Wenklekst (Venclexta)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceVenetoklaksVenetoklaks
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  • Wenklekst
    pills inwards 
    EbbVi Ltd.     Russia
    • Dosage form: & nbspfilm-coated tablets
    Composition:

    1 tablet, film-coated, contains:

    10 mg

    Active substance: venetoclase 10.0 mg;

    Excipients: copovidone K 28, polysorbate 80, silicon dioxide colloid, calcium hydrophosphate anhydrous, sodium fumarate, film coating Opadrai II yellow (Opadry® II Yellow): polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, iron oxide yellow E172).

    50 mg

    Active substance: venetoclase 50.0 mg;

    Excipients: copovidone K 28, polysorbate 80, silicon dioxide colloid, calcium hydrophosphate anhydrous, sodium fumarate, film coating Opadrai II beige (Opadry® II Beige): polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, iron oxide yellow E172, iron oxide red, iron oxide black.

    100 mg

    Active substance: venetoclase 100.0 mg;

    Excipients: Copovidone To 28, polysorbate 80, silicon dioxide colloid, calcium hydrophosphate anhydrous, sodium fumarate, film coating Opadrai II yellow (Opadry® II Yellow): polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, iron oxide yellow E172.

    Description:

    10 mg

    Round biconvex tablets covered with a film coating of light yellow color with engraving "V" on one side and "10" on the other side.

    50 mg

    Oval biconvex tablets covered with a film shell of light brown color with engraving "V" on one side and "50" on the other side.

    100 mg

    Oval biconvex tablets, covered with a film shell of light yellow color with engraving "V" on one side and "100" on the other side.

    Pharmacotherapeutic group:Antineoplastic agents
    ATX: & nbsp

    L.01.X   Other antineoplastic agents

    Pharmacodynamics:

    Mechanism of action

    Venetoklaks is a powerful selective inhibitor of the anti-apoptotic protein of B-cell lymphoma (BCL-2). It was shown that increased expression BCL-2 is observed in cells of patients with chronic lymphocytic leukemia (CLL), where BCL-2 mediates the survival of tumor cells, and is associated with resistance to chemotherapy. Venetoklaks binds directly to the groove of BH3 binding of proteins BCL-2, replacing proapoptotic proteins like BIM, containing the BH3 motif, and initiates the process of increased permeability of the outer mitochondrial membrane (MOMP), caspase activation and programmed cell death. During pre-clinical studies it was found that venetoclase has a cytotoxic effect on tumor cells with increased expression BCL-2.

    Pharmacodynamic action

    Electrophysiology of the heart

    The effect of repeated doses of Wenklekst preparation to 1200 mg once a day on the interval QTc evaluated in an open, uncontrolled study involving 176 patients. It was found that the Wenklekst preparation had no effect on the interval QTc and that the exposure of venetoclase is not related to the variation of the interval QTc.

    Pharmacokinetics:

    Suction

    After repeated oral administration, the maximum concentration of venetoclax in the blood plasma was achieved 5-8 hours after the drug was administered. When a constant concentration was reached, a dose-dependent increase in the values AUC (area under the pharmacokinetic curve "concentration-time") of venetoclax in the dose range of 150-800 mg. When taking the drug at a dose of 400 mg per day, along with food with a low fat content, the mean (± standard deviation) CmOh of the venetoclase at a constant concentration was 2.1 ± 1.1 μg / ml, and the value AUC24 was 32.8 ± 16.9 μg "h / ml.

    Effect of food intake

    Compared with taking the drug on an empty stomach, taking the drug along with a low-fat diet increased the exposure of venetoclax by about 3.4 times,and taking the drug along with food with a high fat content led to a decrease in exposure by about 5.1-5.3 times. It is recommended to take venetoclase during meals (see section Method of administration and dose).

    Distribution

    Venetoklaks intensively binds to the plasma protein of human blood; and in the concentration range of 1-30 μmol (0.87-26 μg / ml), the unbound fraction does not exceed 0.01%. The average ratio of drug concentration in blood and blood plasma was 0.57. Population estimation of the apparent volume of distribution (Vdss/F) Venetoclax varied in the range of 261-321 liters in patients.

    Biotransformation

    In the course of research in conditions in vitro it was found that venetoclase metabolized, mainly, under the action of the enzyme P450 CYP3A4. M27 was identified as the main metabolite of the drug in blood plasma, the inhibitory effect of which on BCL-2, at least 58 times lower than that of the venetoclax in conditions in vitro.

    Research interactions in conditions in vitro

    Simultaneous use with substrates CYP and UGT

    Results of studies in conditions in vitro indicate that in clinically significant concentrations venetoclase Does not inhibit or induce secretion CYP1A2, CYP2B6, CYP2C19, CYP2D6 and CYP3A4. In conditions in vitro Venetoclax slightly inhibits secretion CYP2C8, CYP2C9 and UGT1A1, however, it is assumed that the preparation does not cause clinically significant inhibition of these enzymes. Venetoklaks does not inhibit secretion UGT1A4, UGT1A6, UGT1A9 and UGT2B7.

    Simultaneous application with substrates / inhibitors of conveyors

    Venetoclax is a substrate P-gp and BCRP, as well as an inhibitor P-gp and BCRP and a weak inhibitor of OATP1B1 (a protein-carrier of organic anions) under conditions in vitro (see section Interaction with other drugs). It is assumed that in clinically significant concentrations venetoclase does not inhibit OATP1B3, OST1 (the transporter of organic cations), OST2, OAT1, OATZ and carrier proteins: MATE1 and MATE2K.

    Excretion

    In the studied patient population, the final half-life of venetoclax was approximately 26 hours. It was found that venetoclase accumulates in the body in minimal amounts, while the accumulation coefficient varies in the range of 1.30-1.44. After a single oral administration of 200 mg radiolabelled [14C] venetoclase by healthy volunteers, more than 99.9% of the dose was restored in the feces, and less than 0.1% of the dose was excreted from the body by the kidneys for 9 days.The proportion of unmodified venetoclase was 20.8% of the administered dose of a radiolabeled drug, excreted through the intestine. The pharmacokinetic indices of venetoclase do not change with time.

    Special patient groups

    Patients with impaired renal function

    Based on the results of a population-based pharmacokinetics analysis that included data on 238 patients with mild renal impairment (CC (creatinine clearance) ≥60 and <90 mL / min), 92 patients with moderate renal impairment (CC ≥30 and <60 mL / min ) and 220 patients with normal renal function (CK ≥90 ml / min), it was found that the effects of venetoclase in patients with mild to moderate renal impairment are similar to those in patients with normal renal function. The pharmacokinetics of venetoclase were not studied in patients with severe renal dysfunction (CK <30 mL / min) or patients on dialysis (see section Method of administration and dose).

    Impaired liver function

    Based on the results of a population analysis of pharmacokinetics, including data on 88 patients with mild violations of liver function, 10 patients with moderate impairment of liver function and 453 patients with normal liver function,that the values ​​of venetoclax exposure in patients with mild and moderate impairment of liver function are similar to those in patients with normal liver function. A mild violation of liver function was defined as the normal level of total bilirubin and the level of aspartate transaminase (ACT) above the upper limit of the norm (VGN) or the level of total bilirubin is 1.0-1.5 times higher than the VGN; moderate disturbance of the function of baking - as a level of total bilirubin is 1.5-3.0 times higher than IGN, and severe violation of liver function - as a level of total bilirubin is 3.0 times higher than UGN. The pharmacokinetics of venetoclase were not studied in patients with severe impairment of liver function (see section Method of administration and dose).

    The influence of age, sex and body weight

    Based on the results of a population analysis of pharmacokinetics, it was found that age, sex and body weight do not affect the venetoclax clearance rate.

    Indications:

    Wenklekst is indicated as a monotherapy for the treatment of chronic lymphocytic leukemia (CLL) with 17p-deletion or TP53 mutation in adult patients who are not eligible for or are not eligible for treatment with inhibitors of the B-cell receptor signaling pathway.

    The Wenklekst preparation is indicated as a monotherapy for the treatment of CLL without 17p-deletion or TP53 mutation in adult patients who did not respond to chemoimmunotherapy and treatment with inhibitors of the B-cell receptor signaling pathway.

    Contraindications:

    - Hypersensitivity to the active substance or to any auxiliary substance included in the preparation.

    - Simultaneous application of powerful inhibitors CYP3A at the beginning of treatment and the phase of titration of the dose (see Sections Mode of application and doses and Interaction with other drugs).

    - Simultaneous use of drugs that include St. John's wort extract (see sections special instructions and Interaction with other drugs).

    - Severe liver dysfunction.

    - Children under 18 years.

    Carefully:

    Joint application of venetoclase with substrates P-gp (P-glycoprotein) or BCRP (a protein of breast cancer resistance) with a narrow therapeutic index.

