Venclexta (Tablets) Instructions for Use

Marketing Authorization Holder

AbbVie, LLC (Russia)

Manufactured By

AbbVie Ireland NL, B.V. (Ireland)

Primary Packaging

AbbVie Deutshland, GmbH & Co.KG (Germany)

Packaging and Quality Control Release

AbbVie Deutshland, GmbH & Co.KG (Germany)

Or

PHARMSTANDARD-UfaVITA, JSC (Russia)

ATC Code

L01XX52 (Venetoclax)

Active Substance

Venetoclax (Rec.INN registered by WHO)

Dosage Forms

	Venclexta	Film-coated tablets, 10 mg: 14 pcs.
		Film-coated tablets, 50 mg: 7 pcs.
		Film-coated tablets, 100 mg: 7, 14 or 112 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light yellow in color, round, biconvex, with an engraving “V” on one side and “10” on the other side.

Excipients: copovidone K28, polysorbate 80, colloidal silicon dioxide, anhydrous calcium hydrogen phosphate, sodium stearyl fumarate, film coating Opadry^® II yellow: polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, iron oxide yellow E172.

2 pcs. – blisters made of polyvinyl chloride/polyethylene/polychlorotrifluoroethylene and aluminum foil (7) – cardboard packs.

Film-coated tablets light brown in color, oval, biconvex, with an engraving “V” on one side and “50” on the other side.

Excipients: copovidone K28, polysorbate 80, colloidal silicon dioxide, anhydrous calcium hydrogen phosphate, sodium stearyl fumarate, film coating Opadry^® II beige: polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, iron oxide yellow E172, iron oxide red, iron oxide black.

1 pc. – blisters made of polyvinyl chloride/polyethylene/polychlorotrifluoroethylene and aluminum foil (7) – cardboard packs.

Film-coated tablets light yellow in color, oval, biconvex, with an engraving “V” on one side and “100” on the other side.

Excipients: copovidone K28, polysorbate 80, colloidal silicon dioxide, anhydrous calcium hydrogen phosphate, sodium stearyl fumarate, film coating Opadry^® II yellow: polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, iron oxide yellow E172.

1 pc. – blisters made of polyvinyl chloride/polyethylene/polychlorotrifluoroethylene and aluminum foil (7) – cardboard packs.
2 pcs. – blisters made of polyvinyl chloride/polyethylene/polychlorotrifluoroethylene and aluminum foil (7) – cardboard packs.
4 pcs. – blisters made of polyvinyl chloride/polyethylene/polychlorotrifluoroethylene and aluminum foil (7) – cardboard packs (4) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agents; other antineoplastic agents

Pharmacological Action

Antineoplastic agent, a selective inhibitor of the anti-apoptotic protein B-cell lymphoma (BCL-2). It has been shown that increased expression of BCL-2 is observed in the cells of patients with chronic lymphocytic leukemia (CLL), where BCL-2 mediates tumor cell survival and is associated with resistance to chemotherapy.

Venetoclax binds directly to the BH3-binding groove of BCL-2 proteins, displacing pro-apoptotic proteins like BIM that contain the BH3 motif, and initiates the process of increased mitochondrial outer membrane permeability (MOMP), caspase activation, and programmed cell death.

Preclinical studies have established that Venetoclax exerts a cytotoxic effect on tumor cells with increased BCL-2 expression.

Venetoclax does not affect the QTc interval.

Pharmacokinetics

After multiple oral administration, the C_max of venetoclax in plasma was reached within 5-8 hours. Upon reaching C_ss, a dose-dependent increase in venetoclax AUC values was observed in the dose range of 150-800 mg.

When taken at a dose of 400 mg/day with a low-fat meal, the mean value (± standard deviation) of C_ss for venetoclax was 2.1±1.1 µg/ml, and the AUC₂₄ value was 32.8±16.9 µg×h/ml.

Compared to administration on an empty stomach, administration with a low-fat meal increased venetoclax exposure by approximately 3.4 times, and administration with a high-fat meal led to a decrease in exposure by approximately 5.1-5.3 times. It is recommended to take Venetoclax with a meal.

Venetoclax is highly bound to human plasma proteins. In the concentration range of 1-30 µmol (0.87-26 µg/ml), the unbound fraction does not exceed 0.01%. The mean ratio of drug concentration in blood to plasma was 0.57. The population estimate of the apparent V_d at steady state for venetoclax varied in the range of 261-312 L.

In vitro studies have established that Venetoclax is metabolized primarily by the CYP3A4 isoenzyme. The main metabolite of venetoclax is M27. The inhibitory effect of M27 on BCL-2 is at least 58 times lower than that of venetoclax in vitro.

Venetoclax is a substrate of P-glycoprotein and BCRP, as well as an inhibitor of P-glycoprotein and BCRP and a weak inhibitor of OATP1B1 in vitro.

