BRUKINSA Hard capsule Ref.[110578] Active ingredients: Zanubrutinib

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. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with BRUKINSA. Consider 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.

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). Monitor complete blood counts 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). Advise patients 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). Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate.

Tumour Lysis Syndrome

Tumour lysis syndrome has been infrequently reported with zanubrutinib monotherapy therapy, particularly in patients who were treated for chronic lymphocytic leukaemia (CLL) Assess relevant risks (e.g., high tumour burden or blood uric acid level) and take appropriate precautions. Monitor patients closely and treat 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’.

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 C_max 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 dosenormalized AUC_0-24h and 3.29-fold and 2.01-fold for dose-normalized C_max, 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. Monitor patient closely for toxicity and follow dose modification guidance 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 AUC_0-24h and 1.81-fold and 1.62-fold for dose-normalized C_max, 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 (two capsules) for the duration of the inhibitor use. Monitor patients closely for toxicity and follow dose modification guidance 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. Monitor patients closely for toxicity and follow dose modification guidance as needed.

Grapefruit and Seville oranges should be used with caution during BRUKINSA treatment, as these contain moderate inhibitors of CYP3A (see section 4.2).

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 rifampin (strong CYP3A inducer) decreased zanubrutinib C_max by 92% and AUC by 93% in healthy subjects. Co-administration of multiple doses of rifabutin (moderate CYP3A inducer) decreased zanubrutinib C_max by 48% and AUC by 44% in healthy subjects. 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) C_max 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) C_max 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.

Other CYP substrates

No clinically significant differences were observed with S-warfarin (CYP2C9 substrate) pharmacokinetics when co-administered with zanubrutinib.

Co-administration with transport substrates/inhibitors

Co-administration of multiple doses of zanubrutinib increased digoxin (P-gp substrate) C_max 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 BRUKINSA 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 nonclinical 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 in 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.

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 1550 patients with Bcell 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 in two clinical studies 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=1550):

^* Grades were evaluated based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) 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):

^* Adverse events were graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE 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 1550 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.

Paediatric population

The safety and efficacy of BRUKINSA in children and adolescents below 18 years of age have not been established.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.