Acalabrutinib

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Calquence: 100 mg [contains fd&c blue #2 (indigotine)]

Pharmacology

Mechanism of Action

Acalabrutinib is a selective and irreversible second-generation Bruton’s tyrosine kinase (BTK) inhibitor (Byrd 2016). Acalabrutinib and the active metabolite (ACP-5862) form a bond (covalent) with a cysteine residue in the active BTK site to inhibit BTK enzyme activity. BTK is an integral component of the B-cell receptor (BCR) and cytokine receptor pathways. BTK signals activation of the pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion. BTK inhibition results in decreased malignant B-cell proliferation and tumor growth.

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: Acalabrutinib: ~101 L; ACP-5862: ~67 L.

Metabolism

Hepatic, primarily via CYP3A enzymes, and to a lesser degree by glutathione conjugation and amide hydrolysis; major (active) metabolite: ACP-5862 (geometric mean exposure 2- to 3-fold higher than acalabrutinib, but BTK inhibition by ACP-5862 is ~50% less potent than that of acalabrutinib)

Excretion

Feces (84%; <2% as unchanged drug); Urine (12%; <2% as unchanged drug).

Clearance: Acalabrutinib: 71 L/hour; ACP-5862 13 L/hour.

Time to Peak

Acalabrutinib: 0.9 hours (range: 0.5 to 1.9 hours); ACP-5862: 1.6 hours (range: 0.9 to 2.7 hours).

Half-Life Elimination

Acalabrutinib: 1 hour; ACP-5862 (active metabolite): 3.5 hours.

Protein Binding

Acalabrutinib: 97.5%; ACP-5862: 98.6%; to human plasma protein.

Use in Specific Populations

Special Populations: Hepatic Function Impairment

Acalabrutinib exposure (AUC) was increased 1.9-fold in subjects with mild impairment (Child-Pugh class A), 1.5-fold in subjects with moderate impairment (Child-Pugh class B), and 5.3-fold in subjects with severe impairment (Child-Pugh class C), compared to subjects with normal hepatic function.

Use: Labeled Indications

Chronic lymphocytic leukemia or small lymphocytic lymphoma: Treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma in adults.

Mantle cell lymphoma (previously treated): Treatment of mantle cell lymphoma in adults who have received at least 1 prior therapy.

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to acalabrutinib or any component of the formulation.

Dosage and Administration

Dosing: Adult

Chronic lymphocytic leukemia or small lymphocytic lymphoma: Oral:

Single agent therapy: 100 mg approximately every 12 hours; continue until disease progression or unacceptable toxicity.

Combination therapy with obinutuzumab (previously untreated patients): 100 mg approximately every 12 hours; continue until disease progression or unacceptable toxicity; begin acalabrutinib at cycle 1 (each cycle is 28 days); obinutuzumab is administered for 6 cycles beginning at cycle 2 (Sharman 2019).

Mantle cell lymphoma (previously treated): Oral: 100 mg approximately every 12 hours; continue until disease progression or unacceptable toxicity (Wang 2017).

Missed doses: If a dose is missed by >3 hours, omit that dose and take the next dose at the regularly scheduled time; do not administer extra doses to make up for a missed dose.

Dosage adjustment for concomitant CYP3A inhibitors or inducers:

Strong CYP3A inhibitors: Avoid concomitant use with strong CYP3A inhibitors; if strong CYP3A inhibitors will be used short-term (eg, anti-infectives for ≤7 days), interrupt acalabrutinib treatment.

Moderate CYP3A inhibitors: Reduce acalabrutinib dose to 100 mg once daily.

Strong CYP3A inducers: Avoid concomitant use with strong CYP3A inducers; if strong CYP3A inducers cannot be avoided, increase acalabrutinib dose to 200 mg approximately every 12 hours.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Note: Obinutuzumab may also require dosage modification. Due to the potential bleeding risk, consider benefit-risk of interrupting treatment for 3 to 7 days prior to and after surgery.

