Linparza, 150 mg 56 pcs.

Pharmacotherapeutic group:
antitumor drug

ATX code:
L01XX46

Pharmacological properties

Pharmacodynamics

Pharmacodynamic properties

Olaparib is a potent inhibitor of human poly(ADP-ribose)-polymerase (PARP) PARP-1, PARP-2 and PARP-3 enzymes. Olaparib in monotherapy and in combination with conventional chemotherapeutic drugs has been shown to inhibit the growth of certain tumor cell lines in vitro and tumor growth in vivo.

PARP enzymes are required for efficient repair of single-strand breaks of deoxyribonucleic acid (DNA). PARP-induced repair requires that, after chromatin modification, PARP must self-modify and detach from the DNA to open access for basic excision repair enzymes to the site of the break.

When olaparib binds to the active site of the DNA-bound PARP enzyme, it prevents PARP from detaching and fixes it to DNA, thereby blocking repair. In dividing cells, this causes the replication fork to stop at the location of the PARP-DNA complex and leads to double-stranded DNA breaks.

In normal cells, double-stranded DNA breaks are repaired by homologous recombination. In tumor cells lacking functional components of repair by homologous recombination, such as BRCA1 or BRCA2, double-stranded DNA breaks cannot be accurately and efficiently repaired by homologous recombination.

Instead, repair is carried out by alternative pathways, such as nonhomologous end joining, associated with introducing a large number of errors into the DNA, which increases genomic instability.

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

In the absence of mutations in the BRCA1 or BRCA2 genes, DNA repair through homologous recombination can be disrupted by other mechanisms, although the resulting abnormalities and their manifestations are not fully known.

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

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

Effect on the QT interval

Multiple administration of olaparib at a dose of 300 mg twice daily had no clinically significant effect on myocardial repolarization (based on no effect on the QT interval).

Pharmacokinetics

The pharmacokinetics of olaparib in tablets at the 300 mg dose is characterized by an apparent plasma clearance of approximately 7 L/hour, an apparent distribution volume of approximately 158 L and a half-life of 15 hours. AUC (area under the concentration-time curve) of 1.8 was observed with repeated administration, and pharmacokinetics appeared to be slightly time-dependent.

Absorption

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

Simultaneous intake of the drug with food slowed down absorption rate (time to reach maximum concentration (tmax) increased by 2.5 hours, and maximum concentration (Cmax) decreased by approximately 21%), but did not significantly affect absorption rate of olaparib (therapeutic range AUC: 1.08; 90% confidence interval (CI) 1.01; 1.16). Therefore, Linparza® can be taken independently of meals (see section “Dosage and administration”).

Distribution

Under in vitro conditions the binding of olaparib to plasma proteins is approximately 82% at its plasma concentration of 10 µg/ml, which approximately corresponds to Cmax. In vitro, the degree of binding of olaparib 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 70% at 40 µg/ml.

In purified protein solutions, the albumin-bound fraction of olaparib was approximately 56% and was independent of the 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 trend toward less binding at higher concentrations.

Metabolism

In vitro it has been shown that the main enzymes involved in the metabolism of olaparib are cytochrome P450 CYP3A4/5 isoenzymes.

After oral administration of 14C-olaparib by female patients, most of the radioactivity in plasma was due to unchanged olaparib (70%); it was also the major component detected in urine and feces (15% and 6% of the dose taken, respectively).

Olaparib undergoes a large number of metabolic transformations in the body, which most commonly involve the piperazine and fluorobenzyl rings, mainly by oxidation to form a number of derivatives, which subsequently undergo glucuronide or sulfate conjugation.

Up to 20, 37, and 20 metabolites were detected in plasma, urine, and feces, respectively, most of which were less than 1% of the drug ingested.

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

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

Olaparib inhibited UGT1A1 in vitro, but physiologically valid pharmacokinetic modeling indicates that this phenomenon is not clinically significant.

According to the results of 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, glycoprotein P (IC50 = 76μM), but this fact is probably not clinically relevant.

The results of in vitro studies also showed that olaparib is not a substrate of OATP1B1, OATP1BZ, OCT1, BCRP or MRP2, is a weak inhibitor of BCRP and is not an inhibitor of OATP1BZ, OAT1 or MRP2.

Excretion

After a single administration of 14;C-olaparib, approximately 86% of the total radioactivity was excreted within 7 days, approximately 44% by the kidneys and 42% through the intestine. Most of the administered dose was excreted as metabolites.

Pharmacokinetics in special patient groups

In population pharmacokinetic analyses, age, sex, body weight, or race (including patients of Caucasian race and patients of Japanese origin) had no significant effect on the pharmacokinetics of olaparib.

Renal dysfunction

In patients with mild renal dysfunction (creatinine clearance of 51 to 80 ml/min) after a single oral administration of 300 mg olaparib the AUC was increased by 24% and Cmax by 15% compared to patients with normal renal function. In patients with mild renal dysfunction a dose adjustment of Linparase® preparation is not required.

In patients with moderate renal dysfunction (creatinine clearance from 31 to 50 ml/min) AUC was increased by 44% and Cmax by 26% if compared to patients with normal renal function after a single use of oral 300 mg olaparib.

In patients with moderate renal dysfunction it is recommended to adjust the dose of Linparase® (see section “Dosage and administration”).

Use of olaparib in patients with severe renal dysfunction or terminal renal failure (creatinine clearance ≤30 ml/min) has not been studied.

Hepatic impairment

In patients with mild hepatic impairment (grade A on the Child-Pugh scale) AUC was increased by 15% and Cmax by 13%; In patients with liver dysfunction of moderate severity (Child-Pugh class B) AUC was increased by 8% and Cmax was decreased by 13% compared to patients with normal liver function.

In patients with liver dysfunction of mild to moderate severity, no dose adjustment of Linparza® is required (see section “Dosage and administration”). The use of olaparib in patients with severe hepatic impairment (Child-Pugh class C) has not been studied.

Indications

Ovarian Cancer
Linparza® is indicated as monotherapy:

Breast cancer
Linparza® is indicated as monotherapy:

Composition

How to take, the dosage

Interaction

Clinical studies of olaparib in combination with other antitumor drugs, including DNA-damaging drugs, have shown potentiation and prolongation of myelosuppressive toxicity.

The dose of Linparza® recommended for monotherapy is not appropriate for combination with other myelosuppressive antitumor drugs.

The effect of other drugs on olaparib

Powerful and moderate inhibitors of CYP3A isoenzymes

The metabolism of olaparib is primarily through cytochrome CYP3A4/5 isoenzymes. Concomitant use of olaparib with the potent CYP3A inhibitor itraconazole increased the mean Cmax of olaparib by 42% and the mean AUC by 170%.

Hence it is not recommended to coadminister itraconazole as well as other potent CYP3A inhibitors such as telithromycin, clarithromycin, protease inhibitors enhanced by ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir et al, with the drug Linparza® (see section “Special Indications”).

According to physiologically based pharmacokinetic modeling data, coadministration with moderate CYP3A isoenzyme inhibitors slows down the clearance of olaparib. Therefore, co-administration of olaparib with moderate CYP3A isoenzyme inhibitors such as Ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil, etc. is not recommended (see section “Special indications”).

In cases when concomitant use with a potent or moderate CYP3A inhibitor is required, the dose of the drug Linparza® should be reduced (see section “Dosage and administration”). In addition, grapefruit juice should not be consumed during therapy with Linparza® because it is a CYP3A inhibitor.

Powerful and moderate inducers of CYP3A isoenzymes

In co-administration of olaparib with rifamgscin, a potent inducer of CYP3A, the Cmax of olaparib was reduced by 71% and the AUC by 87%.

Because of the possibility of significant decrease of efficacy of the drug Linparza® when used together with potent CYP3A inducers such as phenytoin, rifabutin, rifampin (rifampicin), carbamazepine, nevirapine, phenobarbital, preparations of Saint John’s wort, etc, their combined use is not recommended (see section “Special Indications”).

According to physiologically based simulations of pharmacokinetics, co-administration with moderate inducers of CYP3A isoenzymes reduces the AUC of olaparib by 60%.

Hence, due to the potential for significant reduction in efficacy of Linparza® when co-administered with moderate CYP3A inducers such as bosentan, efavirenz, etravirine, modanafil, nafcillin, etc., their co-administration is not recommended.

If a moderate CYP3A inhibitor is required, the potential decrease in the clinical effectiveness of Linparza® should be kept in mind (see section “Special Precautions”).

The effect of olaparib on other drugs

In vitro interactions mediated by CYP isoenzyme

In vitro it was shown that olaparib can both inhibit and induce CYP3A4 isoenzyme. However, data from physiologically based pharmacokinetic modeling and clinical data indicate that the resulting effect is weak inhibition of the CYP3A4 isoenzyme in vivo.

In this regard, caution should be exercised when using sensitive CYP3A substrates or substrates with a narrow therapeutic range (e.g. simvastatin, cisapride, cyclosporine, ergot alkaloids, fentanyl, pimozide, sirolimus, tacrolimus and quetiapine) with Linaparza. For patients who receive CYP3A substrates with a narrow therapeutic range concomitantly with olaparib, appropriate clinical monitoring is recommended.

In in vitro conditions, induction of CYP1A2 and 2B6 has been demonstrated, with the CYP2B6 isoenzyme being the most likely to be clinically significant. Therefore, concomitant use with Linparza® may decrease the exposure of substrates of these metabolic enzymes.

