Acalabrutinib

Indications

Acalabrutinib is used for: Mantle Cell Lymphoma

Adult Dose

Mantle Cell Lymphoma Indicated for mantle cell lymphoma (MCL) in patients who have received ?1 prior therapy 100 mg PO every twelve hours Continue until disease progression or unacceptable toxicity Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Indicated for treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) Monotherapy 100 mg PO every twelve hours Continue until disease progression or unacceptable toxicity Combination with obinutuzumab Indicated for patients with previously untreated CLL or SLL Start acalabrutinib at Cycle 1 (each cycle is 28 days) Start obinutuzumab at Cycle 2 for a total of 6 cycles Refer to obinutuzumab for infusion rates Cycle 1 Days 1-28: Acalabrutinib 100 mg PO q12hr Cycle 2 Days 1-28: Acalabrutinib 100 mg PO q12hr Day 1: Obinutuzumab 100 mg IV infusion Day 2: Obinutuzumab 900 mg IV infusion Days 8 and 15: Obinutuzumab 1000 mg IV infusion Cycles 3-7 Day 1-28: Acalabrutinib 100 mg PO q12hr Day 1: Obinutuzumab 1000 mg IV infusion Cycle 8 and subsequent cycles Day 1-28: Acalabrutinib 100 mg PO q12hr Continue until disease progression or unacceptable toxicity

Child Dose

Renal Dose

Renal impairment Mild-to-moderate (eGFR >30 mL/min/1.73m²): No clinically relevant pharmacokinetics (PK) difference observed Severe (eGFR <30 mL/min/1.73m²) or patients on dialysis: Acalabrutinib PK has not been evaluated

Administration

Take with or without food

Contra Indications

Precautions

Serious hemorrhagic events, including fatal events, reported; the mechanism for the bleeding events is not well understood; acalabrutinib may further increase hemorrhage risk in patients receiving antiplatelet or anticoagulant therapies, and patients should be monitored for signs of bleeding; consider the benefit-risk of withholding acalabrutinib for 3-7 days presurgery and postsurgery depending on the type of surgery and the risk of bleeding Serious infections (bacterial, viral, or fungal), including fatal events and opportunistic infections, reported; monitor for infection and consider prophylaxis in patients who are at increased risk for opportunistic infections Cytopenias reported, including neutropenia, anemia, and thrombocytopenia; assess complete blood cell counts monthly during treatment Second primary malignancies, including nonskin carcinomas, have occurred in patients with hematologic malignancies treated with acalabrutinib; the most frequent was skin cancer; advise patients regarding need for protection from sun exposure Atrial fibrillation and flutter occurred (rare) during clinical trials; monitor patients and manage as appropriate Monitoring Parameter Monitor complete blood cell counts monthly during treatment Monitor for symptoms of arrhythmia (eg, palpitations, dizziness, syncope, dyspnea) Evaluate bilirubin and transaminases at baseline and throughout treatment; for patients who develop abnormal liver tests, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity.

Pregnancy-Lactation

Pregnancy Based on findings in animals, may cause fetal harm when administered to pregnant women There are no available data in pregnant women to inform the drug-associated risk Pregnancy testing is recommended for females of reproductive potential before initiating therapy Animal data In animal reproduction studies, administration of acalabrutinib to pregnant rabbits during organogenesis resulted in reduced fetal growth; rabbit maternal exposures (AUC) were ~4 times that of humans given a dose of 100 mg BID Advise pregnant women of the potential risk to a fetus Contraception Embryofetal harm and dystocia may occur when administered to pregnant women Females of reproductive potential: Use effective contraception during treatment and for at least 1 week following the last dose; if used during pregnancy, or if the patient becomes pregnant while taking drug, inform patient of the potential hazard to a fetus Lactation No data are available regarding the presence of acalabrutinib or its active metabolite in human milk, its effects on the breastfed child, or on milk production Acalabrutinib and its active metabolite were present in the milk of lactating rats Owing to the potential for adverse reactions in a breastfed child, advise lactating women not to breastfeed while taking acalabrutinib and for at least 2 weeks after the final dose

Interactions

Coadministration with CYP3A inhibitors or inducers Acalabrutinib is predominantly metabolized by CYP3A enzymes CYP3A inhibitors are expected to increase acalabrutinib systemic exposure CYP3A inducers are expected to decrease acalabrutinib systemic exposure Coadministration with gastric acid-reducing agents Coadministration with PPIs, H2-antagonists, or antacids may decrease acalabrutinib plasma concentrations Contraindicated (0) Serious - Use Alternative (59) alpelisib apalutamide carbamazepine chloramphenicol clarithromycin cobicistat conivaptan dabrafenib danazol darunavir deferiprone dexamethasone dexlansoprazole elvitegravir/cobicistat/emtricitabine/tenofovir DF enzalutamide eslicarbazepine acetate esomeprazole fexinidazole fosamprenavir fosphenytoin grapefruit idelalisib imatinib indinavir isoniazid itraconazole ivosidenib ketoconazole lansoprazole levoketoconazole lonafarnib lopinavir lumacaftor/ivacaftor mitotane nefazodone nelfinavir nevirapine nicardipine omeprazole oxcarbazepine ozanimod palifermin pantoprazole phenobarbital phenytoin posaconazole primidone rabeprazole rifabutin rifampin rifapentine ritonavir ropeginterferon alfa 2b saquinavir St John's Wort talazoparib tipranavir voriconazole voxelotor

Adverse Effects

Side effects of Acalabrutinib : >10% All grades Decreased hemoglobin (46%) Decreased platelets (44%) Headache (39%) Decreased neutrophils (36%) Diarrhea (31%) Fatigue (28%) Myalgia (21%) Bruising (21%) Nausea (19%) Rash (18%) Abdominal pain (15%) Constipation (15%) Vomiting (13%) Grade >3 Decreased neutrophils (15%) Decreased platelets (12%) 1-10% Increased creatinine, 1.5-3X ULN (4.8%) All grades Hemorrhage/hematoma (8%) Epistaxis (6%) Grade >3 Decreased hemoglobin (10%) Diarrhea (3.2%) Abdominal pain (1.6%) Headache (1.6%) Vomiting (1.6%)

Mechanism of Action

Bruton tyrosine kinase (BTK) inhibitor; acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic 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