zanubrutinib: prescribing information – dosing, contraindications, interactions, side effects

BRUKINSA as monotherapy is indicated for the treatment of adult patients with Waldenström’s macroglobulinaemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy.

BRUKINSA as monotherapy is indicated for the treatment of adult patients with marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based therapy.

BRUKINSA as monotherapy is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL).

BRUKINSA in combination with obinutuzumab is indicated for the treatment of adult patients with refractory or relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.

Treatment with this medicinal product should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Posology

The recommended total daily dose of zanubrutinib is 320 mg. The daily dose may be taken either once daily (four 80 mg capsules) or divided into two doses of 160 mg twice daily (two 80 mg capsules). Treatment should be continued until disease progression or unacceptable toxicity.

BRUKINSA in combination with obinutuzumab

Zanubrutinib must be administered before obinutuzumab infusion. The recommended dose is obinutuzumab 1 000 mg intravenously on Days 1, 8, and 15 of Cycle 1, and on Day 1 of every 28-day cycle from Cycles 2 to 6. At the discretion of the physician, obinutuzumab may be administered 100 mg on Day 1 and 900 mg on Day 2 of Cycle 1 instead of 1 000 mg on Day 1 of Cycle 1.
Obinutuzumab maintenance (one infusion every two months for up to two years) may be prescribed.
Refer to the obinutuzumab SmPC for additional dosing information, including premedication before each infusion.

Dose modifications for adverse reactions

Recommended dose modifications of zanubrutinib for Grade 3 or greater adverse reactions are provided in Table 1.

Table 1: Recommended dose modifications for adverse reactions
Adverse reaction
Adverse reaction occurrence
Dose modification
(starting dose: 320 mg once daily or
160 mg twice daily)
≥ Grade 3 non-haematological toxicities

≥ Grade 3 febrile neutropenia

Grade 3 thrombocytopenia with significant bleeding

Grade 4 neutropenia (lasting > 10 consecutive days)

Grade 4 thrombocytopenia (lasting
> 10 consecutive days)
First
Interrupt BRUKINSA
Once toxicity has resolved to ≤Grade 1 or baseline: Resume at 320 mg once daily or 160 mg twice daily Second Interrupt BRUKINSA Once toxicity has resolved to ≤Grade 1 or baseline: Resume at 160 mg once daily or 80 mg twice daily Third Interrupt BRUKINSA Once toxicity has resolved to ≤Grade 1 or baseline: Resume at 80 mg once daily Fourth Discontinue BRUKINSA

Asymptomatic lymphocytosis should not be regarded as an adverse reaction, and these patients should continue taking BRUKINSA.

For dose modification of obinutuzumab for adverse reactions, refer to the SmPC of obinutuzumab.

Dose modifications for concomitant therapy

Dose modifications for use with CYP3A inhibitors or inducers are shown in Table 2 (see also sections 4.4, 4.5 and 5.2):

Table 2: Recommended dose modifications when co-administered with other medicinal products CYP3A Co-administered medicinal product Recommended dose Inhibition Strong CYP3A inhibitor (e.g., posaconazole, voriconazole, ketoconazole, itraconazole, clarithromycin, indinavir, lopinavir, ritonavir, telaprevir) 80 mg once daily Moderate CYP3A inhibitor (e.g., erythromycin, ciprofloxacin, diltiazem, dronedarone, fluconazole, verapamil, aprepitant, imatinib, grapefruit juice, Seville oranges) 160 mg once daily or 80 mg twice daily Induction Strong CYP3A inducer (e.g., carbamazepine, phenytoin, rifampicin, St. John’s wort)

Moderate CYP3A inducer (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) Avoid concomitant use; Consider alternative agents with less CYP3A induction.

Missed dose

A double dose should not be taken to make up for a forgotten dose. If a dose is not taken at the scheduled time, the next dose should be taken according to the normal schedule.

Special populations

Elderly

No specific dose adjustment is required for elderly patients (aged ≥65 years).

Renal impairment

No dose modification is recommended in patients with mild to moderate renal impairment (creatinine clearance (CrCl) ≥30 mL/min, estimated by Cockcroft-Gault). There is limited data on patients with severe renal impairment and end-stage renal disease (n=12). Patients with severe renal impairment (CrCl <30 mL/min) or on dialysis should be monitored for adverse reactions (see section 5.2).

Hepatic impairment

Dose modifications are not needed in patients with mild (Child-Pugh class A) or moderate hepatic impairment (Child-Pugh class B). Patients with mild or moderate hepatic impairment were treated in BRUKINSA clinical studies. The recommended dose of BRUKINSA for patients with severe hepatic impairment (Child-Pugh class C) is 80 mg orally twice daily. The safety of BRUKINSA has not been evaluated in patients with severe hepatic impairment. These patients should be closely monitored for adverse reactions (see section 5.2).

Paediatric population

The safety and efficacy of BRUKINSA in children and adolescents below 18 years of age have not been established. No data are available.

Method of administration

BRUKINSA is for oral use. The hard capsules can be taken with or without food. Patients should be instructed to swallow the capsules whole with water, and not to open, break or chew the capsules.

Treatment with this medicinal product should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Posology

The recommended total daily dose of zanubrutinib is 320 mg. The daily dose may be taken either once daily (two 160 mg tablets once a day) or twice daily (one 160 mg tablet twice a day). Treatment should be continued until disease progression or unacceptable toxicity.

BRUKINSA in combination with obinutuzumab

Zanubrutinib must be administered before obinutuzumab infusion. The recommended dose is obinutuzumab 1 000 mg intravenously on Days 1, 8, and 15 of Cycle 1, and on Day 1 of every 28-day cycle from Cycles 2 to 6. At the discretion of the physician, obinutuzumab may be administered 100 mg on Day 1 and 900 mg on Day 2 of Cycle 1 instead of 1 000 mg on Day 1 of Cycle 1.
Obinutuzumab maintenance (one infusion every two months for up to two years) may be prescribed.
Refer to the obinutuzumab SmPC for additional dosing information, including premedication before each infusion.

Dose modifications for adverse reactions

Recommended dose modifications of zanubrutinib for Grade 3 or greater adverse reactions are provided in Table 1.

