Lynparza^® (Tablets, Capsules) Instructions for Use

ATC Code

L01XK01 (Olaparib)

Active Substance

Olaparib (Prop.INN)

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent

Pharmacological Action

Olaparib is a potent inhibitor of the poly(ADP-ribose) polymerase (PARP) enzymes PARP-1, PARP-2, and PARP-3.

It has been shown that Olaparib, both as monotherapy and in combination with traditional chemotherapeutic agents, inhibits the growth of certain tumor cell lines in vitro and tumor growth in vivo.

PARP enzymes are required for efficient repair of single-strand DNA breaks. For PARP-induced repair, it is necessary that after chromatin modification, PARP itself undergoes a conformational change and dissociates from the DNA to allow access for base excision repair enzymes to the break site.

When Olaparib binds to the active site of the PARP enzyme bound to DNA, it prevents PARP dissociation and traps it on the DNA, thereby blocking repair.

In dividing cells, this leads to stalling of the replication fork at the site of the PARP-DNA complex and the formation of double-strand DNA breaks.

In normal cells, double-strand DNA breaks are repaired by homologous recombination.

In tumor cells lacking functional components of homologous recombination repair (due to inactivation of genes directly or indirectly involved in homologous recombination repair, such as BRCA1 or BRCA2, ATM, CDK12, and others), double-strand DNA breaks cannot be accurately and efficiently repaired by homologous recombination.

Instead, repair is carried out by alternative pathways, such as non-homologous end joining, which are associated with the introduction of a large number of errors into the DNA, increasing genomic instability.

After several replication cycles, genomic instability can reach unacceptable levels and lead to the death of tumor cells, which initially carry a greater mutational load compared to normal cells.

In the absence of deleterious mutations in key homologous recombination repair genes, this DNA repair pathway can be disrupted by other mechanisms, although the abnormalities leading to this and their manifestations are not fully known.

The absence of a fully functional homologous recombination repair pathway is one of the key factors determining the sensitivity of ovarian cancer cells and other types of cancer to platinum drugs.

In BRCA-deficient in vivo models, Olaparib administered after platinum-based therapy resulted in delayed tumor progression and increased overall survival compared to platinum-based therapy alone, which correlated with the duration of olaparib maintenance therapy.

Effect on QT interval

Multiple administration of olaparib at a dose of 300 mg twice daily did not have a clinically significant effect on myocardial repolarization (based on the absence of effect on the QT interval).

Pharmacokinetics

The pharmacokinetics of olaparib tablets at a dose of 300 mg are characterized by an apparent plasma clearance of approximately 7 L/h, an apparent volume of distribution of approximately 158 L, and a half-life of 15 hours.

Upon multiple administration, an AUC (area under the concentration-time curve) accumulation ratio of 1.8 was observed, and the pharmacokinetics appeared to be slightly time-dependent.

Absorption

After oral administration in tablet form (2 tablets of 150 mg each), Olaparib is rapidly absorbed, with a median time to reach maximum plasma concentration (C_max) of 1.5 hours.

Concomitant administration of the drug with food slowed the rate of absorption (time to maximum plasma concentration (T_max) increased by 2.5 hours, and C_max decreased by approximately 21%), but did not significantly affect the extent of olaparib absorption (therapeutic AUC range: 1.08; 90% confidence interval (CI) 1.01; 1.16).

Therefore, the drug Lynparza^® can be taken regardless of food intake (see section “Dosage Regimen”).

Distribution

In vitro, the binding of olaparib to plasma proteins is approximately 82% at its plasma concentration of 10 µg/ml, which approximately corresponds to C_max.

In vitro, the extent of olaparib binding to human plasma proteins was dose-dependent; the bound fraction was approximately 91% at 1 µg/ml, decreasing to 82% at 10 µg/ml and to 70% at 40 µg/ml.

In purified protein solutions, the albumin-bound fraction of olaparib was approximately 56% and was independent of olaparib concentration.

Using the same test system, the fraction bound to alpha-1-acid glycoprotein was 29% at an olaparib concentration of 10 µg/ml, with a tendency for the binding extent to decrease at higher concentrations.

