Lipparza - instructions for use, dose, side effects, contraindications

Active substanceOlaparibOlaparib

Similar drugsTo uncover

Lynparza

capsules inwards

AstraZeneca UK Ltd United Kingdom

Dosage form: & nbspTOthe apsules.

Composition:

One capsule contains:

Active substance: olaparib 50 mg

Excipients: lauryl macrogol-32 glycerides 450 mg; hypromellose capsule shell: hypromellose 93 mg, titanium dioxide 1.8 mg, gellan gum 0.3 mg, potassium acetate 0.2 mg;

ink for inscription on the capsule shell: shellac 0.1 mg *, iron dye oxide black 0.05 mg *, ethanol q.s**, isopropanol q.s**, N-Butanol q.s**, propylene glycol q.s**, ammonia water 28% q.s**.

* Estimated amount.

** Removed during production.

Description:

Capsules from white to almost white, size No. 0, with the inscription "OLAPARIB 50 mgand logo AstraZeneca ( ), deposited in black ink.

Pharmacotherapeutic group:antitumor agent

ATX: & nbsp

L.01.X.X Other antineoplastic agents

L.01.X.X.46 Olaparib

Pharmacodynamics:

Mechanism of action and pharmacodynamic effects

Lingparase is a potent inhibitor of poly (ADP-ribose) -polymerase (PARP) PARP-1, PARP-2 and PARP-3. It has been shown that Lynparz in monotherapy and in combination with traditional chemotherapeutic drugs inhibits the growth of certain tumor cell lines in vitro and tumor growth in vivo.

Enzymes PARP are required for effective repair of single-strand breaks of deoxyribonucleic acid (DNA). For PARP-induced repair it is necessary that after the modification of the chromatin PARP independently changed and separated from DNA to open access to enzymes of basic excision repair to the site of the rupture. When Lingparza binds to the active site of the enzyme PARP, associated with DNA, it prevents detachment PARP and fixes it on DNA, thereby blocking the repair. In dividing cells, this causes the replication plug to stop at the location PARP-DNA complex and to the occurrence of double-strand DNA ruptures. In normal cells, repair by homologous recombination, for which functional genes are required BRCA1 and BRCA2, is effective in the repair of these double-strand DNA ruptures. In the absence of functional genes BRCA1 or BRCA2 double-strand breaks of DNA can not be repaired by homologous recombination. Instead, reparation is carried out by alternative routes, such as a non-homologous termination of the ends, associated with the risk of a large number of errors, which increases genomic instability. After several replications, genomic instability can reach unacceptable levels and lead to the death of tumor cells, as they are exposed to more DNA damage than normal cells.

On in vivo models with a deficit BRCA, olaparib, used after therapy with platinum, led to a delay in the progression of the tumor and increased overall survival compared with platinum-only therapy.

Determination of gene mutation BRCA

Lingparz preparation can be prescribed to patients if they have a confirmed or supposedly "damaging" germinal (hereditary) gene mutation BRCA (ie, a mutation that disrupts the normal functioning of the gene in the cells and tissues of the whole organism) or a somatic mutation in tumor cells (determined by an appropriate validated test).

Pharmacokinetics:

The pharmacokinetics of olaparib 400 mg twice a day in capsules is characterized by an apparent plasma clearance of about 8.6 l / h, an apparent volume distribution of about 167 liters and a half-life of 11.9 hours.

Absorption

After oral administration of olaparib in capsules, absorption is rapid, the maximum plasma concentration (FROM_mOh) usually achieved 1-3 hours after admission. With multiple application of the drug, equilibrium exposures are reached after about 3-4 days, no appreciable cumulation is observed.Simultaneous reception of the drug with food slowed down the rate of absorption (time to reach the maximum concentration (t_mOh) increased by 2 hours) and slightly increased the absorption of olaparib (the area under the pharmacokinetic curve (AUC) increased by approximately 20%). Therefore, it is recommended to take the drug Lingparza, at least 1 hour after eating, and refrain from eating for the next 2 hours (see section "Method of administration and dose").

