VENCLYXTO Film-coated tablet Ref.[9093] Active ingredients: Venetoclax

Tumour lysis syndrome

Tumour lysis syndrome, including fatal events and renal failure requiring dialysis, has occurred in patients treated with venetoclax (see section 4.8).

Venetoclax can cause rapid reduction in tumour, and thus poses a risk for TLS at initiation and during the 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. During post-marketing surveillance, TLS, including fatal events, has been reported after a single 20 mg dose of venetoclax. Information described in section 4.2, including risk assessment, prophylactic measures, dose-titration and modification schedule, laboratory monitoring, and drug interactions should be followed to prevent and reduce the risk of TLS.

The risk of TLS is a continuum based on multiple factors, including comorbidities (particularly reduced renal function), tumour burden, and splenomegaly in CLL.

All 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. More intensive measures (intravenous hydration, frequent monitoring, hospitalisation) should be employed as overall risk increases. Dosing should be interrupted if needed; when restarting venetoclax, dose modification guidance should be followed (see Table 4 and Table 5). The instructions for “Prevention of tumour lysis syndrome (TLS)” 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

In patients with CLL, 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).

In patients with AML, grade 3 or 4 neutropenia are common before starting treatment. The neutrophil counts can worsen with venetoclax in combination with a hypomethylating agent. Neutropenia can recur with subsequent cycles of therapy.

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, dose interruption or reduction, and use of growth factors (e.g., G-CSF) 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).

Excipients with known effect

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium free”.

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 patients increased venetoclax C_max to 2.3-fold and AUC to 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 C_max to 2.4-fold and AUC by 7.9-fold. Compared with venetoclax 400 mg administered alone, co-administration of 300 mg posaconazole, a strong CYP3A and P-gp inhibitor, with venetoclax 50 mg and 100 mg for 7 days in 12 patients increased venetoclax C_max to 1.6-fold and 1.9-fold, and AUC to 1.9-fold and 2.4-fold, respectively. Co-administration of venetoclax with other strong CYP3A4 inhibitors is predicted to increase venetoclax AUC by on average 5.8- to 7.8-fold.

For patients requiring concomitant use of venetoclax with strong CYP3A inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, ritonavir) or moderate CYP3A inhibitors (e.g., ciprofloxacin, diltiazem, erythromycin, fluconazole, verapamil), venetoclax dosing should be administered according to Table 7. Patients should be monitored more closely for signs of toxicities and the dose may need to be further adjusted. The venetoclax dose that was used prior to initiating the CYP3A inhibitor should be resumed 2 to 3 days after discontinuation of the inhibitor (see 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 rifampicin, a P-gp inhibitor, in 11 healthy subjects increased venetoclax C_max 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 rifampicin, a strong CYP3A inducer, for 13 days in 10 healthy subjects decreased venetoclax C_max by 42% and AUC by 71%. Concomitant use of venetoclax with strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampicin) 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 C_max 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 C_max and AUC of R-warfarin and 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 C_max 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 etexilate), 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.

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.

Venclyxto has no or negligible influence on the ability to drive and use machines. Fatigue and dizziness have been reported in some patients taking venetoclax and should be considered when assessing a patient’s ability to drive or operate machines.

Summary of safety profile

Chronic lymphocytic leukaemia

The overall safety profile of Venclyxto is based on data from 758 patients with CLL treated in clinical studies 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 study in which 212 patients with previously untreated CLL and comorbidities received venetoclax in combination with obinutuzumab. MURANO was a randomised, controlled study 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.

Acute myeloid leukaemia

The overall safety profile of Venclyxto is based on data from 314 patients with newly diagnosed acute myeloid leukaemia (AML) treated in clinical studies with venetoclax in combination with a hypomethylating agent (azacitidine or decitabine) (VIALE-A phase 3 randomised, and M14-358 phase 1 non-randomised).

In the VIALE-A study, the most commonly occurring adverse reactions (≥20%) of any grade in patients receiving venetoclax in combination with azacitidine were thrombocytopenia, neutropenia, febrile neutropenia, nausea, diarrhoea, vomiting, anaemia, fatigue, pneumonia, hypokalaemia, and decreased appetite.

