Olaparib

434.469

434.46

1308068-626-2

WOH1JD9AR8

747856

C71721

L01XX46|L - Antineoplastic and immunomodulating agents

29339900

82.1

1.9

1.4±0.1 g/cm3

1.702

IRRITANT

22-38-37-36

24/25-37/39

P201, P202, P260, P264, P270, P281, P301+P310, P308+P313, P314, P321, P330, P405, P501

H301

|Danger|H301 (71.43%): Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P260, P261, P264, P270, P271, P280, P281, P301+P310, P302+P352, P304+P340, P305+P351+P338, P308+P313, P312, P314, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 7 companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The most commonly reported side effects reported during clinical trials included cough, constipation, dysgeusia, peripheral deem, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash. Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) was reported in 2% of patients with deleterious or suspected deleterious germline BRCA-mutated advanced cancers. The majority of cases were fatal and the duration of therapy with olaparib in patients who developed secondary cancers varied from 2 years. Complete blood count should be tested at baseline and monthly following therapy initiation to monitor for MDS/AML. Pneumonitis, including fatal cases, occurred in <1% of patients treated with olaparib. Patients should be monitored for new or worsening respiratory symptoms such as dyspnea, fever, cough, or wheezing. Olaparib was found to be teratogenic and causes embryo-fetal toxicity in rats. It should, therefore, be avoided during pregnancy and its use should be combined with effective contraception during treatment.

In large clinical trials of olaparib, abnormalities in routine liver tests were uncommon with serum aminotransferase elevations occurring in 4% of patients and values above 5 times the upper limit of normal (ULN) in 1% or less. In trials of olaparib in patients with various advanced solid tumors there were no reports of hepatitis with jaundice or liver failure. Subsequent to its approval and more widescale use, there have been no published reports of clinically apparent liver injury attributed to olaparib.

_In vitro_ studies have reported that the plasma protein binding of olaparib was reported to be of 82%.

Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for the treatment of: (I) Ovarian cancer, in which the medication is intended for [a] the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy, or [b] for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for olaparib. [II] Breast cancer, in which the medication is intended for use in patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have previously 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 treatment. Select patients for therapy based on an FDA-approved companion diagnostic for olaparib.|FDA Label|Ovarian cancerLynparza is indicated as monotherapy for the:maintenance treatment of adult patients with advanced (FIGO stages III and IV) BRCA1/2-mutated (germline and/or somatic) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy.maintenance treatment of adult patients with platinum sensitive relapsed high grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum based chemotherapy.Lynparza in combination with bevacizumab is indicated for the:maintenance treatment of adult patients with advanced (FIGO stages III and IV) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy in combination with bevacizumab and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either a BRCA1/2 mutation and/or genomic instability (see section 5.1).Breast cancerLynparza is indicated as monotherapy for the treatment of adult patients with germline BRCA1/2-mutations, who have HER2 negative locally advanced or metastatic breast cancer. Patients should have previously been treated with an anthracycline and a taxane in the (neo)adjuvant or metastatic setting unless patients were not suitable for these treatments (see section 5.1).Patients with hormone receptor (HR)-positive breast cancer should also have progressed on or after prior endocrine therapy, or be considered unsuitable for endocrine therapy.Adenocarcinoma of the pancreasLynparza is indicated as monotherapy for the maintenance treatment of adult patients with germline BRCA1/2-mutations who have metastatic adenocarcinoma of the pancreas and have not progressed after a minimum of 16 weeks of platinum treatment within a first-line chemotherapy regimen.Prostate cancerLynparza is indicated as monotherapy for the treatment of adult patients with metastatic castration-resistant prostate cancer and BRCA1/2-mutations (germline and/or somatic) who have progressed following prior therapy that included a new hormonal agent.Lynparza is indicated as monotherapy for the maintenance treatment of adult patients with platinum sensitive relapsed BRCA mutated (germline and/or somatic) high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete response or partial response) to platinum based chemotherapy. |Treatment of all conditions included in the category of malignant neoplasms (except central nervous system tumours, haematopoietic and lymphoid tissue neoplasms)|Drug: Olaparib

Olaparib is a small molecule inhibitor of poly ADP-ribose polymerase and is used as an antineoplastic agent in the therapy of refractory and advanced ovarian carcinoma. Olaparib therapy is associated with a low rate of transient elevations in serum aminotransferase during therapy and has not been linked to instances of clinically apparent liver injury.

Antineoplastic Agents

The effect of olaparib on cardiac repolarization was assessed in 119 patients following a single dose of 300 mg and in 109 patients following multiple dosing of 300 mg twice daily. No clinically relevant effect of olaparib on QT interval was observed.

Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)|Chemicals and drugs that inhibit the action of POLY(ADP-RIBOSE)POLYMERASES. (See all compounds classified as Poly(ADP-ribose) Polymerase Inhibitors.)

Following oral administration, the absorption of olaparib is very rapid and can reach a peak concentration ranging between 4.7 and 9.1 mcg/ml after 1-3 hours. The reported AUC of olaparib after a dose of 200 mg is of 25.8 mcg.h/L and this AUC can be increased by 26% with constant administration. The consumption of a high-fat diet with olaparib can only decrease the tmax but do not have an effect in the peak concentration.|From the administered dose, approximately 86% of the administered dose is recovered after 7 days from which 44% is found in the urine and 42% is obtained in feces.|After administration of a dose of 100 mg/kg, the reported volume of distribution was of 40.3 L.|The total clearance of olaparib was reported to be 4.6 L/h.

Olaparib is extensively metabolized in the liver by the action of CYP3A isoenzymes. From the administered dose, the unchanged form of olaparib accounted for 70% of the circulating dose and it was considered the major component in urine and feces. The metabolic pathway of olaparib is mainly attributable to oxidation reactions with subsequent glucuronide and sulfate conjugation. However, the over 20 metabolites found in plasma, urine, and feces represented a minor portion of the administered dose. The major circulating metabolites were represented by the mono-oxygenated form and the piperazin-3-ol form.

The reported elimination half-life ranges between 5 to 11 hours.

Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular homeostasis, such as DNA transcription, cell cycle regulation, and DNA repair. Olaparib has been shown to inhibit growth of select tumor cell lines in vitro and decrease tumor growth in mouse xenograft models of human cancer both as monotherapy or following platinum-based chemotherapy. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in disruption of cellular homeostasis and cell death.

AZD 2281

Human drugs -> Lynparza -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human drugs -> Rare disease (orphan)|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients