olaparib vs. placebo was 0.62 (95% CI 0.42-0.93; p=0.02140; median 34.9 months versus 30.2 months). In the olaparib-treated group, 28.4% of patients remained on treatment for ≥2 years and 14.9% for ≥5 years. In the placebo-treated group, 8.1% of patients remained on treatment for ≥2 years and 1.6% for ≥5 years.
A summary of key efficacy findings for patients with BRCA-mutated PSR ovarian cancer in Study 19 is presented in Table 1. (See Table 1.)

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Within the BRCA-mutated population the disease control rate at 24 weeks was 57% and 24% for patients in the olaparib and placebo groups, respectively.
No statistically significant differences were observed between treatment groups in patient reported symptoms or HRQoL.
Effect on the QT Interval: There is no clinically relevant effect of olaparib on cardiac repolarisation (as evaluated by an effect on the QT interval) following 300 mg twice daily multiple dosing of the Lynparza tablet formulation.
FC tablet: Maintenance treatment of newly diagnosed advanced ovarian cancer: SOLO1 Study in newly diagnosed advanced patients with a BRCA mutation: SOLO1 was a Phase III randomised, double-blind, placebo-controlled, multicentre trial that compared the efficacy of Lynparza maintenance treatment (300 mg [2 x 150 mg tablets] twice daily) with placebo in advanced (FIGO Stage III-IV) high-grade serous or endometrioid BRCA-mutated (BRCAm) ovarian cancer. The study randomised 391 patients (2:1 randomisation: 260 olaparib and 131 placebo) who were in response (CR [complete response] or PR [partial response]) following completion of first-line platinum-containing chemotherapy. Patients were stratified by response to first-line platinum chemotherapy (CR or PR). Treatment was continued for 2 years or until progression of the underlying disease. For patients who remained in complete clinical response (i.e. no radiological evidence of disease), the maximum duration of treatment was 2 years; however, patients who had evidence of disease that remained stable (i.e. no evidence of disease progression) could continue to receive Lynparza beyond 2 years.
Patients with BRCA mutations were identified either from germline testing in blood via a local test or central test (i.e. Myriad Integrated BRACAnalysis test, Myriad BRACAnalysis CDx, China BGI test) or from testing a tumour sample using a local test. The BRCAm status of all patients was confirmed where possible using the Myriad Integrated BRACAnalysis test, the Myriad BRACAnalysis CDx or the Foundation Medicine FoundationOne CDx Clinical Trial Assay.
There were 389 patients who were germline BRCAm and 2 who were somatic BRCAm in SOLO1.
Demographic and baseline characteristics were generally well balanced between the olaparib and placebo treatment arms. Median age was 53 years in both arms. Ovarian cancer was the primary tumour in 85% of the patients. The most common histological type was serous (96%), endometrioid histology was reported in 2% of the patients. Most patients were ECOG performance status 0 (78%). All patients had received first-line platinum-based therapy; response to prior platinum chemotherapy was complete in 82% and partial in 18% of the patients. Ninety three percent (93%) of patients were randomised within 8 weeks of their last dose of platinum-based chemotherapy.
The primary endpoint was progression-free survival (PFS), defined as time from randomisation to progression determined by investigator assessment using modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or death. Secondary efficacy endpoints included time from randomisation to second progression or death (PFS2), overall survival (OS), time from randomisation to first subsequent anti-cancer therapy or death (TFST) and health related quality of life (HRQoL). Patients had tumour assessments at baseline and every 12 weeks for 3 years, and then every 24 weeks relative to the date of randomisation, until objective radiological disease progression.
The study demonstrated a clinically relevant and statistically significant improvement in investigator assessed PFS for olaparib compared to placebo, with a hazard ratio (HR) of 0.30 (95% CI 0.23-0.41; p< 0.0001; the median was not reached for olaparib versus 13.8 months for placebo). Based on Kaplan-Meier estimates, the proportion of patients that were progression free at 12, 24 and 36 months were 88%, 74%, and 60% for olaparib versus 51%, 35% and 27% for placebo; the median follow-up time was 41 months for both the olaparib and placebo treatment arms. The investigator assessment of PFS was supported with a blinded independent central radiological (BICR) review of PFS (HR 0.28; 95% CI 0.20-0.39; p< 0.0001; median not reached for olaparib vs. 14.1 months for placebo). A clinically meaningful and statistically significant improvement in PFS2 was also observed with a HR of 0.50 (95% CI 0.35-0.72; p=0.0002; median not reached for olaparib vs. 41.9 months for placebo) indicating that the benefit observed with olaparib continued to be evident even with the use of subsequent therapies (see Table 2.)
At the time of PFS analysis, interim OS data were immature with events in 82/391 (21%) patients (HR 0.95; 95% CI 0.60-1.53; p=0.8903; medians not reached). A clinically meaningful and statistically significant improvement in TFST was observed for olaparib-treated patients (Table 2). (See Table 2 and Figure 1.)

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There was no decrease in HRQoL from baseline for olaparib-treated patients over the 24-month treatment period and no clinically relevant differences in HRQoL compared with placebo-treated patients as assessed by the change from baseline in the Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy - Ovarian (FACT-O).
