Acalabrutinib-Promomed (Capsules) Instructions for Use

Marketing Authorization Holder

Promomed Rus LLC (Russia)

Manufactured By

Biokhimik, JSC (Russia)

ATC Code

L01EL02 (Acalabrutinib)

Active Substance

Acalabrutinib (Rec.INN registered by WHO)

Dosage Form

Acalabrutinib-Promomed

Capsules 100 mg

Dosage Form, Packaging, and Composition

Capsules

10 pcs. – blister packs (6 pcs.) – cardboard packs (60 pcs.) – By prescription
60 pcs. – jars – cardboard packs (60 pcs.) – By prescription

Clinical-Pharmacological Group

Antitumor drug. Bruton’s tyrosine kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agents; protein kinase inhibitors; Bruton’s tyrosine kinase (BTK) inhibitors

Pharmacological Action

Acalabrutinib is a selective, low-molecular-weight inhibitor of Bruton’s tyrosine kinase (BTK). BTK is a signaling molecule of the B-cell antigen receptor pathway and cytokine receptors. In B-lymphocytes, signaling via BTK promotes the survival and proliferation of B-lymphocytes and is necessary for cell adhesion, migration, and chemotaxis.

Pharmacokinetics

The pharmacokinetics of acalabrutinib and its active metabolite ACP-5862 have been studied in trials involving healthy volunteers and patients with B-cell lymphoproliferative disorders. In the dose range from 75 mg to 250 mg, the pharmacokinetic parameters are dose-dependent, and the pharmacokinetic parameters of acalabrutinib and ACP-5862 are nearly linear.

According to population pharmacokinetic modeling, the pharmacokinetic parameters of acalabrutinib and ACP-5862 do not differ significantly among patients with various B-cell lymphoproliferative disorders. In patients with B-cell lymphoproliferative disorders (including mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL)), the geometric mean daily area under the plasma concentration-time curve for acalabrutinib and ACP-5862 was 1893 ng×h/ml and 4091 ng×h/ml, and the C_max of acalabrutinib in plasma was 466 ng/ml and 420 ng/ml, respectively, when the drug was taken at the recommended dose of 100 mg twice daily.

The median time to reach C_max for acalabrutinib and ACP-5862 in plasma was 0.75 h and 1 h, respectively. The absolute bioavailability of the drug was 25%.

Reversible binding to human plasma proteins was 97.5% for acalabrutinib and 98.6% for ACP-5862. The mean blood-to-plasma concentration ratio in vitro was 0.8 for acalabrutinib and 0.7 for ACP-5862. The mean steady-state volume of distribution of acalabrutinib is approximately 34 L.

It is primarily metabolized by cytochrome CYP3A isoenzymes and to a lesser extent by glutathione conjugation and amide hydrolysis.

ACP-5862 is the main metabolite in plasma, the geometric mean area under the plasma concentration-time curve of which is approximately 2-3 times higher than that of acalabrutinib. ACP-5862 is approximately 50% less potent at inhibiting BTK than Acalabrutinib.

It is a weak inhibitor of cytochrome isoenzymes CYP3A4/5, CYP2C8, and CYP2C9, but does not inhibit CYP1A2, CYP2B6, CYP2C19, CYP2D6, UGT1A1, and UGT2B7. ACP-5862 is a weak inhibitor of cytochrome isoenzymes CYP2C8, CYP2C9, and CYP2C19, but does not inhibit CYP1A2, CYP2B6, CYP2D6, CYP3A4/5, UGT1A1, and UGT2B7 in vitro. Acalabrutinib is a weak inducer of mRNA of cytochrome isoenzymes CYP1A2, CYP2B6, and CYP3A4; ACP-5862 is a weak inducer of cytochrome isoenzyme CYP3A4.

Acalabrutinib and its active metabolite ACP-5862 are substrates of P-glycoprotein and BCRP.

After a single oral dose of 100 mg acalabrutinib, the median T_1/2 was 0.9 (range 0.6 to 2.8) h, and for ACP-5862 it was 6.9 (range 2.7 to 9.1) h. The mean apparent clearance of acalabrutinib and ACP-5862 (CL/F) was 70 L/h and 13 L/h, respectively; according to population pharmacokinetic analysis, healthy volunteers and patients had similar pharmacokinetic parameters.

After a single dose of 100 mg of ¹⁴C-radiolabeled acalabrutinib in healthy volunteers, 84% of the administered dose was excreted via the intestine, 12% via the kidneys, and less than 2% was excreted unchanged via the intestine and kidneys.

Indications

Chronic lymphocytic leukemia/small lymphocytic lymphoma in adult patients; mantle cell lymphoma in adult patients who have received at least one prior line of therapy.

ICD codes

Dosage Regimen

Take 100 mgorally approximately every 12 hours for a total of two doses per day.

Swallow the capsules whole with a full glass of water. Do not open, break, or chew the capsules.

Administer the drug with or without food.

If a dose is missed by more than 3 hours, skip the missed dose and resume the usual schedule with the next dose. Do not take a double dose to make up for a missed one.

For patients requiring treatment with a strong CYP3A inducer, increase the dosage to 200 mg twice daily.

When co-administering with antacids (e.g., calcium carbonate) or H2-receptor antagonists (e.g., famotidine), maintain an interval of at least 2 hours before or after taking acalabrutinib.

Avoid concomitant use with proton pump inhibitors (e.g., omeprazole).