Metabolism

In vitro, the main enzymes involved in the metabolism of olaparib were shown to be the cytochrome P450 isoenzymes CYP3A4/5.

After oral administration of ¹⁴C-olaparib to female patients, the majority of radioactivity in blood plasma was due to unchanged olaparib (70%), which was also the main component detected in urine and feces (15% and 6% of the administered dose, respectively).

Olaparib undergoes numerous metabolic transformations in the body, most commonly affecting the piperazine and fluorobenzyl rings, mainly through oxidation to form a series of derivatives that subsequently undergo glucuronide or sulfate conjugation.

Up to 20, 37, and 20 metabolites were identified in plasma, urine, and feces, respectively, most of them accounting for less than 1% of the administered drug.

The main circulating metabolites in blood were the ring-opened piperazine-3-ol fragment and two monooxygenated metabolites (each accounting for approximately 10% of radioactivity), with one of the monooxygenated metabolites also being the main metabolite detected in urine and feces (6% and 5% of radioactivity, respectively).

In vitro, Olaparib minimally inhibited or did not inhibit UGT2B7 or the cytochrome isoenzymes CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and it is not expected to be a clinically significant, time-dependent inhibitor of any of the listed cytochrome P450 isoenzymes.

Olaparib inhibited UGT1A1 in vitro; however, physiologically based pharmacokinetic modeling indicates that this phenomenon is not clinically significant.

Based on enzyme activity assessment, Olaparib was not an inducer of CYP2C9 or CYP2C19 isoenzymes.

In vitro, Olaparib is a substrate and inhibitor of the efflux transporter P-glycoprotein (IC₅₀= 76 µM), but this fact is unlikely to be of clinical significance.

In vitro study results also showed that Olaparib is not a substrate of OATP1B1, OATP1B3, OCT1, BCRP, or MRP2, is a weak inhibitor of BCRP, and is not an inhibitor of OATP1B3, OAT1, or MRP2.

Excretion

After a single dose of ¹⁴C-olaparib, approximately 86% of the total radioactivity was excreted within 7 days, approximately 44% renally and 42% via the intestine.

The majority of the administered dose was excreted as metabolites.

Pharmacokinetics in special patient groups

In population pharmacokinetic analyses, age, sex, body weight, or race (including Caucasian patients and patients of Japanese origin) did not have a significant effect on the pharmacokinetics of olaparib.

Renal impairment. In patients with mild renal impairment (creatinine clearance from 51 to 80 ml/min) after a single oral dose of 300 mg olaparib, AUC increased by 24% and C_max by 15% compared to patients with normal renal function.

In patients with mild renal impairment, dose adjustment of the drug Lynparza^® is not required.

In patients with moderate renal impairment (creatinine clearance from 31 to 50 ml/min), AUC increased by 44% and C_max by 26% compared to patients with normal renal function after a single oral dose of 300 mg olaparib.

In patients with moderate renal impairment, dose adjustment of the drug Lynparza^® is recommended (see section “Dosage Regimen”).

The use of olaparib in patients with severe renal impairment or end-stage renal disease (creatinine clearance ≤30 ml/min) has not been studied.

Hepatic impairment. In patients with mild hepatic impairment (Child-Pugh class A), AUC was increased by 15% and C_max by 13%; in patients with moderate hepatic impairment (Child-Pugh class B), AUC was increased by 8% and C_max was decreased by 13% compared to patients with normal hepatic function.

In patients with mild or moderate hepatic impairment, dose adjustment of the drug Lynparza^® is not required (see section “Dosage Regimen”).

The use of olaparib in patients with severe hepatic impairment (Child-Pugh class C) has not been studied.

Indications

Ovarian cancer

The drug Lynparza^® is indicated for

• Maintenance monotherapy of newly diagnosed advanced epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer of high grade with BRCA mutations in adult patients who have responded (complete or partial response) to first-line platinum-containing chemotherapy;
• Maintenance monotherapy of platinum-sensitive recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer of high grade in adult patients who have responded (complete or partial response) to platinum-containing chemotherapy.

The drug Lynparza^® in combination with bevacizumab is indicated for

• Maintenance therapy of newly diagnosed advanced epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer of high grade in adult patients who have responded (complete or partial response) to first-line platinum-containing chemotherapy in combination with bevacizumab.