Interactions with drug transporter proteins

It has been shown that under in vitro conditions olaparib can inhibit OATP1B1, OST1, OST2, OATZ, MATE1 and MATE2K. The clinical significance of this phenomenon is unknown.

. However, it cannot be excluded that olaparib may increase exposure to the substrates OATP1B1 (e.g., bosentan, glibenclamide, repaglinide, statins and valsartan), OAT1 (e.g., metformin), OAT2 (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.

Special Instructions

Hematologic toxicity

Hematologic toxicity, including clinical and laboratory signs of anemia, neutropenia, thrombocytopenia and lymphopenia, usually of mild to moderate severity (STSAE grade 1 or 2) has been reported in patients receiving olaparib.

Patients should not initiate therapy with Linparza® until they have recovered from hematologic toxicity caused by prior antitumor therapy (hemoglobin concentration, platelet count and neutrophil count should be within grade 1 STSAE severity).

It is recommended that a clinical blood count be performed prior to initiating therapy, repeated monthly for the first 12 months of therapy and periodically thereafter to monitor clinically significant changes in hematologic parameters during treatment (see section “Adverse effects”).

If a patient has severe hematologic toxicity or is dependent on frequent hemotransfusions, therapy with Linparza® should be suspended and appropriate hematologic testing performed.

If abnormal hematologic parameters persist 4 weeks after discontinuation of Linparz® , bone marrow and/or cytogenetic blood tests are recommended.

Myelodysplastic syndrome/acute myeloleukemia

The incidence of myelodysplastic syndrome/acute myeloleukemia (MDS/OML) in patients treated with Linparza® as monotherapy in clinical trials, including long-term follow-up, was less than 1.5%; most cases ended in death. All patients had predisposing factors for the development of MDS/OML.

All patients had previously received platinum-containing chemotherapy, and many had also received other DNA-damaging drugs. Most cases of MDS/OML were seen in carriers of germinal BRCA gene mutations, and some patients had a history of other primary malignancy or bone marrow dysplasia.

If the presence of MDS/OML is confirmed during therapy with Linparza®, it is recommended that Linparza® be withdrawn and the patient be given appropriate therapy.

Pneumonitis

Pneumonitis has been reported in less than 1% of patients treated with Linparza® as monotherapy in clinical trials. Reports of pneumonitis did not have a consistent clinical picture.

The identification of a causal relationship was difficult due to the presence of multiple predisposing factors (cancer and/or lung metastases, background lung disease, a history of smoking and/or prior chemotherapy and radiation therapy).

When using Linparza® in combination with other antitumor drugs there have been cases of fatal pneumonitis. If new symptoms or worsening of existing respiratory symptoms, such as dyspnea, cough, and fever, or changes on x-ray examination are noted in a patient, therapy with Linparza® should be stopped and a further investigation should be performed immediately.

If the diagnosis of pneumonitis is confirmed, treatment with Linparza® should be discontinued and appropriate therapy should be started.

Embryophyte toxicity

Owing to its mechanism of action (PARP inhibition) olaparib may cause fetal growth disorders if the drug is taken by a pregnant woman.

Preclinical studies have shown that olaparib has adverse effects on fetal survival in rats and induces severe fetal malformations at exposures below those expected in humans when the drug is used at the recommended dose of 300 mg twice daily.

The use of Linparza® during pregnancy is contraindicated. If a woman is pregnant when taking Linparza® she should be informed about the possible risk to the fetus. Women with preserved reproductive function should use effective contraception during therapy and for 1 month after the last dose of Linparza®.

Men who take Linparza® and their fertile female partners should use effective contraception during therapy and for 3 months after the last dose of the drug (see section “Use during pregnancy and breastfeeding”).

Breast-feeding period

There have been no studies on the excretion of olaparib into the breast milk of animals or women. Administration of Linparza® is contraindicated during breastfeeding and within 1 month after the last drug administration (see section “Administration during pregnancy and breastfeeding”).

Interaction with other medicinal products

The co-administration of Linparza® with potent or moderate inhibitors of cytochrome CYP3A isoenzymes is not recommended (see section “Interaction with other medicinal products”). If the use of a potent or moderate inhibitor of cytochrome CYP3A isoenzymes is necessary, the dose of the drug Linparza® should be reduced (see section “Dosage and administration”).

The co-administration of Linparza® with potent or moderate inducers of CYP3A cytochrome isoenzymes is not recommended. If a patient who is already receiving Linparza® requires therapy with a potent or moderate CYP3A inducer, the possibility of significant reduction of the clinical effect of Linparza® should be kept in mind (see section “Interaction with other medicinal products”).

Contraindications

Co-administration with potent inducers or inhibitors of cytochrome CYP3A isoenzymes, moderate renal function impairment.

Overdose

Pregnancy use