Venclyxto

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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This medicinal product is subject to additional monitoring. This will allow quick identification of new 
safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 
4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Venclyxto 10 mg film-coated tablets 
Venclyxto 50 mg film-coated tablets 
Venclyxto 100 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Venclyxto 10 mg film-coated tablets 
Each film-coated tablet contains 10 mg of venetoclax. 
 
Venclyxto 50 mg film-coated tablets 
Each film-coated tablet contains 50 mg of venetoclax. 
 
Venclyxto 100 mg film-coated tablets 
Each film-coated tablet contains 100 mg of venetoclax. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
Venclyxto 10 mg film-coated tablet  
Pale yellow, round biconvex shaped tablet 6 mm diameter debossed with V on one side and 10 on the other.  
 
Venclyxto 50 mg film-coated tablet  
Beige, oblong biconvex shaped tablet 14 mm long, 8 mm wide debossed with V on one side and 50 on the 
other.  
 
Venclyxto 100 mg film-coated tablet  
Pale yellow, oblong biconvex shaped tablet 17.2 mm long, 9.5 mm wide debossed with V on one side and 
100 on the other.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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: 

 in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have 
failed a B-cell receptor pathway inhibitor, or 

 in the absence of 17p deletion or TP53 mutation in adult patients who have failed both 
chemoimmunotherapy and a B-cell receptor pathway inhibitor. 



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4.2 Posology and method of administration 
 
Treatment with venetoclax should be initiated and supervised by a physician experienced in the use of 
anticancer medicinal products. 
 
Posology 
 
Dose-titration schedule 
 
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 
 

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 tumour lysis syndrome.  
 
Venetoclax in combination with obinutuzumab 
 
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. 
 
Post-titration dose for venetoclax in combination with rituximab 
 
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). 
 
Post-titration dose for venetoclax monotherapy 
 
The recommended dose of venetoclax is 400 mg once daily. Treatment is continued until disease progression 
or no longer tolerated by the patient. 
 



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Prevention of tumour lysis syndrome (TLS) 
Venetoclax can cause rapid reduction in tumour, and thus poses a risk for TLS in the initial 5-week 
dose-titration phase. 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. 
 
The risk of TLS is a continuum based on multiple factors, including comorbidities. Patients with high tumour 
burden (e.g., any lymph node with a diameter ≥5 cm or high absolute lymphocyte count [ALC ≥25 x 109/l]) 
are at greater risk of TLS when initiating venetoclax. Reduced renal function (creatinine clearance 
[CrCl] <80 ml/min) further increases the 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. The prophylaxis measures listed 
below should be followed. More intensive measures should be employed as overall risk increases. 
 
Hydration  
Patients should be adequately hydrated during the dose-titration phase to reduce the risk of TLS. Patients 
should be instructed to drink plenty of water daily starting 2 days before and throughout the dose-titration 
phase. Patients should be particularly instructed to drink 1.5 to 2.0 L of water daily, 2 days prior to and the 
days of dosing at initiation and each subsequent dose increase. Intravenous fluids should be administered as 
indicated based on overall risk of TLS or for those who cannot maintain an adequate level of oral hydration. 
 
Anti-hyperuricaemic agents 
Anti-hyperuricaemic agents should be administered 2 to 3 days prior to starting treatment with venetoclax in 
patients with high uric acid levels or at risk of TLS and may be continued through the titration phase.  
 
Laboratory assessments 
Pre-dose: For all patients, blood chemistries should be assessed prior to the initial dose to evaluate kidney 
function and correct pre-existing abnormalities. Blood chemistries should be reassessed prior to each 
subsequent dose increase during the titration phase. 
 
Post-dose: For patients at risk of TLS, blood chemistries should be monitored at 6 to 8 hours and at 24 hours 
after the first dose of venetoclax. Electrolyte abnormalities should be corrected promptly. The next 
venetoclax dose should not be administered until the 24-hour blood chemistry results have been evaluated. 
The same monitoring schedule should be followed at the start of the 50 mg dose and then for patients who 
continue to be at risk, at subsequent dose increases.  
 
Hospitalisation  
Based on physician assessment, some patients, especially those at greater risk of TLS, may require 
hospitalisation on the day of the first dose of venetoclax for more intensive prophylaxis and monitoring 
during the first 24 hours (see section 4.8). Hospitalisation should be considered for subsequent dose increases 
based on reassessment of risk.  
 
Dose modifications for tumour lysis syndrome 
If a patient experiences blood chemistry changes suggestive of TLS, the following day’s venetoclax dose 
should be withheld. If resolved within 24 to 48 hours of last dose, treatment with venetoclax can be resumed 
at the same dose. For events of clinical TLS or blood chemistry changes requiring more than 48 hours to 
resolve, treatment should be resumed at a reduced dose (see Table 2). When resuming treatment after 
interruption due to TLS, the instructions for prevention of TLS should be followed (see “Prevention of 
tumour lysis syndrome” above).  
 
Dose modifications for other toxicities 
Treatment with Venclyxto should be withheld for any grade 3 or 4 non-haematological toxicities, grade 3 or 
4 neutropenia with infection or fever, or grade 4 haematological toxicities, except lymphopenia. Once the 
toxicity has resolved to grade 1 or baseline level (recovery), therapy with venetoclax may be restarted at the 
same dose. If the toxicity recurs, and for any subsequent occurrences, the dose reduction guidelines in 



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Table 2 should be followed when resuming treatment with venetoclax following resolution. A larger dose 
reduction may occur at the discretion of the physician. For patients who require dose reductions to less than 
100 mg for more than 2 weeks, discontinuation of venetoclax should be considered.  
 
Table 2: Dose modification for TLS and other toxicities 
 

Dose at interruption 
(mg) 

 

Restart dose 
(mga) 

400 300 

300 200 
200 100 
100 50 
50 20 
20 10 

aThe 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 
2). 
 
Dose modifications for use with CYP3A inhibitors 
Concomitant use of venetoclax with strong or moderate CYP3A inhibitors increases venetoclax exposure and 
may increase the risk for TLS at initiation and during the dose-titration phase and for other toxicities (see 
section 4.5).  
 
Table 3 describes Venclyxto contraindication or dosage modification based on concomitant use with a strong 
or moderate CYP3A inhibitor. 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 3: Management of potential Venclyxto interactions with CYP3A inhibitors 

Inhibitors 
Initiation and titration 

phase a 
Steady daily dose 

(After titration phase) 
Strong CYP3A inhibitor Contraindicated Reduce the Venclyxto dose by at least 75% 

Moderate CYP3A inhibitor Reduce the Venclyxto dose by at least 50% 
aAvoid concomitant use of Venclyxto with moderate CYP3A inhibitors at initiation and during the dose 
titration phase. Consider alternative medications or reduce the Venclyxto dose as described in this table. 
 
Missed dose 
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. 
 
Special populations 
 
Elderly 
 



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No specific dose adjustment is required for elderly patients (aged ≥65 years) (see section 5.1). 
 
Renal impairment 
No dose adjustment is needed for patients with mild or moderate renal impairment (CrCl ≥30 ml/min and 
<90 ml/min) (see section 5.2). 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” above). Safety in patients with severe renal impairment 
(CrCl <30 ml/min) or on dialysis has not been established, and a recommended dose for these patients has 
not been determined. Venetoclax should be administered to patients with severe renal impairment 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).  
 
Hepatic impairment 
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). 
 
Paediatric population 
The safety and efficacy of venetoclax in children aged less than 18 years have not been established. No data 
are available. 
 
Method of administration  
 
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). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  
 
Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase (see sections 
4.2 and 4.5). 
 
Concomitant use of preparations containing St. John’s wort (see sections 4.4 and 4.5). 
 
4.4 Special warnings and precautions for use 
 
Tumour lysis syndrome 
 
Tumour lysis syndrome, including fatal events, has occurred in patients with CLL with high tumour burden 
when treated with venetoclax (see section 4.8). 
 
Venetoclax can cause rapid reduction in tumour, and thus poses a risk for TLS in the initial 5-week 
dose-titration phase. 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. 



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The risk of TLS is a continuum based on multiple factors, including comorbidities. Patients with high tumour 
burden (e.g., any lymph node with a diameter ≥5 cm or high ALC ≥25 x 109/l) are at greater risk of TLS 
when initiating venetoclax. Reduced renal function (CrCl <80 ml/min) further increases the risk. Patients 
should be assessed for risk and should receive appropriate prophylaxis for TLS, including hydration and 
anti-hyperuricaemics. Blood chemistries should be monitored and abnormalities managed promptly. Dosing 
should be interrupted if needed (see section 4.2). More intensive measures (intravenous hydration, frequent 
monitoring, hospitalisation) should be employed as overall risk increases. The instructions for “Prevention of 
tumour lysis syndrome” should be followed (see section 4.2).  
 
Concomitant use of this medicinal product with strong or moderate CYP3A inhibitors increases venetoclax 
exposure and may increase the risk for TLS at initiation and during the dose-titration phase (see sections 4.2 
and 4.3). Also, inhibitors of P-gp or BCRP may increase venetoclax exposure (see section 4.5). 
 
Neutropenia and infections 
 
Grade 3 or 4 neutropenia has been reported in patients treated with venetoclax in combination studies with 
rituximab or obinutuzumab and in monotherapy studies (see section 4.8). Complete blood counts should be 
monitored throughout the treatment period. Dose interruptions or reductions are recommended for patients 
with severe neutropenia (see section 4.2). 
 
Serious infections, including sepsis with fatal outcome, have been reported (see section 4.8). Monitoring of 
any signs and symptoms of infection is required. Suspected infections are to receive prompt treatment, 
including antimicrobials and dose interruption or reduction as appropriate (see section 4.2). 
 
Immunisation 
 
The safety and efficacy of immunisation with live attenuated vaccines during or following venetoclax 
therapy have not been studied. Live vaccines should not be administered during treatment and thereafter until 
B-cell recovery. 
 
CYP3A inducers 
 
Co-administration of CYP3A4 inducers may lead to decreased venetoclax exposure and consequently a risk 
for lack of efficacy. Concomitant use of venetoclax with strong or moderate CYP3A4 inducers should be 
avoided (see sections 4.3 and 4.5). 
 
Women of childbearing potential 
 
Women of childbearing potential must use a highly effective method of contraception while taking 
venetoclax (see section 4.6). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Venetoclax is predominantly metabolised by CYP3A.  
 
