Zanubrutinib

Registered South African indications:

• Waldenström’s macroglobulinaemia (WM)
• Mantle cell lymphoma (MCL)
  - In patients who have received at least one prior therapy
• Marginal zone lymphoma (MZL)
  - In patients who have received at least one prior anti-CD20-based therapy
• Chronic lymphocytic leukaemia /small lymphocytic lymphoma (CLL/SLL)

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Severe renal impairment
• Hepatic impairment

Carcinogenesis and mutagenesis: Second primary malignancies

• Second primary malignancies, including non-skin carcinoma have occurred in 12.4% patients with haematological malignancies treated with zanubrutinib monotherapy
• The most frequent second primary malignancy was skin cancer (basal cell carcinoma, squamous cell carcinoma of skin), reported in 7.4% of patients
• Monitor patients for skin cancer and advise patients to use sun protection

Cardiovascular disease

• Patients with active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia, class 3 or 4 congestive heart failure or recent myocardial infarction, were excluded from clinical trials of zanubrutinib

Atrial fibrillation and flutter

• Atrial fibrillation and atrial flutter have occurred in 3.2% of patients with haematological malignancies treated with zanubrutinib monotherapy 
• This risk may be increased in patients with cardiac risk factors, hypertension, and acute infections 
• Grade 3 and above events were reported in 1.4% of patients 
• Monitor for signs and symptoms of atrial fibrillation and atrial flutter and manage as appropriate 

Cytopenias

• Grade 3 or 4 neutropenia (18.5%, including febrile neutropenia), thrombocytopenia (5.7%) and anaemia (5.2%) based on laboratory measurements were reported in patients with hematologic malignancies treated with zanubrutinib monotherapy
• Monitor complete blood counts regularly during treatment
• Reduce dose, interrupt or discontinue treatment as necessary and treat using growth factors or transfusion as necessary

Infections

• Serious and fatal infections (including bacterial, viral, or fungal) and opportunistic infections have occurred in patients with haematological malignancies treated with zanubrutinib monotherapy
• Grade 3 or higher infections occurred 21.8% of patients treated with zanubrutinib monotherapy. The most common Grade 3 or higher infection was pneumonia
• Infections due to hepatitis B virus (HBV) or varicella zoster reactivation (herpes zoster) have occurred
• Monitor patients for signs and symptoms of infection and treat appropriately. Consider prophylaxis according to standard of care in patients who are at increased risk for infections

Tumour Lysis Syndrome

• Tumour lysis syndrome has been infrequently reported with zanubrutinib therapy, particularly in patients who were treated for CLL/SLL
• Assess the baseline risk (e.g., high tumour burden) and take appropriate precautions. Monitor patients closely and treat as appropriate

Peri-operative considerations

• Patients with major surgery within 4 weeks of the first dose of study drug were excluded from clinical trials with zanubrutinib
• 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

Interstitial lung disease (ILD)

• Cases of suspected ILD have occurred in 0.6% of patients with haematological malignancies treated with zanubrutinib monotherapy. However, none were confirmed by biopsy
• Monitor patients for signs and symptoms of ILD. Advise patients to report promptly any new or worsening respiratory symptoms
• If ILD is suspected, interrupt zanubrutinib and treat promptly and appropriately. If ILD is confirmed, discontinue zanubrutinib

Haemorrhage

• Serious and fatal haemorrhagic events have occurred in patients with haematological malignancies treated with zanubrutinib monotherapy
• Grade 3 or higher bleeding events including intracranial and gastrointestinal haemorrhage, haematuria and haemothorax have been reported in 3.84 % of patients treated with zanubrutinib monotherapy
• Bleeding events of any grade, including purpura and petechiae, occurred in 48,1 % of patients with haematological malignancies treated with zanubrutinib monotherapy
• Zanubrutinib may increase the risk of haemorrhage in patients receiving antiplatelet or anticoagulant therapies
• Patients were excluded from zanubrutinib studies if they had recent history of stroke or intracranial haemorrhage, or if they required warfarin or other vitamin K antagonists
• Patients should be monitored for signs of bleeding. Bleeding events should be managed with supportive measures, including transfusions, and specialized care as needed
• Reduce dose, interrupt or discontinue treatment as necessary. For any intracranial haemorrhage, treatment should be discontinued

Effects on ability to drive and use machines

• No specific studies have been conducted to evaluate the influence of zanubrutinib treatment on the ability to drive or operate heavy machinery
• Fatigue, dizziness, and asthenia have been reported in some patients taking zanubrutinib and should be considered when assessing a patient’s ability to drive or operate machines

Forms avail. in SA and covered in this monograph: cap

South African registered indications and dosages

Treatment with zanubrutinib should be initiated and supervised by a qualified doctor experienced in the use of anticancer therapies

Used for the treatment of

Waldenström’s macroglobulinaemia (WM)
Mantle cell lymphoma (MCL)
- In patients who have received at least one prior therapy
Marginal zone lymphoma (MZL)
- In patients who have received at least one prior anti-CD20-based therapy
Chronic lymphocytic leukaemia /small lymphocytic lymphoma (CLL/SLL)

• Oral (cap): 320mg (four 80mg capsules), once dly OR 160mg (two 80mg capsules), twice dly; Treatment duration: Continue until disease progression or unacceptable toxicity

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Method of administration

For oral use. Zanubrutinib capsules should be swallowed whole with water. Can be taken with or without food. The capsule should not be chewed, dissolved, or opened. Must not be taken with grapefruit juice, grapefruit and /or Seville oranges

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See Additional Prescriber Points for dose modifications for adverse reactions and coadministered agents