Platinum-sensitive relapsed (PSR) ovarian cancer: The efficacy of Lynparza in the maintenance treatment setting in platinum-sensitive relapsed (PSR) ovarian, fallopian tube or primary peritoneal cancer is supported by 2 randomised, double-blind, placebo-controlled trials in patients with PSR and BRCA-mutated disease (SOLO2) and in patients with PSR disease (Study 19). In both studies, PSR patients who were in response following completion of platinum-based chemotherapy and whose disease had recurred >6 months after completion of penultimate platinum-based chemotherapy were enrolled. Patients could not have received prior olaparib or other PARP inhibitor treatment. Patients could have received prior bevacizumab, except in the regimen immediately prior to randomisation. Patients with BRCA mutations were identified either from germline testing in blood via a local test or the Myriad CLIA Integrated BRACAnalysis test or from testing a tumour sample using a local test or a test performed by Foundation Medicine.
SOLO2 Study in PSR patients with a BRCA mutation: The study compared the efficacy of Lynparza maintenance treatment (300 mg [2 x 150 mg tablets] twice daily) taken to progression with placebo treatment in 295 patients with high-grade serous or endometrioid PSR ovarian cancer (2:1 randomisation: 196 olaparib and 99 placebo) who were in response (CR or PR) following completion of platinum-containing chemotherapy. All patients had evidence of germline BRCA mutation (gBRCAm) at baseline.
The primary endpoint was PFS determined by investigator assessment using RECIST 1.1. Secondary efficacy endpoints included PFS2, OS, TDT, TFST, TSST; and HRQoL.
The study met its primary objective demonstrating a clinically meaningful and statistically significant improvement in investigator assessed PFS for olaparib compared with placebo with a HR of 0.30 (95% CI 0.22-0.41; p<0.0001; median 19.1 months for olaparib vs. 5.5 months for placebo). The investigator assessment of PFS was supported with a blinded independent central radiological review of PFS (HR 0.25; 95% CI 0.18-0.35; p<0.0001; median 30.2 months for olaparib vs. 5.5 months for placebo). At 2 years, 43% olaparib-treated patients remained progression-free compared with only 15% placebo-treated patients. A clinically meaningful and statistically significant improvement in PFS2 was also observed with a HR of 0.50 (95% CI 0.34-0.72; p=0.0002; median not reached for olaparib vs. 18.4 months for placebo) indicating that the benefit observed with olaparib continued to be evident even with the use of subsequent therapies. Interim OS was immature with events in only 24% patients (HR 0.80; 95% CI 0.50-1.31; p=0.4267; medians not reached). Clinically meaningful and statistically significant improvements in TDT, TFST and TSST were also observed for olaparib-treated patients (Table 3).
A summary of key efficacy findings for patients with gBRCAm PSR ovarian cancer in SOLO2 is presented in Table 3. (See Table 3 and Figure 2.)

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There was no difference between olaparib and placebo treatment groups in HRQoL as assessed by the change from baseline in the Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy - Ovarian (FACT-O) over 12 months (estimated difference - 0.03; 95% CI: -2.191, 2.2126; p=0.9765).
Study 19 in PSR patients: The study compared the efficacy of Lynparza capsule maintenance treatment (400 mg [8 x 50 mg capsules] twice daily) taken to progression with placebo treatment in 265 (136 olaparib and 129 placebo) PSR patients who were in response (CR or PR) following completion of platinum-containing chemotherapy. The primary endpoint was PFS based on investigator assessment using RECIST 1.0. Secondary efficacy endpoints included OS, disease control rate (DCR), HRQoL, and disease related symptoms. Exploratory analyses TFST and TSST were also performed.
The study met its primary objective demonstrating a statistically significant and clinically relevant improvement in PFS for olaparib compared with placebo with a HR of 0.35 (95% CI 0.25-0.49; p<0.00001; median 8.4 months for olaparib vs. 4.8 months for placebo). At the final analysis (data cut off [DCO] 9 May 2016) for OS at 79% maturity, the HR comparing olaparib with placebo was 0.73 (95% CI 0.55-0.95; p=0.02138 [did not meet pre-specified significance level of <0.0095]; median 29.8 months for olaparib vs. 27.8 months for placebo). TFST and TSST were also longer for olaparib-treated patients (Table 4).
Preplanned subgroup analysis identified patients with BRCAm ovarian cancer (n=136, 51.3%) as the subgroup that derived the greatest clinical benefit from olaparib maintenance monotherapy. There were no multiplicity strategies in place for the sub-group analyses. In BRCAm patients the HR for PFS improvement was 0.18 (95% CI 0.10-0.31; p<0.00001; median 11.2 months for olaparib vs. 4.3 months for placebo). For the secondary endpoint of OS, the HR for olaparib vs. placebo was 0.62 (95% CI 0.42-0.93; p=0.02140; median 34.9 months for olaparib vs. 30.2 months for placebo). In the olaparib-treated group, 28.4% of patients remained on treatment for ≥2 years and 14.9% for ≥5 years. In the placebo-treated group, 8.1% of patients remained on treatment for ≥2 years and 1.6% for ≥5 years. TFST and TSST were also longer for olaparib-treated patients (Table 4).
A summary of key efficacy findings for all patients, patients with BRCAm and patients with BRCAwt/VUS PSR ovarian cancer in Study 19 is presented in Table 4. (See Table 4.)

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Within the overall population, the DCR at 24 weeks was 53% and 25% for patients in the olaparib and placebo groups, respectively and in the BRCAm population was 57% and 24% for patients in the olaparib and placebo groups, respectively.