Agents that may alter venetoclax plasma concentrations 
 
CYP3A inhibitors 
Co-administration of 400 mg once daily ketoconazole, a strong CYP3A, P-gp and BCRP inhibitor, for 7 days 
in 11 previously treated patients with NHL increased venetoclax Cmax by 2.3-fold and AUC∞ by 6.4-fold. Co-
administration of 50 mg once daily ritonavir, a strong CYP3A and P-gp inhibitor, for 14 days in 6 healthy 
subjects increased venetoclax Cmax by 2.4-fold and AUC by 7.9-fold. Co-administration of venetoclax with 
other strong CYP3A4 inhibitors is predicted to increase venetoclax AUC by on average 5.8- to 7.8-fold.  
 



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Concomitant use of venetoclax with strong CYP3A inhibitors (e.g., itraconazole, ketoconazole, 
posaconazole, voriconazole, clarithromycin, ritonavir) at initiation and during the dose-titration phase is 
contraindicated due to increased risk for TLS (see section 4.3). 
 
At initiation and during the dose-titration phase, concomitant use of venetoclax with moderate CYP3A 
inhibitors (e.g., ciprofloxacin, diltiazem, erythromycin, fluconazole, verapamil) should be avoided. 
Alternative treatments should be considered. If a moderate CYP3A inhibitor must be used, the initiation dose 
of venetoclax and the doses for the titration phase (see section 4.2) should be reduced by at least 50%. 
Patients should be monitored more closely for signs and symptoms of TLS.  
 
For patients who have completed the dose-titration phase and are on a steady daily dose of venetoclax, the 
venetoclax dose should be reduced by 50% when used concomitantly with moderate CYP3A inhibitors and 
by 75% when used concomitantly with strong CYP3A inhibitors. 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 
section 4.2).  
 
Grapefruit products, Seville oranges, and starfruit (carambola) should be avoided during treatment with 
venetoclax as they contain inhibitors of CYP3A. 
 
P-gp and BCRP inhibitors 
Venetoclax is a substrate for P-gp and BCRP. Co-administration of a 600 mg single dose of rifampin, a P-gp 
inhibitor, in 11 healthy subjects increased venetoclax Cmax by 106% and AUC∞ by 78%. Concomitant use of 
venetoclax with P-gp and BCRP inhibitors at initiation and during the dose-titration phase should be 
avoided; if a P-gp and BCRP inhibitor must be used, patients should be monitored closely for signs of 
toxicities (see section 4.4).  
 
CYP3A inducers 
Co-administration of 600 mg once daily rifampin, a strong CYP3A inducer, for 13 days in 10 healthy 
subjects decreased venetoclax Cmax by 42% and AUC∞ by 71%. Concomitant use of venetoclax with strong 
CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin) or moderate CYP3A inducers (e.g., bosentan, 
efavirenz, etravirine, modafinil, nafcillin) should be avoided. Alternative treatments with less CYP3A 
induction should be considered. Preparations containing St. John's wort are contraindicated during treatment 
with venetoclax, as efficacy may be reduced (see section 4.3). 
 
Azithromycin 
In a drug-drug interaction study in 12 healthy subjects, co-administration of 500 mg of azithromycin on the 
first day followed by 250 mg of azithromycin once daily for 4 days decreased venetoclax Cmax by 25% and 
AUC∞ by 35%. No dose adjustment is needed during short-term use of azithromycin when administered 
concomitantly with venetoclax. 
 
Gastric acid reducing agents 
Based on population pharmacokinetic analysis, gastric acid reducing agents (e.g., proton pump inhibitors, 
H2-receptor antagonists, antacids) do not affect venetoclax bioavailability. 
 
Bile acid sequestrants 
Co-administration of bile acid sequestrants with venetoclax is not recommended as this may reduce the 
absorption of venetoclax. If a bile acid sequestrant is to be co-administered with venetoclax, the SmPC for 
the bile acid sequestrant should be followed to reduce the risk for an interaction, and venetoclax should be 
administered at least 4-6 hours after the sequestrant. 
 
Agents that may have their plasma concentrations altered by venetoclax 
 
Warfarin 
In a drug-drug interaction study in three healthy volunteers, administration of a single dose of 400 mg 
venetoclax with 5 mg warfarin resulted in an 18% to 28% increase in Cmax and AUC∞ of R-warfarin and 



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S-warfarin. Because venetoclax was not dosed to steady state, it is recommended that the international 
normalized ratio (INR) be monitored closely in patients receiving warfarin. 
 
Substrates of P-gp, BCRP, and OATP1B1 
Venetoclax is a P-gp, BCRP and OATP1B1 inhibitor in vitro. In a drug-drug interaction study, 
administration of a single 100 mg dose of venetoclax with 0.5 mg digoxin, a P-gp substrate, resulted in a 
35% increase in digoxin Cmax and a 9% increase in digoxin AUC∞. Co-administration of narrow therapeutic 
index P-gp, or BCRP substrates (e.g., digoxin, dabigatran, everolimus, sirolimus) with venetoclax should be 
avoided.  
 
If a narrow therapeutic index P-gp or BCRP substrate must be used, it should be used with caution. For an 
orally administered P-gp or BCRP substrate sensitive to inhibition in the gastrointestinal tract (e.g., 
dabigatran exetilate), its administration should be separated from venetoclax administration as much as 
possible to minimise a potential interaction.  
 
If a statin (OATP substrate) is used concomitantly with venetoclax, close monitoring of statin-related toxicity 
is recommended. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/Contraception in females  
 
Women should avoid becoming pregnant while taking Venclyxto and for at least 30 days after ending 
treatment. Therefore, women of childbearing potential must use highly effective contraceptive measures 
while taking venetoclax and for 30 days after stopping treatment. It is currently unknown whether venetoclax 
may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal 
contraceptives should add a barrier method.  
 
Pregnancy 
 
Based on embryo-foetal toxicity studies in animals (see section 5.3), venetoclax may harm the foetus when 
administered to pregnant women.  
 
There are no adequate and well-controlled data from the use of venetoclax in pregnant women. Studies in 
animals have shown reproductive toxicity (see section 5.3). Venetoclax is not recommended during 
pregnancy and in women of childbearing potential not using highly effective contraception.  
 
Breast-feeding 
 
It is unknown whether venetoclax or its metabolites are excreted in human milk. 
 
A risk to the breast-feeding child cannot be excluded. 
 
Breast-feeding should be discontinued during treatment with Venclyxto.   
 
Fertility 
 
No human data on the effect of venetoclax on fertility are available. Based on testicular toxicity in dogs at 
clinically relevant exposures, male fertility may be compromised by treatment with venetoclax (see section 
5.3). Before starting treatment, counselling on sperm storage may be considered in some male patients. 
 
4.7 Effects on ability to drive and use machines 
 
Venclyxto has no or negligible influence on the ability to drive and use machines. Fatigue has been reported 
in some patients taking venetoclax and should be considered when assessing a patient’s ability to drive or 
operate machines. 
 



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4.8 Undesirable effects 
 
Summary of safety profile 
 
The overall safety profile of Venclyxto is based on data from 758 patients with CLL treated in clinical trials 
with venetoclax in combination with obinutuzumab or rituximab or as monotherapy. The safety analysis 
included patients from two phase 3 studies (CLL14 and MURANO), two phase 2 studies (M13-982 and 
M14-032), and one phase 1 study (M12-175). CLL14 was a randomised, controlled trial in which 212 
patients with previously untreated CLL and comorbidities received venetoclax in combination with 
obinutuzumab. MURANO was a randomised, controlled trial in which 194 patients with previously treated 
CLL received venetoclax in combination with rituximab. In the phase 2 and phase 1 studies, 352 patients 
with previously treated CLL, which included 212 patients with 17p deletion and 146 patients who had failed 
a B-cell receptor pathway inhibitor were treated with venetoclax monotherapy (see section 5.1). 
 
The most commonly occurring adverse reactions (≥20%) of any grade in patients receiving venetoclax in the 
combination studies with obinutuzumab or rituximab were neutropenia, diarrhoea, and upper respiratory tract 
infection. In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count 
decreased, diarrhoea, nausea, anaemia, fatigue, and upper respiratory tract infection. 
 
The most frequently reported serious adverse reactions (≥2%) in patients receiving venetoclax in 
combination with obinutuzumab or rituximab were pneumonia, sepsis, febrile neutropenia, and TLS. In the 
monotherapy studies, the most frequently reported serious adverse reactions (≥2%) were pneumonia and 
febrile neutropenia. 
 
Tabulated list of adverse reactions 
 
The frequencies of adverse reactions reported with Venclyxto, either in combination with obinutuzumab or 
rituximab or as monotherapy, are summarised in Table 4. Adverse reactions are listed below by MedDRA 
body system organ class and by frequency. Frequencies are defined as very common (≥1/10), common 
(≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not 
known (cannot be estimated from available data). Within each frequency grouping, undesirable effects are 
presented in order of decreasing seriousness. 
 



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Table 4: Adverse drug reactions reported in patients with CLL treated with venetoclax 

System organ class 
Frequency (all 

grades)a 
Adverse reactions 

 
Grade ≥3a 

Infections and 
infestations 

Very common 
Pneumonia 
Upper respiratory tract 
infection 

 

Common 
Sepsis 
Urinary tract infection 
 

Sepsis 
Pneumonia  
Urinary tract infection  
Upper respiratory tract infection

Blood and lymphatic 
system disorders 

Very common Neutropenia Anaemia  
Lymphopenia

Neutropenia  
Anaemia 

Common Febrile neutropenia  

 
Febrile neutropenia 
Lymphopenia 

Metabolism and 
nutrition disorders 
 

Very common 
Hyperkalaemia 
Hyperphosphataemia 
Hypocalcaemia

 

Common 
Tumour lysis syndrome 
Hyperuricaemia 
 

Tumour lysis syndrome 
Hyperkalaemia 
Hyperphosphataemia 
Hypocalcaemia 
Hyperuricaemia 

Gastrointestinal 
disorders  

Very common 

Diarrhoea 
Vomiting 
Nausea 
Constipation

 

Common  
Diarrhoea 
Vomiting 
Nausea 

Uncommon  
Constipation 

General disorders 
and administration 
site conditions 
 

Very common Fatigue 
 

Common  
Fatigue 

Investigations 
 

Common Blood creatinine increased
 

Uncommon  Blood creatinine increased 
aOnly the highest frequency observed in the trials is reported (based on studies CLL14, MURANO, M13-
982, M14-032, and M12-175). 

 
Discontinuation and dose reductions due to adverse reactions 
Discontinuations due to adverse reactions occurred in 16% of patients treated with venetoclax in 
combination with obinutuzumab or rituximab in the CLL14 and MURANO studies, respectively.  In the 
monotherapy studies with venetoclax, 11% of patients discontinued due to adverse reactions. 
 