Breast cancer

The drug Lynparza^® is indicated for

• Monotherapy of metastatic HER2-negative breast cancer in adult patients with germline BRCA mutations who have previously received neoadjuvant or adjuvant chemotherapy or chemotherapy for metastatic disease.

Pancreatic adenocarcinoma

The drug Lynparza^® is indicated for

• Maintenance monotherapy of metastatic pancreatic adenocarcinoma with germline BRCA mutations in adult patients who have not experienced disease progression on first-line platinum-containing chemotherapy.

Prostate cancer

The drug Lynparza^® is indicated for

• Monotherapy of metastatic castration-resistant prostate cancer with germline or somatic mutations in genes involved in homologous recombination DNA repair in patients with disease progression after therapy with new hormonal agents.

ICD codes

Dosage Regimen

Capsules

Treatment with the drug Lynparza^® should be initiated and conducted under the supervision of a physician experienced in the use of antineoplastic medicinal products.

Patients must have a confirmed BRCA gene mutation – germline (hereditary) or somatic (in tumor cells) – before starting treatment with the drug Lynparza^®.

Determination of the BRCA mutation should be performed in a qualified laboratory using a validated test (see section “Pharmacological Action”).

Data on the use of the drug Lynparza^® in patients with somatic BRCA gene mutation are limited (see section “Pharmacological Action”).

Patients with BRCA gene mutations should receive genetic counseling according to local standards of care.

Method of administration

Orally. The capsules should be swallowed whole, without chewing, dissolving, or opening them.

Due to the effect of food on the absorption of olaparib, the drug should be taken at least 1 hour after a meal and food should be avoided for at least 2 hours after taking the drug.

Doses

The recommended dose of the drug Lynparza^® is 400 mg (8 capsules) twice daily, corresponding to a total daily dose of 800 mg.

Patients should start maintenance therapy with Lynparza^® no later than 8 weeks after completing a course of platinum-containing chemotherapy.

It is recommended to continue therapy until progression of the underlying disease.

There are no data on resuming therapy with Lynparza^® after subsequent relapse.

Missed dose

If a dose is missed, the next regular dose of the drug should be taken at the usual time.

Dose adjustment for adverse reactions

Treatment can be interrupted to manage adverse reactions such as nausea, vomiting, diarrhea, and anemia, and a dose reduction should be considered (see section “Adverse Reactions”).

The recommended reduced dose of the drug is 200 mg twice daily, corresponding to a total daily dose of 400 mg.

If a further dose reduction is required, the dose can be reduced to 100 mg twice daily, corresponding to a total daily dose of 200 mg.

Dose adjustment for concomitant use with CYP3A isoenzyme inhibitors

Concomitant use of strong and moderate CYP3A isoenzyme inhibitors with olaparib is not recommended; alternative medications should be considered.

If therapy with strong or moderate CYP3A inhibitors is necessary during olaparib treatment, the dose of olaparib should be reduced.

The recommended reduced dose of olaparib when used concomitantly with a strong CYP3A inhibitor is 150 mg twice daily, corresponding to a total daily dose of 300 mg, and when used concomitantly with a moderate CYP3A inhibitor – 200 mg twice daily, corresponding to a total daily dose of 400 mg (see sections “Drug Interactions” and “Special Instructions”).

Elderly patients

Adjustment of the initial dose of the drug in elderly patients is not required.

Data on the use of olaparib in patients aged 75 years and older are limited.

Patients with renal impairment

The recommended dose of the drug Lynparza^® for patients with moderate renal impairment (creatinine clearance 31-50 ml/min) is 300 mg twice daily, corresponding to a total daily dose of 600 mg (see section “Pharmacokinetics”).

Dose adjustment of the drug Lynparza^® for patients with mild renal impairment (creatinine clearance 51-80 ml/min) is not required.

Data on the use of the drug Lynparza^® in patients with severe renal impairment (creatinine clearance ≤30 ml/min) are not available, therefore the use of the drug in such patients is contraindicated.