    Pregnancy and lactation:

    Women of childbearing age / methods of contraception in women

    Women should avoid pregnancy during the treatment with Wenklekst and, at least, within 30 days after its completion.Consequently, women capable of childbearing must use highly effective contraception during the use of venetoclax and within 30 days after discontinuation of therapy. At this time, it is not known whether venetoclase to reduce the effectiveness of hormonal contraceptives, therefore women using hormonal contraceptives should additionally use barrier method of contraception.

    Pregnancy

    Based on the results of studies of embryophototoxicity in animals, it was found that venetoclase may cause harm to the fetus when it is used during pregnancy.

    At the moment, there is no proper and properly controlled study of the use of venetoclax during pregnancy. In animal toxicity studies, it was found that venetoclase has a toxic effect on reproductive function. Venetoklaks It is not recommended to use during pregnancy and to appoint to women, capable of childbirth, who do not use highly effective methods of contraception.

    Breastfeeding period

    It is not known whether venetoclase or its metabolites into breast milk.

    It is impossible to exclude the risk for a child who is breastfeeding.

    During the treatment with Wenklekst, breastfeeding should be discontinued.

    Fertility

    Studies of the effects of venetoclax on fertility in humans have not been conducted. Based on the results of a study of toxic effects on gonads in dogs, it was found that with clinically significant exposure values, Wenklekst treatment may have an adverse effect on the fertility of male laboratory animals. Before starting treatment in some male patients, it may be possible to consider counseling about sperm storage.

    Dosing and Administration:

    Treatment with venetoclax should be started and carried out under the supervision of a doctor with experience in the use of antitumoral drugs.

    Mode of application

    The preparation of Venklekst, tablets, covered with a film membrane, are intended for oral administration. Patients should be told that they should take the drug at about the same time, swallowing the pill completely and washing them with water.Tablets should be taken with meals to avoid the risk of insufficient therapy (see section Pharmacokinetic properties). Do not chew, grind or break tablets to facilitate swallowing.

    In the titration phase of the dose venetoclase should be taken in the morning to facilitate laboratory monitoring.

    During the treatment with venetoxil, the use of products containing grapefruit, pomeranian and stellate mustard (carambola) should be avoided (see section Interaction with other drugs).

    Doses

    The initial dose is 20 mg of Wenklekst preparation once a day for 7 days. Within 5 weeks the dose is gradually increased to the recommended daily dose of 400 mg according to the scheme given in Table 1.

    Table 1: Scheme of increasing the dose

    A week

    The daily dose of Wenklekst

    1

    20 mg

    2

    50 mg

    3

    100 mg

    4

    200 mg

    5 and more

    400 mg

    A 5-week dose titration scheme is designed to gradually reduce the tumor burden (tumor volume) and reduce the risk of tumor lysis syndrome (SLO).

    Treatment should continue until the disease progresses or further intolerance of treatment by the patient.

    Dose change in tumor lysis syndrome

    If a patient exhibits a change in the biochemical composition of the blood that indicates an OA, the patient should skip the next daily dose of venetoclax. If within 24 -8 hours after receiving the last dose the revealed deviations can be eliminated, treatment with venetoxax can be resumed in the same dose. In the case of clinical signs of OA or changes in the biochemical composition of the blood, which can take more than 48 hours to recover, treatment should be resumed at a lower dose (see Table 2). When the treatment is resumed after the discontinuation of the drug in connection with the developed UL it is necessary to follow the instructions for the prevention of tumor lysis syndrome (see section Special instructions).

    Dose change for other toxic events

    Treatment with Wenklekst should be suspended if any non-hematological toxic effects of 3 or 4 severity, neutropenia of 3 or 4 severity, which is accompanied by an infectious process or an increase in temperature, or hematological toxic effects of 4 degrees of severity, with the exception of lymphopenia.After reducing the severity of toxic effects to 1 degree or the initial level (recovery), venetoxoclase therapy can be resumed in the same dosage itself. At each renewal of treatment with Wenklekst preparation after elimination of toxic phenomena, it is necessary to follow the indications on dose reduction given in Table 2, in case of recurrence of a toxic phenomenon or in the event of any other phenomenon. At the discretion of the doctor, the dose may be reduced even more. For patients who require a dose reduction below 100 mg for a period of more than 2 weeks, consideration may be given to stopping venetoclax therapy.

