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 Indications

Instruct VENCLEXTA:

For the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Combine with azacitidine, decitabine or low-dose cytarabine for the treatment of newly diagnosed adult acute myeloid leukemia (AML):

75 years or older, or

Patients with comorbidities cannot use intensive induction chemotherapy.

Important safety information

Contraindications

In patients with CLL/SLL, simultaneous use of VENCLEXTA with strong CYP3A inhibitors is contraindicated because it may increase the risk of tumor lysis syndrome (TLS).

Tumor lysis syndrome

Patients treated with VENCLEXTA developed tumor lysis syndromes, including fatal events and renal failure requiring dialysis.

VENCLEXTA can cause rapid tumor reduction, so in all CLL/SLL patients, there is a risk of TLS during the start and the start phase, and during the restart period after the dose is interrupted. Changes in blood chemistry consistent with TLS need to be dealt with in time. It can occur as early as 6 to 8 hours after the first administration of VENCLEXTA, and will occur every time the dose is increased. A 20 mg dose of TLS has been reported, including fatal cases.

Among CLL/SLL patients following the current (5-week) dose increase and TLS prevention and monitoring measures, the incidence of TLS was 2% in the VENCLEXTA CLL single-agent trial. The incidence of TLS is consistent with the incidence of VENCLEXTA combined with obinutuzumab or rituximab. In CLL/SLL patients, with the 2 to 3 week dose increase and higher starting dose, the incidence of TLS was 13%, including death and renal failure.

Following the current 3-day dosing schedule and TLS prevention and monitoring measures for AML patients, the incidence of TLS in patients receiving VENCLEXTA combined with azacitidine was 1.1%. The incidence of TLS in AML patients who followed the 4-day increased dose schedule and TLS prevention and monitoring measures was 5.6%, including death and renal failure in patients receiving VENCLEXTA combined with low-dose cytarabine therapy.

The risk of TLS is a continuous factor based on multiple factors, especially reduced renal function, reduced tumor burden, and reduced malignant tumor types. Splenomegaly may also increase the risk of TLS in CLL/SLL patients.

Assess the risks of all patients and provide appropriate preventive measures for TLS, including hydration and anti-hyperuric acid drugs. Monitor blood chemistry and deal with abnormalities in time. As the overall risk increases, more stringent measures should be taken (intravenous hydration, frequent monitoring, hospitalization). Interrupt the administration if necessary; when restarting VENCLEXTA, follow the dosage adjustment instructions in the complete prescribing information.

Concomitant use of VENCLEXTA and P-gp inhibitors or strong or moderate CYP3A inhibitors can increase venetoclax exposure, which may increase the risk of TLS during and in the initiation phase, and requires dose adjustment of VENCLEXTA.

Neutropenia

Among CLL patients, 63% to 64% of patients treated with combination therapy and monotherapy had grade 3 or 4 neutropenia, while 31% to 33% of patients had 4% of neutropenia. Neutropenia. Febrile neutropenia occurs in 4% to 6% of patients.

Among patients with AML, patients who received VENCLEXTA in combination with azacitidine or decitabine or low-dose cytarabine had a decrease in neutrophil count from 95% to 100%. Neutropenia can recur in subsequent cycles.

Monitor the complete blood count throughout the treatment period. For severe neutropenia, the administration should be interrupted or the course of treatment should be shortened according to the remission state and occurrence. Consider supportive measures including antibacterial agents and growth factors (such as G-CSF).

infectious disease

=Patients treated with VENCLEXTA developed fatal and serious infections, such as pneumonia and sepsis. Monitor patients for signs and symptoms of infection and treat them promptly. Refuse VENCLEXTA for level 3 and 4 infections until resolved.

Immunization

Before, during or after VENCLEXTA treatment, do not give live attenuated vaccines until B cells have recovered. Inform patients that the effect of vaccination may be poor.

Embryo-fetal toxicity

When administered to pregnant women, VENCLEXTA may cause embryo-fetal harm. Advise women of reproductive potential to use effective contraceptive methods during treatment and at least 30 days after the last medication.

After adding VENCLEXTA to bortezomib and dexamethasone, the mortality of multiple myeloma patients increased

In a randomized trial (BELLINI; NCT02755597) in patients with relapsed or refractory multiple myeloma, the addition of VENCLEXTA to bortezomib plus dexamethasone (the use of VENCLEXTA was not shown to increase mortality). Outside of controlled clinical trials, it is not recommended to combine VENCLEXTA with bortezomib and dexamethasone in the treatment of patients with multiple myeloma.