No statistically significant differences were observed between treatment groups in patient reported symptoms or HRQoL.
Germline BRCA-mutated HER2-negative metastatic breast cancer: OlympiAD in HER2-negative metastatic breast cancer patients with a gBRCA mutation: The study was a Phase III randomised, open-label, controlled trial that compared the efficacy of olaparib (300 mg [2 x 150 mg tablets] twice daily) taken to progression with a comparator arm of physician's choice of chemotherapy (capecitabine, eribulin, or vinorelbine). In the study 302 patients with gBRCAm HER2-negative metastatic breast cancer who had previously received up to two lines of chemotherapy for the treatment of metastatic disease were randomised (2:1 randomisation: 205 olaparib and 97 comparator). Patients were stratified based on: receipt of prior chemotherapy regimens for metastatic breast cancer, oestrogen receptor (ER) and/or progesterone receptor (PgR) positive vs ER and PgR negative, prior platinum for breast cancer. The primary endpoint was PFS assessed by BICR using RECIST 1.1. Secondary endpoints included PFS2, OS, objective response rate (ORR) and HRQoL.
All patients had received prior treatment with anthracycline (unless contraindicated) and a taxane in either the neoadjuvant, adjuvant or metastatic setting. Prior therapy with platinum for metastatic breast cancer was allowed provided there had been no evidence of disease progression during platinum treatment. Prior therapy with platinum in the (neo)adjuvant setting was allowed provided the last dose was received at least 12 months prior to randomisation. Patients could not have received prior olaparib or other PARP inhibitor treatment. Patients with ER and/or PgR positive disease must have received and progressed on at least one endocrine therapy (adjuvant or metastatic) or had disease that the treating physician believed to be inappropriate for endocrine therapy. Patients had tumour assessments at baseline and every 6 weeks for the first 24 weeks, and then every 12 weeks relative to date of randomisation, until objective radiological disease progression.
The study met its primary objective demonstrating a statistically significant and clinically meaningful improvement in PFS for olaparib-treated patients compared with those in the comparator arm with a HR of 0.58 (95% CI 0.43-0.80; p=0.0009; median 7.0 months for olaparib vs. 4.2 months for comparator) (Table 5).
A clinically meaningful and statistically significant improvement in PFS2 was also observed with a HR of 0.57 (95% CI 0.40-0.83; p=0.0033; median 13.2 months for olaparib vs 9.3 months for comparator) indicating that the benefit observed with olaparib continued to be evident even with the use of subsequent therapies. In the measurable disease patient population (77%), ORR in olaparib-treated patients was 60% (95% CI 52.0-67.4) and in patients who received comparator was 29% (95% CI 18.3-41.3). The median time to onset of response was 47 days for olaparib vs 45 days for comparator. The median duration of response was 6.4 months for olaparib vs 7.1 months for comparator. Overall survival was 64% mature at the time of the final OS analysis (DCO 25 September 2017). The OS HR comparing olaparib with comparator was 0.90 (95% CI 0.66-1.23; p=0.5131; median 19.3 months for olaparib vs. 17.1 months for comparator). The median follow-up time in censored patients was 25.3 months for olaparib vs 26.3 months for comparator.
Consistent results were observed across patient subgroups. (See Table 5 and Figure 3.)

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A significant difference in global health status/QoL (assessed using the EORTC QLQ-C30 questionnaire which uses a 0-100 point scale) in favour of olaparib was observed (adjusted mean difference in change from baseline score was 7.5 points [95% CI: 2.48-12.44; p=0.0035]). Time to deterioration (≥10 points decrease from baseline) in global health status/QoL score was statistically significantly longer on the olaparib arm (HR 0.44; 95% CI: 0.25-0.77; p=0.0043; median not reached for olaparib vs. 15.3 months for comparator arm). Over the treatment period, the proportion of patients with clinically significant improvement (≥10 points increase from baseline) in global health status/QoL score was 33.7% (n=69) in the olaparib arm and 13.4% (n=13) in the comparator arm.
Maintenance following first-line treatment of germline BRCA-mutated metastatic adenocarcinoma of the pancreas: POLO was a Phase III, randomised, double-blind, placebo-controlled, multicentre trial that compared the efficacy of Lynparza maintenance treatment (300 mg [2 x 150 mg tablets] twice daily) with placebo in gBRCA-mutated metastatic adenocarcinoma of the pancreas. The study randomised 154 patients (3:2 randomisation: 92 olaparib and 62 placebo) whose disease had not progressed following at least 16 weeks of first-line platinum-based chemotherapy. There was no upper limit to the duration of chemotherapy received. After 16 weeks of continuous platinum-based chemotherapy, the platinum could be discontinued at any time for toxicity and the other agents continued; the patients were eligible for randomisation as long as there was no evidence of progression at any time during chemotherapy treatment. All toxicities from previous anti-cancer therapy must have been resolved to CTCAE grade 1, except for alopecia, grade 3 peripheral neuropathy and Hgb ≥ 9 g/dL. Lynparza treatment was continued until progression of the underlying disease.
Patients with germline BRCA mutations were identified from prior local testing results or by central testing using the Myriad BRACAnalysis or Myriad BRACAnalysis CDx test. The BRCAm status of all patients identified using prior local testing results was confirmed, where sent, using the Myriad BRACAnalysis or Myriad BRACAnalysis CDx test.