    Table 2: Dose variation in OA and other toxic events

    Dose on discontinuation of treatment (mg)

    Dose when resuming treatment (mga)

    400

    300

    300

    200

    200

    100

    100

    50

    50

    20

    20

    10

    a The changed dose should be adhered to within 1 week before increasing the dose.

    In patients who discontinued treatment for more than 1 week during the first five weeks of titrating the dose or more than 2 weeks during the 400 mg dose of the drug, a reassessment of the risk of OA should be conducted to determine whether to resume treatment at a lower dose (eg, all or some titration levels of the dose, see Table 2).

    Dose change when using inhibitors CYP3A

    Simultaneous use of Wenklekst and powerful or moderate inhibitors CYP3A increases the exposure of venetoclax and may lead to an increased risk of OA at the beginning of treatment and in the phase of titrating the dose and the development of other toxic phenomena (see section Interaction with other drugs).

    Phase of initiation of treatment and titration dose

    Contraindicated simultaneous use of Wenklekst and powerful inhibitors CYP3A at the beginning of treatment and the phase of titration of the dose (see Sections Contraindications, special instructions and Interaction with other drugs).

    It is necessary to avoid simultaneous application of Wenklekst preparation and moderate inhibitors CYP3A at the start of treatment and the titration phase of the dose. It is necessary to consider the possibility of using alternative treatment options. If the patient is shown the application moderate inhibitor CYP3A, initial and titrated doses should be reduced by at least 50%. These patients should be more closely monitored for signs of development of toxic phenomena (see Sections special instructions and Interaction with other drugs).

    After completion of the titration phase of the dose

    Patients taking a constant daily dose of Wenklekst should avoid using inhibitors CYP3A or should reduce the dose of venetoclax by 50% while using moderate inhibitors CYP3A and on 75% - at simultaneous application of powerful inhibitors CYP3A. These patients should be monitored more closely for signs of toxic effects and may require an additional dose adjustment. 2-3 days after discontinuation of the inhibitor CYP3A treatment with venetoclax can be resumed in the same dose that was used before the initiation of treatment with an inhibitor CYP3A (see sections special instructions and Interaction with other drugs).

    Missing dose

    If the patient is late with taking a dose of venetoclax no more than 8 hours from the time of usual reception, the missed dose should be taken as early as possible on the same day. If the patient is late with a dose of venetoclax more than 8 hours, you should skip this dose and return to the usual treatment the next.

    If the patient vomits after taking a dose, on that day he should not take an additional dose. The next scheduled dose should be taken the next day at the usual time.

    Special patient groups

    Use in elderly patients

    In elderly patients (≥65 years), dose adjustment is not required (see section Pharmacodynamic properties).

    Patients with impaired renal function

    In patients with mild to moderate renal impairment (CC values ​​in the range ≥30 mL / min - <90 mL / min), dose adjustment is not required (see section Pharmacokinetic properties). In patients with impaired renal function (CC <80 mL / min), early initiation of treatment and titration phase of the dose may require more intensive prevention and monitoring in order to reduce the risk of OA development (see section Special instructions). In patients with severe renal dysfunction (CK <30 mL / min) and in patients on dialysis, safety of the drug is not established, and for these patients the recommended dose is not determined.

    In patients with severe renal dysfunction, Wenklekst is prescribed only if the benefits of treatment outweigh the risks associated with it, and, in view of the increased risk of developing OA, these patients should be closely monitored for signs of toxic effects (see section Special instructions). Taking into account the insignificant removal of venetoclax through the kidneys, no significant change in venetoclax exposure is expected in patients with severe renal dysfunction (see section Pharmacokinetics).

    Impaired liver function

    Patients with mild to moderate liver dysfunction are not recommended to adjust the dose, however, since patients with moderate hepatic impairment tend to increase the incidence of adverse events, these patients should be closely monitored for signs of toxic effects at the onset of therapy and dose titration phase (see Side effect).

    The safety of the drug in patients with severe impairment of liver function is not established. The preparation of Wenklekst is contraindicated in patients with severe impairment of liver function.

    Use in children

    The effectiveness and safety of the use of Wenklekst in children under the age of 18 years are not established, therefore, the use is contraindicated.

    Side effects:

    Security Profile Summary

    The safety profile of the Venklekst preparation is based on generalized data for 334 patients,who received venetoclass treatment in two Phase 2 studies and one Phase I study. Overall, the studies involved patients previously treated with CLL, including 207 patients with 17p-deletion and 130 patients who did not respond to treatment with inhibitors of the B-cell receptor signaling pathway. Patients received monotherapy with a Wenklekst preparation at a dose of 400 mg once a day, following the dose titration scheme.