Dosage reductions due to adverse reactions occurred in 21% of patients treated with the combination of 
venetoclax and obinutuzumab in the CLL14 study, in 15% of patients treated with the combination of 



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venetoclax and rituximab in the MURANO study and 14% of patients treated with venetoclax in the 
monotherapy studies. 
 
Dose interruptions due to adverse reactions occurred in 74% of patients treated with the combination of 
venetoclax and obinutuzumab in the CLL14 study and in 71% of patients treated with the combination of 
venetoclax and rituximab in the MURANO study; the most common adverse reaction that led to dose 
interruption of venetoclax was neutropenia (41% and 43% in the CLL14 and MURANO studies, 
respectively). In the monotherapy studies with venetoclax, dose interruptions due to adverse reactions 
occurred in 40% of patients; the most common adverse reaction leading to dose interruption was neutropenia 
(5%). 
 
Description of selected adverse reactions 
 
Tumour lysis syndrome 
Tumour lysis syndrome is an important identified risk when initiating venetoclax. In the initial Phase 1 
dose-finding studies, which had a shorter (2 to 3 week) titration phase and higher starting dose, the incidence 
of TLS was 13% (10/77; 5 laboratory TLS; 5 clinical TLS), including 2 fatal events and 3 events of acute 
renal failure, 1 requiring dialysis.  
 
The risk of TLS was reduced after revision of the dosing regimen and modification to prophylaxis and 
monitoring measures. In venetoclax clinical studies, patients with any measurable lymph node ≥10 cm or 
those with both an ALC ≥25 x 109/l and any measurable lymph node ≥5 cm were hospitalised to enable more 
intensive hydration and monitoring for the first day of dosing at 20 mg and 50 mg during the titration phase 
(see section 4.2).  
 
In 168 patients with CLL starting with a daily dose of 20 mg and increasing over 5 weeks to a daily dose of 
400 mg in studies M13-982 and M14-032, the rate of TLS was 2%. All events were laboratory TLS 
(laboratory abnormalities that met ≥2 of the following criteria within 24 hours of each other: 
potassium >6 mmol/l, uric acid >476 µmol/l, calcium <1.75 mmol/l, or phosphorus >1.5 mmol/l; or were 
reported as TLS events) and occurred in patients who had a lymph node(s) ≥5 cm or ALC ≥25 x 109/l. No 
TLS with clinical consequences such as acute renal failure, cardiac arrhythmias or sudden death and/or 
seizures was observed in these patients. All patients had CrCl ≥50 ml/min. 
 
In the open-label, randomised phase 3 study (MURANO), the incidence of TLS was 3% (6/194) in patients 
treated with venetoclax + rituximab. After 77/389 patients were enrolled in the study, the protocol was 
amended to incorporate the current TLS prophylaxis and monitoring measures described in Posology (see 
section 4.2). All events of TLS occurred during the venetoclax dose-titration phase and resolved within two 
days. All six patients completed the dose titration and reached the recommended daily dose of 400 mg of 
venetoclax. No clinical TLS was observed in patients who followed the current 5-week dose-titration 
schedule and TLS prophylaxis and monitoring measures (see section 4.2). The rates of grade ≥3 laboratory 
abnormalities relevant to TLS were hyperkalaemia 1%, hyperphosphataemia 1%, and hyperuricaemia 1%. 
 
In the open-label, randomised phase 3 study (CLL14), the incidence of TLS was 1.4% (3/212) in patients 
treated with venetoclax + obinutuzumab. All three events of TLS resolved and did not lead to withdrawal 
from the study. Obinutuzumab administration was delayed in two cases in response to the TLS events. 
 

 Neutropenia and infections 
 Neutropenia is an identified risk with Venclyxto treatment. In the CLL14 study, neutropenia (all grades) was 

reported in 58% of patients in the venetoclax + obinutuzumab arm; 41% of patients treated with 
venetoclax + obinutuzumab experienced dose interruption and 2% of patients discontinued venetoclax due to 
neutropenia. Grade 3 neutropenia was reported in 25% of patients and grade 4 neutropenia in 28% of 
patients. The median duration of grade 3 or 4 neutropenia was 22 days (range: 2 to 363 days). Febrile 
neutropenia was reported in 6% of patients, grade ≥3 infections in 19%, and serious infections in 19% of 
patients. Deaths due to infection occurred in 1.9% of patients while on treatment and 1.9% of patients 
following treatment discontinuation. 

 In the MURANO study, neutropenia (all grades) was reported in 61% of patients in the 
venetoclax + rituximab arm. Forty-three percent of patients treated with venetoclax + rituximab experienced 



13 

dose interruption and 3% of patients discontinued venetoclax due to neutropenia. Grade 3 neutropenia was 
reported in 32% of patients and grade 4 neutropenia in 26% of patients. The median duration of grade 3 or 4 
neutropenia was 8 days (range: 1 to 712 days). With venetoclax + rituximab treatment, febrile neutropenia 
was reported in 4% of patients, grade ≥3 infections in 18%, and serious infections in 21% of patients.  

  
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked 
to report any suspected adverse reactions via the national reporting system listed in Appendix V. 
 
4.9 Overdose 
 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: other antineoplastic agents, ATC code: L01XX52 
 
Mechanism of action 
 
Venetoclax is a potent, selective inhibitor of B-cell lymphoma (BCL)-2, an anti-apoptotic protein. 
Overexpression of BCL-2 has been demonstrated in CLL cells where it mediates tumour cell survival and 
has been associated with resistance to chemotherapeutics. Venetoclax binds directly to the BH3-binding 
groove of BCL-2, displacing BH3 motif-containing pro-apoptotic proteins like BIM, to initiate mitochondrial 
outer membrane permeabilization (MOMP), caspase activation, and programmed cell death. In non-clinical 
studies, venetoclax has demonstrated cytotoxic activity in tumour cells that overexpress BCL-2. 
 
Pharmacodynamic effects 
 
Cardiac electrophysiology 
The effect of multiple doses of venetoclax up to 1200 mg once daily on the QTc interval was evaluated in an 
open-label, single-arm study in 176 patients. Venetoclax had no effect on QTc interval and there was no 
relationship between venetoclax exposure and change in QTc interval. 
 
Clinical efficacy and safety 
 
Venetoclax in combination with obinutuzumab for the treatment of patients with previously untreated CLL – 
study BO25323 (CLL14) 
A randomised (1:1), multicenter, open-label phase 3 study evaluated the efficacy and safety of 
venetoclax + obinutuzumab versus obinutuzumab + chlorambucil in patients with previously untreated CLL 
and comorbidities (total Cumulative Illness Rating Scale [CIRS] score >6 or creatinine clearance [CrCl] 
<70 ml/min). Patients in the study were assessed for risk of TLS and received prophylaxis accordingly prior 
to obinutuzumab administration. All patients received obinutuzumab at 100 mg on Cycle 1 Day 1, followed 
by 900 mg which could have been administered on Day 1 or Day 2, then 1000 mg doses on Days 8 and 15 of 
Cycle 1, and on Day 1 of each subsequent cycle, for a total of 6 cycles. On Day 22 of Cycle 1, patients in the 
venetoclax + obinutuzumab arm began the 5-week venetoclax dose-titration schedule, continuing through 
Cycle 2 Day 28. Upon completion of the dose-titration schedule, patients continued venetoclax 400 mg once 



14 

daily from Cycle 3 Day 1 until the last day of Cycle 12. Each cycle was 28 days. Patients randomised to the 
obinutuzumab + chlorambucil arm received 0.5 mg/kg oral chlorambucil on Day 1 and Day 15 of Cycles 
1-12. Patients continued to be followed for disease progression and overall survival after completing therapy. 
 
Baseline demographic and disease characteristics were similar between the study arms. The median age was 
72 years (range: 41 to 89 years), 89% were white, and 67% were male; 36% and 43% were Binet stage B and 
C, respectively. The median CIRS score was 8.0 (range: 0 to 28) and 58% of patients had CrCl <70 ml/min. 
A 17p deletion was detected in 8% of patients, TP53 mutations in 10%, 11q deletion in 19%, and unmutated 
IgVH in 57%. The median follow-up at the time of the primary analysis was 28 months (range: 0 to 
36 months). 
 
At baseline, the median lymphocyte count was 55 x 109 cells/l in both study arms. On Cycle 1 Day 15, the 
median count had decreased to 1.03 x 109 cells/l (range: 0.2 to 43.4 x 109 cells/l) in the 
obinutuzumab + chlorambucil arm and 1.27 x 109 cells/l (range: 0.2 to 83.7 x 109 cells/l) in the 
venetoclax + obinutuzumab arm. 
 
Progression-free survival (PFS) was assessed by investigators and by an Independent Review Committee 
(IRC) using the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National 
Cancer Institute-sponsored Working Group (NCI-WG) guidelines (2008). 
 
Efficacy results for investigator-assessed PFS at the time of the primary analysis (data cut-off date 17 August 
2018) are shown in Table 5. 
 
Table 5: Investigator-assessed progression-free survival in patients with previously untreated CLL in CLL14 
(primary analysis) 
 

 Venetoclax + 
obinutuzumab 

(N = 216 )

Obinutuzumab + chlorambucil
(N = 216) 

Number of events (%)   30 (14) 77 (36) 
    Median, months (95% CI)  NR NR 
    Hazard ratio (95% CI) 0.35 (0.23, 0.53) 
    P-valuea <0.0001
    12-month PFS estimate (95% CI) 94.6 (91.5, 97.7) 92.2 (88.4, 95.8) 
    24-month PFS estimate (95% CI) 88.2 (83.7, 95.1) 64.1 (57.4, 70.8)
CI = confidence interval; NR = not reached 
aStratified P-value. 

 
At an updated efficacy analysis (data cut-off date 23 August 2019 and median follow-up of 40 months), the 
median PFS had not been reached in the venetoclax + obinutuzumab arm and was 35.6 months [95% CI: 
33.7,40.7] in the obinutuzumab + chlorambucil arm with a HR of 0.31 [95% CI: 0.22, 0.44]. The 36-month 
PFS estimate in the venetoclax + obinutuzumab arm was 81.9% [95% CI: 76.5, 87.3] and in the 
obinutuzumab + chlorambucil arm was 49.5% [95% CI: 42.4, 56.6]. The updated Kaplan-Meier curve for 
PFS is shown in Figure 1. 
 
Figure 1: Kaplan-Meier curve of investigator-assessed progression-free survival (ITT population) in CLL14 
with 40 months follow-up 



15 

 
 
Table 6: Additional efficacy results in CLL14 (primary analysis) 

Endpoint Venetoclax + 
obinutuzumab 

(N = 216)

Obinutuzumab + 
chlorambucil 

(N = 216) 
IRC-assessed PFS 
Number of events (%) 29 (13) 79 (37) 
    Median, months  NR NR
    Hazard ratio (95% CI) 0.33 (0.22, 0.51)
    P-valuea <0.0001
    12-month PFS estimate (95% CI) 94.6 (91.5, 97.7) 91.1 (87.3, 95.1) 
    24-month PFS estimate (95% CI) 88.6 (84.2, 93) 63.7 (57, 70.4) 
Response rate   
    ORRb, % (95% CI) 85 (79.2, 89.2) 71 (64.8, 77.2) 
    CR+CRib, (%) 50 23
MRD negativity ratec at end of 
treatment 

 

    Peripheral blood, % (95% CI) 76 (69.17, 81.05) 35 (28.83, 41.95) 
P-value <0.0001

    Bone marrowd, % (95% CI) 57 (50.05, 63.64) 17 (12.36, 22.83) 
P-value <0.0001

CR = complete remission; CRi = complete remission with incomplete marrow recovery; 
IRC = independent review committee; MRD = minimal residual disease; NR = not 
reached; ORR = overall response rate (CR + CRi + PR). 
aStratified P-value. 
bP-values based on Cochran-Mantel-Haenszel test; P=0.0007 for ORR; P<0.0001 for 
CR+CRi. 
cMinimal residual disease was evaluated using allele-specific oligonucleotide polymerase 
chain reaction (ASO-PCR). The cut-off for a negative status was <1 CLL cell per 104 
leukocytes. 
dPer protocol, MRD in bone marrow was to be assessed only in responding patients 
(CR/CRi and PR). 

 
The PFS benefit with venetoclax + obinutuzumab versus obinutuzumab + chlorambucil treatment was 
observed across the following subgroups: sex; age; Binet stage at screening; estimated CrCL; del(17p)/TP53 
mutation; IgVH mutational status.  
 



16 

Venetoclax in combination with rituximab for the treatment of patients with CLL who have received at least 
one prior therapy – study GO28667 (MURANO) 
A randomised (1:1), multicenter, open-label phase 3 study evaluated the efficacy and safety of Venclyxto + 
rituximab versus BR in patients with previously treated CLL. Patients in the Venclyxto + rituximab arm 
completed the Venclyxto 5-week dose-titration schedule and then received 400 mg once daily for 24 months 
from Cycle 1 Day 1 of rituximab in the absence of disease progression or unacceptable toxicity. Rituximab 
was initiated after the 5-week dose-titration schedule at 375 mg/m2 for Cycle 1 and 500 mg/m2 for Cycles 2-
6. Each cycle was 28 days. Patients randomised to BR received bendamustine at 70 mg/m2 on Days 1 and 2 
for 6 cycles and rituximab as described above. 
 
Median age was 65 years (range: 22 to 85); 74% were male, and 97% were white. Median time since 
diagnosis was 6.7 years (range: 0.3 to 29.5). Median prior lines of therapy was 1 (range: 1 to 5); and included 
alkylating agents (94%), anti-CD20 antibodies (77%), B-cell receptor pathway inhibitors (2%) and prior 
purine analogs (81%, including 55% FCR). At baseline, 46.6% of patients had one or more nodes ≥5 cm, and 
67.6% had ALC ≥25 x 109/l. A 17p deletion was detected in 26.9% of patients, TP53 mutations in 26.3%, 
11q deletion in 36.5%, and unmutated IgVH gene in 68.3%. Median follow-up time for primary analysis was 
23.8 months (range: 0.0 to 37.4 months). 
 
Progression-free survival (PFS) was assessed by investigators using the International Workshop for Chronic 
Lymphocytic Leukaemia (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) 
guidelines (2008). 
 
Efficacy results for PFS at the time of pre-specified primary analysis (data cut-off date 8 May 2017) are 
shown in Table 7. 
 
Table 7: Investigator-assessed progression-free survival in patients with previously treated CLL in 
MURANO 

 Venetoclax + rituximab 
N = 194

Bendamustine + rituximab 
N = 195 

Number of events (%)      32 (16.5) 114 (58.5) 
    Disease progression 21 98 
    Death events 11 16 
    Median, months (95% CI)  NR 17.0 (15.5, 21.6)
    Hazard ratio (95% CI) 0.17 (0.11, 0.25) 
    P-valuea <0.0001
    12-month PFS estimate (95% CI) 92.7 (89.1, 96.4) 72.5 (65.9, 79.1) 
    24-month PFS estimate (95% CI) 84.9 (79.1, 90.6) 36.3 (28.5, 44.0)
CI = confidence interval; NR = not reached 
aStratified P-value. 

 
At an updated efficacy analysis with all patients off treatment (data cut-off date 8 May 2018 and median 
follow-up of 36 months) the 36-month PFS estimate in the venetoclax + rituximab arm was 71.4% [95% CI: 
64.8, 78.1] and in the bendamustine + rituximab arm was 15.2% [95% CI: 9.1, 21]. Kaplan-Meier curves of 
investigator-assessed PFS from the updated efficacy analysis are shown in Figure 2. 
 
In total, 130 patients in the venetoclax + rituximab arm completed 2 years of venetoclax treatment without 
progression. Of the 130 patients, 92 patients completed the 6-month post treatment follow-up visit. The 
estimated PFS rate at 6 months post treatment was 92%. 
 
Figure 2: Kaplan-Meier curves of investigator-assessed progression-free survival (intent-to-treat population) 
in MURANO (data cut-off date 8 May 2018) 



17 

 
 
Efficacy results for the pre-specified primary analysis (data cut-off date 8 May 2017) were also assessed by 
an Independent Review Committee (IRC) demonstrating a statistically significant 81% reduction in the risk 
of progression or death for patients treated with venetoclax + rituximab (hazard ratio: 0.19 [95% CI: 0.13, 
0.28]; P<0.0001). Additional efficacy results for the pre-specified primary analysis are shown in Table 8 and 
Figure 3 and Figure 4. 
 
Table 8: Additional efficacy results in MURANO 

 Investigator assessed IRC assessed
Endpoint Venetoclax + 

rituximab 
N = 194

Bendamustine + 
rituximab 
N = 195

Venetoclax + 
rituximab 
N = 194 

Bendamustine + 
rituximab 
N = 195

Response rate   
    ORR, % (95% CI) 93.3  

(88.8, 96.4)
67.7  

(60.6, 74.2)
92.3 

(87.6, 95.6) 
72.3 

(65.5, 78.5)
    CR+CRi, (%) 26.8 8.2 8.2 3.6
    nPR, (%) 3.1 6.2 1.5 0.5
    PR, (%) 63.4 53.3 82.5a 68.2a
MRD negativity rate at end of 
combination treatmentb 

 

    Peripheral blood, % (95% 
CI)c 

62.4  
(55.2, 69.2)

13.3  
(8.9, 18.9)

NA NA 

    Bone marrow, % (95% CI)d 15.5  
(10.7, 21.3)

1.0  
(0.1, 3.7)

NA NA 

Overall Survivale 
    Number of events (%) 15 (7.7) 27 (13.8)
    Hazard ratio (95% CI) 0.48 (0.25, 0.90)
Time to next anti-leukaemic therapy 
    Number of events (%) 23 (11.9) 83 (42.6) NA NA
    Median, months (95% CI) NR 26.4 NA NA
    Hazard ratio 0.19 (0.12, 0.31) NA 
CR = complete remission; CRi = complete remission with incomplete marrow recovery; IRC = 
independent review committee; MRD = minimal residual disease; nPR = nodular partial remission; NA = 
not available; NR = not reached; ORR = overall response rate (CR + CRi + nPR + PR); PR = partial 
remission. 



18 

aThe discrepancy between IRC- and investigator-assessed CR rate was due to interpretation of residual 
adenopathy on CT scans. Eighteen patients in the venetoclax + rituximab arm and 3 patients in the 
bendamustine + rituximab arm had negative bone marrow and lymph nodes <2 cm. 
bMinimal residual disease was evaluated using allele-specific oligonucleotide polymerase chain reaction 
(ASO-PCR) and/or flow cytometry. The cut-off for a negative status was one CLL cell per 104 leukocytes. 
cOf those with MRD assay results available in peripheral blood, 72.5% (121/167) in the venetoclax + 
rituximab arm and 20% (26/128) in the bendamustine + rituximab arm were found to be MRD negative. 
dOf those with MRD assay results available in bone marrow, 76.9% (30/39) in the venetoclax + rituximab 
arm and 6.7% (2/30) in the bendamustine + rituximab arm were found to be MRD negative. 
eOverall survival data are not yet mature.

 
Median DOR was not reached with median follow-up of approximately 23.8 months. 
 
Figure 3: Kaplan-Meier curves of overall survival (intent-to-treat population) in MURANO 
 

 
 
Results of subgroup analyses 
The observed PFS benefit of venetoclax + rituximab  compared with bendamustine + rituximab was 
consistently observed across all subgroups of patients evaluated, including age (< 65, ≥ 65 years and 
< 75, ≥ 75 years), prior lines of therapy (1, >1), bulky disease (< 5 cm, ≥ 5 cm), 17p deletion, 11q deletion, 
TP53 mutation, IgVH mutation, and refractory versus relapse to most recent therapy (Figure 4). 
 
Figure 4: Forest plot of Investigator-Assessed PFS in Subgroups from MURANO 
 



19 

17p deletion status was determined based on central laboratory test results.  
Unstratified hazard  ratio is displayed on the X-axis with logarithmic scale. 
NE=not evaluable. 

 
Venetoclax as monotherapy for the treatment of patients with CLL harbouring 17p deletion or TP53 
mutation – study M13-982 
The safety and efficacy of venetoclax in 107 patients with previously treated CLL with 17p deletion were 
evaluated in a single arm, open-label, multi-center study (M13-982). Patients followed a 4- to 5-week 
dose-titration schedule starting at 20 mg and increasing to 50 mg, 100 mg, 200 mg and finally 400 mg once 
daily. Patients continued to receive venetoclax 400 mg once daily until disease progression or unacceptable 
toxicity was observed. The median age was 67 years (range: 37 to 85 years); 65% were male, and 97% were 
white. The median time since diagnosis was 6.8 years (range: 0.1 to 32 years; N=106). The median number 
of prior anti-CLL treatments was 2 (range: 1 to 10 treatments); 49.5% with a prior nucleoside analogue, 38% 
with prior rituximab, and 94% with a prior alkylator (including 33% with prior bendamustine). At baseline, 
53% of patients had one or more nodes ≥5 cm, and 51% had ALC ≥25 x 109/l. Of the patients, 37% (34/91) 
were fludarabine refractory, 81% (30/37) harboured the unmutated IgVH gene, and 72% (60/83) had TP53 
mutation. The median time on treatment at the time of evaluation was 12 months (range: 0 to 22 months). 
 
