Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061, Ludwigshafen, Germany
Venclyxto in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) (see section 5.1).
Venclyxto in combination with rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy.
Venclyxto monotherapy is indicated for the treatment of CLL:
Venclyxto in combination with a hypomethylating agent is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy.
Treatment with venetoclax should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. Patients treated with venetoclax may develop tumour lysis syndrome (TLS). Information described in this section, including risk assessment, prophylactic measures, dose-titration schedule, laboratory monitoring, and drug interactions should be followed to prevent and reduce the risk of TLS.
The starting dose is 20 mg of venetoclax once daily for 7 days. The dose must be gradually increased over a period of 5 weeks up to the daily dose of 400 mg as shown in Table 1.
Table 1. Dose increase schedule in patients with CLL:
| Week | Venetoclax daily dose |
|---|---|
| 1 | 20 mg |
| 2 | 50 mg |
| 3 | 100 mg |
| 4 | 200 mg |
| 5 | 400 mg |
The 5-week dose-titration schedule is designed to gradually reduce tumour burden (debulk) and decrease the risk of TLS.
Venetoclax is given for a total of 12 cycles, each cycle consisting of 28 days: 6 cycles in combination with obinutuzumab, followed by 6 cycles of venetoclax as a single agent.
Administer obinutuzumab 100 mg on Cycle 1 Day 1, followed by 900 mg which may be administered on Day 1 or Day 2. Administer 1000 mg on Days 8 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle, for a total of 6 cycles.
Start the 5-week venetoclax dose-titration schedule (see Table 1) on Cycle 1 Day 22 and continue through Cycle 2 Day 28.
After completing the dose-titration schedule, the recommended dose of venetoclax is 400 mg once daily from Cycle 3 Day 1 of obinutuzumab to the last day of Cycle 12.
The recommended dose of venetoclax in combination with rituximab is 400 mg once daily (see section 5.1 for details of the combination regimen).
Administer rituximab after the patient has completed the dose-titration schedule and has received the recommended daily dose of 400 mg venetoclax for 7 days.
Venetoclax is taken for 24 months from Cycle 1 Day 1 of rituximab (see section 5.1).
The recommended dose of venetoclax is 400 mg once daily. Treatment is continued until disease progression or no longer tolerated by the patient.
The recommended venetoclax dosing schedule (including dose-titration) is shown in Table 2.
Table 2. Dose increase schedule in patients with AML:
| Day | Venetoclax daily dose |
|---|---|
| 1 | 100 mg |
| 2 | 200 mg |
| 3 and beyond | 400 mg |
Azacitidine should be administered at 75 mg/m² of body surface area (BSA) either intravenously or subcutaneously on Days 1-7 of each 28-day cycle beginning on Cycle 1 Day 1.
Decitabine should be administered at 20 mg/m² of BSA intravenously on Days 1-5 of each 28-day cycle beginning on Cycle 1 Day 1.
Venetoclax dosing may be interrupted as needed for management of hematologic toxicities and blood count recovery (see Table 6).
Venetoclax, in combination with a hypomethylating agent, should be continued until disease progression or unacceptable toxicity is observed.
Patients treated with venetoclax may develop TLS. The appropriate section below should be referred to for specific details on management by disease indication.
Venetoclax can cause rapid reduction in tumour, and thus poses a risk for TLS in the initial 5-week dose-titration phase in all patients with CLL, regardless of tumour burden and other patient characteristics. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of venetoclax and at each dose increase. Patient- specific factors for level of TLS risk should be assessed and prophylactic hydration and anti-hyperuricaemics should be provided to patients prior to first dose of venetoclax to reduce risk of TLS.
The risk of TLS is a continuum based on multiple factors, including comorbidities, particularly reduced renal function (creatinine clearance [CrCl] <80ml/min), and tumour burden. Splenomegaly may contribute to the overall TLS risk. The risk may decrease as tumour burden decreases with venetoclax treatment (see section 4.4).
Prior to initiating venetoclax, tumour burden assessment, including radiographic evaluation (e.g., CT scan), must be performed for all patients. Blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) should be assessed, and pre-existing abnormalities corrected.
