Consumer medicine information

Lynparza Capsules

Olaparib

BRAND INFORMATION

Brand name

Lynparza Capsules

Active ingredient

Olaparib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Lynparza Capsules.

What is in this leaflet

This leaflet answers some common questions about LYNPARZA capsules. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking LYNPARZA capsules against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What LYNPARZA capsules are used for

You will have been prescribed LYNPARZA capsules if you have ovarian cancer and it has responded to treatment with platinum-based chemotherapy and you have a mutation of the BRCA gene. BRCA stands for "BReast CAncer" gene. A genetic test will be done to determine if you have the BRCA gene mutation.

LYNPARZA is a PARP (Poly (ADPRibose) Polymerase enzymes) inhibitor. PARP inhibitors can destroy cancer cells that are not good at repairing DNA damage. These specific cancer cells can be identified by looking for faulty DNA repair genes, such as BRCA (BReast CAncer) genes. Carriers of a mutated BRCA gene have a higher risk of developing certain cancers, including ovarian cancer.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription.

Before you take LYNPARZA capsules

When you must not take it

Do not take LYNPARZA capsules if you have an allergy to:

  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take this medicine if you are pregnant or intend to become pregnant. It may affect your developing baby if you take it during pregnancy.

Do not breast-feed if you are taking this medicine. It is not known if the active ingredient in LYNPARZA capsules passes into breast milk. Breast-feeding mothers are advised not to breast-feed during treatment with LYNPARZA capsules and for one month after receiving the last dose.

Do not give this medicine to children. Safety and effectiveness in children younger than 18 years have not been established.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • problems with your kidneys or liver (renal or hepatic impairment)
  • problems with your blood (e.g. anaemia, low white blood cell counts, low red blood cell counts or low platelet counts).

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding or plan to breast-feed. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you start taking LYNPARZA capsules.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines or foods and LYNPARZA capsules may interfere with each other and reduce effectiveness. These include:

  • medicines used to treat fungal infections (antifungals) with active ingredients such as fluconazole, ketoconazole, itraconazole
  • medicines used to treat bacterial infections (antibiotics) with active ingredients such as clarithromycin, rifampicin, rifabutin, ciprofloxacin, erythromycin
  • medicines used to treat viral infections (especially HIV) with active ingredients such as ritonavir, indinavir, saquinavir, nevirapine, boceprevir, cobicistat, etravine and efavirenz
  • medicines used to treat epilepsy with active ingredients such as phenytoin, carbamazepine, and phenobarbital
  • medicines with active ingredients such as modafinil used to treat a sleep disorder called narcolepsy (where you may experience very sleepy periods at odd times during the day)
  • medicines to treat high blood pressure, angina (chest pain), irregular heartbeat or heart failure such as diltiazem, digoxin, furosemide and verapamil
  • bosentan, a medicine used to treat pulmonary artery hypotension
  • medicines called statins used to treat high cholesterol such as rosuvastatin and atorvastatin
  • medicines used to suppress the immune system such as tacrolimus and ciclosporin
  • methotrexate, a medicine used to treat cancer, rheumatoid arthritis and psoriasis
  • fentanyl, a medicine used to manage pain
  • quetiapine, a medicine used to treat mental disorders
  • colchicine, a medicine used to treat gout
  • dabigatran, a medicine to prevent blood clots
  • grapefruit, Seville oranges and star fruit
  • St John's Wort, used to treat depression
  • medicines used to treat diabetes such as metformin and glibenclamide
  • cisplatin, a medicine used to treat cancer.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

If you have not told your doctor about any of these things, tell them before you take any LYNPARZA capsules.

How to take LYNPARZA capsules

Your doctor has prescribed LYNPARZA capsules for you.

Please note LYNPARZA is also available as 100 mg and 150 mg tablets. The doses of LYNPARZA capsules and tablets are not the same. Taking the wrong dose or a tablet instead of a capsule could lead to LYNPARZA not working properly or to more side effects.

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the pack, ask your doctor or pharmacist for help.

How much to take

The usual dose is eight capsules taken twice each day (a total of 16 capsules each day). You should not take any more or any less capsules unless your doctor tells you to.