The primary efficacy endpoint was overall response rate (ORR) as assessed by an Independent Review 
Committee (IRC) using the IWCLL updated NCI-WG guidelines (2008). Efficacy results are shown in 
Table 9. Efficacy data are presented for 107 patients with data cutoff date 30 April 2015. An additional 
51 patients were enrolled in a safety expansion cohort. Investigator-assessed efficacy results are presented 
for 158 patients with a later data cutoff date 10 June 2016. The median time on treatment for 158 patients 
was 17 months (range: 0 to 34 months). 
 



20 

Table 9: Efficacy results in patients with previously treated CLL with 17p deletion (study M13-982) 
Endpoint IRC assessment 

(N=107)a
Investigator assessment 

(N=158)b 
Data cutoff date 30 April 2015 10 June 2016 

ORR, % 
   (95% CI) 

79 
(70.5, 86.6) 

77 
(69.9, 83.5) 

   CR + CRi, % 7 18 
   nPR, % 3 6 
   PR, % 69 53 
DOR, months, median (95% CI) NR 27.5 (26.5, NR) 
PFS, % (95% CI) 
   12-month estimate  
   24-month estimate 

 
72 (61.8, 79.8) 

NA

 
77 (69.1, 82.6)  

52 (43, 61) 
PFS, months, median  
(95% CI) 

NR 27.2 (21.9, NR) 

TTR, months, median (range) 0.8 (0.1-8.1) 1.0 (0.5-4.4) 

aOne patient did not harbour the 17p deletion. 
bIncludes 51 additional patients from the safety expansion cohort. 
CI = confidence interval; CR = complete remission; CRi = complete remission with incomplete 
marrow recovery, DOR = duration of response; IRC = independent review committee; nPR = 
nodular PR; NA = not available; NR = not reached; ORR = overall response rate; PFS = 
progression-free survival, PR = partial remission; TTR = time to first response. 

 
Minimal residual disease (MRD) was evaluated using flow cytometry in 93 of 158 patients who achieved 
complete remission (CR), complete remission with incomplete marrow recovery (CRi), or partial remission 
(PR) with limited remaining disease with venetoclax treatment. MRD negativity was defined as a result 
below 0.0001 (<1 CLL cell per 104 leukocytes in the sample). Twenty-seven percent (42/158) of patients 
were MRD negative in the peripheral blood, including 16 patients who were also MRD negative in the bone 
marrow.  
 
Venetoclax as monotherapy for the treatment of patients with CLL who have failed a B-cell receptor pathway 
inhibitor – study M14-032 
The efficacy and safety of venetoclax in patients with CLL who had been previously treated with and failed 
ibrutinib or idelalisib therapy were evaluated in an open-label, multi-center, non-randomised, phase 2 study 
(M14-032). Patients received venetoclax via a recommended dose-titration schedule. Patients continued to 
receive venetoclax 400 mg once daily until disease progression or unacceptable toxicity was observed. 
 
At the time of data cut-off (26 July 2017), 127 patients were enrolled and treated with venetoclax. Of these, 
91 patients had received prior ibrutinib therapy (Arm A) and 36 had received prior idelalisib therapy (Arm 
B). The median age was 66 years (range: 28 to 85 years), 70% were male, and 92% were white. The median 
time since diagnosis was 8.3 years (range: 0.3 to 18.5 years; N=96). Chromosomal aberrations were 11q 
deletion (34%, 43/127), 17p deletion (40%, 50/126), TP53 mutation (38%, 26/68) and unmutated IgVH 
(78%, 72/92). At baseline, 41% of patients had one or more nodes ≥5 cm and 31% had ALC ≥25 x 109/l. The 
median number of prior oncology treatments was 4 (range: 1 to 15) in ibrutinib-treated patients and 3 
(range: 1 to 11) in idelalisib-treated patients. Overall, 65% of patients received prior nucleoside analogue, 
86% rituximab, 39% other monoclonal antibodies, and 72% alkylating agent (including 41% with 
bendamustine). At the time of evaluation, median duration of treatment with venetoclax was 14.3 months 
(range: 0.1 to 31.4 months).  
 
The primary efficacy endpoint was ORR according to IWCLL updated NCI-WG guidelines. Response 
assessments were performed at 8 weeks, 24 weeks, and every 12 weeks thereafter. 
 



21 

Table 10: Efficacy results as assessed by investigator in patients who have failed a B-cell receptor pathway 
inhibitor (study M14-032) 

 Arm A  
(ibrutinib failures) 

(N=91)

Arm B  
(idelalisib failures) 

(N=36)

Total 
(N=127) 

ORR, % 
   (95% CI) 

65 
(54.1, 74.6) 

67 
(49.0, 81.4) 

65 
(56.4, 73.6) 

   CR + CRi, % 10 11 10 
   nPR, % 3 0 2 
   PR, % 52 56 53 
PFS, % (95% CI) 
   12-month estimate 
   24-month estimate 
 

 
75 (64.7, 83.2) 
51 (36.3, 63.9) 

 
80 (63.1, 90.1) 
61 (39.6, 77.4) 

 
77 (68.1, 83.4) 
54 (41.8, 64.6) 

PFS, months, median  
(95% CI) 

25 (19.2, NR) NR (16.4, NR) 25 (19.6, NR) 

OS, % (95% CI) 
12-month estimate 

 
91 (82.8, 95.4) 

 
94.2 (78.6, 98.5) 

 
92 (85.6, 95.6) 

TTR, months, median 
(range) 

2.5 (1.6-14.9) 2.5 (1.6-8.1) 2.5 (1.6-14.9) 

17p deletion and/or TP53 mutation status 
ORR, % (95% CI) 
   Yes  (n=28) 

61 (45.4, 74.9) 
(n=7) 

58 (27.7, 84.8) 
(n=35) 

60 (46.6, 73.0) 
   No (n=31) 

69 (53.4, 81.8) 
(n=17) 

71 (48.9, 87.4) 
(n=48) 

70 (57.3, 80.1) 
CI = confidence interval; CR = complete remission; CRi = complete remission with incomplete 
marrow recovery, nPR = nodular PR; NR = not reached, ORR = overall response rate;. OS = overall 
survival; PFS = progression-free survival, PR = partial remission, TTR = time to first response. 

 
The efficacy data were further evaluated by an IRC demonstrating a combined ORR of 70% (Arm A: 70%; 
Arm B: 69%). One patient (ibrutinib failure) achieved complete remission with incomplete marrow recovery. 
The ORR for patients with 17p deletion and/or TP53 mutation was 72% (33/46) (95% CI: 56.5, 84.0) in Arm 
A and 67% (8/12) (95% CI: 34.9, 90.1) in Arm B. For patients without 17p deletion and/or TP53 mutation, 
the ORR was 69% (31/45) (95% CI: 53.4, 81.8) in Arm A and 71% (17/24) (95% CI: 48.9, 87.4) in Arm B. 
 
Median OS and DOR were not reached with median follow-up of approximately 14.3 months for Arm A and 
14.7 months for Arm B. 
 
Twenty-five percent (32/127) of patients were MRD negative in the peripheral blood, including 8 patients 
who were also MRD negative in bone marrow. 
 
Elderly patients 
 
Of the 194 patients with previously treated CLL who received venetoclax in combination with rituximab, 
50% were 65 years or older. 
 
Of the 107 patients who were evaluated for efficacy from M13-982 study, 57% were 65 years or older. Of 
the 127 patients who were evaluated for efficacy from M14-032 study, 58% were 65 years or older.  
 
Of the 352 patients evaluated for safety from 3 open-label monotherapy trials, 57% were 65 years or older. 
 
There were no clinically meaningful differences in safety or efficacy observed between older and younger 
patients in the combination and monotherapy studies. 
 
Paediatric population 



22 

 
The European Medicines Agency has waived the obligation to submit the results of studies with Venclyxto 
in all subsets of the paediatric population in CLL (see section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
Following multiple oral administrations, maximum plasma concentration of venetoclax was reached 
5-8 hours after dose. Venetoclax steady state AUC increased proportionally over the dose range of 
150-800 mg. Under low-fat meal conditions, venetoclax mean (± standard deviation) steady state Cmax was 
2.1 ± 1.1 μg/ml and AUC24 was 32.8 ± 16.9  μg•h/ml at the 400 mg once daily dose. 
 
Effect of food 
 
Administration with a low-fat meal increased venetoclax exposure by approximately 3.4-fold and 
administration with a high-fat meal increased venetoclax exposure by 5.1- to 5.3-fold compared to fasting 
conditions. It is recommended that venetoclax should be administered with a meal (see section 4.2).  
 
Distribution 
 
Venetoclax is highly bound to human plasma protein with unbound fraction in plasma <0.01 across a 
concentration range of 1-30 µM (0.87-26 µg/ml). The mean blood-to-plasma ratio was 0.57. The population 
estimate for apparent volume of distribution (Vdss/F) of venetoclax ranged from 256-321 L in patients. 
 
Biotransformation 
 
In vitro studies demonstrated that venetoclax is predominantly metabolised by cytochrome P450 CYP3A4. 
M27 was identified as a major metabolite in plasma with an inhibitory activity against BCL-2 that is at least 
58-fold lower than venetoclax in vitro.   
 
In vitro interaction studies 
 
Co administration with CYP and UGT substrates 
In vitro studies indicated that venetoclax is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C19, 
CYP2D6 or CYP3A4 at clinically relevant concentrations. Venetoclax is a weak inhibitor of CYP2C8, 
CYP2C9 and UGT1A1 in vitro, but it is not predicted to cause clinically relevant inhibition. Venetoclax is 
not an inhibitor of UGT1A4, UGT1A6, UGT1A9 and UGT2B7. 
 
Co administration with transporter substrates/inhibitors 
Venetoclax is a P-gp and BCRP substrate as well as a P-gp and BCRP inhibitor and a weak OATP1B1 
inhibitor in vitro (see section 4.5). Venetoclax is not expected to inhibit OATP1B3, OCT1, OCT2, OAT1, 
OAT3, MATE1 or MATE2K at clinically relevant concentrations. 
 
