Acalabrutinib

Registered South African indications:

• Mantle cell lymphoma (MCL) in patients who have received at least one prior therapy
• Chronic lymphocytic leukaemia (CLL)

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 
• Severe hepatic impairment

Risk of haemorrhagic events

• Serious bleeding, including fatal outcomes, observed in patients treated for haematologic malignancies
• Potential increased bleeding risk when combined with antithrombotic agents; careful monitoring advised

• Consider the benefit-risk of withholding acalabrutinib for at least 3 days pre- and post surgery

Infection risks

• Serious infections, including fatal outcomes, reported in haematologic malignancy patients treated with acalabrutinib monotherapy
• Grade 3 or higher infections, notably pneumonia, observed in these patients
• Infections include hepatitis B reactivation, aspergillosis, and progressive multifocal leukoencephalopathy (PML)
• Prophylaxis is recommended for patients at higher risk of opportunistic infections
• Vigilant monitoring for infection signs and symptoms is essential; timely medical treatment required

Cytopenias

• Reports of treatment-emergent Grade 3 or 4 cytopenias in patients with haematologic malignancies (neutropenia, anaemia, thrombocytopenia) in patients treated with acalabrutinib
• Monitoring complete blood counts regularly is recommended

Second primary malignancies

• Incidence of second primary malignancies, including non-skin and skin cancers, in patients on acalabrutinib
• Regular monitoring for skin cancer is advised

Atrial fibrillation and flutter

• Grade 3 atrial fibrillation/flutter reported in 1% of patients; Grade 1 or 2 in 3% of patients with haematologic malignancies treated with acalabrutinib
• Monitoring for symptoms (palpitations, dizziness, syncope, chest pain, dyspnoea) and performing ECG as needed is recommended

Sodium content

• Acalabrutinib contains sodium starch glycolate
• The sodium content is less than 1mmol (23mg) per dose, considered essentially 'sodium-free'

Driving and machine use

• Acalabrutinib has no or negligible impact on the ability to operate vehicles or machinery
• Patients experiencing fatigue or dizziness during treatment should avoid driving or using machinery

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

South African registered indications and dosages

Treatment with acalabrutinib should be initiated and supervised by a medical practitioner experienced in the use of anticancer therapies

Mantle cell lymphoma (MCL) in patients who have received at least one prior therapy

• Oral (cap): 100mg, twice a day

Chronic lymphocytic leukaemia (CLL)
- As monotherapy or in combination with obinutuzumab

• Oral (cap): 100mg, twice a day

Refer to the obinutuzumab prescribing information for recommended obinutuzumab dosing information. Doses should be separated by approximately 12 hours

Treatment with acalabrutinib should continue until disease progression or unacceptable toxicity

Missed dose
If a patient misses a dose of acalabrutinib by more than 3 hours, instruct the patient to take the next dose at its regularly scheduled time. Extra capsules of acalabrutinib should not be taken to make up for a missed dose

Acalabrutinib should be swallowed whole with water at approximately the same time each day. Acalabrutinib can be taken with or without food. The capsule should not be chewed, dissolved, or opened

See additional prescribing points for recommended dose modifications of acalabrutinib for Grade ≥3 adverse reactions and when coadministered with specific medicines

• Not established for use in children and adolescents below 18 years

Pregnancy

South African recommendations

• Caution; not recommended
• Acalabrutinib  should not be used during pregnancy
• Women of childbearing potential: Acalabrutinib should not be used by women of childbearing potential, and they should be advised to avoid becoming pregnant while receiving acalabrutinib

Breastfeeding

South African recommendations

• Caution; not recommended
• No data are available regarding the presence of acalabrutinib or its active metabolite in human milk
• Breastfeeding mothers should not breastfeed during treatment with acalabrutinib and for 2 days after receiving the last dose

Fertility

South African recommendations

• There are no data on the effect of acalabrutinib on human fertility

South African recommendations

• Mild to moderate (eGFR ≥30ml/min/1.73m²): No dose adjustment recommended
• Severe (eGFR <29ml/min/1.73m²) or end-stage renal disease: Caution; no information available