Table 3 below describes the recommended TLS prophylaxis and monitoring during venetoclax treatment based on tumour burden determination from clinical study data (see section 4.4). In addition, all patient comorbidities should be considered for risk-appropriate prophylaxis and monitoring, either outpatient or in hospital.
Table 3. Recommended TLS prophylaxis based on tumour burden in patients with CLL:
| Tumour burden | Prophylaxis | Blood chemistry monitoringc,d | ||
|---|---|---|---|---|
| Hydrationa | Anti- hyperuricaemicsb | Setting and frequency of assessments | ||
| Low | All LN <5 cm AND ALC <25 x109/L | Oral (1.5-2 L) | Allopurinol | Outpatient • For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours • For subsequent dose increases: Pre-dose |
| Medium | Any LN 5 cm to <10 cm OR ALC ≥25 x109/L | Oral (1.5-2 L) and consider additional intravenous | Allopurinol | Outpatient • For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours • For subsequent dose increases: Pre-dose • For first dose of 20 mg and 50 mg: Consider hospitalisation for patients with CrCl <80ml/min; see below for monitoring in hospital |
| High | Any LN ≥10 cm OR ALC ≥25 x109/L AND any LN ≥5 cm | Oral (1.5-2 L) and intravenous (150-200 ml/hr as tolerated) | Allopurinol; consider rasburicase if baseline uric acid is elevated | In hospital • For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours Outpatient • For subsequent dose increases: Pre-dose, 6 to 8 hours, 24 hours |
ALC = absolute lymphocyte count; CrCl = creatinine clearance; LN = lymph node.
a Instruct patients to drink water daily starting 2 days before and throughout the dose-titration phase, specifically prior to and on the days of dosing at initiation and each subsequent dose increase. Administer intravenous hydration for any patient who cannot tolerate oral hydration.
b Start allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of venetoclax.
c Evaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in real time.
d At subsequent dose increases, monitor blood chemistries at 6 to 8 hours and at 24 hours for patients who continue to be at risk of TLS.
Dosing interruption and/or dose reduction for toxicities may be required. See Table 4 and Table 5 for recommended dose modifications for toxicities related to venetoclax.
Table 4. Recommended venetoclax dose modifications for toxicitiesa in CLL:
| Event | Occurrence | Action |
|---|---|---|
| Tumour lysis syndrome | ||
| Blood chemistry changes or symptoms suggestive of TLS | Any | Withhold the next day’s dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. |
| For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 5). | ||
| For any events of clinical TLS,b resume at a reduced dose following resolution (see Table 5). | ||
| Non-haematologic toxicities | ||
| Grade 3 or 4 non- haematologic toxicities | 1st occurrence | Interrupt venetoclax. Once the toxicity has resolved to Grade 1 or baseline level, venetoclax therapy may be resumed at the same dose. No dose modification is required. |
| 2nd and subsequent occurrences | Interrupt venetoclax. Follow dose reduction guidelines in Table 5 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician. | |
| Haematologic toxicities | ||
| Grade 3 neutropenia with infection or fever; or Grade 4 haematologic toxicities (except lymphopenia) | 1st occurrence | Interrupt venetoclax. To reduce the infection risks associated with neutropenia, granulocyte-colony stimulating factor (G-CSF) may be administered with venetoclax if clinically indicated. Once the toxicity has resolved to Grade 1 or baseline level, venetoclax therapy may be resumed at the same dose. |
| 2nd and subsequent occurrences | Interrupt venetoclax. Consider using G-CSF as clinically indicated. Follow dose reduction guidelines in Table 5 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician. | |
Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks.
a Adverse reactions were graded using NCI CTCAE version 4.0.
b Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or seizures and/or sudden death (see section 4.8).
Table 5. Dose modification for TLS and other toxicities for patients with CLL:
| Dose at interruption (mg) | Restart dose (mga) |
|---|---|
| 400 | 300 |
| 300 | 200 |
| 200 | 100 |
| 100 | 50 |
| 50 | 20 |
| 20 | 10 |
a The modified dose should be continued for 1 week before increasing the dose.