Your doctor may prescribe a different dose if you have problems with your kidneys or are taking certain medicines that may interact with LYNPARZA capsules or if you experience certain side effects while you are taking LYNPARZA capsules.

Your doctor will tell you how many capsules of LYNPARZA to take and it is important that you take the total recommended daily dose.

How to take it

Swallow the capsules whole with a glass of water. Do not open the capsules.

When to take it

Take LYNPARZA capsules at about the same time each morning and evening. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

Take your medicine on an empty stomach at least 1 hour after food. Once you have taken LYNPARZA capsules, do not eat for 2 hours. Food can interfere with the absorption of this medicine.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

It is important to keep taking your medicine even if you feel well.

Continue taking your medicine until you finish the pack.

If you forget to take it

If you forget to take LYNPARZA capsules, take your next normal dose at its scheduled time. Do not take a double dose (two doses at the same time) to make up for forgotten capsules.

If you are not sure what to do, ask your doctor.

If you have trouble remembering to take your medicine, ask your doctor or pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much LYNPARZA. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using LYNPARZA capsules

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking LYNPARZA capsules.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately. If you are at risk of becoming pregnant you must use effective contraception during treatment and for 1 month after receiving the last dose of LYNPARZA.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects. Your doctor will test your blood every month for the first year of treatment and periodically thereafter.

Things you must not do

Do not take LYNPARZA capsules to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor. If you stop taking it suddenly, your condition may worsen.

Your doctor may interrupt your treatment or reduce your dose if you are having unwanted side effects.

Things to be careful of

Be careful driving or operating machinery until you know how LYNPARZA capsules affect you. This medicine may cause dizziness and tiredness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking LYNPARZA capsules.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor immediately if you notice any of the following:

  • feeling or being sick (nausea or vomiting)
  • dizziness, tiredness or weakness
  • indigestion or heartburn
  • loss of appetite
  • headache
  • change in taste of food (if it worries you)
  • diarrhoea
  • sore mouth
  • pain in the stomach area under the ribs
  • shortness of breath
  • cough

The above list includes serious side effects that may require medical attention and can be life-threatening, especially if not treated.

Tell your doctor immediately if you experience any new or worsening symptoms of shortness of breath, coughing, or wheezing. A small number of patients treated with LYNPARZA reported inflammation of the lungs (pneumonitis). Pneumonitis is a serious condition that can often require hospital treatment.

If any of the following happen, tell your doctor immediately, or go to Accident and Emergency at your nearest hospital:

  • tightness of the chest, wheezing, coughing or difficulty breathing.
  • swelling of the face, lips, tongue or other parts of the body.
  • severe skin reaction which may include rash, itching, redness, blistering or peeling of the skin.

These are very serious side effects. If you have them, you may have had a serious allergic reaction to LYNPARZA. You may need urgent medical attention or hospitalisation.

Some other serious side effects may only become known through tests. Your doctor will test your blood every month for the first year of treatment and periodically thereafter. The blood tests may show:

  • a condition where there is damage to the blood-forming cells in your bone marrow (myelodysplastic syndrome/acute myeloid leukaemia)
  • decrease in the number of red blood cells (anaemia) which can be associated with shortness of breath, fatigue, pale skin, or fast heart beat
  • decrease in the number of white blood cells which can be associated with fever or infection
  • increase in blood creatinine which can mean your kidneys are not working as well
  • decrease in the number of platelets, which can result in bruising or bleeding for longer than normal if injured.

Tell your doctor if you notice any of the symptoms above that may be because of changes in your blood. These conditions may also be life-threatening, especially if not treated.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell or side effects not listed.

Other side effects not listed above may also occur in some people. Your doctor may prescribe other medicines to control unwanted side effects.

After using LYNPARZA capsules

Storage

Keep your capsules in the bottle until it is time to take them. If you take the capsules out of the bottle they may not keep well.

Keep your capsules in a refrigerator where the temperature stays between 2°C and 8°C.

Do not freeze. Throw away any LYNPARZA capsules that have been frozen.

If preferred, you can keep LYNPARZA capsules out of the refrigerator in a cool dry place where the temperature stays below 30°C for up to 3 months. After this period, throw away any capsules that have not been used. It is recommended that you record the date when the capsules are removed from refrigerator.