Patients with hepatic impairment

Dose adjustment of the drug Lynparza^® in patients with mild hepatic impairment (Child-Pugh class A) is not required (see section “Pharmacokinetics”).

The use of the drug Lynparza^® in patients with moderate and severe hepatic impairment is contraindicated, as the efficacy and safety of olaparib in such patients have not been established.

Non-Caucasian patients

Clinical data on the use of the drug Lynparza^® in non-Caucasian patients are limited.

However, dose adjustment based on the ethnic origin of patients is not required (see section “Pharmacokinetics”).

Patients with performance status of 2 to 4

Clinical data on the use of the drug Lynparza^® in patients with a performance status of 2 to 4 are very limited.

Children

The safety and efficacy of the drug Lynparza^® in children and adolescents have not been established.

No data are available.

Tablets

Determination of mutations should be performed in a qualified laboratory using a validated test.

Maintenance monotherapy of newly diagnosed advanced ovarian cancer with BRCA mutations in patients must have a confirmed BRCA gene mutation – germline or somatic – before starting treatment with the drug Lynparza^®.

Metastatic HER2-negative breast cancer in patients must have a confirmed germline BRCA gene mutation before starting treatment with the drug Lynparza^®.

Maintenance therapy of metastatic pancreatic adenocarcinoma after first-line therapy in patients must have a confirmed germline BRCA gene mutation before starting treatment with the drug Lynparza^®.

Metastatic castration-resistant prostate cancer in the presence of mutations in genes involved in homologous recombination DNA repair in patients must have a confirmed mutation in genes involved in homologous recombination DNA repair (when testing DNA from a tumor tissue sample, circulating DNA from plasma, germline DNA from blood, or other non-tumor samples) before starting treatment with the drug Lynparza^®.

Lynparza^® is available as 100 mg and 150 mg film-coated 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 tablets are available for dose reduction if needed.

Duration of Therapy

Maintenance monotherapy for newly diagnosed advanced BRCA-mutated ovarian cancer: Treatment is recommended for up to 2 years or until disease progression. In case of complete response (absence of radiological evidence of disease), treatment should be discontinued after 2 years from initiation. If a partial response is maintained after 2 years of therapy, treatment may be continued beyond 2 years if the physician believes it may benefit the patient.

Platinum-sensitive relapsed ovarian cancer: Treatment is recommended until disease progression.

Maintenance monotherapy for newly diagnosed advanced ovarian cancer in combination with bevacizumab: Treatment is recommended for up to 2 years or until disease progression. In case of complete response (absence of radiological evidence of disease), treatment should be discontinued after 2 years from initiation. If a partial response is maintained after 2 years of therapy, treatment may be continued beyond 2 years if the physician believes it may benefit the patient. Dosing information for bevacizumab is provided in its prescribing information.

Metastatic HER2-negative breast cancer: Treatment is recommended until disease progression.

Maintenance therapy for metastatic pancreatic adenocarcinoma following first-line therapy: Treatment is recommended until disease progression.

Metastatic castration-resistant prostate cancer with homologous recombination repair gene mutations: Treatment is recommended until disease progression.

Important differences in dosing between Lynparza^® tablets and capsules

Lynparza^® is also available as 50 mg capsules. For dosing information regarding the capsules, please refer to the capsule prescribing information. Lynparza^® capsules (50 mg) must not be substituted for an equivalent dose of Lynparza^® tablets (100 mg and 150 mg) due to differences in the dosing and bioavailability of each formulation.

Missed Dose

If a dose is missed, the next prescribed dose should be taken at the usual time.

Dose Adjustment

Dose adjustment for adverse reactions

To manage adverse reactions, therapy may be interrupted and/or the dose reduced. The recommended reduced dose is 250 mg (one 150 mg tablet and one 100 mg tablet) taken twice daily (equivalent to a total daily dose of 500 mg).

If further dose reduction is required, the dose should be reduced to 200 mg (two 100 mg tablets) taken twice daily (equivalent to a total daily dose of 400 mg).