For patients who have had a dosing interruption lasting more than 1 week during the first 5 weeks of dose-titration or more than 2 weeks after completing the dose-titration phase, TLS risk should be reassessed to determine if restarting at a reduced dose is necessary (e.g., all or some levels of the dose-titration; see Table 5).
The venetoclax daily dose-titration is 3 days with azacitidine or decitabine (see Table 2).
Prophylaxis measures listed below should be followed: All patients should have white blood cell count <25 × 109/l prior to initiation of venetoclax and cytoreduction prior to treatment may be required.
All patients should be adequately hydrated and receive anti-hyperuricaemic agents prior to initiation of first dose of venetoclax and during dose-titration phase.
Assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) and correct pre-existing abnormalities prior to initiation of treatment with venetoclax.
Monitor blood chemistries for TLS at pre-dose, 6 to 8 hours after each new dose during titration and 24 hours after reaching final dose.
For patients with risk factors for TLS (e.g., circulating blasts, high burden of leukaemia involvement in bone marrow, elevated pretreatment lactate dehydrogenase [LDH] levels, or reduced renal function) additional measures should be considered, including increased laboratory monitoring and reducing venetoclax starting dose.
Monitor blood counts frequently through resolution of cytopenias. Dose modification and interruptions for cytopenias are dependent on remission status. Dose modifications of venetoclax for adverse reactions are provided in Table 6.
Table 6. Recommended dose modifications for adverse reactions in AML:
| Adverse Reaction | Occurrence | Dosage Modification |
|---|---|---|
| Haematologic Adverse Reactions | ||
| Grade 4 neutropenia (ANC <500/microlitre) with or without fever or infection; or grade 4 thrombocytopenia (platelet count <25 × 103/microlitre) | Occurrence prior to achieving remissiona | In most instances, do not interrupt venetoclax in combination with azacitidine or decitabine due to cytopenias prior to achieving remission. |
| First occurrence after achieving remission and lasting at least 7 days | Delay subsequent cycle of venetoclax in combination with azacitidine or decitabine and monitor blood counts. Administer granulocyte-colony stimulating factor (G-CSF) if clinically indicated for neutropenia. Upon resolution to grade 1 or 2, resume venetoclax at the same dose in combination with azacitidine or decitabine. | |
| Subsequent occurrences in cycles after achieving remission and lasting 7 days or longer | Delay subsequent cycle of venetoclax in combination with azacitidine or decitabine and monitor blood counts. Administer G-CSF if clinically indicated for neutropenia. Upon resolution to grade 1 or 2, resume venetoclax at the same dose in combination with azacitidine or decitabine, and reduce venetoclax duration by 7 days during each of the subsequent cycles, such as 21 days instead of 28 days. Refer to the azacitidine prescribing information for additional information. | |
| Non-Hematologic Adverse Reactions | ||
| Grade 3 or 4 non- hematologic toxicities | Any occurrence | Interrupt venetoclax if not resolved with supportive care. Upon resolution to grade 1 or baseline level, resume venetoclax at the same dose. |
a Consider bone marrow evaluation.
Concomitant use of venetoclax with strong or moderate CYP3A inhibitors increases venetoclax exposure (i.e., Cmax and AUC) and may increase the risk for TLS at initiation and during the dose-titration phase and for other toxicities (see section 4.5).
In patients with CLL, concomitant use of venetoclax with strong CYP3A inhibitors is contraindicated at initiation and during the dose-titration phase (see sections 4.3, 4.4, and 4.5).
In all patients, if a CYP3A inhibitor must be used, follow the recommendations for managing drug-drug interactions summarized in Table 7. Patients should be monitored more closely for signs of toxicities and the dose may need to be further adjusted. The venetoclax dose that was used prior to initiating the CYP3A inhibitor should be resumed 2 to 3 days after discontinuation of the inhibitor (see sections 4.3, 4.4 and 4.5).