Table 1: Recommended dose modifications for adverse reactions
Adverse reaction
Adverse reaction occurrence
Dose modification
(starting dose: 320 mg once daily or
160 mg twice daily)
≥ Grade 3 non-haematological toxicities

≥ Grade 3 febrile neutropenia

Grade 3 thrombocytopenia with significant bleeding

Grade 4 neutropenia (lasting > 10 consecutive days)

Grade 4 thrombocytopenia (lasting
>10 consecutive days)
First
Interrupt BRUKINSA
Once toxicity has resolved to ≤Grade 1 or baseline: Resume at 320 mg once daily or 160 mg twice daily Second Interrupt BRUKINSA Once toxicity has resolved to ≤Grade 1 or baseline: Resume at 160 mg once daily or 80 mg twice daily Third Interrupt BRUKINSA Once toxicity has resolved to ≤Grade 1 or baseline: Resume at 80 mg once daily Fourth Discontinue BRUKINSA

Asymptomatic lymphocytosis should not be regarded as an adverse reaction, and these patients should continue taking BRUKINSA.

For dose modification of obinutuzumab for adverse reactions, refer to the SmPC of obinutuzumab.

Dose modifications for concomitant therapy

Dose modifications for use with CYP3A inhibitors or inducers are shown in Table 2 (see also sections 4.4, 4.5 and 5.2):

Table 2: Recommended dose modifications when co-administered with other medicinal products CYP3A Co-administered medicinal product Recommended dose Inhibition Strong CYP3A inhibitor (e.g., posaconazole, voriconazole, ketoconazole, itraconazole, clarithromycin, indinavir, lopinavir, ritonavir, telaprevir) 80 mg once daily Moderate CYP3A inhibitor (e.g., erythromycin, ciprofloxacin, diltiazem, dronedarone, fluconazole, verapamil, aprepitant, imatinib, grapefruit juice, Seville oranges) 160 mg once daily or 80 mg twice daily Induction Strong CYP3A inducer (e.g., carbamazepine, phenytoin, rifampicin, St. John’s wort)

Moderate CYP3A inducer (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) Avoid concomitant use; Consider alternative agents with less CYP3A induction

Missed dose

A double dose should not be taken to make up for a forgotten dose. If a dose is not taken at the scheduled time, the next dose should be taken according to the normal schedule.

Special populations

Elderly

No specific dose adjustment is required for elderly patients (aged ≥65 years).

Renal impairment

No dose modification is recommended in patients with mild to moderate renal impairment (creatinine clearance (CrCl) ≥30 mL/min, estimated by Cockcroft-Gault). There is limited data on patients with severe renal impairment and end-stage renal disease (n=12). Patients with severe renal impairment (CrCl <30 mL/min) or on dialysis should be monitored for adverse reactions (see section 5.2).

Hepatic impairment

Dose modifications are not needed in patients with mild (Child-Pugh class A) or moderate hepatic impairment (Child-Pugh class B). Patients with mild or moderate hepatic impairment were treated in BRUKINSA clinical studies. The recommended dose of BRUKINSA for patients with severe hepatic impairment (Child-Pugh class C) is 80 mg orally twice daily. The safety of BRUKINSA has not been evaluated in patients with severe hepatic impairment. These patients should be closely monitored for adverse reactions (see section 5.2).

Paediatric population

The safety and efficacy of BRUKINSA in children and adolescents below 18 years of age have not been established. No data are available.

Method of administration

BRUKINSA is for oral use. The film-coated tablets can be taken with or without food. Patients should be instructed to swallow the tablets with water, not to chew or crush the tablets. The tablet can be

divided into two equal halves, in case a dose adjustment is needed (see section 4.2).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Summary of the safety profile

Zanubrutinib monotherapy

The most commonly occurring adverse reactions (≥20%) of zanubrutinib monotherapy were upper respiratory tract infection§ (36%), bruising§ (32%), haemorrhage/haematoma§ (30%), neutropenia§ (30%), musculoskeletal pain§ (27%), rash§ (25%), pneumonia§ (24%), diarrhoea (21%) and cough§ (21%) (Table 3).

The most common Grade 3 or higher adverse reactions (>3%) of zanubrutinib monotherapy were neutropenia§ (21%), pneumonia§ (14%), hypertension§ (8%), thrombocytopenia§ (6%), anaemia (6%) and haemorrhage /haematoma§ (4%).

Of the 1550 patients treated with zanubrutinib, 4.8% of patients discontinued treatment due to adverse reactions. The most frequent adverse reaction leading to treatment discontinuation was pneumonia§ (2.6%). Adverse reactions leading to dose reduction occurred in 5.0% of patients.

Zanubrutinib in combination with obinutuzumab
The most commonly occurring adverse reactions (≥20%) of zanubrutinib in combination with obinutuzumab were thrombocytopenia§ (37%), neutropenia§ (31%) and fatigue§ (27%) (Table 4).

The most common Grade 3 or higher adverse reactions (>3%) of zanubrutinib in combination with obinutuzumab were neutropenia§ (25%), thrombocytopenia§ (16%), pneumonia§ (15%) and anaemia (5%).

Of the 143 patients treated with zanubrutinib in combination with obinutuzumab, 4.9% of patients discontinued treatment due to adverse reactions. The most frequent adverse reaction leading to treatment discontinuation was pneumonia§ (4.2%). Adverse reactions leading to dose reduction occurred in 7.0% of patients.

Platelet count decreased† (based on laboratory values) was observed in 65% (all grade) and 12% (grade 3 or 4) patients receiving zanubrutinib in combination with obinutuzumab compared to 43% (all grade) and 11% (grade 3 or 4) in patients receiving obinutuzumab. All grade and grade 3 or 4 platelet counts decreased were reported for 39% and 7.8% patients who received zanubrutinib monotherapy.

Tabulated list of adverse reactions

The safety profile of zanubrutinib monotherapy is based on pooled data from 1 550 patients with B- cell malignancies, including patients with chronic lymphocytic leukaemia (N = 938), Waldenström macroglobulinemia (N = 249), mantle cell lymphoma (N = 140), marginal zone lymphoma (N = 93), follicular lymphoma (N = 59) and other types of B-cell malignancies (N = 71), treated with BRUKINSA in clinical studies with a median duration of exposure of 34.41 months.