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Caution; not recommended
• There are no adequate and well-controlled studies of zanubrutinib in pregnant women
• Based on findings in animals, zanubrutinib may cause foetal harm when administered to pregnant women
• If zanubrutinib is used during pregnancy or if the patient becomes pregnant while taking zanubrutinib, the patient should be apprised of the potential hazard to the foetus

Women of childbearing potential/ Contraception in males and females

• Women of child-bearing potential must use highly effective contraceptive measures while taking zanubrutinib and at least for one week after stopping treatment. Women who use hormonal methods of birth control must add a barrier method

Breastfeeding

South African recommendations

• Caution; not recommended
• It is unknown if zanubrutinib is excreted in human milk. Because many medicines are excreted in human milk and because of the potential for serious adverse reactions from zanubrutinib in a breastfed child, advise lactating women not to breastfeed during treatment with zanubrutinib and for at least two weeks following the last dose

Fertility

South African recommendations

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

South African recommendations

• Mild to moderate (CrCl ≥ 30ml/min): No dose adjustment recommended
• Severe (CrCl < 30 mL/min) or dialysis: Caution; no dose adjustment recommended
  Monitor for zanubrutinib adverse reactions

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended
  Monitor closely for adverse reactions of zanubrutinib in patients with hepatic impairment
• Severe: Caution; dose adjustment recommended
  Oral (cap): 80mg, twice dly
  The safety of zanubrutinib has not been evaluated in patients with severe hepatic impairment

South African recommendations

• No dose adjustment recommended
  No clinically relevant differences in safety or efficacy were observed between patients ≥ 65 years and those younger than 65 years

Infections and Infestations

Very common

• Upper respiratory tract infection
• Pneumonia
• Urinary tract infection

Common

• Lower respiratory tract infection
• Bronchitis

Uncommon

• Hepatitis B reactivation

Blood and Lymphatic System Disorders

Very common

• Neutropenia
• Thrombocytopenia
• Anaemia

Common

• Febrile neutropenia

Nervous System Disorders

Very common

• Dizziness

Cardiac Disorders

Common

• Atrial fibrillation and flutter

Vascular Disorders

Very common

• Bruising
• Contusion
• Haemorrhage/Haematoma
• Haematuria
• Hypertension

Common

• Petechiae
• Purpura
• Ecchymosis
• Epistaxis

Uncommon

• Gastrointestinal haemorrhage

Respiratory, Thoracic and Mediastinal Disorders

Very common

• Cough

Gastrointestinal Disorders

Very common

• Diarrhoea
• Constipation
• Nausea

Common

• Vomiting

Skin and Subcutaneous Tissue Disorders

Very common

• Rash

Common

• Pruritus

Frequency unknown

• Dermatitis exfoliative general

Musculoskeletal and Connective Tissue Disorders

Very common

• Musculoskeletal pain
• Arthralgia
• Back pain

General Disorders and Administration Site Conditions

Very common

• Fatigue

Common

• Asthenia
• Oedema peripheral

Metabolism and Nutrition Disorders

Uncommon

• Tumour lysis syndrome

Investigations

Very common

• Absolute neutrophil count decreased
• Platelets decreased
• Haemoglobin decreased

• Strong CYP3A inducers
• Carbamazepine
• Phenytoin
• Rifampin
• Strong CYP3A inhibitors 
• Posaconazole
• Voriconazole
• Ketoconazole
• Itraconazole
• Clarithromycin
• Indinavir
• Lopinavir
• Ritonavir
• Telaprevir
• Moderate CYP3A inhibitors
• Erythromycin
• Ciprofloxacin
• Diltiazem
• Dronedarone
• Fluconazole
• Verapamil
• Aprepitant
• Moderate CYP3A inducers
• Rifabutin
• Bosentan
• Efavirenz
• Etravirine
• Modafinil
• Nafcillin
• P-glycoprotein substrates 
  • Digoxin
• CYP3A substrates
  • Midazolam
• CYP2C19 substrates
  • Omeprazole
• CYP2C9 substrates 
  • Warfarin
• CYP2C8 substrates 
  • Rosiglitazone
• BCRP substrates 
  • Rosuvastatin

Other interactions

• Grapefruit
• Grapefruit juice
• Seville oranges
• St. John's wort

• Full blood count

Specific cases may require

• Electrocardiogram (ECG)
• Skin cancer monitoring

Additional observations

• Signs and symptoms of atrial fibrillation and atrial flutter
• Appearance of skin cancers
• Signs and symptoms of infection
• Signs of bleeding

Recommended dose modifications for adverse reactions and coadministered agents

Table 1: Event recommended dose modification for adverse reaction

Event	Adverse reaction occurrence	Dose Modification (Starting Dose: 160mg 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 zanubrutinib Once toxicity has resolved to ≤ Grade 1 or baseline: Resume at 160mg twice daily or 320mg once daily
	Second	Interrupt zanubrutinib Once toxicity has resolved to ≤ Grade 1 or baseline: Resume at 80mg twice daily or 160mg once daily
	Third	Interrupt zanubrutinib Once toxicity has resolved to ≤ Grade 1 or baseline: Resume at 80mg once daily
	Fourth	Discontinue zanubrutinib

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

Table 2: Use with CYP3A inhibitors or inducers

CYP3A Modulation	Co-administered agent	Recommended dose
Inhibition	Strong CYP3A inhibitor	80mg once daily
	Moderate CYP3A inhibitor	80mg twice daily Modify dose as recommended for adverse reactions
Induction	Strong CYP3A inducer	Avoid concomitant use; Consider alternative agents with less CYP3A induction
	Moderate CYP3A inducer	Use with caution

• After discontinuation of a CYP3A inhibitor, resume previous dose of zanubrutinib

Zanubrutinib is a potent and highly selective small-molecule inhibitor of BTK. Zanubrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. In nonclinical studies, zanubrutinib inhibited malignant B-cell proliferation and reduced tumor growth.