Do not store LYNPARZA or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

LYNPARZA 50 mg capsules are white and are marked with "OLAPARIB 50 mg" and the AstraZeneca logo printed in black ink.

LYNPARZA capsules are available in cartons containing 4 plastic bottles. Each bottle contains 112 capsules.

Ingredients

LYNPARZA capsules contains 50 mg of olaparib as the active ingredient and the following inactive ingredients:

  • lauroyl macrogolglycerides

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes. The capsule shell is made of hypromellose, gellan gum, titanium dioxide and potassium acetate and does not contain gelatin. The printing ink used contains shellac and iron oxide black.

Manufacturer/Distributor/ Supplier

LYNPARZA is Sponsored and supplied in Australia by:

AstraZeneca Pty Ltd
ABN 54 009 682 311
66 Talavera Road
MACQUARIE PARK NSW 2113
Telephone: 1800 805 342

© Copyright 2018

This leaflet was prepared 10 July 2019

AUST R 234008

Doc ID-003097735 v12.0

Published by MIMS September 2019

BRAND INFORMATION

Brand name

Lynparza Capsules

Active ingredient

Olaparib

Schedule

S4

 

1 Name of Medicine

Olaparib.

2 Qualitative and Quantitative Composition

Lynparza capsules consist of 50 mg olaparib drug substance suspended in the semi-solid lipidic excipient lauroyl macrogol glycerides, within a hypromellose capsule shell which also contains gellan gum, titanium dioxide and potassium acetate. The printing ink used contains shellac and iron oxide black.

3 Pharmaceutical Form

Lynparza capsules are white and are marked with "OLAPARIB 50 mg" and the AstraZeneca logo printed in black ink.

4 Clinical Particulars

4.1 Therapeutic Indications

Lynparza is indicated as monotherapy for the maintenance treatment of patients with platinum sensitive relapsed BRCA mutated (germline or somatic) high grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete response or partial response) after platinum based chemotherapy. Prior treatment must have included at least 2 courses of platinum based regimens.

4.2 Dose and Method of Administration

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

Important administration information.

Lynparza is also available as a 100 mg and 150 mg tablet. Do not substitute Lynparza capsules (50 mg) with Lynparza tablets (100 mg and 150 mg) on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation. See full prescribing information for Lynparza tablets for specific tablet dosing.
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.

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). The capsules should not be opened. Once Lynparza is taken, refrain from eating for 2 hours.
It is recommended that treatment be continued until progression of the underlying disease. There are no data to support retreatment with olaparib as maintenance following subsequent relapse.

Missing dose.

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

Dose adjustments.

Treatment may be interrupted to manage adverse reactions such as nausea, vomiting, diarrhoea, and anaemia and dose reduction can be considered.
Gastrointestinal toxicities are frequently reported with olaparib therapy (see Section 4.8 Adverse Effects (Undesirable Effects)) and are generally low grade (CTCAE grade 1 or 2) and intermittent. In addition to dose interruption or reduction, concomitant medicinal products (e.g. antiemetic therapy) may also be considered. Antiemetic prophylaxis is not required.
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.

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 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). The patient should be carefully monitored for adverse events (see Section 4.5 Interactions with Other Medicines and Other Forms of 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.

Use in men.

Lynparza is not indicated for use in men, as safety and efficacy of Lynparza in men 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.

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 Section 5.2 Pharmacokinetic Properties). Patients should be monitored closely 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 however, patients should be monitored closely for hepatic function and adverse events (see Section 5.2 Pharmacokinetic Properties). 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.

Women of childbearing potential.

Women of childbearing potential must use effective contraception during therapy and for 1 month after receiving the last dose of Lynparza (see Section 4.6 Fertility, Pregnancy and Lactation).

Non-Caucasian patients.

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

Patients with performance status 2 to 4.

There are very limited clinical data available in patients with performance status 2 to 4.

4.3 Contraindications

Hypersensitivity to the active substance (olaparib) or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Haematological toxicity.