The most frequently reported serious adverse reactions (≥5%) in patients receiving venetoclax in combination with azacitidine were febrile neutropenia, pneumonia, sepsis and haemorrhage. In the M14-358 study, the most commonly occurring adverse reactions (≥20%) of any grade in patients receiving venetoclax in combination with decitabine were thrombocytopenia, febrile neutropenia, nausea, haemorrhage, pneumonia, diarrhoea, fatigue, dizziness/syncope, vomiting, neutropenia, hypotension, hypokalaemia, decreased appetite, headache, abdominal pain, and anaemia. The most frequently reported serious adverse reactions (≥5%) were febrile neutropenia, pneumonia, bacteraemia and sepsis.

The 30-day mortality rate in the VIALE-A study was 7.4% (21/283) with venetoclax in combination with azacitidine and 6.3% (9/144) in the placebo with azacitidine arm.

The 30-day mortality rate in the M14-358 study with venetoclax in combination with decitabine was 6.5% (2/31).

Tabulated list of adverse reactions

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.

Chronic lymphocytic leukaemia

The frequencies of adverse reactions reported with Venclyxto, in combination with obinutuzumab, rituximab, or as monotherapy in patients with CLL are summarised in Table 8.

Table 8. Adverse drug reactions reported in patients with CLL treated with venetoclax:

^a Only the highest frequency observed in the studies is reported (based on studies CLL14, MURANO, M13-982, M14-032, and M12-175).

Acute myeloid leukaemia

The frequencies of adverse reactions reported with Venclyxto in combination with a hypomethylating agent in patients with AML are summarised in Table 9.

Table 9. Adverse drug reactions reported in patients with AML treated with venetoclax:

^a Only the highest frequency observed in the studies is reported (based on studies VIALE-A and M14-358).
^b Includes multiple adverse reaction terms.

Discontinuation and dose reductions due to adverse reactions

Chronic lymphocytic leukaemia

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 venetoclax and rituximab in the MURANO study and in 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%).

Acute myeloid leukaemia

In the VIALE-A study, discontinuations of venetoclax due to adverse reactions occurred in 24% of patients treated with the combination of venetoclax and azacitidine. Venetoclax dosage reductions due to adverse reactions occurred in 2% of patients. Venetoclax dose interruptions due to adverse reactions occurred in 72% of patients. Among patients who achieved bone marrow clearance of leukaemia, 53% underwent dose interruptions for ANC <500/microlitre. The most common adverse reaction that led to dose interruption (>10%) of venetoclax were febrile neutropenia, neutropenia, pneumonia, and thrombocytopenia.

In the M14-358 study, discontinuations due to adverse reactions occurred in 26% of patients treated with the combination of venetoclax and decitabine. Dosage reductions due to adverse reactions occurred in 6% of patients. Dose interruptions due to adverse reactions occurred in 65% of patients; the most common adverse reactions that led to dose interruption (≥5%) of venetoclax were febrile neutropenia, neutropenia/neutrophil count decreased, pneumonia, platelet count decreased, and white blood cell count decreased.

Description of selected adverse reactions

Tumour lysis syndrome

Tumour lysis syndrome is an important identified risk when initiating venetoclax.

Chronic lymphocytic leukaemia

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 × 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 × 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.

During post-marketing surveillance, TLS, including fatal events, has been reported after a single 20 mg dose of venetoclax (see sections 4.2 and 4.4).

Acute myeloid leukaemia

In the randomised, phase 3 study (VIALE-A) with venetoclax in combination with azacitidine the incidence of TLS was 1.1% (3/283, 1 clinical TLS). The study required reduction of white blood cell count to <25 × 10⁹/l prior to venetoclax initiation and a dose-titration schedule in addition to standard prophylaxis and monitoring measures (see section 4.2). All cases of TLS occurred during dose-titration.

In M14-358 study, no events of laboratory or clinical TLS were reported with venetoclax in combination with decitabine.

Neutropenia and infections

Neutropenia is an identified risk with Venclyxto treatment.

Chronic lymphocytic leukaemia

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 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.

Acute myeloid leukaemia

In the VIALE-A study, grade ≥3 neutropenia was reported in 45% of patients. The following were also reported in the venetoclax + azacitidine arm versus the placebo + azacitidine arm, respectively: febrile neutropenia 42% versus 19%, grade ≥3 infections 64% versus 51%, and serious infections 57% versus 44%.

In the M14-358 study, neutropenia was reported in 35% (all grades) and 35% (grade 3 or 4) of patients in the venetoclax + decitabine arm.

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.

Not applicable.