    In patients receiving Wenklekst preparation, the most frequent adverse events (≥20%) were of any severity: neuropathy / reduction in neutrophil count, diarrhea, nausea, anemia, upper respiratory tract infection, fatigue. The most frequently reported serious adverse reactions (> 2%) were pneumonia, febrile neutropenia.

    List of unwanted reactions in the form of a table

    Table 3 provides an overview of the registered indicators of the incidence of adverse drug reactions (NLR) against the background of the Wenklekst preparation. Below is a list of undesirable reactions grouped according to the class of organ systems by MedDRA and frequency of occurrence. Frequency of occurrence of undesirable reactions is defined as: very often (≥1 / 10), often (≥1 / 100, but <1/10), infrequently (≥1 / 1000, but <1/100), rarely (≥1 / 10000 - <1/1 000), very rarely (<1/10000),It is not known (can not be estimated on the basis of available data). In all groups formed according to frequency of occurrence, the side effects are listed in descending order of their severity.

    Table 3: Undesirable drug reactions observed in patients with CLL, treated with Wenklekst preparation

    Class of organ systems

    Frequency

    (all degrees of severity)

    Undesirable reactions (N = 334)
    Infectious and parasitic diseases

    Often

    Upper respiratory tract infection
    Pneumonia

    Often

    Urinary tract infection
    Violations of the blood and lymphatic system

    Often

    		 Neutropenia
    Anemia

    Often

    		 Febrile neutropenia
    Lymphopenia

    Disorders from the metabolism and nutrition

    Often

    		 Hyperphosphatemia
    Hyperkalemia
    Hypocalcemia

    Often

    		 Tumor lysis syndrome
    Hyperuricemia
    Disorders from the gastrointestinal tract

    Often

    		 Diarrhea
    Vomiting
    Nausea
    Constipation

    General disorders and disorders at the site of administration

    Often

    Fatigability

    Results of laboratory and instrumental studies

    Often

    Increased level of creatinine in the blood

    Discontinuation of treatment and dose reduction due to development of NLP

    Due to adverse reactions, treatment was discontinued in 10.2 % patients.

    Correction of the dose due to adverse reactions was performed in 12.9% of patients.

    Description of individual adverse reactions

    Tumor lysis syndrome

    When treated with Wenklekst preparation, the tumor lysis syndrome is an important identified risk. In the initial phase 1 studies of dose selection with a shorter (2-3 weeks) titration phase and a higher initial dose, the incidence of OA was 13% (in 10/77, 5 cases of SLO established on the basis of laboratory indicators and 5 cases of SLO with clinical manifestations), including 2 deaths and 3 cases of acute renal failure, one of which required dialysis.

    The risk of developing OA decreased after a review of the treatment regimen and changes in prevention and monitoring methods. In clinical studies of venetoclax in patients with any measurable lymph node of at least 10 cm in size and patients with an AFL value of at least 25 x 109/ l and any measurable lymph node of at least 5 cm size was hospitalized for more intensive hydration and monitoring on the first day of application of the drug at a dose of 20 mg and 50 mg in the titration phase of the dose (see section Method of administration and dose).

    In 160 patients with CLL who started treatment with a daily dose of 20 mg, which for 5 weeks was increased to a daily dose of 400 mg, the incidence was 3%. All the phenomena were laboratory-confirmed UO (deviations from the norm of laboratory parameters, which within 24 hours met 2 or more criteria: potassium content> 6 mmol / l, uric acid> 476 μmol / L, calcium <1.75 mmol / l or phosphorus> 1.5 mmol / l, or were recorded as an AO phenomenon) and occurred in patients with a lymph node (nodes) of at least 5 cm in size or an AFL of at least 25 x 109/ l. None of the patients with OA had a clinical picture of acute renal failure, cardiac arrhythmias, or sudden death and / or seizures. In all patients, the CC values ​​were ≥50 ml / min.

    Overdose:

    There is no special antidote for venetoclax. Patients who have taken an excessive dose of the drug should be carefully screened and assigned appropriate supportive care. During the titration phase of the dose, it is necessary to discontinue treatment and carefully examine the patient for signs and symptoms of SLE (fever, chills, nausea, vomiting,confusion, dyspnea, convulsions, irregular heartbeats, dark or cloudy urine, fatigue, pain in the muscles or joints, abdominal pain and bloating) and other toxic effects (see section Method of administration and dose). Considering the large volume of venetoclax distribution and its significant binding to proteins, it seems unlikely that dialysis will lead to a significant excretion of venetoclax from the body.