Demographic and baseline characteristics were generally well balanced between the olaparib and placebo arms. Median age was 57 years in both arms; 30% of patients in the olaparib arm were ≥ 65 years compared to 21% in the placebo arm. Fifty-eight per-cent (58%) of patients were male. Most patients were ECOG performance status 0 (67%). Ninety-six per-cent (96%) of patients were randomised within 8 weeks of their last dose of platinum-based chemotherapy. The median time from initiation of first-line platinum-based chemotherapy to randomisation was 5.8 months (range 3.4 to 33.4 months) and 49% of patients were in complete or partial response to their most recent platinum-based regimen.
The primary endpoint was progression-free survival (PFS), defined as time from randomisation to progression determined by BICR using modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or death. Secondary efficacy endpoints included overall survival (OS), time from randomisation to second progression or death (PFS2), time from randomisation to first subsequent anti-cancer therapy or death (TFST), time from randomisation to discontinuation of treatment or death (TDT), objective response rate (ORR), duration of response (DoR), response rate, time to response and health related quality of life (HRQoL). Patients had tumour assessments at baseline and every 8 weeks for 40 weeks, and then every 12 weeks relative to the date of randomisation, until objective radiological disease progression. For PFS, the median follow-up time for censored patients was 9.1 months in the olaparib arm and 3.8 months in the placebo arm. For OS, the median follow-up time for censored patients was 13.4 months in the olaparib arm and 12.5 months in the placebo arm.
The study demonstrated a clinically meaningful and statistically significant improvement in PFS for olaparib compared to placebo, with a HR of 0.53 (95% CI 0.35 - 0.82; p=0.0038; the median was 7.4 months for olaparib vs 3.8 months for placebo). The sensitivity analysis of PFS by investigator assessment (HR 0.51; 95% CI 0.34 to 0.78; p=0.0017; median 6.3 months vs 3.7 months for olaparib vs placebo, respectively) was consistent with the PFS analysis by BICR. Based on Kaplan-Meier estimates, the proportion of patients that were alive and progression-free at 12, 24 and 36 months were 34%, 28% and 22% for olaparib vs 15%, 10% and 10% for placebo.
A clinically meaningful positive trend in PFS2 was observed with a HR of 0.76 (p=0.2597 [nominal]; median PFS2 was 13.2 months for olaparib vs 9.2 months for placebo) indicating that the benefit observed with olaparib continued to be evident even with the use of subsequent therapies. A clinically meaningful and statistically significant improvement in TFST and TDT was observed for olaparib-treated patients. The median DoR was longer in the olaparib arm (24.9 months) compared to the placebo arm (3.7 months), with a longer median time to onset of response (5.4 months for olaparib vs 3.6 months for placebo). At the interim analysis of OS (46% maturity) the HR was 0.91 (95% CI 0.56 - 1.46; p=0.6833; median 18.9 months for olaparib vs 18.1 months for placebo). (See Table 6 and Figure 4.)

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Patient-reported HRQoL was assessed using the EORTC QLQ-C30. A 10-point change was pre-defined as clinically meaningful on a 0-100 points global HRQoL scale. The adjusted mean change from baseline in global HRQoL score across all timepoints up to 6 months was -1.20 ± 1.42 in the olaparib group (n=84) and 1.27 ± 1.95 in the placebo group (n=54), with a corresponding estimated difference of -2.47 points (95% CI, -7.27 to 2.33). These results should be interpreted cautiously as this secondary endpoint was not adjusted for multiplicity testing in the statistical analysis.
Effect on the QT interval: There is no clinically relevant effect of olaparib on cardiac repolarisation (as evaluated by an effect on the QT interval) following 300 mg twice daily multiple dosing of olaparib.
Pharmacokinetics: General: Hard capsule: The pharmacokinetics of olaparib at the 400 mg twice daily capsule dose are characterised by an apparent plasma clearance of ~8.6 L/h, an apparent volume of distribution of ~167 L and a terminal half-life of 11.9 hours.
FC tablet: The pharmacokinetics of olaparib at the 300 mg tablet dose are characterised by an apparent plasma clearance of ~7 L/h, an apparent volume of distribution of ~158 L and a terminal half-life of 15 hours. On multiple dosing, an AUC accumulation ratio of 1.8 was observed and PK appeared to be time-dependent to a small extent.
Absorption: Hard capsule: Following oral administration of olaparib via the capsule formulation, absorption is rapid with peak plasma concentrations typically achieved between 1 to 3 hours after dosing. On multiple-dosing there is no marked accumulation, with steady state exposures achieved within ~3 to 4 days.
Co-administration with food slowed the rate (Tmax delayed by 2 hours) and increased the extent of absorption of olaparib (AUC increased by approximately 20%). Consequently, patients should take Lynparza at least one hour after food, and should refrain from eating for 2 hours afterwards (see Dosage & Administration).
FC tablet: Following oral administration of olaparib via the tablet formulation (2 x 150 mg), absorption is rapid with median peak plasma concentrations typically achieved 1.5 hours after dosing.
Co-administration with food slowed the rate (tmax delayed by 2.5 hours and Cmax reduced by approximately 21%) but did not significantly affect the extent of absorption of olaparib (AUC treatment ratio: 1.08; 90% CI: 1.01, 1.16). Consequently, patients should take Lynparza without regard to food (see Dosage & Administration).
Distribution: The in vitro plasma protein binding is approximately 82% at 10 μg/mL which is approximately Cmax.