In the studied patient population, the terminal T_1/2 of venetoclax was approximately 26 hours. Venetoclax was found to accumulate minimally in the body, with an accumulation ratio ranging from 1.30-1.44.

After a single oral administration of 200 mg of radioactively labeled [¹⁴C] venetoclax to healthy volunteers, more than 99.9% of the dose was recovered in feces, and less than 0.1% of the dose was excreted by the kidneys over 9 days. The proportion of unchanged venetoclax was 20.8% of the administered dose of the radioactively labeled drug excreted via the intestine. The pharmacokinetic parameters of venetoclax do not change over time.

Indications

As monotherapy for the treatment of chronic lymphocytic leukemia (CLL) with 17p deletion or TP53 mutation in adult patients for whom treatment with B-cell receptor signaling pathway inhibitors is unsuitable or has not shown the expected result.

As monotherapy for the treatment of CLL without 17p deletion or TP53 mutation in adult patients who have not responded to chemoimmunotherapy and treatment with B-cell receptor signaling pathway inhibitors.

ICD codes

Dosage Regimen

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

The initial dose is 20 mg once daily for 7 days. Over 5 weeks, the dose is gradually increased to the recommended daily dose of 400 mg according to a specific schedule.

The 5-week dose titration schedule is designed to gradually reduce tumor burden (tumor volume) and lower the risk of tumor lysis syndrome (TLS).

During the dose titration phase, Venetoclax should be taken in the morning to facilitate laboratory monitoring.

If adverse reactions occur, the dose should be adjusted according to a specific schedule or venetoclax treatment should be discontinued.

Treatment should be continued until disease progression or further treatment intolerance.

Adverse Reactions

From the hematopoietic system very common – neutropenia, anemia; common – febrile neutropenia, lymphopenia.

From the metabolism very common – hyperphosphatemia, hyperkalemia, hypocalcemia; common – tumor lysis syndrome (TLS), hyperuricemia.

From the digestive system very common – diarrhea, vomiting, nausea, constipation.

From the respiratory system very common – upper respiratory tract infection, pneumonia.

From the urinary system common – urinary tract infection.

General reactions very common – fatigue.

Contraindications

Severe hepatic impairment, children under 18 years of age, concomitant use of strong CYP3A inhibitors at the start of treatment and during the dose titration phase, concomitant use of preparations containing St. John’s wort extract, hypersensitivity to venetoclax.

Use in Pregnancy and Lactation

Women of childbearing potential should use highly effective contraception during venetoclax use and for 30 days after discontinuation of therapy. It is not currently known whether Venetoclax can reduce the effectiveness of hormonal contraceptives, so women using hormonal contraceptives should additionally use a barrier method of contraception.

Based on the results of embryofetotoxicity studies in animals, it has been established that Venetoclax may cause harm to the fetus when used during pregnancy and has toxic effects on reproductive function.

Venetoclax should not be used during pregnancy and in women of childbearing potential who are not using highly effective methods of contraception.

It is not known whether Venetoclax or its metabolites are excreted in breast milk. A risk to the breastfed child cannot be excluded. Breastfeeding should be discontinued during treatment.

Studies on the effect of venetoclax on human fertility have not been conducted. Based on the results of a study on toxic effects on the gonads in dogs, it was established that at clinically relevant exposure levels, administration of venetoclax may have an adverse effect on the fertility of male laboratory animals.

Special Precautions

Venetoclax should be used with caution concomitantly with substrates of P-glycoprotein or BCRP (breast cancer resistance protein) with a narrow therapeutic index.

In patients with high tumor burden who have previously received treatment for CLL, tumor lysis syndrome, including fatal cases, has been observed with the use of venetoclax. Venetoclax can cause rapid tumor reduction, thereby creating a risk of TLS during the initial 5-week dose titration phase. Changes in electrolyte balance consistent with TLS and requiring urgent treatment may occur 6-8 hours after the first dose of venetoclax and with each dose increase.

The risk of TLS is due to many factors, including comorbidities. Patients with high tumor burden (e.g., any lymph node with a diameter of at least 5 cm or ALC value not less than 25×10⁹/L) are at higher risk of developing TLS at the start of venetoclax therapy. Reduced renal function (CrCl value <80 ml/min) further increases the risk of TLS.

Before starting treatment, the risk of TLS should be assessed and appropriate TLS prophylaxis should be prescribed, including hydration and hypouricemic drugs. Blood biochemical tests should be monitored and any abnormalities identified should be promptly corrected. Treatment should be discontinued if necessary. As the overall risk increases, the intensity of TLS prophylaxis measures should be increased (IV hydration, frequent monitoring, hospitalization).

The risk of developing TLS may gradually decrease as tumor burden decreases during venetoclax treatment.