Adverse reactions

In CLL patients receiving the combination therapy of Obituximab, serious adverse reactions are usually caused by febrile neutropenia and pneumonia (5% each). The most common adverse reactions (≥20%) in any grade were neutropenia (60%), diarrhea (28%) and fatigue (21%). According to reports, fatal adverse reactions that occurred in 2% (4/212) of patients in the absence of disease progression and within 28 days after the last study treatment occurred, most of which were caused by infection.

In CLL patients receiving rituximab combination therapy, the most common serious adverse reaction (≥5%) is pneumonia (9%). The most common adverse reactions (≥20%) in any grade are neutropenia (65%), diarrhea (40%), upper respiratory tract infection (39%), fatigue (22%) and nausea (21%) . In 2% (4/194) of patients, fatal adverse reactions that occurred in the absence of disease progression and within 30 days after the last VENCLEXTA treatment and/or within 90 days of the last rituximab were reported .

Among CLL/SLL patients receiving monotherapy, the most common serious adverse reactions (≥5%) were pneumonia (9%), febrile neutropenia (5%) and sepsis (5%). The most common adverse reactions (≥20%) in any grade are neutropenia (50%), diarrhea (43%), nausea (42%), upper respiratory tract infection (36%), and anemia (33%) , Fatigue (32%), thrombocytopenia (29%), musculoskeletal pain (29%), edema (22%) and cough (22%). In the VENCLEXTA single-agent study, 2% of patients reported fatal adverse reactions that occurred within 30 days after treatment with Venetoclax without disease progression, most of which were septic shock (2 cases).

In AML patients receiving azacitidine combination therapy, the most common serious adverse reactions (≥5%) are febrile neutropenia (30%), pneumonia (22%), and sepsis (excluding fungi; 19 %) and bleeding (6%). . The most common adverse reactions (≥30%) in any grade were neutropenia (98%), thrombocytopenia (94%), lymphopenia (91%), hemoglobin reduction (61%), nausea (44%) ), diarrhea (43%), febrile neutropenia (42%), musculoskeletal pain (36%), pneumonia (33%), fatigue (31%) and vomiting (30%). Fatal adverse reactions occurred in 23% of patients receiving VENCLEXTA combined with azacitidine. The most common (≥2%) were pneumonia (4%), sepsis (excluding fungi; 3%) and bleeding (2%) .

Among AML patients receiving combination therapy with decitabine, the most common serious adverse reactions (≥10%) were sepsis (excluding fungi; 46%), febrile neutropenia (38%), and pneumonia ( 31%). The most common adverse reactions (≥30%) in any grade were febrile neutropenia (69%), fatigue (62%), constipation (62%), musculoskeletal pain (54%), and dizziness (54 %), nausea (54%), abdominal pain (46%), diarrhea (46%), pneumonia (46%), sepsis (excluding fungus; 46%), cough (38%), fever (31%), low Blood pressure (31%), oropharyngeal pain (31%), edema (31%) and vomiting (31%). Within 30 days after starting treatment, a fatal adverse reaction of bacteremia occurred (8%).

In AML patients receiving low-dose cytarabine combination therapy, the most common serious adverse reactions (≥10%) were pneumonia (17%), febrile neutropenia (16%) and sepsis (not including Fungus; 12%). The most common adverse reactions (≥30%) in any grade were thrombocytopenia (97%), neutropenia (95%), lymphopenia (92%), hemoglobin reduction (63%), nausea (42%) ) And febrile neutropenia (32%). Fatal adverse reactions occurred in 23% of patients receiving VENCLEXTA in combination with LDAC, of ​​which the most common (≥5%) were pneumonia (6%) and sepsis (excluding fungi; 7%).

medicine interactions

Concomitant use with P-gp inhibitors or strong or moderate CYP3A inhibitors can increase VENCLEXTA exposure, which may increase the toxicity of VENCLEXTA, including the risk of TLS. Consider using alternative drugs or adjust the dose of VENCLEXTA and monitor adverse reactions more frequently. Resume the VENCLEXTA dose 2 to 3 days before stopping the use of P-gp inhibitors or strong or moderate CYP3A inhibitors.

Patients should avoid grapefruit products, Seville oranges and star fruit during treatment, because they contain CYP3A inhibitors.

Avoid using strong or moderate CYP3A inducers at the same time.

Patients receiving warfarin should monitor the International Normalized Ratio (INR) more frequently.

Avoid using VENCLEXTA and P-gp substrate at the same time. If simultaneous use is unavoidable, P-gp substrates should be dosed separately at least 6 hours before VENCLEXTA.

Lactation period

It is recommended that breastfeeding women not breastfeed during VENCLEXTA treatment and within 1 week after the last dose.

Men and women of reproductive potential

Advise women of reproductive potential to use effective contraceptive methods during treatment with VENCLEXTA and at least 30 days after the last dose.

Based on findings in animals, VENCLEXTA may damage male fertility.

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