BEQALZI Film-coated tablet Ref.[116693] Active ingredients: Sonrotoclax

5.1 Tumor Lysis Syndrome

BEQALZI can cause serious or life-threatening tumor lysis syndrome (TLS). BEQALZI can cause rapid reduction in tumor and changes in blood chemistries consistent with TLS that require prompt management. This can occur as early as 4 hours after the first dose, at any dose increases, and upon restart following dosage interruption. Laboratory or clinical TLS occurred in 7% of the 115 patients with MCL who followed the recommended dose ramp-up.

Risk factors for TLS include higher tumor burden such as bulky lymphadenopathy or lymphocytosis and reduced renal function.

Assess all patients for TLS risk and provide appropriate prophylaxis, including hydration and anti-hyperuricemics begun prior to the first dose of BEQALZI. Correct relevant chemistry abnormalities prior to starting BEQALZI. Consider hospitalization with intravenous hydration and monitoring and employ more frequent monitoring for patients with high TLS risk. Monitor blood chemistries and manage abnormalities promptly. Interrupt dosing if needed; when restarting BEQALZI, follow the dose modification guidance [see Dosage and Administration (2.3)].

Concomitant use of sonrotoclax with strong or moderate CYP3A inhibitors increases sonrotoclax exposure, which may increase the risk of TLS at initiation and during the ramp-up phase [see Dosage and Administration (2.4) and Drug Interactions (7.1)].

5.2 Serious Infections

BEQALZI can cause fatal or serious infections [see Adverse Reactions (6.1)]. Among patients who received BEQALZI at the recommended dosage in the clinical trial, serious infections occurred in 14% of patients and Grade 3 or higher infections in 17%, with fatal infections in 2.6% of patients. The most common Grade 3 or greater infection was pneumonia (10%). Monitor for signs and symptoms of infection and treat appropriately. Consider prophylactic antimicrobials and immunoglobulins according to guidelines. Withhold or dose reduce BEQALZI based on severity [see Dosage and Administration (2.3)].

5.3 Neutropenia

BEQALZI can cause serious or severe cytopenias, including neutropenia. Among 115 patients with MCL who received BEQALZI, new or worsening Grade 3 or 4 decrease in neutrophils developed in 18% (Grade 4, 6%). Febrile neutropenia occurred in 1.7% of patients. Monitor complete blood counts throughout treatment. Based on severity, reduce dose, interrupt, or permanently discontinue BEQALZI [see Dosage and Administration (2.3)].

5.4 Embryo-Fetal Toxicity

Based on findings in animals and its mechanism of action, BEQALZI can cause fetal harm when administered to a pregnant woman. In embryo-fetal development toxicity studies conducted in pregnant mice and rabbits, oral administration of sonrotoclax during the period of organogenesis caused adverse developmental outcomes, including structural abnormalities and altered fetal growth at approximately ≥2 times the clinical exposure based on the area under the concentration-time curve (AUC) at the recommended dose in humans (320 mg/day).

Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with BEQALZI and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Tumor Lysis Syndrome [see Warnings and Precautions (5.1)]
• Serious Infections [see Warnings and Precautions (5.2)]
• Neutropenia [see Warnings and Precautions (5.3)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Mantle Cell Lymphoma

The safety of BEQALZI was evaluated in 115 adult patients with previously treated MCL in a single-arm, multicenter clinical trial, BGB-11417-201 (NCT05471843) [see Clinical Studies (14.1)]. The trial required prior receipt of anti-CD20–based therapy and a BTK inhibitor. The trial excluded patients on moderate or strong CYP3A inhibitors or strong CYP3A inducers and required an absolute neutrophil count (ANC) ≥1000/mm³; platelets ≥75,000/mm³; creatinine clearance ≥50 mL/min; AST and ALT ≤3 × upper limit of normal (ULN); and serum total bilirubin ≤2 × ULN.

Patients received BEQALZI 320 mg orally once daily following completion of a 4-week ramp-up dosing schedule. Of the 115 patients who received BEQALZI, 52% were exposed for at least 6 months and 34% were exposed for at least 1 year.

Serious adverse reactions were reported in 37% of patients who received BEQALZI, most frequently (≥2%) from pneumonia (10%). Fatal adverse reactions occurred in 4.3% of patients, including from pneumonia (2.6%) and sudden death (1.7%).

Adverse reactions led to dose interruption of BEQALZI in 27% of patients, dose reduction in 0.9%, and permanent discontinuation in 8%. The most common reasons for dose interruption were infections (10%) and neutropenia (5%). The most common adverse reaction leading to treatment discontinuation was infection (1.7%).

Table 7 summarizes select adverse reactions in Study BGB-11417-201, excluding laboratory terms.