Concomitant use of venetoclax and strong or moderate CYP3A inhibitors increases venetoclax exposure and may increase the risk of TLS at the start of treatment and during the dose titration phase. P-gp or BCRP inhibitors may also increase venetoclax exposure.

Throughout the entire treatment period, patients should have their complete blood count monitored. If any signs of infection occur, the possibility of using supportive measures, including antimicrobial drugs, should be considered.

The safety and efficacy of immunization with live attenuated vaccines during or after venetoclax treatment have not been studied. Immunization with live vaccines is not permitted during treatment and after its completion until B-cell recovery.

Concomitant use of venetoclax and strong or moderate CYP3A4 inducers should be avoided.

To reduce the risk of TLS during the dose titration phase, all patients should receive adequate hydration. Depending on the overall risk of TLS, patients who cannot maintain the required level of hydration by oral fluid intake should receive infusion therapy.

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

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

After the first dose, in patients at high risk for TLS, a blood biochemical test should be performed 6-8 hours and 24 hours after the first dose of venetoclax. All abnormalities in electrolyte balance must be corrected immediately. The patient should take the next dose of venetoclax only after assessing the results of the blood biochemical test from the sample taken 24 hours after the previous dose. The same monitoring scheme should be followed after the patient is switched to the 50 mg dose and then with each subsequent dose increase in patients who continue to have a high risk of TLS.

Based on the physician’s assessment, some patients, especially those at high risk for TLS, may require hospitalization on the day of the first dose of venetoclax for more intensive TLS prophylaxis and monitoring in the first 24 hours after the dose. Depending on the results of the repeated risk assessment, hospitalization should be considered for each subsequent dose increase.

Effect on ability to drive vehicles and operate machinery

Fatigue may occur during venetoclax use, which should be taken into account when assessing patients’ ability to drive vehicles and operate machinery.

Drug Interactions

Venetoclax is metabolized primarily by the CYP3A enzyme.

At the start of treatment and during the dose titration phase, concomitant use of venetoclax and moderate CYP3A inhibitors (e.g., erythromycin, ciprofloxacin, diltiazem, fluconazole, verapamil) should be avoided. The possibility of using alternative treatment options should be considered. If treatment with moderate CYP3A inhibitors is indicated for a patient, the initial and titrated doses of venetoclax must be reduced by at least 50%. Such patients should be more closely monitored for signs and symptoms of TLS.

In patients who have completed the dose titration phase and are taking a constant daily dose of venetoclax, the drug dose should be reduced by 50% when used concomitantly with moderate CYP3A inhibitors and by 75% when used concomitantly with strong CYP3A inhibitors. These patients should be monitored more closely for signs of toxicity and may require additional dose adjustment. Two to three days after discontinuation of the CYP3A inhibitor, venetoclax treatment can be resumed at the same dose that was used before starting the CYP3A inhibitor.

During venetoclax treatment, consumption of products containing grapefruit, Seville oranges, and star fruit (carambola) should be avoided, as these plants contain CYP3A inhibitors.

Venetoclax is a substrate for P-glycoprotein and breast cancer resistance protein inhibitors. In 11 healthy volunteers, concomitant single administration of 600 mg rifampin, a P-glycoprotein inhibitor, caused an increase in the C_max of venetoclax by 106% and the AUC_∞ by 78%. Concomitant use of venetoclax and P-glycoprotein and BCRP inhibitors should be avoided at the start of treatment and during the dose titration phase; if treatment with P-glycoprotein and BCRP inhibitors is indicated for patients, then careful monitoring for signs of toxicity should be carried out.

Concomitant use of venetoclax and strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin) or moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) should be avoided. The possibility of alternative treatment with less potent CYP3A inducers should be considered.

Concomitant use of Venetoclax and bile acid sequestrants is not recommended, as this may reduce the absorption of venetoclax. If it is necessary to use a bile acid sequestrant and Venetoclax concomitantly, the patient should follow the instructions in the bile acid sequestrant’s prescribing information to reduce the risk of drug interaction, and Venetoclax should be taken at least 4-6 hours after taking the sequestrant.

When venetoclax is used concomitantly in patients taking warfarin, careful monitoring of INR is recommended.

Concomitant use of substrates of P-glycoprotein or BCRP with a narrow therapeutic index (e.g., digoxin, dabigatran, everolimus, sirolimus) and venetoclax should be avoided.

If the use of a P-glycoprotein or BCRP substrate with a narrow therapeutic index is indicated, treatment should be prescribed with caution. The interval between oral administration of P-glycoprotein or BCRP substrates subject to inhibition in the gastrointestinal tract (e.g., dabigatran etexilate) and venetoclax should be as long as possible to minimize the likelihood of a drug interaction.

When statins (OATP substrates) and venetoclax are used concomitantly, careful monitoring for toxicity associated with statins is recommended.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

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