Elimination 
 
The population estimate for the terminal phase elimination half-life of venetoclax was approximately 
26 hours. Venetoclax shows minimal accumulation with accumulation ratio of 1.30-1.44. After a single oral 
administration of 200 mg radiolabeled [14C]-venetoclax to healthy subjects, >99.9% of the dose was 
recovered in faeces and <0.1% of the dose was excreted in urine within 9 days. Unchanged venetoclax 
accounted for 20.8% of the administered radioactive dose excreted in faeces. The pharmacokinetics of 
venetoclax do not change over time. 
 



23 

Special populations 
 
Renal impairment 
Based on a population pharmacokinetic analysis that included 219 subjects with mild renal impairment 
(CrCl ≥60 and <90 ml/min), 86 subjects with moderate renal impairment (CrCl ≥30 and <60 ml/min) and 
217 subjects with normal renal function (CrCl ≥90 ml/min), venetoclax exposures in subjects with mild or 
moderate renal impairment are similar to those with normal renal function. The pharmacokinetics of 
venetoclax has not been studied in subjects with severe renal impairment (CrCl <30 ml/min) or patients on 
dialysis (see section 4.2). 
 
Hepatic impairment 
Based on a population pharmacokinetic analysis that included 74 subjects with mild hepatic impairment, 
7 subjects with moderate hepatic impairment and 442 subjects with normal hepatic function, venetoclax 
exposures are similar in subjects with mild and moderate hepatic impairment and normal hepatic function. 
Mild hepatic impairment was defined as normal total bilirubin and aspartate transaminase (AST) > upper 
limit of normal (ULN) or total bilirubin >1.0 to 1.5 times ULN, moderate hepatic impairment as total 
bilirubin >1.5 to 3.0 times ULN, and severe hepatic impairment as total bilirubin >3.0 ULN.  
 
In a dedicated hepatic impairment study, venetoclax Cmax and AUC in subjects with mild (Child-Pugh A; 
n=6) or moderate (Child-Pugh B; n=6) hepatic impairment were similar to subjects with normal hepatic 
function, after receiving a 50 mg single dose of venetoclax. In subjects with severe (Child-Pugh C; n=5) 
hepatic impairment, the mean venetoclax Cmax was similar to subjects with normal hepatic function but 
venetoclax AUCinf was on average 2.7-fold higher (range: no change to 5-fold higher) than venetoclax 
AUCinf in the subjects with normal hepatic function (see section 4.2). 
 
Effects of age, sex, and weight 
 
Based on population pharmacokinetic analyses, age, sex, and weight do not have an effect on venetoclax 
clearance. 
 
5.3 Preclinical safety data 
 
Toxicities observed in animal studies with venetoclax included dose-dependent reductions in lymphocytes 
and red blood cell mass. Both effects were reversible after cessation of dosing with venetoclax, with 
recovery of lymphocytes occurring 18 weeks post treatment. Both B- and T-cells were affected, but the most 
significant decreases occurred with B-cells.  
 
Venetoclax also caused single cell necrosis in various tissues, including the gallbladder and exocrine 
pancreas, with no evidence of disruption of tissue integrity or organ dysfunction; these findings were 
minimal to mild in magnitude.  
 
After approximately 3 months of daily dosing in dogs, venetoclax caused progressive white discoloration of 
the hair coat, due to loss of melanin pigment in the hair. 
 
Carcinogenicity/genotoxicity 
 
Venetoclax and the M27 major human metabolite were not carcinogenic in a 6-month transgenic (Tg.rasH2) 
mouse carcinogenicity study at oral doses up to 400 mg/kg/day of venetoclax and at a single dose level of 
250 mg/kg/day of M27. Exposure margins (AUC), relative to the clinical AUC at 400 mg/day, were 
approximately 2-fold for venetoclax and 5.8-fold for M27. 
 
Venetoclax was not genotoxic in bacterial mutagenicity assay, in vitro chromosome aberration assay and in 
vivo mouse micronucleus assay. The M27 metabolite was negative for genotoxicity in the bacterial 
mutagenicity and chromosomal aberration assays. 
 



24 

Reproductive toxicity 
 
No effects on fertility were observed in fertility and early embryonic development studies in male and female 
mice. Testicular toxicity (germ cell loss) was observed in general toxicity studies in dogs at exposures of 0.5 
to 18 times the human AUC exposure at a dose of 400 mg. Reversibility of this finding has not been 
demonstrated. 
 
In embryo-foetal development studies in mice, venetoclax was associated with increased post-implantation 
loss and decreased foetal body weight at exposures of 1.1 times the human AUC exposure at a dose of 
400 mg. The major human metabolite M27 was associated with post-implantation loss and resorptions at 
exposures approximately 9-times the human M27-AUC exposure at a 400 mg dose of venetoclax. In rabbits, 
venetoclax produced maternal toxicity, but no foetal toxicity at exposures of 0.1 times the human AUC 
exposure at a 400 mg dose. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Venclyxto 10 mg film-coated tablets 
 
Tablet core 
Copovidone (K 28) 
Colloidal anhydrous silica (E551) 
Polysorbate 80 (E433) 
Sodium stearyl fumarate 
Anhydrous calcium hydrogen phosphate (E341 (ii))  
 
Film-coating  
Iron oxide yellow (E172) 
Polyvinyl alcohol (E1203) 
Titanium dioxide (E171) 
Macrogol 3350 (E1521) 
Talc (E553b) 
 
Venclyxto 50 mg film-coated tablets  
 
Tablet core 
Copovidone (K 28) 
Colloidal anhydrous silica (E551) 
Polysorbate 80 (E433) 
Sodium stearyl fumarate 
Anhydrous calcium hydrogen phosphate (E341 (ii))  
 
Film-coating 
Iron oxide yellow (E172)  
Iron oxide red (E172) 
Iron oxide black (E172) 
Polyvinyl alcohol (E1203) 
Titanium dioxide (E171) 
Macrogol 3350 (E1521) 
Talc (E553b) 
 



25 

Venclyxto 100 mg film-coated tablets 
 
Tablet core 
Copovidone (K 28) 
Colloidal anhydrous silica (E551) 
Polysorbate 80 (E433) 
Sodium stearyl fumarate 
Anhydrous calcium hydrogen phosphate (E341 (ii))  
 
Film-coating  
Iron oxide yellow (E172) 
Polyvinyl alcohol (E1203) 
Titanium dioxide (E171) 
Macrogol 3350 (E1521) 
Talc (E553b) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
Venclyxto 10 mg film-coated tablets 
2 years. 
 
Venclyxto 50 mg film-coated tablets 
2 years. 
 
Venclyxto 100 mg film-coated tablets 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container  
 
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 tablets  
The film-coated tablets are supplied in cartons containing either 10 or 14 tablets (in blisters of 2 tablets).  
 
Venclyxto 50 mg tablets  
The film-coated tablets are supplied in cartons containing either 5 or 7 tablets (in blisters of 1 tablet). 
 
Venclyxto 100 mg 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 x 28 tablets (in blisters of 4 tablets)).  
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 



26 

 
7. MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1138/001 (10 mg, 10 tablets) 
EU/1/16/1138/002 (10 mg, 14 tablets) 
EU/1/16/1138/003 (50 mg, 5 tablets) 
EU/1/16/1138/004 (50 mg, 7 tablets) 
EU/1/16/1138/005 (100 mg 7 tablets) 
EU/1/16/1138/006 (100 mg, 14 tablets) 
EU/1/16/1138/007 (100 mg, 112 (4 x 28) tablets) 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 5 December 2016 
Date of latest renewal: 6 September 2018 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

  



27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
ANNEX II 

 
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND 

USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 

SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

 
 



28 

A.  MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
 
 Periodic safety update reports (PSURs)  
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 months 
following authorisation. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE 

OF THE MEDICINAL PRODUCT 
 
 Riskmanagement plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and 
interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any 
agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new information being 

received that may lead to a significant change to the benefit/risk profile or as the result of an important 
(pharmacovigilance or risk minimisation) milestone being reached.  

 
 

  



29 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



30 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



31 

PARTICULARS TO APPEAR ON THE OUTER CARTON  
 
CARTON (5 day pack) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Venclyxto 10 mg film-coated tablets 
venetoclax 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 10 mg venetoclax 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
10 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Take your dose in the morning with a meal and water. Drink 1.5–2 litres of water a day. 
Read the package leaflet before use. It is important to follow all of the instructions in the ‘how to take’ 
section of the leaflet. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 



32 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1138/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
venclyxto 10 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
  



33 

PARTICULARS TO APPEAR ON THE OUTER CARTON  
 
CARTON (7 day pack) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Venclyxto 10 mg film-coated tablets 
venetoclax 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 10 mg venetoclax 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
14 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Take your dose in the morning with a meal and water. Drink 1.5–2 litres of water a day. 
Read the package leaflet before use. It is important to follow all of the instructions in the ‘how to take’ 
section of the leaflet. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 



34 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1138/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
venclyxto 10 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN  



35 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Venclyxto 10 mg tablets 
venetoclax 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie (as logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



36 

PARTICULARS TO APPEAR ON THE OUTER CARTON  
 
CARTON (5 day pack) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Venclyxto 50 mg film-coated tablets 
venetoclax 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 50 mg venetoclax 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
5 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Take your dose in the morning with a meal and water. Drink 1.5–2 litres of water a day. 
Read the package leaflet before use. It is important to follow all of the instructions in the ‘how to take’ 
section of the leaflet. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 



37 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1138/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
venclyxto 50 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



38 

PARTICULARS TO APPEAR ON THE OUTER CARTON  
 
CARTON (7 day pack) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Venclyxto 50 mg film-coated tablets 
venetoclax 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 50 mg venetoclax 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
7 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Take your dose in the morning with a meal and water. Drink 1.5–2 litres of water a day. 
Read the package leaflet before use. It is important to follow all of the instructions in the ‘how to take’ 
section of the leaflet. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 



39 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1138/004 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
venclyxto 50 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



40 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Venclyxto 50 mg tablets 
venetoclax 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie (as logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



41 

PARTICULARS TO APPEAR ON THE OUTER CARTON  
 
CARTON (7 day pack) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Venclyxto 100 mg film-coated tablets 
venetoclax 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 100 mg venetoclax 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
7 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Take your dose in the morning with a meal and water. Drink 1.5–2 litres of water a day. 
Read the package leaflet before use. It is important to follow all of the instructions in the ‘how to take’ 
section of the leaflet. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 



42 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1138/005 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
venclyxto 100 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



43 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Venclyxto 100 mg tablets 
venetoclax 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie (as logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



44 

PARTICULARS TO APPEAR ON THE OUTER CARTON  
 
CARTON (7 day pack) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Venclyxto 100 mg film-coated tablets 
venetoclax 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 100 mg venetoclax 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
14 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Take your dose in the morning with a meal and water. Drink 1.5–2 litres of water a day. 
Read the package leaflet before use. It is important to follow all of the instructions in the ‘how to take’ 
section of the leaflet. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 



45 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1138/006 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
venclyxto 100 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN  



46 

PARTICULARS TO APPEAR ON THE OUTER CARTON 
 
CARTON Multipack (with blue box) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Venclyxto 100 mg film-coated tablets 
venetoclax 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 100 mg venetoclax 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
Multipack: 112 (4 x 28) film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. It is important to follow all of the instructions in the ‘how to take’ 
section of the leaflet. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 
 



47 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1138/007 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
venclyxto 100 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



48 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
CARTON multipack (without blue box) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Venclyxto 100 mg film-coated tablets 
venetoclax 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 100 mg venetoclax 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets 
Component of a multipack, can’t be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Take your dose at the same time each day with a meal and water. 
Read the package leaflet before use. It is important to follow all of the instructions in the ‘how to take’ 
section of the leaflet. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 
 



49 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1138/007 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
venclyxto 100 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Not applicable. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Not applicable. 
 