Distribution

In conditions in vitro the binding of olaparib to plasma proteins is approximately 82% at plasma concentrations achieved with the administration of olaparib 400 mg twice daily.

Metabolism

In vitro, cytochrome P450 isoenzyme 3A4 (CYP3A4) is the main enzyme involved in the metabolism of olaparib. After oral administration ¹⁴C-olaparib by the patients the bulk of the radioactivity in the blood plasma was due to unchanged olaparib (70%), which was the main component found in urine and feces (15% and 6% of the dose, respectively). The metabolism of olaparib proceeds intensively, mainly by oxidation with the formation of a number of components that are subsequently subjected to glucuronide or sulfate conjugation.Up to 20, 37 and 20 metabolites were detected in plasma, urine and feces, respectively, most of them were less than 1% of the received drug. The open-ring hydroxycyclopropyl compound and two monooxidized metabolites (each of the order of 10%) were the main circulating metabolites in the blood, with one of the monooxidized metabolites also being the main metabolite found in urine and feces (6% and 5% radioactivity, respectively).

In vitro, olaparib did not inhibit or caused minimal inhibition of cytochrome isoenzymes CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 or 2E1, and is not expected to be a clinically relevant, time-dependent inhibitor of any of the cytochrome P450 isoenzymes. Research results in vitro They also showed that olaparib is not a substratum of OATP1B1, OATP1B3, OST1, BCRP or MRP2 and is not an inhibitor of OATP1B3, OAT1 or MRP2.

Excretion

After a single dose ¹⁴C-olaparib about 86% of the total radioactivity was excreted for 7 days, about 44% by the kidneys and 42% by the intestine. Basically, the drug was taken in the form of metabolites.

Pharmacokinetics in specific patient groups

Impaired renal function

The effect of renal dysfunction on the exposure of olaparib has not been studied. Olaparib can be prescribed to patients with impaired renal function of mild severity (creatinine clearance> 50 ml / min). Data on the use of olaparib in patients with impaired renal function of moderate severity (creatinine clearance <50 mL / min) or severe renal impairment (creatinine clearance <30 mL / min) are limited.

Impaired liver function

The effect of liver function impairment on the exposure of olaparib has not been studied. Therefore, the use of olaparib in patients with impaired liver function (increased serum bilirubin concentration more than 1.5 times the upper limit of the norm) is contraindicated.

Elderly age

Data on the use of olaparib in patients aged 75 years and older are limited. A population-based analysis of the available data did not reveal a relationship between the plasma concentrations of olaparib and the age of the patients.

Body mass

No data are available in obese patients (body mass index (BMI)> 30 kg / m²) or with a deficiency of body weight (BMI <18 kg / m²). Population analysis of the available data does not confirm the influence of the patient's body weight on the plasma concentrations of olaparib.

Race

Data for assessing the potential impact of race on the parameters of the pharmacokinetics of olaparib is not enough, as the experience of clinical use of the drug is mainly based on patients of the Caucasoid race (94% of patients included in the population analysis were Caucasian). When analyzing the available limited data, there were no obvious ethnic differences in the parameters of the pharmacokinetics of olaparib in Japanese patients and patients of the Caucasoid race.

Children

Studies of the pharmacokinetics of olaparib in children have not been conducted.

Indications:

Supportive monotherapy with platinum-sensitive relapse of serous epithelial ovarian cancer, fallopian tubes or primary peritoneal cancer of high degree of malignancy with the presence of germinal (hereditary) mutation of the gene BRCA and / or somatic mutation of the gene BRCA (originated in tumor cells) in adult patients responding (complete or partial response) to the platinum-containing regimen of chemotherapy.

Contraindications:

- Hypersensitivity to olaparib or any of the components of the drug;

- pregnancy and the period of breastfeeding (during therapy and within 1 month after the last drug intake);

- impaired renal function of medium and severe degree;

- impaired liver function (increased serum bilirubin concentration more than 1.5 times the upper limit of the norm);

- children and adolescents under the age of 18 (data not available).

Carefully:FROMValuable reception with powerful inducers or inhibitors of cytochrome isoenzymes CYP3A and inhibitors P-gp.