Treatment should be continued until disease progression or unacceptable toxicity occurs.

Dose modifications (interruption or reduction) may be required based on individual tolerance and the severity of adverse reactions.

Adverse Reactions

Blood and lymphatic system disorders very common – leukopenia, neutropenia, anemia; common – thrombocytopenia.

Cardiac disorders common – atrial fibrillation/flutter.

Nervous system disorders very common – headache, dizziness.

Respiratory system disorders: common – epistaxis.

Gastrointestinal disorders very common – diarrhea, nausea, constipation, abdominal pain, vomiting.

Metabolism and nutrition disorders tumor lysis syndrome.

Musculoskeletal and connective tissue disorders very common – arthralgia, muscle and bone pain.

Skin and subcutaneous tissue disorders very common – bruising, rash, hemorrhage, hematoma.

Investigations very common – decreased absolute neutrophil count, decreased hemoglobin concentration, decreased platelet count.

Neoplasms very common – second primary malignancy; common – second primary malignant neoplasm (excluding non-melanoma skin cancer); non-melanoma skin cancer.

General disorders very common – fatigue; common – asthenia.

Other very common – infections.

Contraindications

Hypersensitivity, children under 18 years of age, patients with severe hepatic impairment, patients with severe renal impairment, and patients requiring dialysis.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

The drug is contraindicated for use in severe hepatic impairment (Child-Pugh class C or total bilirubin concentration > 3 x ULN with any AST activity).

Use in Renal Impairment

The drug is contraindicated for use in severe renal impairment (eGFR less than 29 ml/min/1.73 m²), in end-stage renal disease.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

The drug is approved for use in elderly patients.

Special Precautions

Serious hemorrhagic events, including fatal ones, have been observed in patients with hematologic malignancies receiving monotherapy. Major bleeding (grade 3 or higher bleeding, serious bleeding, or bleeding involving the central nervous system) was reported in 3.6% of patients, with fatal bleeding occurring in 0.1% of patients. Overall, hemorrhagic events, including bruising and petechiae, were observed in 46% of patients with hematologic malignancies.

Serious infections (bacterial, viral, or fungal), including fatal events, have been reported in patients with hematologic malignancies receiving monotherapy. Grade 3 or higher infections were reported in 18% of these patients. The most common grade 3 or higher infection was pneumonia. Cases of infections caused by hepatitis B virus reactivation, aspergillosis, as well as cases of progressive multifocal leukoencephalopathy have been reported.

In patients at increased risk of opportunistic infections, prophylaxis should be considered. Patients should be closely monitored for signs and symptoms of infection and necessary therapy should be administered according to accepted practice.

According to laboratory results, grade 3 and 4 cytopenias developing during therapy, including neutropenia (21%), anemia (10%), and thrombocytopenia (7%), occurred in patients with hematologic malignancies receiving monotherapy.

Cases of second primary malignancies, including cancers other than skin cancer, were observed in 12% of patients with hematologic malignancies receiving monotherapy. The most common second primary malignancy was skin cancer, which was detected in 7% of patients. Patients should be monitored for the development of skin cancer.

Grade 1 or 2 atrial fibrillation/flutter was observed in 3% of patients, and grade 3 in 1% of patients with hematologic malignancies receiving monotherapy. Patients should be monitored for symptoms of atrial fibrillation/flutter (e.g., palpitations, dizziness, syncope, chest pain, dyspnea), and an ECG should be performed if necessary.

Drug Interactions

When co-administered with a strong inhibitor of cytochrome CYP3A isoenzyme (200 mg itraconazole once daily for 5 days) in healthy volunteers (n=17), the C_max of acalabrutinib increased 3.7-fold, and the AUC increased 5.1-fold. Consideration should be given to prescribing alternative drugs that are not strong CYP3A inhibitors. Patients taking strong CYP3A inhibitors (e.g., ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole, ritonavir, telaprevir, posaconazole, voriconazole) should be closely monitored for possible adverse reactions.

When co-administered with a strong inducer of cytochrome CYP3A isoenzyme (600 mg rifampin once daily for 9 days) in healthy volunteers (n=24), the C_max of acalabrutinib decreased by 68%, and the AUC decreased by 77%. Consideration should be given to prescribing alternative drugs that are not strong CYP3A inducers (such as phenytoin, rifampin, carbamazepine).

Concomitant use of St. John’s wort preparations should be avoided, as they may unpredictably reduce the plasma concentration of acalabrutinib. If the use of a strong CYP3A inducer is necessary, an increase in the dose of this drug to 200 mg twice daily is recommended.

The solubility of acalabrutinib decreases with increasing pH. Concomitant use of acalabrutinib with an antacid (1 g calcium carbonate) reduced the AUC by 53% in healthy volunteers. Concomitant use with a proton pump inhibitor (40 mg omeprazole for 5 days) reduced the AUC of acalabrutinib by 43%.

If therapy with drugs that reduce gastric acid secretion is necessary, therapy with an antacid (e.g., calcium carbonate) or an H₂-receptor antagonist (e.g., ranitidine or famotidine) should be considered. In case of concomitant use, an interval of at least 2 hours between doses should be maintained.

When co-administered with BCRP substrates (e.g., methotrexate), Acalabrutinib may increase their exposure.

ACP-5862 may increase the exposure of MATE1 substrates (e.g., metformin) when co-administered by inhibiting MATE1.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.