    Interaction:

    Venotoklaks is metabolized, mainly, under the action of an enzyme CYP3A.

    Preparations, able to increase concentrations of venetoclase in blood plasma

    Inhibitors CYP3A

    In 11 patients concurrent use of ketoconazole 400 mg / day, a potent inhibitor CYP3A, P-gp and BCRP, within 7 days led to an increase in the value of CmOh Venetoclax is 2.3 times and the values AUC* - in 6,4 times.

    Joint use of 50 mg of ritonavir once a day and strong inhibitors CYP3A, P-glycoprotein and inhibitors of OATP1B1 / B3 for 14 days by six healthy volunteers increased CmOh в2.4 times and AUC in 7,9 times.

    It is assumed that the simultaneous use of venetoclax and other potent inhibitors CYP3A4 can lead to an increase in the value AUC veneklasses in the average in 5,8-7,8 times.Contraindicated concurrent use of venetoclax and potent inhibitors CYP3A (eg, ketoconazole, ritonavir, clarithromycin, itraconazole, voriconazole, posaconazole) at the beginning of the treatment and the phase of titration of the dose in view of the increased risk of developing an OA (see section Contraindications).

    At the beginning of treatment and the titration phase of the dose, simultaneous use of venetoclax and moderate inhibitors should be avoided CYP3A (for example, erythromycin, ciprofloxacin, diltiazem, fluconazole, verapamil). It is necessary to consider the possibility of using alternative treatment options. If the patient is treated with moderate inhibitors CYP3A, initial and titrated doses of venetoclase (see section Dosing and Administration) must be reduced by at least 50%. These patients should more closely monitor the signs and symptoms of the development of OA.

    In patients who completed the phase of titrating the dose and taking a constant daily dose of venetoclase, the dose of the drug should be reduced by 50% with the simultaneous use of moderate inhibitors CYP3A and on 75% - at simultaneous application of powerful inhibitors CYP3A. These patients should be monitored more closely for signs of toxic effects and may require an additional dose adjustment. 2-3 days after discontinuation of the inhibitor CYP3A treatment with venetoclax can be resumed in the same dose that was used before the initiation of treatment with an inhibitor CYP3A (see section Method of administration and dose).

    During the treatment with venetoxil, the use of products containing grapefruit, pomeranian and stellate carpal (carambola) should be avoided, since these fruits contain inhibitors CYP3A.

    P-glycoprotein inhibitors (P-gp) and breast cancer resistance protein (BCRP)

    Venetoclax is a substrate for P-gp and BCRP. In 11 healthy volunteers, simultaneous single administration of 600 mg of rifampin, an inhibitor P-gp, caused an increase in the value of CmOh of the venetoclax by 106% and the values ​​of AUC ∞ - by 78%. The simultaneous use of venetoclase and inhibitors should be avoided P-gp and BCRP at the beginning of treatment and the phase of titration of the dose; If patients are treated with inhibitors P-gp and BCRP, These patients should be carefully monitored for signs of toxic effects (see section Special instructions).

    Preparations, can reduce the concentration of venetoclase in blood plasma

    Inductors CYP3A

    In 10 healthy volunteers, simultaneous application of rifampin 600 mg / day, a powerful inductor CYP3A, within 13 days led to a decrease in the value of CmOh valentoclax by 42% and values AUC ∞ - at 71 %. It should avoid simultaneous application of Wenklekst preparation and powerful inducers CYP3A (eg, carbamazepine, phenytoin, rifampin) or moderate inducers CYP3A (E.g., bosentan, efavirenz, etravirine, modafinil, nafcillin). Alternative treatment with less potent inducers should be considered CYP3A. During treatment venetoklaksom contraindicated the use of preparations containing the extract of Hypericum, Hypericum as may reduce the effectiveness of therapy (see. Section Contraindications).

    Preparations, reducing the acidity of gastric juice

    it was found that drugs that reduce gastric acidity (e.g., proton pump inhibitors, H2 receptor antagonists, antacids), no effect on the bioavailability venetoklaksa Based on the results of a population pharmacokinetic analysis.