Table 7. Management of potential venetoclax interactions with CYP3A inhibitors:
| Inhibitor | Phase | CLL | AML |
|---|---|---|---|
| Strong CYP3A inhibitor | Initiation and dose- titration phase | Contraindicated | Day 1 – 10 mg Day 2 – 20 mg Day 3 – 50 mg Day 4 – 100 mg or less |
| Steady daily dose (After dose-titration phase) | Reduce the venetoclax dose to 100 mg or less (or by at least 75% if already modified for other reasons) | ||
| Moderate CYP3A inhibitora | All | Reduce the venetoclax dose by at least 50% | |
a In patients with CLL, avoid concomitant use of venetoclax with moderate CYP3A inhibitors at initiation and during the dose-titration phase. Consider alternative medicinal products or reduce the venetoclax dose as described in this table.
If a patient misses a dose of venetoclax within 8 hours of the time it is usually taken, the patient should take the missed dose as soon as possible on the same day. If a patient misses a dose by more than 8 hours, the patient should not take the missed dose and should resume the usual dosing schedule the following day.
If a patient vomits following dosing, no additional dose should be taken that day. The next prescribed dose should be taken at the usual time the following day.
No specific dose adjustment is required for elderly patients (aged ≥65 years) (see section 5.1).
Patients with reduced renal function (CrCl <80 ml/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS at initiation and during the dose-titration phase (see “Prevention of tumour lysis syndrome (TLS)” above). Venetoclax should be administered to patients with severe renal impairment (CrCl ≥15 ml/min and <30 ml/min) only if the benefit outweighs the risk and patients should be monitored closely for signs of toxicity due to increased risk of TLS (see section 4.4).
No dose adjustment is needed for patients with mild, moderate or severe renal impairment (CrCl ≥15 ml/min and <90 ml/min) (see section 5.2).
No dose adjustment is recommended in patients with mild or moderate, hepatic impairment. Patients with moderate hepatic impairment should be monitored more closely for signs of toxicity at initiation and during the dose-titration phase (see section 4.8).
A dose reduction of at least 50% throughout treatment is recommended for patients with severe hepatic impairment (see section 5.2). These patients should be monitored more closely for signs of toxicity (see section 4.8).
The safety and efficacy of venetoclax in children aged less than 18 years have not been established. No data are available.
Venclyxto film-coated tablets are for oral use. Patients should be instructed to swallow the tablets whole with water at approximately the same time each day. The tablets should be taken with a meal in order to avoid a risk for lack of efficacy (see section 5.2). The tablets should not be chewed, crushed, or broken before swallowing.
During the dose-titration phase, venetoclax should be taken in the morning to facilitate laboratory monitoring.
Grapefruit products, Seville oranges, and starfruit (carambola) should be avoided during treatment with venetoclax (see section 4.5).
There is no specific antidote for venetoclax. Patients who experience overdose should be closely monitored and appropriate supportive treatment provided. During dose-titration phase, treatment should be interrupted, and patients should be monitored carefully for signs and symptoms of TLS (fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, muscle or joint pain, abdominal pain, and distension) along with other toxicities (see section 4.2). Based on venetoclax large volume of distribution and extensive protein binding, dialysis is unlikely to result in significant removal of venetoclax.
Venclyxto 10 mg film-coated tablets: 2 years.
Venclyxto 50 mg film-coated tablets: 2 years.
Venclyxto 100 mg film-coated tablets: 3 years.
This medicinal product does not require any special storage conditions.
Venclyxto film-coated tablets are supplied in PVC/PE/PCTFE aluminium foil blisters containing either 1, 2 or 4 film-coated tablets.
Venclyxto 10 mg film-coated tablets: The film-coated tablets are supplied in cartons containing either 10 or 14 tablets (in blisters of 2 tablets).
Venclyxto 50 mg film-coated tablets: The film-coated tablets are supplied in cartons containing either 5 or 7 tablets (in blisters of 1 tablet).
Venclyxto 100 mg film-coated tablets: The film-coated tablets are supplied in cartons containing either 7 (in blisters of 1 tablet) or 14 tablets (in blisters of 2 tablets); or a multipack containing 112 tablets (4 × 28 tablets (in blisters of 4 tablets)).
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