Haematological toxicity occurs commonly in patients treated with Lynparza. While the majority were generally mild or moderate (CTCAE grade 1 or 2), grade 3 or higher events of anaemia (decrease in haemoglobin) occurred in 7.4% of patients in study 19, and one patient died from a haemorrhagic stroke associated with thrombocytopenia. Patients should not start treatment with Lynparza until they have recovered from haematological toxicity caused by previous anticancer therapy (haemoglobin, platelet, and neutrophil levels should be ≤ CTCAE grade 1). Baseline testing, followed by monthly monitoring, of complete blood counts is recommended for the first 12 months of treatment and periodically after this time to monitor for clinically significant changes in any parameter during treatment (see Section 4.8 Adverse Effects (Undesirable Effects)).
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 Myelodysplastic syndrome/Acute Myeloid Leukaemia (MDS/AML) in patients treated in clinical studies 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 predisposing 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.

Paediatric use.

The safety and efficacy of Lynparza in children and adolescents have not been established.

Use in men.

The safety and efficacy of Lynparza in men have not been established.

Use in renal impairment.

Exposure is increased in renal impairment (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).

Use in hepatic impairment.

Exposure is increased in hepatic impairment (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).

Use in the elderly.

There are limited clinical data in patients aged 75 years and over (see Section 4.2 Dose and Method of Administration).

Effects on laboratory tests.

No data available.

Interactions with other medicinal products.

Lynparza co-administration with strong or moderate CYP3A inhibitors is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). If a strong or moderate CYP3A inhibitor must be co-administered, the dose of Lynparza should be reduced (see Section 4.2 Dose and Method of Administration).
Olaparib co-administration with strong or moderate CYP3A inducers is not recommended. In the event that a patient already receiving olaparib requires treatment with a strong or moderate CYP3A inducer, the prescriber should be aware that the efficacy of olaparib may be substantially reduced (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.5 Interactions with Other Medicines and Other Forms of 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.

Elimination of olaparib is likely to be independent of formulation, therefore the drug interaction and organ impairment findings from studies using the tablet formulation (see Section 5 Pharmacological Properties, Special populations) have been extrapolated to inform Lynparza capsule dose adjustment (see Section 4.2 Dose and Method of Administration).

Strong and moderate CYP3A inhibitors.

CYP3A4/5 are the isozymes predominantly responsible for the metabolic clearance of olaparib. Clinical studies [conducted with a tablet formulation] have shown that co-administration of olaparib [tablet formulation] with a strong CYP3A inhibitor (itraconazole) increased olaparib Cmax by 42% (90% CI: 33% to 52%) and mean AUC by 170% (90% CI: 144% to 197%). It is therefore recommended that known strong inhibitors of these isozymes are not co-administered with Lynparza. These include but are not limited to inhibitors such as itraconazole, clarithromycin, boosted protease inhibitors with ritonavir or cobicistat, indinavir, saquinavir and boceprevir.
Physiologically-based pharmacokinetic (PBPK) modelling has suggested that moderate CYP3A 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.
If a strong or moderate CYP3A inhibitor must be co-administered, the dose of Lynparza should be reduced (see Section 4.2 Dose and Method of Administration).
Patients should avoid star fruit, grapefruit and Seville oranges because these foods are known to inhibit CYP3A enzymes.

Strong and moderate CYP3A inducers.

A clinical study to evaluate the impact of rifampicin, a known CYP3A inducer has shown that co-administration with olaparib [tablet formulation] decreased olaparib Cmax by 71% (90% CI: 76% to 67%) and mean AUC by 87% (90% CI: 89% to 84%). 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, rifampicin, carbamazepine, nevirapine, phenobarbital and St John's wort (Hypericum perforatum) is not recommended with Lynparza (see Section 4.4 Special Warnings and Precautions for Use).
PBPK modelling has suggested that moderate CYP3A inducers will decrease olaparib AUC by approximately 50% and therefore concomitant use of moderate CYP3A inducers such as, but not limited to, bosentan, efavirenz, etravirine and modafinil 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 Section 4.4 Special Warnings and Precautions for Use).

Effect of olaparib on other drugs.

CYP and UGT 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. Caution should be exercised when sensitive CYP3A substrates or substrates with a narrow therapeutic margin (e.g. simvastatin, ciclosporin, midazolam, ergot alkaloids, sirolimus, fentanyl, 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. Therefore, Lynparza upon co administration may reduce the exposure to substrates of these metabolic enzymes.
Olaparib produced little/no direct inhibition in vitro of UGT1A4, UGT1A9, UGT2B7 or CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 or 2E1. Olaparib was not a time dependent inhibitor of CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2D6 or 2E1. 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.