  



50 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 

B. PACKAGE LEAFLET 



51 

Package leaflet: Information for the patient 
 

Venclyxto 10 mg film-coated tablets 
Venclyxto 50 mg film-coated tablets 

Venclyxto 100 mg film-coated tablets 
venetoclax 

 
This medicine is subject to additional monitoring. This will allow quick identification of new safety 

information. You can help by reporting any side effects you may get. See the end of section 4 for how to 
report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains important 

information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if 

their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Venclyxto is and what it is used for 
2. What you need to know before you take Venclyxto 
3. How to take Venclyxto 
4. Possible side effects  
5. How to store Venclyxto 
6. Contents of the pack and other information 
 
 
1. What Venclyxto is and what it is used for 
 
What Venclyxto is 
Venclyxto is a cancer medicine that contains the active substance venetoclax. It belongs to a group of 
medicines called “BCL-2 inhibitors”. 
 
What Venclyxto is used for 
Venclyxto is used to treat patients with chronic lymphocytic leukaemia (CLL). 
 
Venclyxto may be given to you in combination with other medicines or alone. 
 
CLL is a type of cancer affecting white blood cells called lymphocytes and the lymph nodes. In CLL, the 
lymphocytes multiply too quickly and live for too long, so that there are too many of them in the blood. 
 
How Venclyxto works 
Venclyxto works by blocking a protein in the body called “BCL-2”. This protein helps cancer cells survive. 
Blocking this protein helps to kill and lower the number of cancer cells. It also slows down the worsening of 
the disease. 
 
 
2. What you need to know before you take Venclyxto 
 
Do not take Venclyxto if: 
- you are allergic to the active substance venetoclax or any of the other ingredients of this medicine (listed 

in section 6).  
 



52 

- you are taking any of the medicines listed below when you start your treatment and while your dose is 
gradually being increased (usually over 5 weeks). This is because serious and life-threatening effects can 
occur when Venclyxto is taken with these medicines: 

 
 itraconazole ketoconazole, posaconazole, or voriconazole for fungal infections 
 clarithromycin for bacterial infections 
 ritonavir for HIV infection. 

 
When your Venclyxto dose has been increased to the full standard dose, check with your doctor if you 
can start taking these medicines again. 
 

- you are taking a herbal medicine called St. John’s wort, used for depression. If you are not sure about 
this, talk to your doctor, pharmacist or nurse before taking Venclyxto. 

 
It is important that you tell your doctor, pharmacist, or nurse about all the medicines you take, including 
prescription and over-the-counter medicines, vitamins, and herbal supplements. Your doctor may need to 
stop certain medicines when you first start taking Venclyxto and during the first five weeks when your dose 
is gradually increased to the full standard dose.  
 
Warnings and precautions  
Talk to your doctor, pharmacist, or nurse before taking Venclyxto if: 
 
 you have any kidney problems as your risk for a side effect called tumour lysis syndrome may increase 
 you have liver problems as this may increase your risk for side effects. Your doctor may need to reduce 

your dose of Venclyxto  
 you think you may have an infection or have had a long-lasting or repeated infection 
 you are due to have a vaccine.  
 
If any of the above apply to you, or you are not sure, talk to your doctor, pharmacist, or nurse before taking 
this medicine. 
 
Tumour Lysis Syndrome 
Some people may develop unusual levels of some body salts (such as potassium and uric acid) in the blood 
caused by the fast breakdown of cancer cells during treatment. This may lead to changes in kidney function, 
abnormal heartbeat, or seizures. This is called tumour lysis syndrome (TLS). The risk for TLS is in the first 5 
weeks of treatment with Venclyxto.  
 
Your doctor, pharmacist or nurse will do blood tests to check for TLS.  
 
Your doctor may also give you medicines to help prevent the build up of uric acid in your body before you 
start treatment with Venclyxto. 
 
Drinking plenty of water, at least 1.5 to 2 litres per day, helps to remove cancer cell breakdown products 
from your body through urine, and may decrease your risk of getting TLS (see section 3). 
 
Tell your doctor, pharmacist or nurse immediately if you get any of the symptoms of TLS listed in section 4. 
 
If you are at risk of TLS you may be treated in hospital so that you can be given fluids into the vein if 
needed, have blood tests done more often and to check for side effects. This is to see if you can continue to 
take this medicine safely.  
 
Children and adolescents 
Venclyxto should not be used in children and adolescents. This is because it has not been studied in these age 
groups. 
 
Other medicines and Venclyxto 



53 

Tell your doctor or pharmacist if you take any of the following medicines as they can increase or decrease 
the amount of venetoclax in your blood: 
 
- medicines for fungal infections – fluconazole, itraconazole, ketoconazole, posaconazole, or voriconazole 
- antibiotics to treat bacterial infections – ciprofloxacin, clarithromycin, erythromycin, nafcillin, or 

rifampicin 
- medicines to prevent seizures or to treat epilepsy – carbamazepine, phenytoin  
- medicines for HIV infection – efavirenz, etravirine, ritonavir 
- medicines to treat raised blood pressure or angina – diltiazem, verapamil 
- medicines to lower cholesterol levels in the blood – cholestyramine, colestipol, colesevelam 
- a medicine used to treat a lung condition called pulmonary arterial hypertension – bosentan  
- a medicine to treat sleep disorder (narcolepsy) known as modafinil 
- a herbal medicine known as St. John’s wort 

 
Your doctor may change your dose of Venclyxto. 
 
Tell your doctor if you take any of the following medicines as Venclyxto may affect how they work: 
 
 medicines that prevent blood clots, warfarin, dabigatran 
 a medicine used to treat heart problems known as digoxin 
 a medicine for cancer known as everolimus 
 a medicine used to prevent organ rejection known as sirolimus 
 medicines to lower cholesterol levels in the blood known as statins 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This 
includes medicines obtained without a prescription, herbal medicines and supplements. This is because 
Venclyxto may affect the way some other medicines work. Also, some other medicines can affect the way 
Venclyxto works.  
 
Venclyxto with food and drink 
Do not eat grapefruit products, Seville oranges (bitter oranges), or starfruit (carambola) while you are taking 
Venclyxto – this includes eating them, drinking the juice or taking a supplement that might contain them. 
This is because they can increase the amount of venetoclax in your blood. 
 
Pregnancy 
- Do not get pregnant while you are taking this medicine. If you are pregnant, think you may be pregnant 

or are planning to have a baby, ask your doctor, pharmacist, or nurse for advice before taking this 
medicine. 

- Venclyxto should not be used during pregnancy. There is no information about the safety of venetoclax 
in pregnant women. 

 
Contraception 
- Women of childbearing age must use a highly effective method of contraception during treatment and for 

at least 30 days after receiving Venclyxto to avoid becoming pregnant. If you are using hormonal 
contraceptive pills or devices, you must also use a barrier method of contraception (such as condoms) as 
the effect of hormonal contraceptive pills or devices may be affected by Venclyxto.  

- Tell your doctor immediately if you become pregnant while you are taking this medicine. 
 
Breast-feeding 
Do not breast-feed while you are taking this medicine. It is not known whether the active substance in 
Venclyxto passes into breast milk.  
 
Fertility 
Based on findings in animals, Venclyxto may cause male infertility (low or no sperm count). This may affect 
your ability to father a child. Ask your doctor for advice on sperm storage before starting treatment with 
Venclyxto.  
 



54 

Driving and using machines 
You may feel tired after taking Venclyxto, which may affect your ability to drive or use tools or machines.  
 
 
3. How to take Venclyxto 
 
Always take this medicine exactly as your doctor, pharmacist, or nurse has told you. Check with your doctor, 
pharmacist, or nurse if you are not sure. 
 
How much to take 
You will begin treatment with Venclyxto at a low dose for 1 week. Your doctor will gradually increase the 
dose over the next 4 weeks to the full standard dose. For the first 4 weeks you will get a new pack each 
week. 
 
 the starting dose is 20 mg (two 10 mg tablets) once a day for 7 days. 
 the dose will be increased to 50 mg (one 50 mg tablet) once a day for 7 days. 
 the dose will be increased to 100 mg (one 100 mg tablet) once a day for 7 days. 
 the dose will be increased to 200 mg (two 100 mg tablets) once a day for 7 days. 
 the dose will be increased to 400 mg (four 100 mg tablets) once a day for 7 days. 

 When you are receiving Venclyxto therapy alone, you will stay on the 400 mg daily dose, which 
is the standard dose, for as long as necessary.  

 When you are receiving Venclyxto therapy in combination with rituximab, you will receive the 
400 mg daily dose for 24 months. 

 When you are receiving Venclyxto therapy in combination with obinutuzumab, you will receive 
the 400 mg daily dose for approximately 10 months. 

 
Your dose may need to be adjusted for side effects. Your doctor will advise what your dose should be. 
 
How to take Venclyxto 
 Take the tablets with a meal at around the same time each day  
 Swallow the tablets whole with a glass of water 
 Do not chew, crush, or break the tablets 
 During the first 5 weeks of treatment, you should take the tablets in the morning to help you follow-up 

with blood tests, if needed. 
 
If you vomit after taking Venclyxto, do not take an extra dose that day. Take the next dose at the usual time 
the next day. If you have problems taking this medicine, talk to your doctor. 
 