Pregnancy and lactation:

Women of reproductive age / contraception in women

In women of reproductive age, pregnancy should be excluded before therapy begins and pregnancy avoided during therapy. A pregnancy test should be performed for all premenopausal women before starting treatment. Women of reproductive age should use effective contraception during therapy and within 1 month after the last dose of Lynparz. Taking into account the possibility of drug interaction of olaparib and hormonal contraceptives, during the therapy it is necessary to consider the possibility of using an additional non-hormonal method of contraception and to regularly conduct a pregnancy test (see "Interaction with other drugs and other types of drug interactions".

Pregnancy

In animal studies, reproductive toxicity has been demonstrated, including serious teratogenic effects and effects on embryo-fetal survival in female rats at lower system exposures of the drug than systemic exposures in humans when using olaparib in therapeutic doses. There are no data on the use of olaparib in pregnant women, however, based on the mechanism of action of olaparib, Lingparza should not be used during pregnancy and in women of reproductive age who do not use reliable contraceptive methods during therapy and within 1 month after the last dose of Lynparase .

Breastfeeding period

Studies of the excretion of olaparib in the breast milk of animals have not been conducted. It is not known whether olaparib or its metabolites in the breast milk of women. The drug Lynparza is contraindicated in the period of breastfeeding; given the pharmacological properties of the drug, breastfeeding is contraindicated within 1 month after the last dose (see "Contraindications").

Fertility

There are no clinical data on the effect of the drug on fertility. In studies on animals, the effect of the drug on fertilization was not observed, but undesirable effects on embryo-fetal survival were detected.

Dosing and Administration:

Therapy with Lingparz should be started and carried out under the supervision of a doctor who has experience in the treatment of antitumor drugs.

Patients should be confirmed by mutation of the gene BRCA - germinal (hereditary) or somatic (in tumor cells) prior to the use of Lingparz preparation. Definition of a mutation BRCA it is necessary to conduct in a qualified laboratory with the help of a validated test (see the section "Pharmacodynamics"). Data on the use of Lingparza in patients with somatic mutation of the gene BRCA are limited (see the section "Pharmacodynamics"). Patients with gene mutations BRCA Genetic counseling should be conducted according to local treatment standards.

Mode of application

Inside. Capsules should be swallowed whole, not chewing, not dissolving and not opening them. Due to the influence of food on the absorption of olaparib, the drug should be taken at least 1 hour after meals and refrained from eating for at least 2 hours after taking the drug.

Doses

The recommended dose of Lingparz is 400 mg (8 capsules) 2 times a day, which corresponds to a daily dose of 800 mg. Patients should begin maintenance therapy with Lingparz preparation no later than 8 weeks after completion of a chemotherapy course containing a platinum drug. It is recommended to continue therapy until the progression of the underlying disease. There are no data on the resumption of therapy with Lynparz after the subsequent relapse.

Skipping doses

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

Correction of the dose of the drug

Treatment can be stopped to stop unwanted reactions, such as nausea, vomiting, diarrhea and anemia, and consider reducing the dose of the drug (see the "Side effect" section).

The recommended reduced dose of the drug is 200 mg twice a day, which corresponds to a daily dose of 400 mg.

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

Elderly patients

Correction 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 impaired renal function

The effect of renal dysfunction on the exposure of Lingparz was not studied. The drug Lingparza can be prescribed to patients with impaired renal function of mild severity (creatinine clearance> 50 ml / min). Data on the use of Lynparz in patients with impaired renal function of moderate severity (creatinine clearance <50 ml / min) or severe renal impairment (creatinine clearance <30 ml / min) are limited, so the use of the drug in such patients is contraindicated.

Patients with impaired hepatic function

The effect of liver function impairment on the exposure of Lingparz was not studied. Therefore, the use of Lingparza in patients with impaired liver function (increased serum bilirubin concentration more than 1.5 times the upper limit of the norm) is contraindicated, since the effectiveness and safety of olaparib in such patients is not established.

Patients of non-Caucasoid race

Clinical data on the use of the drug Lynpars in patients of non-Caucasoid race are limited.However, it is not necessary to adjust the dose of the drug depending on the ethnic origin of the patients (see the section "Pharmacokinetics").