The safety profile of zanubrutinib in combination with obinutuzumab is based on ROSEWOOD study data from 143 patients with FL treated with BRUKINSA in combination with obinutuzumab with a median duration of exposure of 12.35 months.

Adverse reactions in patients treated with BRUKINSA as monotherapy or in combination with obinutuzumab for B-cell malignancies are listed in Table 3 and Table 4, respectively, by system organ class and frequency grouping. Frequencies are defined as follows: 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 the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 3: Adverse reactions of zanubrutinib monotherapy reported in clinical studies in patients with B-cell malignancies(n=1 550) MedDRA SOC MedDRA Terms All Grades* (%) Grade 3 or higher (%) Infections and infestations Upper respiratory tract infection§ Very Common (36) Pneumonia§# Very Common (24) Pneumonia Very Common (15) Lower respiratory tract infection Common (5) <1 Urinary tract infection§ Very Common (14) Bronchitis Common (4) <1 Hepatitis B reactivation Uncommon (<1) <1 Blood and lymphatic system disorders Neutropenia§ Very Common (30) Febrile neutropenia Common ( 2) Thrombocytopenia§ Very Common (18) Anaemia§ Very Common (16) Metabolism and nutrition disorders Tumour lysis syndrome§# Uncommon (<1) <1 Nervous system disorder Dizziness§ Very Common (12) <1 Cardiac disorders Atrial fibrillation and flutter Common (5)

Vascular disorders
Bruising§
Very Common (32)
<1
Contusion
Very Common (20)
Petechiae
Common (7)
<1
Purpura
Common (5)
<1
Ecchymosis
Common (3)
<1
Haemorrhage/Haematoma§ #
Very Common (30)
Haematuria
Very common (11)
<1
Epistaxis
Common (8)
<1
Gastrointestinal haemorrhage
Uncommon (<1)
<1
Hypertension§
Very Common (17)
Respiratory, thoracic and mediastinal disorders
Cough§
Very Common (21)
<1
Gastrointestinal disorders
Diarrhoea
Very Common (21)
Constipation
Very Common (14)
<1
Nausea
Very Common (12)
<1
Skin and subcutaneous tissue disorders
Rash§
Very Common (25)
<1
Pruritus
Common (8)
<1

Dermatitis exfoliative generalized Unknown
Unknown
Musculoskeletal and connective tissue disorders
Musculoskeletal pain§
Very Common (27)
Arthralgia
Very Common (15)
<1
Back pain
Very common (12)
<1

General disorders and administration site conditions
Fatigue§
Very common (18)
Fatigue
Very common (14)
Asthenia
Common (4)
<1
Oedema peripheral
Common (9)
<1
Investigations†
Neutrophil count decreased†± Very common (52)
Platelets decreased†±
Very common (39)
Haemoglobin decreased†±
Very common (26)
* Grades were evaluated based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI- CTCAE) version 4.03.
† Based on laboratory measurements.
± Percentages are based on number of patients with both baseline and at least one postbaseline assessment available.
§ Includes multiple adverse reaction terms
# Includes events with fatal outcome.

Table 4: Adverse reactions of zanubrutinib in combination with obinutuzumab reported in clinical study BGB-3111-212 in patients with follicular lymphoma (n=143)

MedDRA SOC
MedDRA Terms

All grades* (%)
Grade ≥3
(%)
Infections and infestations
Upper respiratory tract infection§
Very common (14)
<1
Pneumonia§#
Very common (20)
Pneumonia
Very common (13)
Lower respiratory tract infection
Common (4)
<1
Urinary tract infection§
Common (10)
Bronchitis
Common (2)
Blood and lymphatic system disorders
Thrombocytopenia§
Very common (37)
Neutropenia§
Very common (31)
Anaemia§
Very common (12)
Nervous system disorder
Dizziness§
Common (4)
Cardiac disorders
Atrial fibrillation and flutter§
Common (3)
Vascular disorders
Haemorrhage/hematoma§
Very common (16)
<1
Epistaxis
Common (5)
Hematuria
Common (<1)
Bruising§
Very common (15)
Contusion
Very common (8)
Petechiae
Common (6)
Purpura
Common (2)
Ecchymosis
Common (1)
Hypertension§
Common (4)
<1
Respiratory, thoracic and mediastinal disorders
Cough§
Very common (13)
Gastrointestinal disorders
Diarrhoea
Very common (19)
Constipation
Very common (13)
Nausea
Common (9)
Rash§
Very common (10)

Skin and subcutaneous tissue disorders
Pruritus
Common (7)
Dermatitis exfoliative generalized
Unknown
Unknown
Musculoskeletal and connective tissue disorders
Musculoskeletal Pain§
Very common (18)
Back pain
Very common (11)
<1
Arthralgia
Common (4)
General disorders and administration site conditions
Fatigue§
Very common (27)
Fatigue
Very common (15)
Asthenia
Common (12)
<1
Oedema peripheral
Common (2)

Investigations†±
Platelets decreased†±
Very common (65)
Neutrophil count decreased†±
Very common (48)
Haemoglobin decreased†±
Very common (31)
<1
* Adverse events were graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version 5.0.) † Based on laboratory measurements.
§ Includes multiple adverse reaction terms.
# Includes events with fatal outcome.
± Percentages are based on number of patients with both baseline and at least one postbaseline assessment available.

Other special population

Elderly

Of the 1 550 patients treated with BRUKINSA monotherapy, 61.3% were 65 years of age or older.
The incidence of Grade 3 or higher adverse events was slightly higher among elderly patients treated with zanubrutinib (69.6% of patients age ≥65 versus 62.7% of patients <65 years of age). No clinically relevant differences in safety were observed between patients ≥65 years and younger.

Of the 143 patients treated with BRUKINSA in combination with obinutuzumab, 42.0% were 65 years of age or older. The incidence of Grade 3 or higher adverse events was slightly higher among elderly patients treated with zanubrutinib in combination with obinutuzumab (70.0% of patients age ≥65 versus 62.7% of patients <65 years of age). No clinically relevant differences in safety were observed between patients ≥65 years and younger.

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.