Drink plenty of water 
It is very important that you drink plenty of water when taking Venclyxto during the first 5 weeks of 
treatment. This will help to remove cancer cell breakdown products from your blood through your urine.  
 
You should start drinking at least 1.5 to 2 litres of water daily two days before starting Venclyxto. You may 
also include non-alcoholic and non-caffeinated drinks in this amount, but exclude grapefruit, Seville orange, 
or starfruit (carambola) juices. You should continue to drink at least 1.5 to 2 litres of water on the day you 
start Venclyxto. Drink the same amount of water (at least 1.5 to 2 litres daily) two days before and on the day 
that your dose is increased.  
 
If your doctor thinks that you are at risk of TLS, you may be treated in the hospital so that you can be given 
extra fluids into the vein if needed, have your blood tests more often and be checked for side effects. This is 
to see if you can continue to take this medicine safely.  
 
If you take more Venclyxto than you should 
If you take more Venclyxto than you should, talk to your doctor, pharmacist, or nurse or go to hospital 
immediately. Take the tablets and this leaflet with you. 
 



55 

If you forget to take Venclyxto 
 If it is less than 8 hours since the time you usually take your dose, take it as soon as possible. 
 If it is more than 8 hours since the time you usually take your dose, do not take the dose that day. 

Return to your normal dose schedule the next day. 
 Do not take a double dose to make up for a forgotten dose. 
 If you are not sure talk to your doctor, pharmacist or nurse.  
 
Do not stop taking Venclyxto 
Do not stop taking this medicine unless your doctor tells you to. If you have any further questions on the use 
of this medicine, ask your doctor, pharmacist, or nurse.  
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. The following 
serious side effects may happen with this medicine: 
 
Tumour lysis syndrome (common – may affect up to 1 in 10 people) 
Stop taking Venclyxto and seek medical attention immediately if you notice any of the symptoms of TLS: 
 fever or chills  
 feeling or being sick (nausea or vomiting) 
 feeling confused  
 feeling short of breath  
 irregular heart beat  
 dark or cloudy urine  
 feeling unusually tired  
 muscle pain or uncomfortable joints  
 fits or seizures 
 abdominal pain and distension 

 
Low white blood cell count (neutropenia) and infections  (very common – may affect more than 1 in 10 
people) 
Your doctor will check your blood count during treatment with Venclyxto. Low white blood cell count can 
increase your risk for infection. Signs may include fever, chills, feeling weak or confused, cough, pain or 
burning feeling when passing urine. Some infections can be serious and may lead to death. Tell your doctor 
immediately if you have signs of an infection while taking this medicine. 
 
Tell your doctor if you notice any of the following side effects: 
 
Very common (may affect more than 1 in 10 people) 
 pneumonia 
 upper respiratory tract infection – signs include runny nose, sore throat or cough 
 diarrhoea 
 feeling or being sick (nausea or vomiting) 
 constipation 
 feeling tired 
 
Blood tests may also show 
 lower number of red blood cells 
 lower number of white blood cells called lymphocytes  
 higher level of potassium  
 higher level of a body salt (electrolyte) called phosphate 
 lower level of calcium 
 
Common (may affect up to 1 in 10 people)  
 severe infection in the blood (sepsis) 



56 

 urinary tract infection 
 low number of white blood cells with fever (febrile neutropenia) 

 
Blood tests may also show: 
 higher level of creatinine  
 higher level of urea 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 
 
 
5. How to store Venclyxto 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP.  
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw 
away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Venclyxto contains  
 
The active substance is venetoclax. 
 Venclyxto 10 mg film-coated tablets: Each film-coated tablet contains 10 mg venetoclax. 
 Venclyxto 50 mg film-coated tablets: Each film-coated tablet contains 50 mg venetoclax.  
 Venclyxto 100 mg film-coated tablets: Each film-coated tablet contains 100 mg venetoclax. 
 
The other ingredients are: 
 In the tablet core: copovidone (K 28), polysorbate 80 (E433), colloidal anhydrous silica (E551), 

anydrous calcium hydrogen phosphate (E341 (ii)), sodium stearyl fumarate.   
 
In the film-coating: 
 Venclyxto 10 mg film-coated tablets: iron oxide yellow (E172), polyvinyl alcohol (E1203), titanium 

dioxide (E171), macrogol 3350 (E1521), talc (E553b). 
 Venclyxto 50 mg film-coated tablets: iron oxide yellow (E172), iron oxide red (E172), iron oxide black 

(E172), polyvinyl alcohol (E1203), titanium dioxide (E171), macrogol 3350 (E1521), talc (E553b) 
 Venclyxto 100 mg film-coated tablets: iron oxide yellow (E172), polyvinyl alcohol (E1203), titanium 

dioxide (E171), macrogol 3350 (E1521), talc (E553b). 
 

What Venclyxto looks like and contents of the pack 
Venclyxto 10 mg film-coated tablet is pale yellow, round 6 mm diameter, with V on one side and 10 on the 
other. 
Venclyxto 50 mg film-coated tablet is beige, oblong 14 mm long, with V on one side and 50 on the other. 
Venclyxto 100 mg film-coated tablet is pale yellow, oblong 17.2 mm long with V on one side and 100 on the 
other. 
 
Venclyxto tablets are provided in blisters which are packed in cartons as follows:  
 
Venclyxto 10 mg film-coated tablets: 



57 

 10 tablets (5 blisters each with 2 tablets) 
 14 tablets (7 blisters each with 2 tablets) 
 
Venclyxto 50 mg film-coated tablets: 
 5 tablets (5 blisters each with 1 tablet) 
 7 tablets (7 blisters each with 1 tablet) 
  
Venclyxto 100 mg film-coated tablets: 
 7 tablets (7 blisters each with 1 tablet) 
 14 tablets (7 blisters each with 2 tablets) 
 112 (4 x 28) tablets (4 cartons of 7 blisters each with 4 tablets). 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
AbbVie SA 
Tél/Tel: +32 10  477811 

Lietuva 
AbbVie UAB  
Tel: +370 5 205 3023 

 
България 
АбВи ЕООД 
Тел:+359 2 90 30 430 

 
Luxembourg/Luxemburg 
AbbVie SA 
Belgique/Belgien 
Tél/Tel: +32 10 477811 

 
Česká republika 
AbbVie s.r.o.  
Tel: +420 233 098 111 

 
Magyarország 
AbbVie Kft. 
Tel:+36 1 455 8600 

 
Danmark 
AbbVie A/S 
Tlf: +45 72 30-20-28 

 
Malta 
V.J.Salomone Pharma Limited  
Tel: +356 22983201 

 
Deutschland 
AbbVie Deutschland GmbH & Co. KG 
Tel: 00800 222843 33 (gebührenfrei) 
Tel: +49 (0) 611 / 1720-0 

 
Nederland 
AbbVie B.V. 
Tel:  +31 (0)88 322 2843 

 
Eesti 
AbbVie Biopharmaceuticals GmbH Eesti filiaal  
Tel: +372 623 1011 

 
Norge 
AbbVie AS 
Tlf: +47 67 81 80 00 

 
Ελλάδα 
AbbVie ΦΑΡΜΑΚΕΥΤΙΚΗ Α.Ε. 
Τηλ: +30 214 4165 555 

 
Österreich 
AbbVie GmbH  
Tel: +43 1 20589-0 



58 

 
España 

AbbVie Spain, S.L.U. 
Tel:  +34 91 384 09 10 

 
Polska 
AbbVie Polska Sp. z o.o. 
Tel: +48 22 372 78 00  

 
France 
AbbVie 
Tél: +33 (0) 1 45 60 13 00 

 
Portugal 
AbbVie, Lda.  
Tel: +351 (0)21 1908400 

 
Hrvatska  
AbbVie d.o.o. 
Tel: + 385 (0)1 5625 501 

 
România 
AbbVie S.R.L. 
Tel: +40 21 529 30 35 

 
Ireland 
AbbVie Limited  
Tel: +353 (0)1 4287900 

 
Slovenija 
AbbVie Biofarmacevtska družba d.o.o. 
Tel: +386 (1)32 08 060 

 
Ísland 
Vistor hf. 
Tel: +354 535 7000 

 
Slovenská republika 
AbbVie s.r.o. 
Tel: +421 2 5050 0777 

 
Italia 
AbbVie S.r.l.  
Tel: +39 06 928921 

 
Suomi/Finland 
AbbVie Oy  
Puh/Tel:  +358 (0)10 2411 200 

 
Κύπρος 
Lifepharma (Z.A.M.) Ltd 
Τηλ: +357 22 34 74 40 

 
Sverige 
AbbVie AB 
Tel:  +46 (0)8 684 44 600 

 
Latvija 
AbbVie SIA  
Tel: +371 67605000 

 
United Kingdom 
AbbVie Ltd  
Tel: +44 (0)1628 561090 

 
This leaflet was last revised in  
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  
 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 
 
To listen to or request a copy of this leaflet in <Braille>, <large print> or <audio>, please contact the 
local representative of the Marketing Authorisation Holder. 
  



59 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 
 

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE 
MARKETING AUTHORISATION(S) 

 
 
 
 

 



60 

Scientific conclusions 
 
Taking into account the PRAC Assessment Report on the PSUR(s) for venetoclax, the scientific 
conclusions of CHMP are as follows: 
 
The serious infections (such as sepsis, pneumonia, septic shock etc.) are considered to be the most common 
cause of death (after those associated with the underlying malignancy or disease progression) in relation to 
venetoclax treatment. In this reporting interval, a total of 765 reports of serious infections were identified. 
Since the overall number of events of serious infections is high, the healthcare professionals should be 
explicitly reminded of these cases. Section 4.4 of the SmPC for Venclyxto should therefore include a 
standalone undersection entitled “infections”, including the warning statement regarding the risk of infections 
and their monitoring. The Package leaflet should be updated accordingly. 
 
In addition, the actual format of text for recommendation for dose reduction in case of concomitant use with 
CYP3A inhibitors is considered difficult to read and respective data would be more easily readable when 
displayed in tabular format. The relevant information in section 4.2 of the SmPC for Venclyxto should be 
amended accordingly. 
 
The CHMP agrees with the scientific conclusions made by the PRAC. 
 
Grounds for the variation to the terms of the marketing authorisation(s) 
 
On the basis of the scientific conclusions for venetoclax the CHMP is of the opinion that the benefit-risk 
balance of the medicinal product(s) containing venetoclax is unchanged subject to the proposed changes to 
the product information 
 
The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USEOF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THEMARKETING AUTHORISATION(S)