Patients with objective status from 2 to 4

Clinical data on the use of Lynparz in patients in patients with objective status from 2 to 4 are very limited.

Children

The safety and efficacy of Lynpard's drug in children and adolescents have not been established. No data available.

Side effects:

Overview of Security Profiles

Monotherapy with olaparib was associated with undesirable reactions of usually mild to moderate severity (grade 1 or 2 according to the General Classification of Terminology of Adverse Events (STAAE)), which do not require discontinuation of therapy. The most frequent adverse reactions in clinical trials in patients who received monotherapy with olaparib (≥ 10%) were nausea, vomiting, diarrhea, dyspepsia, fatigue, headache, taste distortion, decreased appetite, dizziness, anemia, neutropenia, lymphopenia, volume of erythrocytes and increase in creatinine concentration.

The list of undesirable reactions

Table 1 shows the undesirable reactions found in patients who received monotherapy with Lynparz's drug in completed clinical trials. Undesirable reactions are presented using preferred terms according to the classes of systems and organs and indicating the absolute frequency. The frequency of occurrence of reactions is presented in the following gradation: very often (≥ 1/10), often (≥ 1/100, <1/10), infrequently (≥ 1/1000, <1/100), rarely (≥ 1/10000, <1/1000), very rarely (<1/10000).

Table 1. Undesirable reactions to Lingparz preparation detected in clinical trials monotherapy

Undesirable reactions

Class of systems and organs

Frequency of reactions of all degrees of STAAE

Frequency of reactions 3 and above degrees STAEE

Metabolic and nutritional disorders

Often

Decreased appetite

Infrequently

Decreased appetite

Disturbances from the nervous system

Often

Headache, dizziness, perversion of taste

Infrequently

Headache, dizziness

Violations from side of the gastrointestinal tract

Often

Nausea, vomiting, diarrhea, indigestion

Often

Pain in the upper abdomen, stomatitis

Often

Nausea, vomiting, diarrhea

Infrequently

Pain in the upper abdomen, stomatitis

Are common disorders and reactions at the site of administration

Often

Fatigue (including asthenia)

Often

Fatigue (including asthenia)

Changes parameters of laboratory and instrumental research

Often

Anemia (decrease in hemoglobin concentration)^1,2, neutropenia (a decrease in the absolute number of neutrophils)^1,2, lymphopenia (decrease in the number of lymphocytes)^1,2, an increase in the concentration of creatinine in the blood ^1,4, an increase in the average volume of red blood cells ^1,3

Often

Thrombocytopenia (decrease in the number of platelets)^1,2

Often

Anemia (decrease concentration of hemoglobin)^1,2, lymphopenia (decrease in the number of lymphocytes)^1,2

Often

Neutropenia (decrease in the absolute number of neutrophils)^1,2, thrombocytopenia (decrease in the number of platelets)^1,2

Infrequently

Increase in the concentration of creatinine in the blood ^1,4

¹The frequency of deviations in the results of laboratory tests is presented, and undesirable reactions are not noted.

²Reduction of hemoglobin concentration, absolute number of neutrophils, number of platelets and lymphocytes were 2 degrees of STSAE or higher.

³The increase in the average volume of red blood cells is higher than the upper limit of the norm from the initial value.The indicator returned to normal after discontinuation of therapy, without clinical consequences.

⁴Data from a double-blind, placebo-controlled study showed that the median of the increase (a change in percentage of the original value) to 23% remained constant over time; After the abolition of therapy, the indicator returns to its original value without obvious clinical consequences. In 90% of patients, initially there was 0 grade of CACAE, and in 10% of patients - 1 degree of STAAE.

Description of some unwanted reactions

Manifestations of toxicity from the gastrointestinal tract are often noted against the background of therapy with olaparib, usually represented by phenomena of 1 or 2 degrees of STAAE and are periodic. These phenomena could be cured by the suspension of therapy, a decrease in the dose of the drug and / or concomitant medications (for example, antiemetics). Prophylactic antiemetics are not required.