    Bile acid sequestrants

    It is not recommended to apply simultaneously venetoclase and bile acid sequestrants, as this can reduce the absorption of venetoclase. If necessary, simultaneously use a sequestrant of bile acids and venetoclase the patient should follow the instructions in the instruction on the use of bile acid sequestrant to reduce the risk of drug interaction, and at the same time venetoclase should be taken at least 4-6 hours after taking the sequestrant.

    Drugs, the concentration of which in the blood plasma can change under the action of venetoclase

    Warfarin

    In a study of drug interaction involving three healthy volunteers, the simultaneous single administration of venetoclax 400 mg and warfarin 5 mg resulted in an increase in the value of CmOh and values AUC ∞ R-warfarin and S-warfarin by 18-28%. Since the used dose of venetoclase did not allow reaching an equilibrium state, in patients taking warfarin, it is recommended that a thorough monitoring of the international normalized relationship (INR) be conducted.

    Substrates P-gp, BCRP and OATP1B1

    In studies in conditions in vitro venetoclase inhibits P-gp, BCRP and OATP1B1. The use of a single dose of venetoclax 100 mg with digoxin increases Cmax digoxin by 35% and by 9% AUC ∞. The simultaneous use of substrates should be avoided P-gp or BCRP with a narrow therapeutic index (for example, digoxin, dabigatran, everolimus, sirolimus) and Wenklekst preparation.

    If the application of the substrate is shown P-gp or BCRP with a narrow therapeutic index, treatment should be administered with caution. Interval between intake of substrates P-gp or BCRP. (eg, dabigatran ethexilate), and venetoclax should be as large as possible in order to minimize the likelihood of drug interaction.

    With the simultaneous use of statin (substrate of the AETR) and venetoclase, careful monitoring of toxic phenomena associated with statins is recommended.

    Special instructions:

    Tumor lysis syndrome

    Tumor lysis syndrome, including fatal cases, was observed in patients with high tumor burden who had previously received CLL treatment with Wenklekst.

    The Wenklekst preparation can cause a rapid reduction in the tumor, thereby creating a risk of developing an OA in the initial 5-week phase of the titration dose.Changes in the balance of electrolytes that correspond to BF and require urgent treatment can be observed 6-8 hours after the first dose of venetoclax and at each dose increase.

    The risk of SLO is caused by many factors, including concomitant diseases. Patients with a large tumor burden (for example, any lymph node with a diameter of at least 5 cm or an AFL value of at least 25 x 109/ l) are at a higher risk of developing OA at the beginning of Venetoxax therapy. Reduced renal function (CC value <80 ml / min) further increases the risk of developing VLF. Patients should assess the risk of developing OAF and prescribe appropriate prophylaxis for SLOs, including hydration and hypo-uricemic drugs. A biochemical blood test should be monitored and the identified abnormalities rectified immediately. If necessary, discontinue treatment (see section Method of administration and dose). As the overall risk increases, the intensity of prophylaxis measures should be increased (intravenous hydration, frequent monitoring, hospitalization). Follow the instructions given in subsection Prophylaxis of tumor lysis syndrome (see below).

    Simultaneous use of Wenklekst and powerful or moderate inhibitors CYP3A increases the exposure of venetoclax and may lead to an increased risk of OA at the beginning of treatment and the phase of titration of the dose (see Sections Dosing and Administration and Contraindications). Inhibitors P-gp or BCRP can also increase the exposure of the venetoclaxy (see section Interaction with other drugs).

    Prophylaxis of tumor lysis syndrome

    The Wenklekst preparation can cause a rapid reduction in the tumor, thereby creating a risk of developing an OA in the initial 5-week phase of the titration dose. Changes in the balance of electrolytes that correspond to BF and require urgent treatment can be observed 6-8 hours after the first dose of venetoclax and at each dose increase.

    The risk of OA development may gradually decrease as the tumor burden decreases during venetoclax treatment.

    Before initiating venetoxoclase therapy, all patients should be evaluated for tumor burden, including an X-ray examination (eg, CT). It is necessary to conduct a biochemical blood test (potassium, uric acid, phosphorus, calcium and creatinine) and eliminate the detected abnormalities.It is necessary to take the preventive measures described in section Method of administration and dose. As the overall risk increases, prevention measures should become more intense.

    Neutropenia

    In patients who took venetoclase, neutropenia of 3 and 4 degrees of severity was observed. During the whole period of treatment, patients should monitor the parameters of the general blood test. In the case of severe neutropenia, it is recommended to stop treatment or reduce the dose of the drug (see section Method of administration and dose). In case of any signs of infection, it is necessary to consider the possibility of using supportive measures, including the use of antimicrobials.