Summary of the safety profile

Zanubrutinib monotherapy

The most commonly occurring adverse reactions (≥20%) of zanubrutinib monotherapy were upper respiratory tract infection§ (36%), bruising§ (32%), haemorrhage/haematoma§ (30%), neutropenia§ ( 30%), musculoskeletal pain§ (27%), rash§ (25%), pneumonia§ (24%), diarrhoea (21%) and cough§ (21%) (Table 3).

The most common Grade 3 or higher adverse reactions (>3%) of zanubrutinib monotherapy were neutropenia§ (21%), pneumonia§ (14%), hypertension§ (8%), thrombocytopenia§ (6%), anaemia (6%) and haemorrhage /haematoma§ (4%).

Of the 1550 patients treated with zanubrutinib, 4.8% of patients discontinued treatment due to adverse reactions. The most frequent adverse reaction leading to treatment discontinuation was pneumonia§ (2.6%). Adverse reactions leading to dose reduction occurred in 5.0% of patients.

Zanubrutinib in combination with obinutuzumab
The most commonly occurring adverse reactions (≥20%) of zanubrutinib in combination with obinutuzumab were thrombocytopenia§ (37%), neutropenia§ (31%) and fatigue§ (27%) (Table 4).

The most common Grade 3 or higher adverse reactions (>3%) of zanubrutinib in combination with obinutuzumab were neutropenia§ (25%), thrombocytopenia§ (16%), pneumonia§ (15%) and anaemia (5%).

Of the 143 patients treated with zanubrutinib in combination with obinutuzumab, 4.9% of patients discontinued treatment due to adverse reactions. The most frequent adverse reaction leading to treatment discontinuation was pneumonia§ (4.2%). Adverse reactions leading to dose reduction occurred in 7.0% of patients.

Platelet count decreased† (based on laboratory values) was observed in 65% (all grade) and 12% (grade 3 or 4) patients receiving zanubrutinib in combination with obinutuzumab compared to 43% (all grade) and 11% (grade 3 or 4) in patients receiving obinutuzumab. All grade and grade 3 or 4 platelet counts decreased were reported for 39% and 7.8% patients who received zanubrutinib monotherapy.

Tabulated list of adverse reactions

The safety profile of zanubrutinib monotherapy is based on pooled data from 1 550 patients with B- cell malignancies, including patients with chronic lymphocytic leukaemia (N = 938), Waldenström macroglobulinemia (N = 249), mantle cell lymphoma (N = 140), marginal zone lymphoma (N = 93), follicular lymphoma (N = 59) and other types of B-cell malignancies (N = 71), treated with BRUKINSA in clinical studies with a median duration of exposure of 34.41 months.

The safety profile of zanubrutinib in combination with obinutuzumab is based on ROSEWOOD study data from 143 patients with FL treated with BRUKINSA in combination with obinutuzumab with a median duration of exposure of 12.35 months.

Adverse reactions in patients treated with BRUKINSA as monotherapy or in combination with obinutuzumab for B-cell malignancies are listed in Table 3 and Table 4, respectively, by system organ class and frequency grouping. Frequencies are defined as follows: 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 the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 3: Adverse reactions of zanubrutinib monotherapy reported in clinical studies in patients with B-cell malignancies(n=1 550) MedDRA SOC MedDRA Terms All Grades* (%) Grade 3 or higher (%) Infections and infestations Upper respiratory tract infection§ Very Common (36) Pneumonia§# Very Common (24) Pneumonia Very Common (15) Lower respiratory tract infection Common (5) <1 Urinary tract infection§ Very Common (14) Bronchitis Common (4) <1 Hepatitis B reactivation Uncommon (<1) <1

Blood and lymphatic system disorders
Neutropenia§
Very Common (30)
Febrile neutropenia
Common ( 2)
Thrombocytopenia§
Very Common (18)
Anaemia§
Very Common (16)
Metabolism and nutrition disorders
Tumour lysis syndrome§#
Uncommon (<1)
<1
Nervous system disorder
Dizziness§
Very Common (12)
<1
Cardiac disorders
Atrial fibrillation and flutter
Common (5)
Vascular disorders
Bruising§
Very Common (32)
<1
Contusion
Very Common (20)
Petechiae
Common (7)
<1
Purpura
Common (5)
<1
Ecchymosis
Common (3)
<1
Haemorrhage/Haematoma§ #
Very Common (30)
Haematuria
Very common (11)
<1
Epistaxis
Common (8)
<1
Gastrointestinal haemorrhage Uncommon (<1)
<1
Hypertension§
Very Common (17)
Respiratory, thoracic and mediastinal disorders
Cough§
Very Common (21)
<1
Gastrointestinal disorders
Diarrhoea
Very Common (21)
Constipation
Very Common (14)
<1
Nausea
Very common (12)
<1
Skin and subcutaneous tissue disorders
Rash§
Very Common (25)
<1
Pruritus
Common (8)
<1
Dermatitis exfoliative generalized
Unknown
Unknown
Musculoskeletal and connective tissue disorders
Musculoskeletal pain§
Very Common (27)
Arthralgia
Very Common (15)
<1
Back pain
Very common (12)
<1
General disorders and administration site conditions
Fatigue§
Very common (18)
Fatigue
Very common (14)
Asthenia
Common (4)
<1
Oedema peripheral
Common (9)
<1
Investigations†
Neutrophil count decreased†±
Very common (52)
Platelets decreased†±
Very common (39)
Haemoglobin decreased†±
Very common (26)
* Grades were evaluated based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI- CTCAE) version 4.03.
† Based on laboratory measurements.
± Percentages are based on number of patients with both baseline and at least one postbaseline assessment available.
§ Includes multiple adverse reaction terms
# Includes events with fatal outcome.