Table 7. Adverse Reactions (≥10%) in Patients with MCL Who Received BEQALZI in BGB-11417-201:

^* Additionally includes three fatal cases (2.6%) of pneumonia.
^a Includes pneumonia, COVID-19 pneumonia, pneumonia bacterial, and other related terms.
^b Includes upper respiratory tract infection, pharyngitis, sinusitis, and other related terms.
^c Includes fatigue and asthenia.
^d Includes edema peripheral, generalized edema, and other related terms.
^e Includes rash, dermatitis, drug eruption, and other related terms.
^f Includes musculoskeletal pain, back pain, bone pain, and other related terms.

Clinically relevant adverse reactions in <10% of patients who received BEQALZI included: TLS, headache, nausea, vomiting, mucositis, peripheral sensory neuropathy, febrile neutropenia, pneumonitis, herpes zoster infection, and sepsis.

Table 8 summarizes new or worsening laboratory abnormalities throughout treatment. Grade 4 laboratory abnormalities in ≥2% of patients included decreases in neutrophils (6%) and platelet count (3.5%).

Table 8. Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with Previously Treated MCL Who Received BEQALZI:

^a The denominator used to calculate the rate varied from 103 to 115 based on the number of patients with a baseline value and at least one post-treatment value.

7.1 Effects of Other Drugs on BEQALZI

Strong or Moderate CYP3A Inhibitors

Concomitant use of strong CYP3A inhibitors during the initiation and ramp-up phase with BEQALZI is contraindicated. After the ramp-up phase, reduce the target dose of BEQALZI as in Table 5 [see Dosage and Administration (2.4)].

For dose modifications of sonrotoclax with moderate CYP3A inhibitors, see Dosage and Administration (2.4).

Sonrotoclax is a CYP3A substrate [see Clinical Pharmacology (12.3)]. Concomitant use with strong and moderate CYP3A inhibitors increase sonrotoclax exposure [see Clinical Pharmacology (12.3)], which may increase the risk of BEQALZI adverse reactions.

Strong or Moderate CYP3A Inducers

Avoid concomitant use of strong or moderate CYP3A inducers with BEQALZI.

Sonrotoclax is a CYP3A substrate [see Clinical Pharmacology (12.3)]. Concomitant use with strong CYP3A inducers decreases sonrotoclax exposure [see Clinical Pharmacology (12.3)], which may reduce effectiveness of sonrotoclax.

Risk Summary

Based on findings in animals and its mechanism of action [see Clinical Pharmacology (12.1)], BEQALZI can cause embryo-fetal harm when administered to pregnant women. There are no available data on BEQALZI use in pregnant women to evaluate for a drug-associated risk.

In animal reproduction studies, oral administration of sonrotoclax to pregnant mice and rabbits during the period of organogenesis resulted in adverse developmental outcomes, including structural abnormalities and altered fetal growth, at maternal exposures approximately ≥2 times the human exposure (AUC) at the recommended dose of 320 mg daily (see Data). Advise patients of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Sonrotoclax was administered orally to pregnant mice at doses of 100, 300, and 1000 mg/kg/day during organogenesis (gestation days 6-15). Decreased fetal body weight and crown-rump length were noted at all doses. At the dose of 100 mg/kg/day in mice, the maternal exposure was approximately 8 times the human exposure at the recommended dose of 320 mg once daily.

Sonrotoclax was administered orally to pregnant rabbits at doses of 15, 75, and 300 mg/kg/day during organogenesis (gestation days 6-19). Fetal external (absent or open eye, cleft lip, misshapen mouth, acephalostoma) malformations were noted at 300 mg/kg/day. At the dose of 300 mg/kg/day in rabbits, the maternal exposure was approximately 2 times the human exposure at the recommended dose of 320 mg once daily.

Risk Summary

There are no data on the presence of sonrotoclax or its metabolites in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with BEQALZI and for 1 week after the last dose.

Based on findings in animals and its mechanism of action, BEQALZI can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating BEQALZI.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with BEQALZI and for 1 week after the last dose.

Males

Advise males with female partners of reproductive potential to use effective contraception during treatment with BEQALZI and for 1 week after the last dose.

Infertility

Based on findings in animals, BEQALZI may impair male and female fertility. Fertility findings were reversible in animals [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of BEQALZI in pediatric patients have not been established.

Of the 115 patients with MCL who were treated with BEQALZI, 74 (64%) were 65 years old or older and 26 (23%) were 75 years old or older. Patients aged 65 years and older experienced higher rates of serious adverse reactions (42%) compared to younger patients (29%). Clinical studies of BEQALZI did not include sufficient numbers of patients to determine whether efficacy differs in patients 65 years of age or older compared to younger patients.

No dose adjustments are recommended for patients with mild or moderate renal impairment (estimated glomerular filtration rate (eGFR) ≥30 mL/min). BEQALZI has not been studied in patients with severe renal impairment (eGFR <30 mL/min) [see Clinical Pharmacology (12.3)].

No dose adjustments are recommended for patients with mild or moderate hepatic impairment (bilirubin ≤3× upper limit of normal [ULN] and any aspartate aminotransferase [AST]). BEQALZI has not been studied in patients with severe hepatic impairment (bilirubin >3× ULN and any AST) [see Clinical Pharmacology (12.3)].