    Immunization

    The safety and effectiveness of immunization with live attenuated vaccines during or after venetoclax treatment have not been studied. Immunization with live vaccines during the treatment period and after it is completed until the B cells are restored is not allowed.

    Inductors CYP3A

    Simultaneous application of inducers CYP3A4 may lead to a decrease in venetoclax exposure and subsequent risk of ineffective therapy.It should avoid the simultaneous use of venetoclax and powerful or moderate inducers CYP3A4 (see sections Contraindications and Interaction with other drugs).

    The use in women of childbearing age

    During the period of application of venetoclax, women capable of childbearing should use effective methods of contraception (see section Application during pregnancy and during breastfeeding).

    Hydration

    To reduce the risk of developing OA in the titration phase of the dose, all patients should receive proper hydration. Patients should be instructed that, starting from the second day before the start of treatment and throughout the titration phase of the dose, they should consume large amounts of water during the day. Patients should be told that they should drink 1.5-2.0 liters of water daily, starting from the second day before treatment, at the beginning of treatment and at each subsequent increase in the dose of the drug. Depending on the overall risk of developing SLO, patients who can not maintain the required level of hydration by ingesting fluid inside, are shown with infusion therapy.

    Hypo uricemic drugs

    Patients with high levels of uric acid or a high risk of developing OA should take hypouricemic drugs for 2-3 days before starting treatment with venetoxax and throughout the titration phase of the dose.

    Laboratory research

    Before taking the first dose: in all patients before taking the first dose, a biochemical blood test must be performed to assess the kidney function and eliminate existing abnormalities. A biochemical blood test should be performed before each subsequent dose increase in the titration phase.

    After taking the first dose: in patients at high risk of developing OA, a biochemical blood test should be performed 6-8 hours and 24 hours after the first dose of venetoclax. All deviations from the norm of electrolyte balance should be immediately eliminated. The patient should take the next dose of venetoclax only after evaluating the results of the biochemical analysis of the blood sample obtained 24 hours after the previous dose. It is necessary to follow the same monitoring pattern after transferring the patient to a dose of 50 mg and then, at each subsequent dose increase, in patients who have a high risk of developing APS.

    Hospitalization

    Based on the doctor's assessment, some patients, especially those who are at high risk of developing OA, may require hospitalization on the day of the first dose of venetoclax for more intensive prevention and monitoring of OA in the first 24 hours after taking the dose (see section Side effect). Depending on the outcome of the reassessment of the risk, consideration should be given to the possibility of hospitalization at each subsequent dose increase.

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

    The Venklekst drug has no effect or has little effect on the ability to drive vehicles and control mechanisms. Some patients who took Wenklekst had fatigue, which should be taken into account when assessing their ability to drive vehicles and manage mechanisms.

    Form release / dosage:

    Film-coated tablets.

    Packaging:

    Tablets 10 mg

    2 tablets, film-coated in blister of polyvinyl chloride / polyethylene / polychlorotrifluoroethylene and aluminum foil. By 7 blisters together with instructions for use in a pack of cardboard.

    50 mg tablets

    One tablet covered with a film sheath in blister of Polyvinyl chloride / polyethylene / polychlorotrifluoroethylene and aluminum foil. By 7 blisters together with instructions for use in a pack of cardboard.

    Tablets 100 mg

    One tablet covered with a film sheath in blister of Polyvinyl chloride / polyethylene / polychlorotrifluoroethylene and aluminum foil. By 7 blisters together with instructions for use in a pack of cardboard.

    2 tablets, film-coated in blister of Polyvinyl chloride / polyethylene / polychlorotrifluoroethylene and aluminum foil. By 7 blisters together with instructions for use in a pack of cardboard.

    For 4 tablets, film-coated in blister of Polyvinyl chloride / polyethylene / polychlorotrifluoroethylene and aluminum foil. For 7 blisters together with instructions for use in a pack of cardboard, four packs of cardboard in a pack of cardboard.

    Storage conditions:

    At a temperature of no higher than 30 ° C.

    Shelf life:

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

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004678
    Date of registration:02.02.2018
    Expiration Date:02.02.2023
    The owner of the registration certificate:EbbVi Ltd.EbbVi Ltd. Russia
    Manufacturer: & nbsp
    Representation: & nbspEbbVi Ltd.EbbVi Ltd.Russia
    Information update date: & nbsp26.03.2018
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