Dose adjustment for concomitant use with CYP3A inhibitors

Concomitant use of strong or moderate CYP3A inhibitors is not recommended; alternative agents should be considered. If concomitant use of a strong CYP3A inhibitor is necessary, the dose of Lynparza^® should be reduced to 100 mg (one 100 mg tablet) twice daily (equivalent to a total daily dose of 200 mg). If concomitant use of a moderate CYP3A inhibitor is necessary, the dose of Lynparza^® should be reduced to 150 mg (one 150 mg tablet) twice daily (equivalent to a total daily dose of 300 mg) (see sections “Drug Interactions” and “Special Instructions”).

Use in Special Patient Groups

Children

Lynparza^® is contraindicated in children and adolescents because safety and efficacy in this population have not been established.

Elderly patients (over 65 years)

No initial dose adjustment is required for elderly patients. Data on the use of olaparib in patients aged 75 years and older are limited.

Renal impairment

In 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^® is contraindicated in patients with severe renal impairment or end-stage renal disease (creatinine clearance ≤30 mL/min) because the safety and pharmacokinetics of olaparib have not been studied in these patients.

No dose adjustment is required for patients with mild renal impairment (creatinine clearance 51 to 80 mL/min).

Patients with hepatic impairment

Lynparza^® can be used in patients with mild or moderate hepatic impairment (Child-Pugh class A or B) without dose adjustment (see section “Pharmacokinetics”). Lynparza^® is contraindicated in patients with severe hepatic impairment (Child-Pugh class C) because its safety and pharmacokinetics have not been studied in these patients.

Method of Administration

For oral use. The tablets should be swallowed whole, not chewed, dissolved, crushed, or broken. Lynparza^® can be taken with or without food.

Adverse Reactions

Summary of the safety profile

Monotherapy with olaparib was commonly associated with laboratory abnormalities and/or clinical symptoms of mild or moderate severity (Grade 1 or 2 according to the Common Terminology Criteria for Adverse Events (CTCAE)), which generally did not require therapy discontinuation.

List of adverse reactions

The safety profile is based on pooled data from 2351 patients with solid tumors receiving Lynparza^® monotherapy and 535 patients receiving Lynparza^® monotherapy in combination with bevacizumab in clinical studies at the recommended dose.

The safety profile of Lynparza^® in combination with bevacizumab was consistent with the known safety profiles of each drug.

The following table lists adverse reactions by preferred term, grouped by system organ class, reported in completed Lynparza^® monotherapy clinical studies with known patient exposure. Within each system organ class, adverse reactions are listed in order of decreasing frequency and then decreasing severity. The following frequency conventions are used: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), including isolated reports.

Table 1. Adverse reactions reported in Lynparza^® monotherapy clinical studies

¹Anemia includes the preferred terms: anemia, macrocytic anemia, erythropenia, hematocrit decreased, hemoglobin decreased, normochromic anemia, normochromic normocytic anemia, normocytic anemia, and red blood cell count decreased; Neutropenia includes the preferred terms: agranulocytosis, febrile neutropenia, granulocyte count decreased, granulocytopenia, idiopathic neutropenia, neutropenia, neutropenic infection, neutropenic sepsis, and neutrophil count decreased; Thrombocytopenia includes the preferred terms: platelet count decreased, platelet production decreased, thrombocrit decreased, and thrombocytopenia; Leukopenia includes the preferred terms: leukopenia and white blood cell count decreased; Lymphopenia includes the preferred terms: B-lymphocyte count decreased, lymphocyte count decreased, lymphopenia, and T-lymphocyte count decreased; Cough includes the preferred terms: cough and productive cough; Rash includes the preferred terms: exfoliative rash, generalized erythema, erythematous rash, generalized rash, macular rash, maculo-papular rash, papular rash, and pruritic rash; Hypersensitivity includes the preferred terms: drug hypersensitivity and hypersensitivity; Dermatitis includes the preferred terms: dermatitis, allergic dermatitis, and exfoliative dermatitis; Dyspnea includes the preferred terms: dyspnea and exertional dyspnea; Stomatitis includes the preferred terms: aphthous ulcer, mouth ulceration, and stomatitis.

