Lynparza 100, 150 mg

/ Astra Zeneca

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.
Ovarian cancer: Patients should start treatment with Lynparza no later than 8 weeks after completion of their final dose of the platinum-containing regimen.
It is recommended that treatment be continued until progression of the underlying disease. There are no data on retreatment with Lynparza following subsequent relapse.
Important differences in posology between Lynparza tablets and capsules: Lynparza tablets (100 mg and 150 mg) should not be substituted for Lynparza capsules (50 mg) on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation.
Therefore, the specific dose recommendations for each formulation should be followed.
Missing dose: If a patient misses a dose of Lynparza, they should take their next normal dose at its scheduled time.
Dose adjustments for adverse reactions: Treatment may be interrupted to manage adverse reactions such as nausea, vomiting, diarrhoea, and anaemia and dose reduction can be considered.
The recommended dose reduction is to 250 mg (one 150 mg tablet and one 100 mg tablet) twice daily (equivalent to a total daily dose of 500 mg).
If a further dose reduction is required, then reduction to 200 mg (two 100 mg tablets) twice daily (equivalent to a total daily dose of 400 mg) is recommended.
Dose adjustments for co-administration with CYP3A inhibitors: Concomitant use of strong or moderate CYP3A inhibitors is not recommended and alternative agents should be considered. If a strong CYP3A inhibitor must be co-administered, the recommended Lynparza dose reduction is to 100 mg (one 100 mg tablet) taken twice daily (equivalent to a total daily dose of 200 mg). If a moderate CYP3A inhibitor must be co-administered, the recommended Lynparza dose reduction is to 150 mg (one 150 mg tablet) taken twice daily (equivalent to a total daily dose of 300 mg).
Elderly: No adjustment in starting dose is required for elderly patients. There are limited clinical data in patients aged 75 years and over.
Renal impairment: For patients with moderate renal impairment (creatinine clearance 31 to 50 ml/min) the recommended dose of Lynparza is 200 mg (two 100 mg tablets) twice daily (equivalent to a total daily dose of 400 mg).
Lynparza can be administered in patients with mild renal impairment (creatinine clearance 51 to 80 ml/min) with no dose adjustment.
Lynparza is not recommended for use in patients with severe renal impairment or end-stage renal disease (creatinine clearance ≤ 30 ml/min), as safety and pharmacokinetics have not been studied in these patients.
Lynparza may only be used in patients with severe renal impairment if the benefit outweighs the potential risk, and the patient should be carefully monitored for renal function and adverse events.
Hepatic impairment: Lynparza can be administered to patients with mild or moderate hepatic impairment (Child-Pugh classification A or B) with no dose adjustment. Lynparza is not recommended for use in patients with severe hepatic impairment (Child-Pugh classification C), as safety and pharmacokinetics have not been studied in these patients.
Non-Caucasian patients: There are limited clinical data available in non-Caucasian patients. However, no dose adjustment is required on the basis of ethnicity.
Patients with performance status 2 to 4: There are very limited clinical data available in patients with performance status 2 to 4.
Paediatric population: Lynparza tablets is not indicated for children.
Method of administration: Lynparza is for oral use. Lynparza tablets should be swallowed whole and not chewed, crushed, dissolved or divided. Lynparza tablets may be taken without regard to meals.

Ovarian cancer
Maintenance Treatment of Recurrent Ovarian Cancer: Lynparza is indicated as monotherapy for the 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.
Germline BRCA‐mutated HER2‐negative Metastatic Breast Cancer
Lynparza is indicated in patients with deleterious or suspected deleterious gBRCAm, HER2-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)- positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy.

Hypersensitivity to the active substance or to any of the excipients.
Breast-feeding during treatment and for 1 month after the last dose.

Haematological toxicity: Haematological toxicity has been reported in patients treated with olaparib, including clinical diagnoses and/or laboratory findings of generally mild or moderate (CTCAE grade 1 or 2) anaemia, neutropaenia, thrombocytopaenia and lymphopaenia. Patients should not start treatment with Olaparib until they have recovered from haematological toxicity caused by previous anticancer therapy (haemoglobin, platelet, and neutrophil levels should be within normal  range or CTCAE grade 1). Baseline testing, followed by monthly monitoring, of complete blood counts is recommended for the first 12 months of treatment and periodically after this time to monitor for clinically significant changes in any parameter during treatment.
If a patient develops severe haematological toxicity or blood transfusion dependence, treatment with Olaparib should be interrupted and appropriate haematological testing should be initiated. If the blood parameters remain clinically abnormal after 4 weeks of Olaparib dose interruption, bone marrow analysis and/or blood cytogenetic analysis are recommended.
Myelodysplastic syndrome/Acute Myeloid Leukaemia: The 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% and; the majority of events had a fatal outcome. The duration of therapy with olaparib in patients who developed MDS/AML varied from < 6 months to > 2 years. All patients had potential contributing factors for the development of MDS/AML; having received previos 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 (gBRCA 1/2) mutation carriers. Some of the patients had a history of previous cancer or of bone marrow dysplasia. If MDS and/or AML are confirmed while on treatment with Lynparza, it is recommended that Lynparza should be discontinued and the patient be treated 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.
Embryofoetal toxicity: Based on its mechanism of action (PARP inhibition), olaparib 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 400 mg twice daily.
Pregnancy/contraception: Olaparib should not be used during pregnancy and in women of childbearing potential not using reliable contraception during therapy and for 1 month after receiving the last dose of Olaparib.
Interactions: Lynparza co-administration with strong or moderate CYP3A inhibitors is not recommended. If a strong or moderate CYP3A inhibitor must be coadministered, the dose of Lynparza should be reduced.
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.