Table 4: Adverse reactions of zanubrutinib in combination with obinutuzumab reported in clinical study BGB-3111-212 in patients with follicular lymphoma (n=143) MedDRA SOC MedDRA Terms

All grades* (%)
Grade ≥3
(%)
Infections and infestations
Upper respiratory tract infection§
Very common (14)
<1
Pneumonia§#
Very common (20)
Pneumonia
Very common (13)
Lower respiratory tract infection
Common (4)
<1
Urinary tract infection§
Common (10)
Bronchitis
Common (2)
Blood and lymphatic system disorders
Thrombocytopenia§
Very common (37)
Neutropenia§
Very common (31)
Anaemia§
Very common (12)
Nervous system disorder
Dizziness§
Common (4)
Cardiac disorders
Atrial fibrillation and flutter§
Common (3)
Vascular disorders
Haemorrhage/hematoma§
Very common (16)
<1
Epistaxis
Common (5)
Hematuria
Common (<1)
Bruising§
Very common (15)
Contusion
Very common (8)
Petechiae
Common (6)
Purpura
Common (2)
Ecchymosis
Common (1)
Hypertension§
Common (4)
<1
Respiratory, thoracic and mediastinal disorders
Cough§
Very common (13)
Gastrointestinal disorders
Diarrhoea
Very common (19)
Constipation
Very common (13)
Nausea
Common (9)
Skin and subcutaneous tissue disorders
Rash§
Very common (10)
Pruritus
Common (7)
Dermatitis exfoliative generalized
Unknown
Unknown
Musculoskeletal and connective tissue disorders
Musculoskeletal Pain§
Very common (18)
Back pain
Very common (11)
<1
Arthralgia
Common (4)
General disorders and administration site conditions
Fatigue§
Very common (27)
Fatigue
Very common (15)
Asthenia
Common (12)
<1
Oedema peripheral
Common (2)
Investigations†±
Platelets decreased†±
Very common (65)
Neutrophil count decreased†±
Very common (48)
Haemoglobin decreased†±
Very common (31)
<1
* Adverse events were graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI- CTCAE version 5.0.)

† Based on laboratory measurements.
§ Includes multiple adverse reaction terms.
# Includes events with fatal outcome.
± Percentages are based on number of patients with both baseline and at least one postbaseline assessment available.

Other special population

Elderly

Of the 1 550 patients treated with BRUKINSA monotherapy, 61.3% were 65 years of age or older.
The incidence of Grade 3 or higher adverse events was slightly higher among elderly patients treated with zanubrutinib (69.6% of patients age ≥65 versus 62.7% of patients <65 years of age). No clinically relevant differences in safety were observed between patients ≥65 years and younger.

Of the 143 patients treated with BRUKINSA in combination with obinutuzumab, 42.0% were 65 years of age or older. The incidence of Grade 3 or higher adverse events was slightly higher among elderly patients treated with zanubrutinib in combination with obinutuzumab (70.0% of patients age ≥65 versus 62.7% of patients <65 years of age). No clinically relevant differences in safety were observed between patients ≥65 years and younger.

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.

Haemorrhage

Serious and fatal haemorrhagic events have occurred in patients treated with BRUKINSA. Grade 3 or higher bleeding events including intracranial and gastrointestinal haemorrhage, haematuria and haemothorax have been reported in patients (see section 4.8). Bleeding events of any grade including purpura and petechiae occurred in patients with haematological malignancies. The mechanism for the bleeding events is not well understood.

BRUKINSA may increase the risk of haemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Dose modification may be necessary for Grade 3 or greater adverse reactions as recommended (see section 4.2). Warfarin or other vitamin K antagonists should not be administered concomitantly with BRUKINSA. Patients should be monitored for signs and symptoms of bleeding and complete blood counts should be monitored. The risks and benefits of anticoagulant or antiplatelet therapy when co-administered with BRUKINSA should be considered.

The benefit-risk of withholding zanubrutinib for 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding should be considered.

Infections

Fatal and non-fatal infections (including bacterial, viral, fungal infections, or sepsis) and opportunistic infections (e.g., herpes viral, cryptococcal, aspergillus and pneumocystis jiroveci infections) have occurred in patients treated with BRUKINSA. Grade 3 or higher infections occurred in patients (see section 4.8). The most common Grade 3 or higher infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation have also occurred. Before initiating treatment with BRUKINSA, patients’ HBV status should be established. Consultation with a liver disease expert physician is recommended for patients who test positive for HBV or have positive hepatitis B serology, before initiating treatment. Patients should be monitored and managed according to the medical standards to prevent hepatitis B reactivation. Consider prophylaxis according to standard of care in patients who are at increased risk for infections. Patients should be monitored for signs and symptoms of infection and treat appropriately.

Cytopenia

Grade 3 or 4 cytopenias including neutropenia, thrombocytopenia, and anaemia based on laboratory measurements were reported in patients treated with BRUKINSA (see section 4.8). Complete blood counts should be monitored monthly during treatment (see section 4.2).

Second primary malignancies

Second primary malignancies, including non-skin carcinoma have occurred in patients treated with BRUKINSA. The most frequent second primary malignancy was skin cancer (basal cell carcinoma and squamous cell carcinoma of skin). Patients should be advised to use sun protection.

Atrial fibrillation and flutter

Atrial fibrillation and atrial flutter have occurred in patients treated with BRUKINSA, particularly in patients with cardiac risk factors, hypertension, acute infections and elderly (≥ 65 years). Signs and symptoms for atrial fibrillation and atrial flutter should be monitored and managed as appropriate.

Tumour lysis syndrome

Tumour lysis syndrome has been uncommonly reported with zanubrutinib monotherapy therapy, particularly in patients who were treated for chronic lymphocytic leukaemia (CLL) (see section 4.8).
Relevant risks (e.g., high tumour burden or blood uric acid level) should be assessed and appropriate precautions should be taken. Patients should be closely monitored and treated as appropriate.

Women of childbearing potential

Women of childbearing potential must use a highly effective method of contraception while taking BRUKINSA (see section 4.6).

BRUKINSA contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Haemorrhage

Serious and fatal haemorrhagic events have occurred in patients treated with BRUKINSA. Grade 3 or higher bleeding events including intracranial and gastrointestinal haemorrhage, haematuria and haemothorax have been reported in patients (see section 4.8). Bleeding events of any grade including purpura and petechiae occurred in patients with haematological malignancies. The mechanism for the bleeding events is not well understood.

BRUKINSA may increase the risk of haemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Dose modification may be necessary for Grade 3 or greater adverse reactions as recommended (see section 4.2). Warfarin or other vitamin K antagonists should not be administered concomitantly with BRUKINSA. Patients should be monitored for signs and symptoms of bleeding and monitor complete blood counts. The risks and benefits of anticoagulant or antiplatelet therapy when co-administered with BRUKINSA should be considered.

The benefit-risk of withholding zanubrutinib for 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding should be considered.

Infections

Fatal and non-fatal infections (including bacterial, viral, fungal infections, or sepsis) and opportunistic infections (e.g., herpes viral, cryptococcal, aspergillus and pneumocystis jiroveci infections) have occurred in patients treated with BRUKINSA. Grade 3 or higher infections occurred in patients (see section 4.8). The most common Grade 3 or higher infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation have also occurred. Before initiating treatment with BRUKINSA, patients’ HBV status should be established. Consultation with a liver disease expert physician is recommended for patients who test positive for HBV or have positive hepatitis B serology, before initiating treatment. Patients should be monitored and managed according to the medical standards to prevent hepatitis B reactivation. Prophylaxis according to standard of care in patients who are at increased risk for infections should be considered. Patients should be monitored for signs and symptoms of infection and treat appropriately.

Cytopenia

Grade 3 or 4 cytopenias including neutropenia, thrombocytopenia, and anaemia based on laboratory measurements were reported in patients treated with BRUKINSA (see section 4.8). Complete blood counts should be monitored monthly during treatment (see section 4.2).

Second primary malignancies

Second primary malignancies, including non-skin carcinoma have occurred in patients treated with BRUKINSA. The most frequent second primary malignancy was skin cancer (basal cell carcinoma and squamous cell carcinoma of skin). Patients should be advised to use sun protection.

Atrial fibrillation and flutter

Atrial fibrillation and atrial flutter have occurred in patients treated with BRUKINSA, particularly in patients with cardiac risk factors, hypertension, acute infections and elderly (≥ 65 years). Signs and symptoms for atrial fibrillation and atrial flutter should be monitored and managed as appropriate.

Tumour Lysis Syndrome

Tumour lysis syndrome has been uncommonly reported with zanubrutinib monotherapy therapy, particularly in patients who were treated for chronic lymphocytic leukaemia (CLL) (see section 4.8).
Relevant risks (e.g., high tumour burden or blood uric acid level) should be assessed and appropriate precautions should be taken. Patients should be closely monitored and treated as appropriate.

Women of childbearing potential

Women of childbearing potential must use a highly effective method of contraception while taking BRUKINSA (see section 4.6).

Excipients with known effects

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Zanubrutinib is primarily metabolized by cytochrome P450 enzyme 3A (CYP3A).

Agents that may increase zanubrutinib plasma concentrations

Concomitant use of BRUKINSA and medicinal products that strongly or moderately inhibit CYP3A can increase zanubrutinib exposure.

Strong CYP3A inhibitors

The coadministration of multiple doses of itraconazole (strong CYP3A inhibitor) in healthy volunteers increased the Cmax of zanubrutinib by 2.6-fold and AUC by 3.8-fold. The coadministration of multiple doses of strong CYP3A inhibitors voriconazole and clarithromycin in patients with B-cell malignancies resulted in increased zanubrutinib exposures by 3.30-fold and 1.92-fold for dose- normalized AUC0-24h and 3.29-fold and 2.01-fold for dose-normalized Cmax, respectively.

If a strong CYP3A inhibitor must be used (e.g., voriconazole, ketoconazole, itraconazole, clarithromycin, indinavir, lopinavir, ritonavir, telaprevir), reduce the BRUKINSA dose to 80 mg (one capsule) for the duration of the inhibitor use. Patients should be closely monitored for toxicity and dose modification guidance should be followed as needed (see section 4.2).

Moderate CYP3A inhibitors

The coadministration of multiple doses of moderate CYP3A inhibitors fluconazole and diltiazem in patients with B-cell malignancies resulted in increased zanubrutinib exposures by 1.88-fold and 1.62- fold for dose-normalized AUC0-24h and 1.81-fold and 1.62-fold for dose-normalized Cmax, respectively.

If a moderate CYP3A inhibitor must be used (e.g., erythromycin, ciprofloxacin, diltiazem, dronedarone, fluconazole, verapamil, aprepitant, imatinib, grapefruit juice, Seville oranges), the BRUKINSA dose should be reduced to 160 mg (two capsules) for the duration of the inhibitor use.
Patients should be closely monitored for toxicity and dose modification guidance should be followed as needed (see section 4.2).

Mild CYP3A inhibitors

Simulations using fasted conditions suggested that the mild CYP3A inhibitors (e.g., cyclosporine and fluvoxamine) may increase the AUC of zanubrutinib by <1.5-fold. No dose adjustment is required in combination with mild inhibitors. Patients should be closely monitored for toxicity and dose modification guidance should be followed as needed.

Agents that may decrease zanubrutinib plasma concentrations

Concomitant use of zanubrutinib and strong or moderate inducers of CYP3A can decrease zanubrutinib plasma concentrations.

CYP3A inducers

Co-administration of multiple doses of rifampicin (strong CYP3A inducer) decreased zanubrutinib Cmax by 92% and AUC by 93% in healthy subjects. Co-administration of multiple doses of rifabutin (moderate CYP3A inducer) decreased zanubrutinib Cmax by 48% and AUC by 44% in healthy subjects. Concomitant use of zanubrutinib and strong or moderate CYP3A inducers should be avoided (see section 4.2). Mild CYP3A inducers may be used with caution during BRUKINSA treatment.

Gastric acid reducing agents

No clinically significant differences in zanubrutinib pharmacokinetics were observed when co-administered with gastric acid reducing agents (proton pump inhibitors, H2-receptor antagonists).

Agents that may have their plasma concentrations altered by zanubrutinib

Zanubrutinib is a mild inducer of CYP3A and CYP2C19. Concomitant use of zanubrutinib can decrease the plasma concentrations of these substrate medicinal products.

CYP3A substrates

Co-administration of multiple doses of zanubrutinib decreased midazolam (CYP3A substrate) Cmax by 30% and AUC by 47%. Narrow therapeutic index medicinal products that are metabolised by CYP3A (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) should be used with caution, as zanubrutinib may decrease the plasma exposures of these medicinal products.

CYP2C19 substrates

Co-administration of multiple doses of zanubrutinib decreased omeprazole (CYP2C19 substrate) Cmax by 20% and AUC by 36%. Narrow therapeutic index medicinal products that are metabolized by CYP2C19 (e.g., S-mephenytoin) should be used with caution, as zanubrutinib may decrease the plasma exposures of these medicinal products.

Co-administration with transport substrates/inhibitors

Co-administration of multiple doses of zanubrutinib increased digoxin (P-gp substrate) Cmax by 34% and AUC by 11%. No clinically significant differences in the pharmacokinetics of rosuvastatin (BCRP substrate) were observed when co-administered with zanubrutinib.

The coadministration of oral P-gp substrates with a narrow therapeutic index (e.g., digoxin) should be done with caution as zanubrutinib may increase their concentrations.

Zanubrutinib is primarily metabolized by cytochrome P450 enzyme 3A (CYP3A).

Agents that may increase zanubrutinib plasma concentrations

Concomitant use of BRUKINSA and medicinal products that strongly or moderately inhibit CYP3A can increase zanubrutinib exposure.

Strong CYP3A inhibitors

The coadministration of multiple doses of itraconazole (strong CYP3A inhibitor) in healthy volunteers increased the Cmax of zanubrutinib by 2.6-fold and AUC by 3.8-fold. The coadministration of multiple doses of strong CYP3A inhibitors voriconazole and clarithromycin in patients with B-cell malignancies resulted in increased zanubrutinib exposures by 3.30-fold and 1.92-fold for dose- normalized AUC0-24h and 3.29-fold and 2.01-fold for dose-normalized Cmax, respectively.

If a strong CYP3A inhibitor must be used (e.g., voriconazole, ketoconazole, itraconazole, clarithromycin, indinavir, lopinavir, ritonavir, telaprevir), reduce the BRUKINSA dose to 80 mg (one- half tablet) for the duration of the inhibitor use. Patients should be closely monitored for toxicity and dose modification guidance should be followed as needed (see section 4.2).

Moderate CYP3A inhibitors

The coadministration of multiple doses of moderate CYP3A inhibitors fluconazole and diltiazem in patients with B-cell malignancies resulted in increased zanubrutinib exposures by 1.88-fold and 1.62- fold for dose-normalized AUC0-24h and 1.81-fold and 1.62-fold for dose-normalized Cmax, respectively.

If a moderate CYP3A inhibitor must be used (e.g., erythromycin, ciprofloxacin, diltiazem, dronedarone, fluconazole, verapamil, aprepitant, imatinib, grapefruit juice, Seville oranges), reduce

the BRUKINSA dose to 160 mg (one tablet) for the duration of the inhibitor use. Patients should be closely monitored for toxicity and dose modification guidance should be followed as needed (see section 4.2).

Mild CYP3A inhibitors

Simulations using fasted conditions suggested that the mild CYP3A inhibitors (e.g., cyclosporine and fluvoxamine) may increase the AUC of zanubrutinib by <1.5-fold. No dose adjustment is required in combination with mild inhibitors. Patients should be closely monitored for toxicity and dose modification guidance should be followed as needed.

Agents that may decrease zanubrutinib plasma concentrations

Concomitant use of zanubrutinib and strong or moderate inducers of CYP3A can decrease zanubrutinib plasma concentrations.

CYP3A inducers

Co-administration of multiple doses of rifampicin (strong CYP3A inducer) decreased zanubrutinib Cmax by 92% and AUC by 93% in healthy subjects. Co-administration of multiple doses of rifabutin (moderate CYP3A inducer) decreased zanubrutinib Cmax by 48% and AUC by 44% in healthy subjects. Concomitant use of zanubrutinib and strong or moderate CYP3A inducers should be avoided (see section 4.2). Mild CYP3A inducers may be used with caution during BRUKINSA treatment.

Gastric acid reducing agents

No clinically significant differences in zanubrutinib pharmacokinetics were observed when co-administered with gastric acid reducing agents (proton pump inhibitors, H2-receptor antagonists).

Agents that may have their plasma concentrations altered by zanubrutinib

Zanubrutinib is a mild inducer of CYP3A and CYP2C19. Concomitant use of zanubrutinib can decrease the plasma concentrations of these substrate medicinal products.

CYP3A substrates

Co-administration of multiple doses of zanubrutinib decreased midazolam (CYP3A substrate) Cmax by 30% and AUC by 47%. Narrow therapeutic index medicinal products that are metabolised by CYP3A (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) should be used with caution, as zanubrutinib may decrease the plasma exposures of these medicinal products.

CYP2C19 substrates

Co-administration of multiple doses of zanubrutinib decreased omeprazole (CYP2C19 substrate) Cmax by 20% and AUC by 36%. Narrow therapeutic index medicinal products that are metabolized by CYP2C19 (e.g., S-mephenytoin) should be used with caution, as zanubrutinib may decrease the plasma exposures of these medicinal products.

Co-administration with transport substrates/inhibitors

Co-administration of multiple doses of zanubrutinib increased digoxin (P-gp substrate) Cmax by 34% and AUC by 11%. No clinically significant differences in the pharmacokinetics of rosuvastatin (BCRP substrate) were observed when co-administered with zanubrutinib.

The coadministration of oral P-gp substrates with a narrow therapeutic index (e.g., digoxin) should be done with caution as zanubrutinib may increase their concentrations.

Women of childbearing potential/Contraception in females

Based on findings in animals, BRUKINSA may cause foetal harm when administered to pregnant women (see section 5.3). Women should avoid becoming pregnant while taking BRUKINSA and for up to 1 month after ending treatment. Therefore, women of childbearing potential must use highly effective contraceptive measures while taking BRUKINSA and for up to 1 month after stopping treatment. It is currently unknown whether zanubrutinib may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method.
Pregnancy testing is recommended for women of reproductive potential prior to initiating therapy.

Pregnancy

BRUKINSA should not be used during pregnancy. There are no data from the use of zanubrutinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Breast-feeding

It is not known whether zanubrutinib or its metabolites are excreted in human milk and no non- clinical studies were conducted. A risk to breast-fed children cannot be excluded. Breast-feeding should be discontinued during treatment with BRUKINSA.

