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Acalabrutinib

Pronunciation

(a KAL a broo ti nib)

Index Terms

  • ACP-196
  • BTK Inhibitor ACP-196

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 aluminum lake]

Brand Names: U.S.

  • Calquence

Pharmacologic Category

  • Antineoplastic Agent
  • Antineoplastic Agent, Bruton Tyrosine Kinase Inhibitor
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor

Pharmacology

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 survival.

Distribution

Vdss: ~34 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%; <1% as unchanged drug); Urine (12%; <1% as unchanged drug)

Time to Peak

0.75 hours

Half-Life Elimination

Acalabrutinib: 0.9 hours (range: 0.6 to 2.8 hours); ACP-5862 (active metabolite): 6.9 hours

Protein Binding

97.5% to human plasma protein

Special Populations: Hepatic Function Impairment

Acalabrutinib exposure (AUC) was increased by less than 2-fold in subjects with mild and moderate hepatic impairment (Child-Pugh classes A and B), compared to subjects with normal hepatic function.

Use: Labeled Indications

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

Contraindications

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

Dosing: Adult

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 more than 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 twice daily.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

eGFR ≥30 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling; however, renal excretion is minimal.

eGFR <30/mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment

Mild to moderate impairment (Child-Pugh classes A and B): There are no dosage adjustments provided in the manufacturer's labeling; however, no pharmacokinetic differences have been observed in patients with mild to moderate hepatic impairment versus patients with normal hepatic function.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Adjustment for Toxicity

Note: 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 longer than 7 days:

First and second occurrence: Interrupt treatment; may resume at 100 mg twice daily after toxicity resolves to grade 1 or baseline.

Third occurrence: Interrupt treatment; may resume at 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 twice daily after toxicity resolves to grade 1 or baseline.

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

Fourth occurrence: Discontinue acalabrutinib.

Administration

Administer doses with or without food, approximately 12 hours apart. Swallow capsule whole with water; do not open, break, or chew capsules. 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

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

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

Ceritinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of ceritinib with a narrow therapeutic index CYP3A substrate (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) should be avoided when possible. Monitor therapy

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

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

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

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

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

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

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

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

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

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. 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, and thrombocytopenia have occurred in patients with hematologic malignancies treated with acalabrutinib (as a single agent). In studies, CBC was monitored monthly.

• Cardiovascular adverse effects: Atrial fibrillation and atrial flutter (any grade) occurred in a small percentage of patients with hematologic malignancies treated with acalabrutinib (as a single agent); grade 3 events were reported. Monitor for atrial fibrillation and atrial flutter 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. Overall, bleeding events, including bruising and petechiae (any grade), occurred in approximately half of patients with hematological malignancies who received acalabrutinib. Grade 3 or higher bleeding events (including GI, intracranial, and epistaxis) have been reported rarely. While the mechanism for bleeding events is not well understood, acalabrutinib may further increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies; monitor these 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 bacterial, viral, or fungal infections (including fatal events and opportunistic infections) have occurred in patients with hematologic malignancies treated with acalabrutinib (as a single agent). Consider prophylaxis in patients who are at increased risk for opportunistic infections. Grade 3 or higher infections occurred in about one-fifth of these patients; pneumonia was the most frequent grade 3 or 4 infection. Infections due to hepatitis B virus (HBV) reactivation and progressive multifocal leukoencephalopathy (PML) have also occurred. Monitor for signs and symptoms of infection and manage as medically appropriate.

• Secondary malignancies: Second primary malignancies, including non-skin carcinomas, have occurred in about one-tenth of patients with hematologic malignancies treated with acalabrutinib (as a single agent); the most frequent second primary malignancy was skin cancer. 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.

Monitoring Parameters

CBC (was monitored monthly in studies). 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 Considerations

Adverse events were observed in some animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience muscle pain, diarrhea, nausea, vomiting, abdominal pain, or constipation. Have patient report immediately to prescriber signs of progressive multifocal leukoencephalopathy (confusion, depression, memory impairment, behavioral changes, change in strength on one side is greater than the other, difficulty speaking, change in balance, or vision changes), signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; 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), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), severe headache, dizziness, passing out, angina, tachycardia, abnormal heartbeat, shortness of breath, severe loss of strength and energy, mole changes, or skin growth (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

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