In vitro, human plasma protein binding of olaparib was dose-dependent; the fraction bound was approximately 91% at 1 μg/mL, reducing to 82% at 10 μg/mL and to 70% at 40 μg/mL. In solutions of purified proteins, the olaparib fraction bound to albumin was approximately 56%, which was independent of olaparib concentrations. Using the same assay, the fraction bound to alpha-1 acid glycoprotein was 29% at 10 μg/mL with a trend of decreased binding at higher concentrations.
Metabolism: In vitro, CYP3A4/5 were shown to be the enzymes primarily responsible for the metabolism of olaparib.
Following oral dosing of 14C-olaparib to female patients, unchanged olaparib accounted for the majority of the circulating radioactivity in plasma (70%) and was the major component found in both urine and faeces (15% and 6% of the dose respectively). The metabolism of olaparib is extensive with the main site of metabolism being the piperazine and fluorobenzyl ring structures. The majority of the metabolism was attributable to oxidation reactions with a number of the components produced undergoing subsequent glucuronide or sulphate conjugation. Up to 20, 37 and 20 metabolites were detected in plasma, urine and faeces respectively, the majority of them representing <1% of the dosed material. A ring-open piperazin-3-ol moiety, and two mono-oxygenated metabolites (each ~10%) were the major circulating components, with one of the mono-oxygenated metabolites also being the major metabolite in the excreta (6% and 5% of the urinary and faecal radioactivity respectively).
In vitro, olaparib produced little/no inhibition of UGT1A4, UGT1A9, UGT2B7, or CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and is not expected to be a clinically significant time dependent inhibitor of any of these CYP enzymes. Olaparib inhibited UGT1A1 in vitro, however, PBPK simulations suggest this is not of clinical importance. Based on evaluation using enzyme activity, olaparib was not an inducer of CYP2C9 or 2C19. In vitro, olaparib is a substrate of and inhibits the efflux transporter P-gp (IC50=76 μM), however, this is unlikely to be of clinical significance.
In vitro, data also show that olaparib is not a substrate for OATP1B1, OATP1B3, OCT1, BCRP or MRP2, is a weak inhibitor of BCRP and not an inhibitor of OATP1B3, OAT1 or MRP2.
Excretion: Following a single dose of 14C-olaparib, ~86% of the dosed radioactivity was recovered within a 7-day collection period, ~44% via the urine and ~42% via the faeces. The majority of the material was excreted as metabolites.
Special populations: In population based PK analyses, patient age, gender, bodyweight or race (including White and Japanese patients) were not significant covariates.
Effect of renal impairment: Following a single oral 300 mg dose of olaparib (tablet formulation) to patients with mild renal impairment (creatinine clearance: 51 to 80 mL/min), AUC increased by 24% and Cmax by 15% compared with patients with normal renal function. No Lynparza dose adjustment is required for patients with mild renal impairment.
Following a single oral 300 mg dose of olaparib (tablet formulation) to patients with moderate renal impairment (creatinine clearance: 31 to 50 mL/min), AUC increased by 44% and Cmax by 26% compared with patients with normal renal function. Lynparza dose adjustment is recommended for patients with moderate renal impairment (see Dosage & Administration).
Olaparib has not been studied in patients with severe renal impairment or end-stage renal disease (creatinine clearance ≤30 ml/min).
Effect of hepatic impairment: Following a single oral 300 mg dose of olaparib (tablet formulation) to patients with mild hepatic impairment (Child-Pugh classification A) AUC increased by 15% and Cmax by 13% and to patients with moderate hepatic impairment (Child-Pugh classification B) AUC increased by 8% and Cmax decreased by 13% compared with patients with normal hepatic function. No Lynparza dose adjustment is required in patients with mild or moderate hepatic impairment (see Dosage & Administration).
Olaparib has not been studied in patients with severe hepatic impairment (Child-Pugh classification C).
Toxicology: Preclinical safety data: Mutagenicity: Olaparib showed no mutagenic potential, but was clastogenic in mammalian cells in vitro. When dosed orally to rats, olaparib induced micronuclei in bone marrow. This clastogenicity is consistent with the primary pharmacology of olaparib and indicates potential for genotoxicity in man.
Repeat-dose toxicity: In repeat-dose toxicity studies of up to 6 months duration in rats and dogs, daily oral doses of olaparib were well-tolerated. The major primary target organ for toxicity in both species was the bone marrow, with associated changes in peripheral haematology parameters. These findings occurred at exposures below those seen clinically and were largely reversible within 4 weeks of cessation of dosing. Studies using human bone marrow cells also showed that direct exposure to olaparib can result in toxicity to bone marrow cells in ex vivo assays.
Reproductive toxicology: Olaparib had no effect on fertility in male rats. In a female fertility study in rats, extended oestrus was observed in some animals although mating performance and fertility was not affected. Embryofoetal survival was reduced in this study.
In rat embryofoetal development studies, olaparib caused reduced embryofoetal survival, reduced foetal weight and foetal developmental abnormalities (including visceral and skeletal abnormalities, and major eye and vertebral/rib malformations) at dose levels that did not induce significant maternal toxicity.
Carcinogenicity: Carcinogenicity studies have not been conducted with olaparib.
Indications/Uses
Hard capsule: Lynparza is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic) high grade serous ovarian cancer (including fallopian tube or primary peritoneal) who are in response (complete response or partial response) to platinum-based chemotherapy.
