Venetoclax

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.

Co-administration of 600 mg once daily rifampin, 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, 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.

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.

The table below describes venetoclax 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.

Management of potential venetoclax interactions with CYP3A inhibitors:

^a Avoid concomitant use of venetoclax with moderate CYP3A inhibitors at initiation and during the dose titration phase. Consider alternative medications or reduce the venetoclax dose as described in this table.

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 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.

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 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.

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 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.

Grapefruit products, Seville oranges, and starfruit (carambola) should be avoided during treatment with venetoclax as they contain inhibitors of CYP3A.

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.

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.

A dose reduction of at least 50% throughout treatment is recommended for patients with severe hepatic impairment. These patients should be monitored more closely for signs of toxicity.

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.

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. Before starting treatment, counselling on sperm storage may be considered in some male patients.

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.

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.

Tumour lysis syndrome, including fatal events, has occurred in patients with CLL with high tumour burden when treated with venetoclax.

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 ALC ≥25 × 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. 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.

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. Also, inhibitors of P-gp or BCRP may increase venetoclax exposure.

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 × 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.

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. 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. When resuming treatment after interruption due to TLS, the instructions for prevention of TLS should be followed (see “Prevention of tumour lysis syndrome” above).

Serious infections, including sepsis with fatal outcome, have been reported. 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.

Grade 3 or 4 neutropenia has been reported in patients treated with venetoclax in combination studies with rituximab or obinutuzumab and in monotherapy studies. Complete blood counts should be monitored throughout the treatment period. Dose interruptions or reductions are recommended for patients with severe neutropenia.

Based on embryo-foetal toxicity studies in animals, 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. Venetoclax is not recommended during pregnancy and in women of childbearing potential not using highly effective contraception.

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 venetoclax.

Women of childbearing potential/Contraception in females

Women should avoid becoming pregnant while taking venetoclax 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.

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. Before starting treatment, counselling on sperm storage may be considered in some male patients.

Venetoclax 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.

Summary of safety profile

The overall safety profile of venetoclax 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.

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 venetoclax, either in combination with obinutuzumab or rituximab or as monotherapy, are summarised in the table below. 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.

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

^a Only 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 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 × 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.

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. 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. 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 venetoclax 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 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.