Ovarian Cancer: Lynparza monotherapy has been associated with adverse reactions generally of mild or moderate severity (CTCAE 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, vomiting, diarrhoea, dyspepsia, fatigue, headache, dysgeusia, decreased appetite, dizziness, and anaemia.
Treatment of gBRCAm HER2-negative Metastatic Breast Cancer:
Anemia, Leukopenia, Neutropenia, nausea, vomiting, diarrhoea, Respiratory tract infection, Fatigue (including asthenia), headache.
See prescribing information for full details.

Pharmacodynamic interactions
Clinical studies of olaparib in combination with other anticancer medicinal products, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. The recommended Lynparza monotherapy dose is not suitable for combination with myelosuppressive
anticancer medicinal products.
Combination of olaparib with vaccines or immunosuppressant agents has not been studied.
Therefore, caution should be taken if these medicinal products are co-administered with Lynparza and patients should be closely monitored.
Pharmacokinetic interactions
Effect of other medicinal products on olaparib: CYP3A4/5 are the isozymes predominantly responsible for the metabolic clearance of olaparib.
A clinical study to evaluate the impact of itraconazole, a known CYP3A inhibitor has shown that co-administration with olaparib increased mean olaparib Cmax by 42-% (90% CI: 33-52%) and mean AUC by 170% (90% CI: 144-197%). Therefore, known strong (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, boceprevir, telaprevir) or moderate (e.g. erythromycin, diltiazem, fluconazole, verapamil) inhibitors of this
isozyme are not recommended with Lynparza. If strong or moderate CYP3A inhibitors must be co-administered, the dose of Lynparza should be reduced. The recommended Lynparza dose reduction is to 150 mg taken twice daily (equivalent to a total daily dose of 300 mg) with a strong CYP3A inhibitor or 200 mg taken twice daily (equivalent to a total daily dose of 400 mg) with a moderate CYP3A inhibitor. It is also not recommended to consume grapefruit juice while on Lynparza therapy as it is a CYP3A inhibitor.
A clinical study to evaluate the impact of rifampicin, a known CYP3A inducer, has shown that co-administration with olaparib decreased olaparib mean Cmax by 71% (90% CI: 76-67%) and mean AUC by 87% (90% CI: 89-84%). Therefore, known strong inducers of this isozyme (e.g. phenytoin, rifampicin, rifapentine, carbamazepine, nevirapine, phenobarbital, and St John’s Wort) are not recommended with Lynparza, as it is possible that the efficacy of Lynparza could be substantially reduced. The magnitude of the effect of moderate to strong inducers (e.g. efavirenz, rifabutin) on olaparib exposure is not established, therefore the co-administration of Lynparza with these medicinal products is also not recommended.
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.
In vitro, olaparib inhibits the efflux transporter P-gp (IC50 = 76µM), therefore it cannot be excluded that olaparib may cause clinically relevant drug interactions with substrates of P-gp (e.g. simvastatin, pravastatin, dabigatran, digoxin and colchicine). Appropriate clinical monitoring is recommended for patients receiving this type of medicinal product concomitantly.
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 significant interaction was observed with anastrozole or letrozole whereas tamoxifen decreased exposure to olaparib by 27%. The clinical relevance of this effect is unknown. Olaparib does not affect the pharmacokinetics of tamoxifen.

Pregnancy: Women of childbearing potential should not become pregnant while on Olaparib and not be pregnant at the beginning of treatment. A pregnancy test should be performed on all premenopausal women prior to treatment. Women of childbearing potential must use effective contraception during therapy and for 1 month after receiving the last dose of Olaparib. 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 1 month after receiving the last dose of Lynparza.
Lactation: There are no animal studies on the excretion of olaparib in breast milk. It is unknown whether olaparib/or its metabolites are excreted in human milk. Olaparib is contraindicated during breastfeeding and for 1 month after receiving the last dose, given the pharmacologic property of the product.
See prescribing information for full details.

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