Anemia and other phenomena of hematological toxicity were usually 1 or 2 degrees of CACAE, however, the development of phenomena of 3 and higher degrees of STAAE was noted. It is recommended to perform a clinical blood test before starting therapy,repeat it monthly for the first 12 months of therapy, and then periodically to monitor clinically relevant changes in hematological parameters during treatment that may require suspension of therapy or a reduction in the dose of the drug and / or additional treatment.

Children

Studies involving children were not conducted.

Other special patient groups

Data on the use of the drug in elderly patients (age ≥ 75 years) and patients not of Caucasoid race are limited.

Overdose:

Symptoms of an overdose of Lingparza are not established, there is no specific therapy.

In case of an overdose, symptomatic therapy should be given.

Interaction:

Studies on the study of drug interaction were not conducted.

Pharmacodynamic interactions

Clinical studies of olaparib in combination with other antitumor drugs, including drugs that damage DNA, indicate the potentiation and elongation of myelosuppressive toxicity. The dose of Lingparz, recommended as a monotherapy,It is not suitable for combined use with other antitumoral drugs.

The combined use of olaparib with vaccines or immunosuppressive drugs has not been studied. Therefore, if you use these drugs in combination with olaparib, you should be careful and closely monitor the condition of the patients.

Pharmacokinetic interactions

Effect of other drugs on the olaparib

The metabolic clearance of olaparib occurs predominantly with the participation of cytochrome P450 isoenzymes CYP3A4/5. Clinical studies on the interaction with known inhibitors or inducers CYP3A not conducted. Therefore, it is recommended that the simultaneous use of olaparib with known potent inhibitors of these isoenzymes (for example, itraconazole, telithromycin, clarithromycin, enhanced protease inhibitors, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or inductors (for example, phenobarbital, phenytoin, rifampicin, rifabutin, rifapentin, carbamazepine, nevirapine and preparations of St. John's wort perfumed) (see section "Special instructions").

In vitro Olaparib is the substrate of the efflux transporter P-gp. Clinical studies assessing the effect of known inhibitors and inducers P-gp on olaparib, were not conducted.

Effect of olaparib on other drugs

Olaparib can suppress the cytochrome isoenzyme CYP3A4 in vitro, and it is impossible to exclude the possibility of increasing the exposure of the substrates of this isoenzyme in vivo. Therefore, it is necessary to use substrates carefully CYP3A4 in combination with olaparib, especially preparations with a small breadth of therapeutic effect (for example, simvastatin, cisapride, ciclosporin, ergot alkaloids, fentanyl, pimozide, sirolimus, tacrolimus and quetiapine).

It is not known whether olaparib induce isoenzymes CYP3A, CYP1A2, CYP2B6, CYP2C9, CYP2C19 and P-gp. Therefore, it can not be ruled out that olaparib when combined, can reduce the exposure of the substrates of these metabolic enzymes and the carrier protein. The effectiveness of hormonal contraceptives can be reduced when combined with olaparib (see also the sections on "Application during pregnancy and during breastfeeding" and "Special instructions").

In conditions in vitro Olaparib may inhibit P-gp; inhibition was also shown BRCP, OATP1B1, OST1 and OST2. It can not be ruled out that olaparib can increase the exposure of substrates P-gp (for example, statins, digoxin, dabigatran, colchicine), BRCP (eg, methotrexate, rosuvastatin, sulfasalazine), OATP1B1 (for example, bosentan, glibenclamide, repaglinide, statins and valsartan), OST1 (for example, metformin), OST2 (for example, serum creatinine). In particular, caution should be exercised olaparib simultaneously with any drug from the group of statins.

Special instructions:

Hematological toxicity

Hematologic toxicity was registered in patients who received olaparib, including clinical diagnoses and / or laboratory abnormalities of mild to moderate degree (grade 1 or 2) - anemia, neutropenia, thrombocytopenia and lymphopenia. Patients should not initiate therapy with Lingparz until their condition recovers from hematologic toxicity caused by previous antitumor therapy (hemoglobin concentration, platelet count and neutrophil counts should be within the norm or grade 1 of STACEA).It is recommended to perform a clinical blood test before the beginning of therapy, repeat it monthly for the first 12 months of therapy and then periodically to monitor clinically significant changes in hematological parameters during treatment.