Drug transporter interactions.

In vitro, olaparib inhibits the efflux transporter P-gp (IC50 = 76 micromolar). The excipient, lauroyl macrogol-32 glycerides is also a P-gp inhibitor. Therefore, it cannot be excluded that Lynparza may cause clinically relevant drug interactions with substrates of P-gp (e.g. simvastatin, pravastatin, dabigatran, digoxin, colchicine). Appropriate clinical monitoring is recommended for patients receiving this type of medication concomitantly. The potential for olaparib to induce P-gp has not been evaluated.
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.
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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

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. Exposures achieved in these studies were subclinical and the full effects on fertility may not have been revealed.
(Category D)
Based on its mechanism of action (PARP inhibition), Lynparza could cause foetal harm when administered to a pregnant woman. Studies in rats have shown that olaparib causes embryofetal lethality and induces major fetal malformations (major eye and vertebral/ rib malformations) at exposures below those expected at the recommended human dose of 400 mg twice daily.
Lynparza should not be used during pregnancy due to the teratogenic and genotoxic potential of olaparib. No studies have been conducted in pregnant women.
If a patient becomes pregnant while receiving Lynparza, she should be informed of the potential hazard to the foetus or potential risk of loss of the pregnancy.
Women of childbearing potential must use effective contraception during therapy and for 1 month after receiving the last dose of Lynparza. 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.
 There are no data on the use of Lynparza in breastfeeding women. The excretion of olaparib in milk has not been studied in animals or in breastfeeding mothers. A risk to the newborn breastfeeding child cannot be excluded. Breastfeeding mothers are advised not to breastfeed during treatment with Lynparza and for one month after receiving the last dose.

4.7 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.

4.8 Adverse Effects (Undesirable Effects)

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.

Adverse drug reactions during clinical trials.

The safety profile is based on pooled data from 2351 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 organised by MedDRA System Organ Class (SOC) and then by MedRA 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) including isolated reports.

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. 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.
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 Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

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.

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.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

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.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Olaparib is an orally active 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 mice either as a standalone treatment or in combination with established chemotherapies.
PARP enzymes 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 automodifies 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 leads to DNA double strand breaks (DSBs) when replication forks meet the PARP DNA adduct. In normal cells, homologous recombination repair (HRR), which requires functional BRCA1 and 2 genes, is effective at repairing these DNA double strand breaks. In the absence of functional BRCA1 or 2, DNA DSBs cannot be repaired via HRR. Instead, alternative and error prone pathways are activated, such as the nonhomologous 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 have a high DNA damage load relative to normal cells. Thus, olaparib induces synthetic lethality in BRCA1 and 2 mutated cancer cells.
In BRCA deficient animal models, olaparib given after platinum treatment resulted in a delay in tumour progression and an increase in overall survival compared to platinum treatment alone.
There was no correlation between the dose and degree of PARP-1 inhibition observed in the pharmacodynamic studies, with maximal inhibition achieved at relatively low doses. Therefore, the dose selection was based upon the higher clinical response rates observed at higher doses.

Clinical trials.

Platinum sensitive relapsed (PSR) ovarian cancer.

The safety and efficacy of Lynparza as a maintenance therapy in the treatment of patients with PSR ovarian, fallopian tube or primary peritoneal cancer with a histology type of serous, or a serous component, following treatment with two or more platinum containing regimens, was studied in a phase II randomised, double blind placebo controlled trial (study 19). The study compared the efficacy of Lynparza maintenance treatment taken to progression with no maintenance treatment in 265 (136 Lynparza 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.
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 Lynparza 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 Lynparza 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 Lynparza 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. 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). The investigator assessment of PFS was consistent with a blinded independent central radiological review of PFS. For the secondary endpoint of OS, the HR of 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.
In the gBRCA mutated subgroup (n = 96) there was a statistically significant improvement in PFS. The median PFS improvement was 7.1 months over placebo (HR 0.17; 95% CI: 0.09-0.31; p < 0.00001; median 11.2 months vs 4.1 months). For the secondary endpoint of OS, the HR for olaparib vs placebo was 0.68 (95% CI: 0.42-1.10; p = 0.11363; median 32.9 months versus 27.3 months). In the olaparib-treated group, 24.5% of patients remained on treatment for ≥ 2 years and 11.3% for ≥ 5 years. In the placebo-treated group, 7.0% of patients remained on treatment for ≥ 2 years and 2.3% for ≥ 5 years.
Within the BRCA mutated population the disease control rate at 24 weeks was 57% and 24% for patients in the Lynparza and placebo groups, respectively.
No statistically significant differences were observed between treatment groups in patient reported symptoms or HRQoL.
A summary of key efficacy findings for patients with BRCA mutated and gBRCA mutated PSR ovarian cancer in study 19 is presented in Table 2 and Figures 1 and 2.