FC tablet: 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 response or partial response) to platinum-based chemotherapy.
Breast cancer: Lynparza is indicated as monotherapy for the: treatment of adult patients with germline BRCA-mutated HER2-negative metastatic breast cancer who have previously been treated with chemotherapy. These patients could have received chemotherapy in the neoadjuvant, adjuvant or metastatic setting.
Adenocarcinoma of the pancreas: Lynparza is indicated as monotherapy for the: maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) metastatic adenocarcinoma of the pancreas whose disease has not progressed on a minimum of 16 weeks of first-line platinum-based chemotherapy. Germline BRCA mutation must be confirmed before LYNPARZA treatment is initiated.
Dosage/Direction for Use
Treatment with Lynparza should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.
Hard capsule: Patients must have confirmation of a breast cancer susceptibility gene (BRCA) mutation (germline or tumour) before Lynparza treatment is initiated. BRCA mutation status should be determined by an experienced laboratory using a validated test method (see Pharmacology: Pharmacodynamics under Actions).
There are limited data in patients with somatic BRCA-mutated tumours.
Patients should start treatment with Lynparza no later than 8 weeks after completion of their final dose of the platinum-containing regimen.
Dosage in adults: The recommended dose of Lynparza is 400 mg (eight 50 mg capsules) taken twice daily, equivalent to a total daily dose of 800 mg.
Lynparza should be taken on an empty stomach (at least 1 hour after a meal). Once Lynparza is taken, refrain from eating for 2 hours.
It is recommended that treatment be continued until progression of the underlying disease.
FC tablet: Detection of BRCA mutations: BRCA mutation status should be determined by an experienced laboratory using a validated test method.
Maintenance treatment of newly diagnosed advanced ovarian cancer: Patients must have confirmation of a breast cancer susceptibility gene (BRCA) mutation (identified by either germline or tumour testing) before Lynparza treatment is initiated.
Metastatic HER2-negative breast cancer: Patients must have confirmation of a BRCA mutation (identified by germline testing) before Lynparza treatment is initiated.
Maintenance treatment of patients with gBRCAm metastatic adenocarcinoma of the pancreas who are in response to first-line platinum-based chemotherapy: Patients must have confirmation of a deleterious or suspected deleterious BRCA mutation (identified by germline testing) before LYNPARZA treatment is initiated.
Dosage in adults: Lynparza is available as 100 mg and 150 mg tablets.
The recommended dose of Lynparza 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.
Duration of treatment: Maintenance treatment of newly diagnosed advanced ovarian cancer: patients can continue treatment for 2 years or until disease progression. Patients with a complete response (no radiological evidence of disease) at 2 years should stop 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.
Platinum-sensitive relapsed ovarian cancer: it is recommended that treatment be continued until progression of the underlying disease.
Metastatic HER2-negative breast cancer: it is recommended that treatment be continued until progression of the underlying disease.
Maintenance following first-line treatment of metastatic adenocarcinoma of the pancreas: it is recommended that treatment be continued until progression of the underlying disease.
Lynparza is also available as a 50 mg capsule. Refer to the capsules label for specific dosing information. Lynparza capsules (50mg) should not be substituted for Lynparza tablets (100 mg and 150 mg) on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation.
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 events: Treatment may be interrupted to manage adverse events and dose reduction can be considered.
Hard capsule: The recommended dose reduction is to 200 mg twice daily (equivalent to a total daily dose of 400 mg).
If a further dose reduction is required, then reduction to 100 mg twice daily (equivalent to a total daily dose of 200 mg) is recommended.
FC tablet: 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.
Co-administration with CYP3A inhibitors: Concomitant use of strong or moderate CYP3A inhibitors is not recommended and alternative agents should be considered.
Hard capsule: If a strong CYP3A inhibitor must be co-administered, the recommended Lynparza 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 Lynparza dose reduction is to 200 mg taken twice daily (equivalent to a total daily dose of 400 mg) (see Precautions and Interactions).
FC tablet: 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 Precautions and Interactions).
Special patient populations: Children or adolescents: Lynparza is not indicated for use in paediatric patients, as safety and efficacy of Lynparza in children and adolescents have not been established.
Elderly (>65 years): No adjustment in starting dose is required for elderly patients. There are limited clinical data in patients aged 75 years and over.
Renal impairment: Hard capsule: For patients with moderate renal impairment (creatinine clearance 31-50 ml/min) the recommended dose of Lynparza is 300 mg twice daily (equivalent to a total daily dose of 600 mg). Lynparza is not recommended for patients with severe renal impairment or end-stage renal disease (creatinine clearance ≤30 ml/min) as safety and efficacy have not been studied in these patients. Lynparza can be administered to patients with mild renal impairment (creatinine clearance 51-80 ml/min) with no dose adjustment (see Pharmacology: Pharmacokinetics under Actions).
FC tablet: For patients with moderate renal impairment (creatinine clearance 31 - 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). Lynparza is not recommended for 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 can be administered to patients with mild renal impairment (creatinine clearance 51 - 80 ml/min) with no dose adjustment (see Pharmacology: Pharmacokinetics under Actions).
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 Pharmacology: Pharmacokinetics under Actions). 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.
Method of administration: FC tablet: For oral use. Lynparza tablets should be swallowed whole and not chewed, crushed, dissolved or divided. Lynparza tablets can be taken with or without food.