Description of selected adverse reactions

Hematological toxicity

Anemia and other hematological toxicities were generally of mild to moderate severity (CTCAE Grade 1 or 2), but Grade 3 and higher events were also reported. Anemia was the most frequently reported CTCAE Grade ≥3 adverse reaction in clinical studies and was typically first identified within the first 3 months of therapy. An exposure-response relationship was demonstrated between olaparib exposure and decreased hemoglobin levels. In Lynparza^® monotherapy clinical studies, the incidence of shifts (decreases) from baseline to CTCAE Grade ≥2 was approximately 23% for hemoglobin, 19% for absolute neutrophil count, 6% for platelet count, 29% for lymphocyte count, and 20% for white blood cell count (all values approximate).

The incidence of an increase in mean corpuscular volume from a low or normal baseline to above the upper limit of normal was approximately 55%. The value returned to normal after discontinuation of therapy without apparent clinical consequences.

A complete blood count is recommended prior to initiating therapy, to be repeated monthly for the first 12 months of therapy and periodically thereafter to monitor for clinically significant changes in hematological parameters during treatment, which may require therapy interruption or dose reduction and/or additional treatment (see sections “Dosage and Administration” and “Special Instructions”).

Other laboratory abnormalities

In Lynparza^® clinical studies, the incidence of shifts (increases) to CTCAE Grade ≥2 for blood creatinine was approximately 11%. Data from a double-blind, placebo-controlled study showed that the median increase in blood creatinine of up to 23% from baseline remained constant over time; the value returned to baseline after therapy discontinuation without apparent clinical consequences. At baseline, 90% of patients had CTCAE Grade 0 and 10% had CTCAE Grade 1 for increased blood creatinine.

Nausea and vomiting

Nausea typically occurs very early, appearing in most patients within the first month of Lynparza^® therapy. Vomiting also occurs early, appearing in most patients within the first two months of Lynparza^® therapy. In most patients, nausea and vomiting occur intermittently.

Contraindications

• Hypersensitivity to olaparib or to any of the excipients;
• Severe renal impairment;
• Severe hepatic impairment (Child-Pugh class C);
• Pregnancy and breastfeeding (during therapy and for 1 month after the last dose);
• Children and adolescents under 18 years of age (efficacy and safety have not been established).

With caution

Concomitant use with strong inducers or inhibitors of cytochrome CYP3A isoenzymes, moderate renal impairment.

Use in Pregnancy and Lactation

Olaparib is contraindicated during pregnancy due to its teratogenic and genotoxic potential. Pregnancy should also be avoided in female partners of male patients taking Lynparza^®. No studies have been conducted in pregnant women.

If pregnancy occurs in a female patient or in the female partner of a male patient during Lynparza^® treatment, the patient should be informed of the potential risk to the fetus and the potential risk of spontaneous abortion (see section “Special Instructions”).

Contraception and pregnancy testing

Women of childbearing potential must use effective contraception during therapy and for 1 month after the last dose of Lynparza^® (see section “Special Instructions”). A pregnancy test should be performed in all women of childbearing potential prior to initiating therapy, and repeated regularly during therapy and 1 month after the last dose.

It is not known whether olaparib or its metabolites are excreted in semen. Male patients should use a condom when having sexual intercourse with pregnant women or women of childbearing potential during therapy and for 3 months after the last dose of Lynparza^®. Female partners of male patients should also use effective contraception if they are of childbearing potential (see section “Special Instructions”). Male patients should not donate sperm during therapy and for 3 months after the last dose of Lynparza^®.

Breastfeeding period

There are no data on the use of Lynparza^® during breastfeeding. Studies on the excretion of olaparib into human or animal milk have not been conducted. A risk to breastfed infants cannot be excluded. Lynparza^® is contraindicated during breastfeeding and for 1 month after the last dose (see section “Contraindications”).

Use in Hepatic Impairment

Contraindication: severe hepatic impairment (Child-Pugh class C).

Use in Renal Impairment

Contraindication: severe renal impairment.

Pediatric Use

Contraindication: children and adolescents under 18 years of age.

Geriatric Use

No initial dose adjustment is required for elderly patients. Data on the use of olaparib in patients aged 75 years and older are limited.