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 olaparib tablet formulation.

Retreatment on relapse.

There are no data to support retreatment with olaparib as maintenance following subsequent relapse.

5.2 Pharmacokinetic Properties

Olaparib displays high interpatient variability in PK parameters, including Cmax, AUC, Vd and CL/F.
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.

Absorption.

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.

Food effects.

Coadministration 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.

Distribution.

In vitro, human plasma protein binding of olaparib was dose-dependent; the fraction bound was approximately 91% at 1 microgram/mL, reducing to 82% at 10 microgram/mL and to 70% at 40 microgram/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 microgram/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).

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, bodyweight or race (including White and Japanese patients) were not significant covariates.

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% (90% CI: 6% to 47% and Cmax by 15% (90% CI: 4 to 27%) compared with patients with normal renal function. No Lynparza dose adjustment is required for patients with mild renal impairment, but patients should be monitored closely for renal function and adverse events (see Section 4.2 Dose and Method of Administration).
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% (90% CI: 10% to 89%) and Cmax by 26% (90% CI: 6% to 48%) compared with patients with normal renal function. Lynparza dose adjustment is recommended for patients with moderate renal impairment and patients should be monitored closely for renal function and adverse events (see Section 4.2 Dose and Method of Administration). Renal clearance of olaparib was lower in patients with mild and moderate renal impairment compared to patients with normal renal function (1.48 L/h). For patients with mild or moderate renal impairment, arithmetic mean CLR was 59% (0.614 L/h) and 80% (0.299 L/h) lower, respectively, than that observed in patients with normal renal function.
Olaparib has not been studied in patients with severe renal impairment or end-stage renal disease (creatinine clearance ≤ 30 mL/min).

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% (90% CI: -23% to 28%) and Cmax by 13% (90% CI: -18% to 55%) and to patients with moderate hepatic impairment (Child-Pugh classification B) AUC increased by 8% (90% CI: 0.66, 1.73) and Cmax decreased by 13% (90% CI: 0.63, 1.22) compared with patients with normal hepatic function. No Lynparza dose adjustment is required in patients with mild or moderate hepatic impairment, however, patients should be monitored closely for hepatic function and adverse events (see Section 4.2 Dose and Method of Administration).
Olaparib has not been studied in patients with severe hepatic impairment (Child-Pugh classification C).

5.3 Preclinical Safety Data

Genotoxicity.

Olaparib showed no mutagenic potential in bacterial cells, 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.

Carcinogenicity.

Carcinogenicity studies have not been conducted with olaparib.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2°C to 8°C (Refrigerate. Do not freeze). Store in original container.
Lynparza capsules can be stored for up to 3 months below 30°C. The capsules must be discarded after this period and not returned to the refrigerator.

6.5 Nature and Contents of Container

Lynparza is supplied in cartons containing four HDPE plastic bottles. Each bottle contains 112 capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Olaparib is a white to pale yellow crystalline powder, which is very slightly soluble in aqueous solutions (0.10 - 0.13 mg/mL at 37°C), slightly soluble in ethanol (5.5 mg/mL at 37°C) and has a pKa of 12.07.

Chemical structure.

The chemical name for olaparib is: 4-[[3-[[4-(cyclopropylcarbonyl)-1-piperazinyl] carbonyl]-4-fluorophenyl]methyl]-1(2H)-phthalazinone.
The chemical structure of olaparib is:
Molecular formula: C24H23FN4O3.
Molecular weight: 434.46.

CAS number.

CAS number: 763113-22-0.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes