Brukinsa - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

BRUKINSA 80 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 80 mg of zanubrutinib.

For the full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Hard capsule.

White to off-white opaque hard capsule of 22 mm in length, marked with “ZANU 80” in black ink.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

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

4.2 Posology and method of administration

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).

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

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

Dose modifications for concomitant therapy

Dose modifications for use with CYP3A inhibitors or inducers (see sections 4.4, 4.5 and 5.2):

Table 2: Recommended dose modifications when co-administered with other medicinal products

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=5). 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. Monitor these patients closely for adverse events of BRUKINSA (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.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Haemorrhage

Serious and fatal haemorrhagic events have occurred in patients treated with BRUKINSA monotherapy. 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.

Infections

Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred in patients treated with BRUKINSA monotherapy. 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’s 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 monotherapy (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 monotherapy. 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 monotherapy, particularly in patients with cardiac risk factors, hypertension, and acute infections. Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage 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’

4.5 Interaction with other medicinal products and other forms of interaction

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) increased the Cmax of zanubrutinib by 2.6-fold and AUC by 3.8-fold in healthy subjects.

If a strong CYP3A inhibitor must be used (e.g., posaconazole, 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

Physiologically based pharmacokinetics simulations indicate that coadministration of multiple doses of a moderate CYP3A inhibitor may increase the Cmax and AUC of zanubrutinib by approximately 2-fold. 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 Cmax by 92% and AUC by 93% in healthy subjects. Concomitant use with strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) and moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) should be avoided (see section 4.2). Co-administration of multiple doses of rifabutin (moderate CYP3A inducer) decreased zanubrutinib Cmax 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) 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.

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) 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.

4.6 Fertility, pregnancy and lactation

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

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 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).

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

Summary of the safety profile

The most commonly occurring adverse reactions (>20%) were neutropenia1 (56.2%), thrombocytopenia1 (45.1%), upper respiratory tract infection§ (44.3%), haemorrhage/ha­ematoma§ (32.2%), rash§ (29.8%), bruising§ (29.1%), anaemia1 (28.9%), musculoskeletal pain§ (24.3%), diarrhoea (23.6%), pneumonia§ (22.1%) and cough (21.7%).

The most common Grade 3 or higher adverse reactions (>5%) were neutropenia1 (28.0%), pneumonia§ (11.6%), thrombocytopenia1' (11.4%), and anaemia1 (6.9%).

Of the 779 patients treated with zanubrutinib, 3.6% of patients discontinued treatment due to adverse reactions. The most frequent adverse reaction leading to treatment discontinuation was pneumonia§ (1.8%). Adverse reaction leading to dose reduction occurred in 4.9% of patients.

Tabulated list of adverse reactions

The safety profile is based on pooled data from 779 patients with B-cell malignancies treated with BRUKINSA in clinical studies with a median duration of exposure of 30.3 months.

Adverse reactions in patients treated with BRUKINSA for B-cell malignancies are listed below 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 reported in clinical studies in patients with B-cel malignancies

* Grades were evaluated based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03.

t Based on laboratory measurements

§ Includes multiple adverse reaction terms

# Includes events with fatal outcome.

Other special population

Elderly

Of the 779 patients treated with BRUKINSA, 52% 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 (71% of patients age >65 versus 64% 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.

4.9 Overdose

There is no specific antidote for BRUKINSA. For patients who experience overdose, closely monitor and provide appropriate supportive treatment.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic 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

The safety and efficacy of BRUKINSA in WM were evaluated in a randomized, open-label, multicentre study comparing zanubrutinib and ibrutinib (ASPEN study) 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-naive 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 Waldenstrom’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).

In Cohort 1 (MYD88MUT), the median age was 70 years (range, 38 to 90 years), with 71% and 60% of patients treated with ibrutinib and zanubrutinib respectively being >65 years old. 33% of patients in the zanubrutinib arm and 22% in the ibrutinib were >75 years. 67% were male, and 91% were Caucasian. At study entry, 44% of patients in the ibrutinib arm and 46% of patients in the zanubrutinib arm had an International Prognostic Scoring System (IPSS) high. One hundred and sixty-four patients had relapsed or refractory disease; the median number of prior therapies was 1 (range, 1 to 8).

The primary outcome measure was rate of Complete Response (CR) or Very Good Partial Response (VGPR), as assessed by an independent review committee (IRC) with adaptation of the response criteria updated at the Sixth IWWM. The secondary endpoints for Cohort 1 include major response rate (MRR), duration of response, rate of CR or VGPR determined by investigator, and progressionfree survival (PFS).

The testing for the superiority of the primary endpoint of VGPR or CR rate required testing in the Relapsed/Refractory Analysis Set prior to testing in the ITT Analysis Set. Median follow-up was 19.4 months. In the relapsed/refractory patients, 19.8% and 28.9% achieved VGPR or CR on the ibrutinib and zanubrutinib arms, respectively. The primary efficacy endpoint was not significant in the Relapsed/Refractory Analysis Set (2-sided p=0.1160).sum­marizes the responses as assessed by IRC for the Relapsed/Refractory and intent-to-treat (ITT) Analysis Set. Responses were observed with zanubrutinib across subgroups, including MYD88WT patients (Cohort 2) who had a VGPR or CR rate of 26.9% and an MRR of 50%.

Table 4: Primary analysis of disease response by independent review committee (ASPEN

Study)

Percentages are based on N.

a 2-sided Clopper-Pearson 95% confidence interval.

b Mantel-Haenszel common risk difference with the 95% confidence interval calculated using a normal approximation and Sato's standard error stratified by the stratification factors per IRT (strata CXCR4 WT and UNK are combined) and age group (<65 and >65). Ibrutinib is the reference group.

c Based on CMH test stratified by the stratification factors per IRT (strata CXCR4 WT and UNK are combined) and age group (<65 and >65)

d Event-free rates are estimated by Kaplan-Meier method with 95% CIs estimated using the Greenwood’s for­mula.

Based on an updated data cut-off the progression free-survival event-free rate by investigator assessment was 77.6% vs 84.9% at 30 months (ibrutinib vs zanubrutinib), with an estimated overall hazard ratio of 0.734 (95% CI: 0.380, 1.415).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with BRUKINSA in all subsets of the paediatric population for the treatment lymphoplasmacytic lymphoma (see section 4.2 for information on paediatric use).

The European Medicines Agency has deferred the obligation to submit the results of studies with BRUKINSA in one or more subset of the paediatric population in the treatment of mature B-cell lymphoma. See section 4.2 for information on paediatric use.

5.2 Pharmacokinetic properties

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 (t % ) 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 62±14.5) had no clinically meaningful effect on zanubrutinib pharmacokinetics based on population PK analysis (N=632).

Paediatric population

No pharmacokinetic studies were performed with zanubrutinib in patients under 18 years of age.

Gender

Gender (444 males and 188 females) had no clinically meaningful effect on zanubrutinib pharmacokinetics based on population PK analysis.

Race

Race (428 White, 146 Asian, 26 Black, and 19 categorized as Other) had no clinically meaningful effect on zanubrutinib pharmacokinetics based on population PK analysis.

Body weight

Body weight (36 to 144 kg, mean weight 76.5±16.9 kg) had no clinically meaningful effect on zanubrutinib pharmacokinetics based on population PK analysis (N=632).

Renal impairment

Zanubrutinib undergoes minimal renal elimination. Based on population PK analysis, mild and moderate renal impairment (CrCl >30 mL/min as estimated by Cockcroft-Gault equation) had no influence on the exposure of zanubrutinib. The analysis was based on 204 patients with normal renal function, 231 with mild renal impairment, 96 with moderate renal impairment, 10 with severe renal impairment, and one with ESRD. The effects of severe renal impairment (CrCl <30 mL/min) and dialysis on zanubrutinib pharmacokinetics is unknown.

Hepatic impairment

The total AUC of zanubrutinib increased by 11% in subjects with mild hepatic impairment (Child-Pugh class A), by 21% in subjects with moderate hepatic impairment (Child-Pugh class B), and by 60% in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with normal liver function. The unbound AUC of zanubrutinib increased by 23% in subjects with mild hepatic impairment (Child-Pugh class A), by 43% in subjects with moderate hepatic impairment (Child-Pugh class B), and by 194% in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with normal liver function. A significant correlation was observed between the Child-Pugh score, baseline serum albumin, baseline serum bilirubin and baseline prothrombin time with unbound zanubrutinib AUC.

In vitro studies

CYP enzymes

Zanubrutinib is a weak inducer of CYP2B6 and CYP2C8. Zanubrutinib is not an inducer of CYP1A2.

Co-administration with transport substrates/in­hibitors

Zanubrutinib is likely to be a substrate of P-gp. Zanubrutinib is not a substrate or inhibitor of OAT1, OAT3, OCT2, OATP1B1, or OATP1B3.

Pharmacodynamic interactions

An in vitro study showed that the potential pharmacodynamic interaction between zanubrutinib and rituximab is low and zanubrutinib is unlikely to interfere with the anti-CD20 antibody-induced antibody-dependent cellular cytotoxicity (ADCC) effect.

In vitro , ex vivo , and animal studies showed that zanubrutinib had no or minimal effects on platelet activation, glycoprotein expression, and thrombus formation.

5.3 Preclinical safety data

General toxicity

The general toxicologic profiles of zanubrutinib were characterized orally in Sprague-Dawley rats for up to 6-month treatment and in beagle dogs for up to 9-month treatment.

In rat repeat dose studies up to 6-month treatment, test article related mortality was noted at the dose of 1,000 mg/kg/day (81× clinical AUC) with histopathologic findings in the gastrointestinal tract. Other findings were mainly noted in the pancreas (atrophy, fibroplasia, haemorrhage, and/or inflammatory cell infiltration) at the doses > 30 mg/kg/day (3× clinical AUC), in the skin around the nose/mouth/eyes (inflammatory cell infiltration, erosion/ulcer) from the dose of 300 mg/kg/day (16× clinical AUC), and in the lung (presence of macrophages in the alveolar) at the dose of

300 mg/kg/day. All these findings were fully or partially reversed after a 6-week recovery except for the pancreatic findings which were not considered clinically relevant.

In dog repeat dose studies up to 9-month treatment, test article related findings were mainly noted in the gastrointestinal tract (soft/watery/mucoid stool), skin (rash, red discoloration, and thickened/ scaling), and in the mesenteric, mandibular, and gut associated lymph nodes and spleen (lymphoid depletion or erythrophagocy­tosis) at the doses from 10 mg/kg/day (3× clinical AUC) to

100 mg/kg/day (18× clinical AUC). All these findings were fully or partially reversed after a 6-week recovery.

Carcinogenici­ty/genotoxici­ty

Carcinogenicity studies have not been conducted with zanubrutinib.

Zanubrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a chromosome aberration assay in mammalian (Chinese hamster ovary) cells, nor was it clastogenic in an in vivo bone marrow micronucleus assay in rats.

Developmental and reproductive toxicity

A combined male and female fertility and early embryonic development study was conducted in rats at oral zanubrutinib doses of 30, 100 and 300 mg/kg/day. No effect on male or female fertility was noted but at the highest dose tested, morphological abnormalities in sperm and increased postimplantation loss were noted. The dose of 100 mg/kg/day is approximately 13-fold higher than the human therapeutic exposure.

Embryo-foetal development toxicity studies were conducted in both rats and rabbits. Zanubrutinib was administered orally to pregnant rats during the period of organogenesis at doses of 30, 75, and 150 mg/kg/day. Malformations in the heart (2– or 3-chambered hearts with the incidence of 0.3%-1.5%) were noted at all dose levels in the absence of maternal toxicity. The dose of 30 mg/kg/day is approximately 5-fold higher than the human therapeutic exposure.

Administration of zanubrutinib to pregnant rabbits during the period of organogenesis at 30, 70, and 150 mg/kg/day resulted in post-implantation loss at the highest dose. The dose of 70 mg/kg is approximately 25-fold higher than the human therapeutic exposure and was associated with maternal toxicity.

In a pre- and post-natal developmental toxicity study, zanubrutinib was administered orally to rats at doses of 30, 75, and 150 mg/kg/day from implantation through weaning. The offspring from the middle and high dose groups had decreased body weights preweaning, and all dose groups had adverse ocular findings (e.g., cataract, protruding eye). The dose of 30 mg/kg/day is approximately 5-fold higher than the human therapeutic exposure.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Capsule content

Microcrystalline cellulose

Croscarmellose sodium

Sodium lauryl sulfate (E487)

Silica, colloidal anhydrous

Magnesium stearate

Capsule shell

Gelatin

Titanium dioxide (E171)

Printing ink

Shellac glaze (E904)

Iron oxide black (E172)

Propylene glycol (E1520)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

HDPE bottles with a child-resistant polypropylene closure. Each bottle contains 120 hard capsules.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

BeiGene Ireland Limited.

10 Earlsford Terrace

Dublin 2

D02 T380

Ireland

Tel. +353 1 566 7660

E-mail

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/21/1576/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22 November 2021