South African recommendations

• Mild or moderate (Child-Pugh A and B or total bilirubin between 1.5 to 3 times upper limit of normal [ULN] and any AST: No dose adjustment recommended
• Severe (Child-Pugh C, or total bilirubin between >3 times the ULN and any AST): Caution; not recommended

South African recommendations

• No dose adjustment recommended

• Strong CYP3A inhibitors
• Itraconazole
• Ketoconazole
• Conivaptan
• Clarithromycin
• Indinavir
• Ritonavir
• Telaprevir
• Posaconazole
• Voriconazole
• Strong CYP3A inducers
• Rifampin
• Phenytoin
• Carbamazepine
• Gastric acid reducing medicines
• Proton pump inhibitors
• Omeprazole
• Antacids (see additional prescribing points)
• Calcium carbonate
• H₂ receptor antagonist (see additional prescribing points)
• Ranitidine
• Famotidine
• BCRP substrates
• Methotrexate
• MATE1 substrates
• Metformin

Other interactions

• St. John’s wort 

• Complete blood count (CBC) regularly during treatment
• Pregnancy status
  - Prior to use in patients who could become pregnant
• Hepatitis B virus (HBV) screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen
  - Prior to beginning (or at the beginning of) systemic anticancer therapy; treatment should not be delayed for screening/results
  - To determine the need for antiviral prophylaxis, monitoring, and follow-up, assessing the risk of chronic or past HBV infection is required
• Cardiovascular assessment
  - Comprehensive assessment prior to treatment including a history and physical examination
  - Cardiovascular disease risk factors screening such as hypertension, diabetes, dyslipidaemia, obesity, and smoking
• Blood pressure
  - At baseline and each clinical visit (as well as weekly home monitoring for initial 3 months)
• Electrocardiogram
  - At each clinical visit, obtain a baseline echocardiography (transthoracic preferred) in high-risk patients
  - Echocardiography is also recommended in all patients who develop atrial fibrillation

Additional observations

• Monitor for signs/symptoms of atrial fibrillation and atrial flutter (eg, palpitations, dizziness, syncope, dyspnoea)
• Monitor for signs/symptoms of bleeding (patients on antiplatelet or anticoagulant therapies), infection, and/or secondary malignancies
• Monitor adherence

Dose Adjustments

Recommended dose modifications of acalabrutinib for Grade ≥3 adverse reactions

Dose modifications for use with CYP3A inhibitors or inducers and gastric acid reducing medicines

Gastric acid reducing medicines

• Acalabrutinib solubility decreases with increasing pH
• Coadministration with a proton pump inhibitor (40mg omeprazole for 5 days), decreased acalabrutinib AUC by 43%
• If treatment with an acid reducing medicine is required, consider using an antacid (e.g., calcium carbonate), or an H₂-receptor antagonist (e.g., ranitidine or famotidine). For use with antacids, separate dosing by at least 2 hours
• For H₂-receptor antagonists, take acalabrutinib 2 hours before taking the H₂-receptor antagonist
• Due to the long-lasting effect of proton pump inhibitors, separation of doses with proton pump inhibitors may not eliminate the interaction with acalabrutinib

Acalabrutinib is a selective small-molecule inhibitor of Bruton tyrosine kinase (BTK). BTK is a signalling molecule of the B cell antigen receptor (BCR) and cytokine receptor pathways. In B cells, BTK signalling results in B-cell survival and proliferation, and is required for cellular adhesion, trafficking, chemotaxis.  Acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK active site, leading to irreversible inactivation of BTK (IC50 ≤5nM) with minimal off-target interactions.  In nonclinical studies, acalabrutinib inhibited BTK-mediated activation of downstream signalling proteins CD86 and CD69 and inhibited malignant B-cell proliferation and survival and had minimal activity on other immune cells (T cells and NK cells).