Overdosage
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.
Contraindications
None.
Special Precautions
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. Patients should not start treatment with Lynparza until they have recovered from haematological toxicity caused by previous anti-cancer 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 Adverse Reactions).
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.
Myelodysplastic Syndrome/Acute Myeloid Leukaemia: The incidence of MDS/AML in patients treated in clinical trials with Lynparza monotherapy, including long-term survival follow up, was <1.5% and the majority of events had a fatal outcome. 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 treatments. The majority of reports were in germline BRCA mutation (gBRCAm) carriers and some of the patients had a history of more than one primary malignancy or of bone marrow dysplasia. If MDS and/or AML are confirmed while on treatment with Lynparza, it is recommended that Lynparza should be discontinued and the patient be treated appropriately.
Pneumonitis: Pneumonitis has been reported in <1.0% patients treated with Lynparza monotherapy 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). When Lynparza was used in clinical studies in combination with other therapies there have been events with a fatal outcome. 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.
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 (FC tablet); 400 mg twice daily (Hard capsule).
Lynparza should not be taken during pregnancy. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a foetus. Women of childbearing potential should be advised that they must use effective contraception during Lynparza treatment and for one month after receiving the last dose of Lynparza (see Use in Pregnancy & Lactation).
FC tablet: Male patients and their female partners of childbearing potential should be advised that they must use effective contraception during Lynparza treatment and for 3 months after receiving the last dose of Lynparza (see Use in Pregnancy & Lactation).
Interactions with other medicinal products: Co-administration of Lynparza with strong or moderate CYP3A inhibitors is not recommended (see Interactions). If a strong or moderate CYP3A inhibitor must be co-administered, the dose of Lynparza should be reduced (see Dosage & Administration).
Co-administration of Lynparza 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 Interactions).
Effects on ability to drive and use machines: No studies to establish the effects of olaparib on the ability to drive and use machinery have been conducted. However, during treatment with Lynparza, asthenia, fatigue, and dizziness have been reported and those patients who experience these symptoms should observe caution when driving or using machines.
Use in Lactation: The excretion of olaparib in milk has not been studied in animals or in breast-feeding mothers. Breast-feeding mothers are advised not to breast-feed during treatment with Lynparza and for one month after receiving the last dose of Lynparza (see Use in Pregnancy & Lactation).
Use In Pregnancy & Lactation
Olaparib should not be used during pregnancy due to the teratogenic and genotoxic potential of olaparib.
No studies have been conducted in pregnant women (see Pharmacology: Toxicology: Preclinical safety data under Actions).
If a female patient or a female partner of a male patient receiving Lynparza becomes pregnant, she should be apprised of the potential hazard to the foetus or potential risk of loss of the pregnancy (see Precautions).
FC tablet: Female partners of male patients taking Lynparza should also avoid pregnancy.
Contraception and pregnancy testing: Women of childbearing potential must use effective contraception during therapy and for one month after receiving the last dose of Lynparza (see Precautions). A pregnancy test should be performed on all women of childbearing potential prior to treatment, and pregnancy tests should be performed at regular intervals during treatment and at one month after receiving the last dose.
FC tablet: 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 effective contraception if they are of childbearing potential (see Precautions). Male patients should not donate sperm during therapy and for 3 months after receiving the last dose of Lynparza.
Breast-feeding: There are no data on the use of Lynparza in breast-feeding women. The excretion of olaparib in milk has not been studied in animals or in breast-feeding mothers. A risk to the newborn breast-feeding child cannot be excluded. Breast-feeding mothers are advised not to breast-feed during treatment with Lynparza and for one month after receiving the last dose (see Precautions).
Adverse Reactions
Overall summary of adverse drug reactions: Lynparza monotherapy has been associated with laboratory findings and/or clinical diagnoses generally of mild or moderate severity (CTCAE grade 1 or 2) and generally not requiring treatment discontinuation.
Tabulated list of adverse drug reactions from clinical trials: Hard capsule: The safety profile is based on pooled data from 2351 patients with solid tumours treated with Lynparza monotherapy in clinical trials.
FC tablet:
The safety profile is based on pooled data from 2095 patients with solid tumours treated with Lynparza monotherapy in clinical trials at the recommended dose.
The following adverse reactions have been identified in completed clinical trials with patients receiving Lynparza monotherapy where patient exposure is known. Adverse Drug Reactions are organized by MedDRA System Organ Class (SOC) and then by MedDRA preferred term in Tables 7 and 8. 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); and very rare (<1/10,000) including isolated reports.
Hard capsule: See Table 7.

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FC tablet: See Table 8.

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Description of selected adverse reactions: Haematological toxicity: Anaemia and other haematological toxicities are generally low grade (CTCAE grade 1 or 2), however, there are reports of CTCAE grade 3 and higher events. Anaemia was the most common CTCAE grade ≥3 adverse reaction reported in clinical studies with first onset generally reported in the first 3 months of treatment. An exposure-response relationship between olaparib and decreases in haemoglobin has been demonstrated.
Hard capsule: In clinical studies with Lynparza the incidence of CTCAE grade ≥2 shifts (decreases) from baseline in haemoglobin was 23%, absolute neutrophils 19%, platelets 6%, lymphocytes 29% and leucocytes 20% (all % approximate).