Special Precautions

Hematological toxicity

Cases of hematological toxicity, including clinical and laboratory signs of anemia, neutropenia, thrombocytopenia, and lymphopenia, generally of mild or moderate severity (CTCAE Grade 1 or 2), have been reported in patients receiving olaparib. Patients should not start Lynparza^® therapy until they have recovered from hematological toxicity caused by previous anticancer therapy (hemoglobin level, platelet count, and neutrophil count should be within CTCAE Grade 1). A complete blood count is recommended prior to initiating therapy, to be repeated monthly for the first 12 months of therapy and periodically thereafter to monitor for clinically significant changes in hematological parameters during treatment (see section “Adverse Reactions”).

If a patient develops severe hematological toxicity or becomes dependent on frequent blood transfusions, Lynparza^® therapy should be interrupted and appropriate hematological investigation performed. If hematological abnormalities persist for 4 weeks after discontinuing Lynparza^®, a bone marrow examination and/or cytogenetic analysis of peripheral blood is recommended.

Myelodysplastic syndrome/Acute myeloid leukemia

The frequency of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) in patients receiving Lynparza^® monotherapy in clinical studies, including long-term follow-up, was less than 1.5%; most cases were fatal. All patients had predisposing factors for developing MDS/AML. All patients had received prior platinum-containing chemotherapy, and many had also received other DNA-damaging agents. Most MDS/AML cases were observed in carriers of germline BRCA mutations; some patients had another primary malignancy or a history of bone marrow dysplasia. If MDS/AML is confirmed during Lynparza^® therapy, it is recommended to discontinue Lynparza^® and provide the patient with appropriate therapy.

Pneumonitis

Pneumonitis was reported in less than 1% of patients receiving Lynparza^® as monotherapy in clinical studies. Reports of pneumonitis did not have a uniform clinical presentation. Establishing a causal relationship was difficult due to the presence of multiple predisposing factors (lung cancer and/or lung metastases, underlying lung disease, history of smoking, and/or prior chemotherapy and radiation therapy). Cases of pneumonitis with fatal outcome have been observed when Lynparza^® was used in combination with other anticancer drugs. If a patient experiences new or worsening respiratory symptoms, such as dyspnea, cough, and fever, or if radiographic changes are detected, therapy with Lynparza^® should be interrupted and further investigation should be promptly conducted. If pneumonitis is confirmed, therapy with Lynparza^® should be discontinued and appropriate treatment initiated.

Embryo-fetal Toxicity

Due to its mechanism of action (PARP inhibition), Olaparib can cause fetal harm when administered to a pregnant woman. Preclinical studies have shown that Olaparib adversely affects embryo-fetal survival in rats and induces serious fetal malformations at exposures below those expected in humans at the recommended dose of 300 mg twice daily.

The use of Lynparza^® during pregnancy is contraindicated. If pregnancy occurs while a woman is taking Lynparza^®, she should be informed of the potential risk to the fetus. Women of childbearing potential should use effective contraception during therapy and for 1 month after the last dose of Lynparza^®. Men taking Lynparza^® and their female partners of childbearing potential should use effective contraception during therapy and for 3 months after the last dose (see section “Pregnancy and Lactation”).

Breastfeeding Period

Studies on the excretion of olaparib into animal or human breast milk have not been conducted. The use of Lynparza^® is contraindicated during breastfeeding and for 1 month after the last dose (see section “Pregnancy and Lactation”).

Drug Interactions

Concomitant use of Lynparza^® with strong or moderate inhibitors of cytochrome CYP3A isoenzymes is not recommended (see section “Drug Interactions”). If the use of a strong or moderate inhibitor of cytochrome CYP3A isoenzymes is necessary, the dose of Lynparza^® should be reduced (see section “Dosage and Administration”).

Concomitant use of Lynparza^® with strong or moderate inducers of cytochrome CYP3A isoenzymes is not recommended. If a patient already receiving Lynparza^® requires therapy with a strong or moderate CYP3A inducer, the possibility of a significant reduction in the clinical effect of Lynparza^® should be considered (see section “Drug Interactions”).

Effect on Ability to Drive and Operate Machinery

Studies on the effect of olaparib on the ability to drive and operate machinery have not been conducted. Asthenia, fatigue, and dizziness may occur during the use of Lynparza^®; patients with such symptoms should exercise caution when driving and operating machinery.