If a patient has severe hematologic toxicity or the need for frequent blood transfusions, therapy with Lingparz should be suspended and an appropriate hematologic examination performed. If deviations from the norm of hematologic indices remain after 4 weeks after discontinuation of Lingparz preparation, it is recommended that a bone marrow examination and / or a cytogenetic blood test be performed.

Myelodysplastic syndrome / acute myelogenous leukemia

Myelodysplastic syndrome / acute myelogenous leukemia (MDS / AML) was noted in a small number of patients who received Lingparz as a monotherapy or in combination with other antitumor drugs; most cases ended in a fatal outcome. The duration of therapy with olaparib in patients with MDS / AML subsequently developed ranged from <6 months to> 2 years.Cases were a typical secondary MDS / AML associated with antitumor therapy. All patients had predisposing factors for the development of MDS / AML; most cases of MDS / AML have been observed in carriers of the germinal (hereditary) mutation of the BRCA gene (gBRCA), and some patients have had a history of bone marrow cancer or dysplasia. All patients had previously received chemotherapy containing a platinum drug, and many also received other drugs that damage DNA and radiation therapy. When confirming the presence of MDS / AML during therapy with Lingparz, it is recommended to appoint the appropriate therapy to the patient. If additional antitumor therapy is recommended, Lingparz should be discontinued and not prescribed in combination with other antitumor drugs.

Pneumonitis

Pneumonitis was registered in a small number of patients who received olaparib, and some cases were fatal. Reports of pneumonitis had no clinical pattern and were characterized by predisposing factors (cancer and / or lung metastases, background lung disease, history of smoking and / or previous chemotherapy and radiation therapy).If the patient has new symptoms or worsening of existing symptoms on the part of the respiratory system, such as dyspnoea, cough and fever, or changes in radiographic examination have been identified, Lingparz therapy should be suspended and immediately examined. When confirming the diagnosis of pneumonitis, therapy with Lingparz should be discontinued and appropriate treatment should be prescribed.

Embryo-fetal toxicity

Due to its mechanism of action (inhibition PARP) olaparib may cause impaired development of the fetus in the case of taking the drug by a pregnant woman. Pre-clinical studies have shown that olaparib had an unfavorable effect on embryo-fetal survival in rats and induced the development of significant defects in the fetus at exposures below expected in humans when the drug was administered at a recommended dose of 400 mg twice daily.

Pregnancy / Contraception

The drug Lingparza is contraindicated during pregnancy. It should not be used in women of reproductive age who do not use reliable contraceptive methods during therapy and within 1 month after the last administration of Lynparz preparation (see.section "Application during pregnancy and during breast-feeding").

Interactions with other drugs

It should avoid the use of olaparib simultaneously with powerful inducers or inhibitors of cytochrome isoenzymes CYP3A (see the section "Use with other medicines and other forms of interaction").

If the patient already receiving olaparib, requires therapy with an inhibitor of cytochrome isoenzymes CYP3A or an inhibitor P-gp, it is recommended to closely monitor undesirable phenomena associated with olaparib, and to stop these phenomena by reducing the dose.

Effect on the ability to drive transp. cf. and fur:

When using the drug Lingparza can occur asthenia, fatigue and dizziness; Patients with such symptoms should be careful when driving vehicles and working with mechanisms.

Form release / dosage:Capsules, 50 mg.

Packaging:

At 112 capsules vial of high density polyethylene with a polypropylene screw cap with child protection system; 4 bottles with instructions for use in a cardboard pack with the control of the first autopsy.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

18 months.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003716

Date of registration:11.07.2016

Expiration Date:11.07.2021

The owner of the registration certificate:AstraZeneca UK LtdAstraZeneca UK Ltd United Kingdom

Manufacturer: & nbsp

ASTRAZENECA UK, Ltd. United Kingdom

Representation: & nbspAstraZeneca Pharmaceuticals Ltd.AstraZeneca Pharmaceuticals Ltd.

Information update date: & nbsp01.09.2016

Illustrated instructions

Instructions

Lynparza (Lynparza)