The incidence of elevations in mean corpuscular volume from low to normal at baseline to above the upper limit of normal was approximately 58%. Levels appeared to return to normal after treatment discontinuation and did not appear to have any clinical consequences.
FC tablet: In clinical studies with Lynparza 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 to normal at baseline to above the upper limit of normal 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 (see Dosage & Administration and Precautions).
Other laboratory findings: Hard capsule: In clinical studies with Lynparza the incidence of CTCAE grade ≥2 shifts (elevations) from baseline in blood creatinine was approximately 11%.
FC tablet:
In clinical studies with Lynparza 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.
Nausea and vomiting: 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.
Drug Interactions
Clinical studies of olaparib in combination with other anticancer agents, 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 agents.
Effect of other drugs on olaparib: Hard capsule: Elimination of olaparib is likely to be independent of formulation, therefore the tablet drug interaction and organ impairment findings (see Pharmacology: Pharmacokinetics under Actions) have been extrapolated to inform Lynparza capsule dose adjustment (see Dosage & Administration).
Strong and moderate CYP3A inhibitors: CYP3A4/5 are the isozymes predominantly responsible for the metabolic clearance of olaparib. Co-administration of olaparib [tablet formulation] with a strong CYP3A inhibitor (itraconazole) increased olaparib Cmax by 42% and increased AUC by 170%. Therefore, concomitant use of itraconazole as well as other strong CYP3A inhibitors such as, but not limited to telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir and telaprevir is not recommended with Lynparza (see Precautions).
Physiologically-based pharmacokinetic (PBPK) modelling has shown that moderate inhibitors will alter the clearance of olaparib and therefore concomitant use of moderate CYP3A inhibitors such as, but not limited to ciprofloxacin, erythromycin, diltiazem, fluconazole and verapamil is not recommended with Lynparza (see Precautions).
If strong or moderate CYP3A inhibitors must be co-administered, the dose of Lynparza should be reduced (see Dosage & Administration).
Hard capsule: It is also not recommended to consume grapefruit juice while on Lynparza therapy as it is a CYP3A inhibitor.
FC tablet: Avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during Lynparza treatment since they are CYP3A inhibitors.
Strong and moderate CYP3A inducers: Co-administration of olaparib [tablet formulation] with a strong CYP3A inducer (rifampicin) decreased olaparib Cmax by 71% and AUC by 87%. It is therefore possible that CYP3A inducers could substantially diminish the clinical efficacy of Lynparza and as such concomitant use of strong inducers such as, but not limited to phenytoin, rifabutin, rifampin (rifampicin), rifapentine, carbamazepine, nevirapine, phenobarbital and St John's Wort (Hypericum perforatum) is not recommended with Lynparza (see Precautions).
PBPK modelling has shown that moderate CYP3A inducers will decrease olaparib AUC by approximately 60% (FC tablet) or 50% (Hard capsule) and therefore concomitant use of moderate CYP3A inducers such as, but not limited to bosentan, efavirenz, etravirine, modafinil and nafcillin is not recommended with Lynparza. If a moderate CYP3A inducer must be co-administered, the prescriber should be aware of a potential for decreased efficacy of Lynparza (see Precautions).
Effect of olaparib on other drugs: CYP Interactions: Both induction and inhibition of CYP3A4 has been shown in vitro, however, PBPK simulations and clinical data suggest that the net effect of olaparib in vivo is weak inhibition of CYP3A. 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 Lynparza. Appropriate clinical monitoring is recommended for patients receiving CYP3A substrates with a narrow therapeutic margin concomitantly with Lynparza.
Induction of CYP1A2 and 2B6 has been shown in vitro with CYP2B6 being most likely to be induced to a clinically relevant extent. Therefore, Lynparza upon co-administration may reduce the exposure to substrates of these metabolic enzymes.
Drug transporter interactions: Olaparib has also been shown to be an in vitro inhibitor of OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K. The clinical relevance of these findings is unknown, however, it cannot be excluded that Lynparza may increase the exposure to substrates of 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 cisplatin) and MATE2K (e.g. metformin). In particular, caution should be exercised if Lynparza is administered in combination with any statin.
Hard capsule: Food interactions: The effect of food on olaparib has been studied. Co-administration with food slowed the rate (Tmax delayed by 2 hours) of absorption and increased the extent of absorption of olaparib (AUC increased by approximately 20%).
Caution For Usage
Instructions for use, handling and disposal: Hard capsule: No special requirements.
FC tablet: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Not applicable.
Storage
Hard capsule: Store in a refrigerator (2°C - 8°C).
Should refrigeration be unavailable, Lynparza capsules can be stored for up to 3 months below 30°C. The capsules must be discarded after this period.
Do not freeze. Any capsules that have been frozen must be discarded.
FC tablet: Store at or below 30°C.
Store in the original package in order to protect from moisture.
Shelf-life: Hard capsule: 2 years.
ATC Classification
L01XX46 - olaparib ; Belongs to the class of other antineoplastic agents. Used in the treatment of cancer.
Presentation/Packing
FC tab 100 mg (yellow to dark yellow, oval, bi-convex debossed with 'OP100' on one side and plain on the reverse) x 112's. 150 mg (green to green/grey, oval, bi-convex debossed with 'OP150' on one side and plain on the reverse) x 112's. Hard cap 50 mg (white, opaque, size 0, marked with "OLAPARIB 50 mg" and the AstraZeneca logo in black ink) x 4 x 112's.
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