Fertility

No effect on male or female fertility was noted in rats but morphological abnormalities in sperm and increased post-implantation loss were noted at 300 mg/kg/day (see section 5.3).

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

There is no specific antidote for BRUKINSA. Patients who experience overdose should be closely monitored and provided with appropriate supportive treatment.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents, Bruton’s tyrosine kinase inhibitors, ATC code:
L01EL03.

Mechanism of action

Zanubrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK). Zanubrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK activity. BTK is a signalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.

Pharmacodynamic effects

BTK occupancy in PBMCs and lymph node biopsies

The median steady-state BTK occupancy in peripheral blood mononuclear cells was maintained at 100% over 24 hours at a total daily dose of 320 mg in patients with B-cell malignancies. The median steady-state BTK occupancy in lymph nodes was 94% to 100% following the recommended dose.

Effect on QT/QTc interval and cardiac electrophysiology

At the recommended doses (320 mg once daily or 160 mg twice daily), there were no clinically relevant effects on the QTc interval. At a single dose 1.5 times the maximum recommended dose (480 mg), zanubrutinib did not prolong the QT interval to any clinically relevant extent (i.e., ≥10 msec).

Clinical efficacy and safety

Patients with Waldenström Macroglobulinemia (WM)

The safety and efficacy of BRUKINSA in WM were evaluated in a randomized, open-label, multicentre study comparing zanubrutinib and ibrutinib (ASPEN study, BGB-3111-302) in patients who were BTK inhibitor naive. Eligible patients were at least 18 years of age with a clinical and definite histological diagnosis of relapsed/refractory WM or treatment-naïve when considered unsuitable for standard chemo-immunotherapy regimens by their treating physician. Patients had to meet at least one criterion for treatment according to consensus panel criteria from the Seventh International Workshop on Waldenström’s Macroglobulinemia (IWWM) and have measurable disease, as defined by a serum IgM level >0.5 g/dl. Patients with MYD88 mutation (MYD88MUT) were assigned to Cohort 1 (N=201) and were randomized 1:1 to receive either zanubrutinib 160 mg twice daily (Arm A) or ibrutinib 420 mg once daily (Arm B) until disease progression or unacceptable toxicity. Subjects found to have MYD88 wildtype (MYD88WT) by gene sequencing (estimated to be present in approximately 10% of enrolled subjects), were enrolled to Cohort 2 (N = 28) and received zanubrutinib 160 mg twice daily on a third, non-randomized, study arm (Arm C).

Zanubrutinib maximum plasma concentration (Cmax) and area under the plasma drug concentration over time curve (AUC) increase proportionally over a dose range from 40 mg to 320 mg (0.13 to 1 time the recommended total daily dose). Limited systemic accumulation of zanubrutinib was observed following repeated administration for one week.

The geometric mean (%CV) zanubrutinib steady-state daily AUC is 2 099 (42%) ng h/mL following 160 mg twice daily and 1 917 (59%) ng h/mL following 320 mg once daily. The geometric mean (%CV) zanubrutinib steady-state Cmax is 299 (56%) ng/mL following 160 mg twice daily and 533 (55%) ng/mL following 320 mg once daily.

Absorption

The median tmax of zanubrutinib is 2 hours. No clinically significant differences in zanubrutinib AUC or Cmax were observed following administration of a high-fat meal (approximately 1 000 calories with 50% of total caloric content from fat) in healthy subjects.

Distribution

The geometric mean (%CV) apparent steady-state volume of distribution of zanubrutinib during the terminal phase (Vz/F) was 522 L (71%). The plasma protein binding of zanubrutinib is approximately 94% and the blood-to-plasma ratio was 0.7-0.8.

Metabolism

Zanubrutinib is primarily metabolized by cytochrome P450(CYP)3A.

Elimination

The mean half-life (t½) of zanubrutinib is approximately 2 to 4 hours following a single oral zanubrutinib dose of 160 mg or 320 mg. The geometric mean (%CV) apparent oral clearance (CL/F) of zanubrutinib during the terminal phase was 128 (61%) L/h. Following a single radiolabelled zanubrutinib dose of 320 mg to healthy subjects, approximately 87% of the dose was recovered in faeces (38% unchanged) and 8% in urine (less than 1% unchanged).

Special populations

Elderly

Age (19 to 90 years; mean age 65±12.5) had no clinically meaningful effect on zanubrutinib pharmacokinetics based on population PK analysis (N=1291).

Gender

Brukinsa is available as hard capsules (80 mg) and film-coated tablets (160 mg). Comparative bioavailability and bioequivalence studies indicated that under fasted conditions, the Cmax is 1.2-fold higher and the AUC is bioequivalent for the tablet formulation versus the capsule formulation. Under fed conditions, the Cmax was 1.5- to 1.8-fold higher and the AUC 1.1- to 1.2-fold higher for the tablet formulation versus the capsule formulation. Exposure-safety relationship showed that the higher exposure with the tablet formulation does not lead to additional safety issues.

Zanubrutinib maximum plasma concentration (Cmax) and area under the plasma drug concentration over time curve (AUC) increase proportionally over a dose range from 40 mg to 320 mg (0.13 to 1 time the recommended total daily dose). Limited systemic accumulation of zanubrutinib was observed following repeated administration for one week.

The geometric mean (%CV) zanubrutinib steady-state daily AUC is 2 099 (42%) ng h/mL following 160 mg twice daily and 1 917 (59%) ng h/mL following 320 mg once daily. The geometric mean (%CV) zanubrutinib steady-state Cmax is 299 (56%) ng/mL following 160 mg twice daily and 533 (55%) ng/mL following 320 mg once daily.

Absorption

The median tmax of zanubrutinib is 2 hours. No clinically significant differences in zanubrutinib AUC or Cmax were observed following administration of a high-fat meal (approximately 1 000 calories with 50% of total caloric content from fat) in healthy subjects.

Distribution

The geometric mean (%CV) apparent steady-state volume of distribution of zanubrutinib during the terminal phase (Vz/F) was 522 L (71%). The plasma protein binding of zanubrutinib is approximately 94% and the blood-to-plasma ratio was 0.7-0.8.

Metabolism

Zanubrutinib is primarily metabolized by cytochrome P450(CYP)3A.

Elimination