Hematologic toxicities: Grade 3 thrombocytopenia with bleeding, grade 4 thrombocytopenia, or grade 4 neutropenia lasting >7 days:

First and second occurrence: Interrupt treatment; may resume at 100 mg approximately every 12 hours after toxicity resolves to grade 1 or baseline.

Third occurrence: Interrupt treatment; may resume with the dose reduced to 100 mg once daily after toxicity resolves to grade 1 or baseline.

Fourth occurrence: Discontinue acalabrutinib.

Nonhematologic toxicities: Grade 3 or higher toxicity:

First and second occurrence: Interrupt treatment; may resume at 100 mg approximately every 12 hours after toxicity resolves to grade 1 or baseline.

Third occurrence: Interrupt treatment; may resume with the dose reduced to 100 mg once daily after toxicity resolves to grade 1 or baseline.

Fourth occurrence: Discontinue acalabrutinib.

Administration

Oral:

Administer doses with or without food, ~12 hours apart. Swallow capsule whole with water; do not open, break, or chew capsules. When administered on the same day as obinutuzumab (in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma), administer acalabrutinib prior to obinutuzumab.

Avoid concomitant use with proton pump inhibitors; administer acalabrutinib 2 hours prior to H₂-receptor antagonists; separate acalabrutinib from antacids by at least 2 hours.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): Acalabrutinib may enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Antacids: May decrease the serum concentration of Acalabrutinib. Management: Separate administration of acalabrutinib from the administration of any antacids by at least 2 hours in order to minimize the potential for a significant interaction. Consider therapy modification

Anticoagulants: Acalabrutinib may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Acalabrutinib. Management: Avoid co-administration of strong CYP3A inducers in patients taking acalabrutinib. If strong CYP3A inducers cannot be avoided, increase the dose of acalabrutinib to 200 mg twice daily. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Acalabrutinib. Management: Reduce acalabrutinib dose to 100 mg once daily with concurrent use of a moderate CYP3A4 inhibitor. Monitor patient closely for both acalabrutinib response and evidence of adverse effects with any concurrent use. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Acalabrutinib. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Histamine H2 Receptor Antagonists: May decrease the serum concentration of Acalabrutinib. Management: To minimize the potential for a significant interaction, separate administration of these agents by giving acalabrutinib 2 hours before ingestion of a histamine-2 receptor antagonist. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Proton Pump Inhibitors: May decrease the serum concentration of Acalabrutinib. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

>10%:

Central nervous system: Headache (39%), fatigue (28%)

Dermatologic: Skin rash (18%)

Gastrointestinal: Diarrhea (31%), nausea (19%), abdominal pain (15%), constipation (15%), vomiting (13%)

Hematologic & oncologic: Neutropenia (grade 3 or 4: 23%), bruise (21%; grade 1: 19%), anemia (grade 3 or 4: 11%), malignant neoplasm (11%)

Neuromuscular & skeletal: Myalgia (21%)

1% to 10%:

Cardiovascular: Atrial fibrillation (≤3%), atrial flutter (≤3%)

Hematologic & oncologic: Thrombocytopenia (grade 3 or 4: 8%), hematoma (≤8%; grade ≥3: ≤1%), hemorrhage (≤8%; grade ≥3: ≤1%), skin carcinoma (7%)

Renal: Increased serum creatinine (grade 2: 5%)

Respiratory: Epistaxis (6%)

Frequency not defined:

Central nervous system: Progressive multifocal leukoencephalopathy

Infection: Opportunistic infection, reactivation of HBV, serious infection

Respiratory: Pneumonia

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Grade 3 or 4 cytopenias including neutropenia, anemia, thrombocytopenia, and lymphopenia have occurred in patients with hematologic malignancies treated with acalabrutinib. Monitor CBC regularly during acalabrutinib treatment. Hematologic toxicity may require treatment interruption, dose reduction, and/or discontinuation.
• Cardiovascular adverse effects: Atrial fibrillation and atrial flutter (any grade) occurred in a small percentage of patients with hematologic malignancies treated with acalabrutinib; grade 3 events were reported. The risk may be increased in patients with cardiac risk factors, hypertension, prior arrhythmia, and acute infection. Monitor for symptoms of arrhythmia (palpitations, dizziness, syncope, dyspnea) and manage as appropriate.
• GI toxicity: Diarrhea, nausea, and vomiting may commonly occur, although generally mild.
• Hemorrhage: Serious hemorrhagic events (some fatal) have been reported in patients with hematologic malignancies who received acalabrutinib. Major hemorrhages (serious or ≥ grade 3 bleeding or any CNS bleeding) have been reported in a small percentage of patients. Bleeding events of any grade (excluding bruising and petechiae) occurred in almost one-fourth of patients. Acalabrutinib may further increase the risk of hemorrhage in patients receiving antithrombotic agents (assess risks versus benefits of concomitant therapy). Monitor patients for signs of bleeding. Depending upon the type of surgery and the risk of bleeding, consider the benefit-risk of withholding acalabrutinib treatment for 3 to 7 days before and after surgery.
• Infection: Serious and fatal infections (including opportunistic infections) have occurred in patients with hematologic malignancies treated with acalabrutinib. Serious or ≥ grade 3 infections (bacterial, viral, or fungal) occurred in about one-fifth of these patients, most often due to respiratory infections. Infections usually occurred in the absence of grade 3 or 4 neutropenia (neutropenic infection occurred in a small percentage of patients). Opportunistic infections have included (although were not limited to) hepatitis B virus reactivation, fungal pneumonia, pneumocystis jirovecii pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy. Consider prophylaxis in patients who are at increased risk for opportunistic infections. Monitor for signs and symptoms of infection and manage (promptly) as medically appropriate.
• Secondary malignancies: Second primary malignancies, including skin cancers and other solid tumors, have occurred in patients treated with acalabrutinib; the most frequent second primary malignancy was skin cancer. Monitor for skin cancers and advise patients to utilize protection from sun exposure.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Drugs that affect gastric pH: Avoid concomitant use with proton pump inhibitors; administer acalabrutinib 2 hours prior to H₂-receptor antagonists; separate acalabrutinib from antacids by at least 2 hours.

Special populations:

• Elderly: Patients ≥65 years of age experienced a higher incidence of serious or ≥ grade 3 adverse reactions.

Monitoring Parameters

CBC (was monitored monthly in studies). Evaluate pregnancy status prior to use in females of reproductive potential. Monitor for atrial fibrillation and atrial flutter; monitor for signs/symptoms of bleeding (in patients receiving antiplatelet or anticoagulant therapies), infection, secondary malignancies. Monitor adherence.

Pregnancy

Pregnancy Considerations

Based on data from animal reproduction studies, in utero exposure to acalabrutinib may cause fetal harm.

Evaluate pregnancy status prior to use in females of reproductive potential. Females of reproductive potential should use effective contraception during therapy and for at least 1 week after the last acalabrutinib dose.

Patient Education

What is this drug used for?

• It is used to treat types of leukemia and lymphoma.

Frequently reported side effects of this drug

• Muscle pain
• Headache
• Loss of strength and energy
• Back pain
• Bone pain
• Joint pain
• Neck pain
• Common cold symptoms
• Diarrhea
• Nausea
• Vomiting
• Abdominal pain
• Constipation

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Progressive multifocal leukoencephalopathy like confusion, depression, trouble with memory, behavioral changes, change in strength on one side is greater than the other, trouble speaking, change in balance, or vision changes
• Infection
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Severe cerebrovascular disease like change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or vision changes
• Severe headache
• Dizziness
• Passing out
• Chest pain
• Fast heartbeat
• Abnormal heartbeat
• Shortness of breath
• Mole changes
• Skin growth
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.