Overdose

Symptoms of Lynparza^® overdose have not been established.

Treatment There is no specific antidote. In case of overdose, general supportive measures and symptomatic treatment should be provided.

Drug Interactions

Clinical studies of olaparib in combination with other anticancer drugs, including DNA-damaging agents, indicate potentiation and prolongation of myelosuppressive toxicity. The dose of Lynparza^® recommended for monotherapy is not suitable for combination use with other myelosuppressive anticancer drugs.

Effect of Other Drugs on Olaparib

Strong and Moderate Inhibitors of CYP3A Isoenzymes

Metabolism of olaparib occurs primarily via cytochrome CYP3A4/5 isoenzymes. Concomitant administration of olaparib with the strong CYP3A inhibitor itraconazole increased the mean C_max of olaparib by 42% and the mean AUC by 170%. Therefore, concomitant use of itraconazole, as well as other strong CYP3A inhibitors such as telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir, with Lynparza^® is not recommended (see section “Special Instructions”).

According to physiologically based pharmacokinetic modeling, concomitant use with moderate inhibitors of CYP3A isoenzymes slows the clearance of olaparib. Therefore, concomitant use of olaparib with moderate inhibitors of CYP3A isoenzymes, including ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil, is not recommended (see section “Special Instructions”).

In cases where concomitant use with a strong or moderate CYP3A inhibitor is required, the dose of Lynparza^® should be reduced (see section “Dosage and Administration”). Furthermore, consumption of grapefruit juice, as it is a CYP3A inhibitor, is not recommended during therapy with Lynparza^®.

Strong and Moderate Inducers of CYP3A Isoenzymes

Concomitant use of olaparib with rifampicin, a strong CYP3A inducer, decreased the C_max of olaparib by 71% and the AUC by 87%. Due to the potential for a significant reduction in the efficacy of Lynparza^® when used concomitantly with strong CYP3A inducers, including phenytoin, rifabutin, rifampin (rifampicin), carbamazepine, nevirapine, phenobarbital, St. John’s wort preparations, etc., their concomitant use is not recommended (see section “Special Instructions”).

According to physiologically based pharmacokinetic modeling, concomitant use with moderate inducers of CYP3A isoenzymes reduces the AUC of olaparib by 60%. Therefore, due to the potential for a significant reduction in the efficacy of Lynparza^® when used concomitantly with moderate CYP3A inducers, including bosentan, efavirenz, etravirine, modafinil, nafcillin, etc., their concomitant use is not recommended. If the use of a moderate CYP3A inhibitor is necessary, the possible decrease in the clinical efficacy of Lynparza^® should be considered (see section “Special Instructions”).

Effect of Olaparib on Other Drugs

Interactions Mediated by CYP Isoenzymes

In vitro, Olaparib has been shown to both inhibit and induce the CYP3A4 isoenzyme. However, physiologically based pharmacokinetic modeling data and clinical data indicate that the net effect is weak inhibition of the CYP3A4 isoenzyme in vivo. Therefore, caution is advised when using sensitive CYP3A substrates or substrates with a narrow therapeutic index (e.g., simvastatin, cisapride, cyclosporine, ergot alkaloids, fentanyl, pimozide, sirolimus, tacrolimus, and quetiapine) concomitantly with Lynparza^®. For patients receiving substrates of CYP3A with a narrow therapeutic index concomitantly with olaparib, appropriate clinical monitoring is recommended.

In vitro conditions demonstrated induction of CYP1A2 and 2B6, with the highest likelihood of clinically significant induction for the CYP2B6 isoenzyme. Therefore, concomitant use with Lynparza^® may reduce the exposure of substrates of these metabolic enzymes.

Interactions with Drug Transporter Proteins

In vitro, Olaparib has been shown to inhibit OATP1B1, OCT1, OCT2, OAT3, MATE1, and MATE2K. The clinical significance of this is unknown. However, it cannot be excluded that Olaparib may increase the exposure of 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 when prescribing Olaparib concomitantly with any drug from the statin group.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life when manufactured at AbbVie Deutschland GmbH & Co. KG (Germany) is 3 years, and at AbbVie Ltd. (Puerto Rico) is 2 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.