Brukinsa^® (Capsules) Instructions for Use

Marketing Authorization Holder

Beijing Pharmaceuticals GmbH (Switzerland)

Manufactured By

Catalent CTS LLC (USA)

Labeled By

ANDERSONBRECON, Inc. (USA)

Or

NANOLEK, LLC (Russia)

Quality Control Release

NANOLEK, LLC (Russia)

ATC Code

L01EL03 (Zanubrutinib)

Active Substance

Zanubrutinib (Rec.INN registered by WHO)

Dosage Form

Brukinsa®

Capsules 80 mg: 120 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size No. 0, opaque, with a white to off-white body and cap; the cap is imprinted with “ZANU 80” in black ink; the capsule contents are a white to off-white powder.

Excipients: microcrystalline cellulose (type 102) – 263.8 mg, croscarmellose sodium – 10.8 mg, sodium lauryl sulfate – 1.8 mg, colloidal silicon dioxide – 1.8 mg, magnesium stearate – 1.8 mg.

Composition of the hard gelatin capsule shell body: gelatin – 56.45 mg, titanium dioxide – 1.15 mg; cap: gelatin – 37.63 mg, titanium dioxide – 0.77 mg, capsule printing ink* – 0.03 mg.
* Composition of the capsule printing ink shellac glaze (20% esterified) in ethanol^Δ – 59.42%, black iron oxide dye – 24.65%, N-butanol^Δ – 9.75%, purified water^Δ – 3.249%, propylene glycol – 1.3%, ethanol^Δ – 1.08%, isopropanol^Δ – 0.55%, aqueous ammonia 28%^Δ – 0.001%.

^Δ these solvents/liquids are not contained in the medicinal product, they are removed during the ink drying process.

120 pcs. – polyethylene bottles (1) – cardboard packs with first-opening control.

Clinical-Pharmacological Group

Antitumor drug. Bruton’s tyrosine kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agent, protein kinase inhibitor, Bruton’s tyrosine kinase inhibitor

Pharmacological Action

Zanubrutinib is a selective, low-molecular-weight inhibitor of Bruton’s tyrosine kinase (BTK). BTK is a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways. In B-cells, BTK signaling leads to the activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. Zanubrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to irreversible inhibition of BTK activity. In preclinical studies, Zanubrutinib suppressed malignant B-cell proliferation and reduced tumor growth.

In patients with B-cell malignancies treated with a dose of 320 mg/day, the median sustained BTK occupancy in peripheral blood mononuclear cells at 100% was maintained for 24 hours. The mean steady-state BTK occupancy rate in lymph nodes ranged from 94% to 100% after administration of the approved recommended dose.

No clinically significant effect on the QTc interval was observed at the approved recommended doses (160 mg twice daily or 320 mg once daily). The effect of zanubrutinib on the QTc interval at supratherapeutic concentrations has not been evaluated.

Pharmacokinetics

The median time to reach C_max of zanubrutinib is 2 hours. Zanubrutinib plasma protein binding is approximately 94%. The blood-to-plasma concentration ratio is 0.7-0.8. The geometric mean (%CV) steady-state V_d is 881 (95%) L. Zanubrutinib is primarily metabolized by CYP3A isoenzymes. Zanubrutinib is a substrate of P-glycoprotein. It is not a substrate or inhibitor of the renal uptake transporters OAT1, OAT3, OCT2, or the hepatic uptake transporters OATP1B1 or OATP1B3.

Following a single oral dose of 160 mg or 320 mg of zanubrutinib, the median T_1/2 of zanubrutinib is approximately 2 to 4 hours. The mean apparent clearance (CL/F) of zanubrutinib is 182 L/h. Following a single 320 mg dose of radiolabeled zanubrutinib in healthy volunteers, approximately 87% of the dose was excreted in the feces (38% as unchanged drug) and 8% in the urine (less than 1% as unchanged drug).

Indications

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

ICD codes

Dosage Regimen

Administer Brukinsa^® orally for mantle cell lymphoma at a total daily dose of 320 mg.

Choose one of two approved schedules: take 160 mg (two 80 mg capsules) twice daily or take 320 mg (four 80 mg capsules) once daily.

Swallow capsules whole with water; do not open, crush, or chew them.

Take doses approximately 12 hours apart for the twice-daily regimen.

You may take Brukinsa with or without food.

Continue therapy until disease progression or the development of unacceptable toxicity.

For severe adverse reactions, interrupt dosing, reduce the dose, or permanently discontinue based on severity and clinical presentation.

Monitor complete blood counts regularly as clinically indicated.

If a dose is missed, take it as soon as possible on the same day, then resume the normal schedule; do not take an extra dose to make up for a missed one.

Adverse Reactions

Blood and lymphatic system disorders neutropenia and decreased neutrophil count, thrombocytopenia and decreased platelet count, leukopenia and decreased white blood cell count, lymphocytosis, anemia and decreased hemoglobin.

Infections and infestations: upper respiratory tract infection, pneumonia, urinary tract infection.

Skin and subcutaneous tissue disorders rash, bruising.

Gastrointestinal disorders diarrhea, constipation, increased ALT, increased bilirubin concentration.

Cardiac and vascular disorders arterial hypertension, bleeding.

Metabolism and nutrition disorders hypokalemia, increased blood uric acid concentration.

Respiratory system disorders: cough.

Contraindications

Hypersensitivity to zanubrutinib, children and adolescents under 18 years of age.

With caution

Patients with severe hepatic impairment, patients with severe renal impairment, and patients requiring dialysis; pregnancy, breastfeeding period.

Use in Pregnancy and Lactation

Based on animal studies, Zanubrutinib can cause fetal harm when administered during pregnancy. There are no available data on the use of zanubrutinib in pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of zanubrutinib to pregnant rats during organogenesis, at exposures 5 times those reported in patients at the recommended dose of 160 mg twice daily, was associated with fetal heart malformations. Avoiding pregnancy during treatment with zanubrutinib is recommended. If use during pregnancy is necessary or if pregnancy occurs during treatment, the patient should be informed of the potential hazard to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

There are no data on the presence of zanubrutinib or its metabolites in human milk, their effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions in breastfed children, women should not breastfeed during treatment with zanubrutinib and for at least 2 weeks after the last dose.

Use in Hepatic Impairment

Patients with severe hepatic impairment.

Use in Renal Impairment

Patients with severe renal impairment, and patients requiring dialysis.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

No dose adjustment is required in elderly patients.

Special Precautions

Serious hemorrhagic events, including fatalities, have been reported in patients with hematologic malignancies treated with zanubrutinib monotherapy. Major hemorrhages (Grade 3 or higher bleeding, including intracranial and gastrointestinal hemorrhage, hematuria, and hemothorax) were reported in 2% of patients. Bleeding events of any grade, including purpura and petechiae, were observed in 50% of patients with hematologic malignancies. Concomitant use with antiplatelet agents, anticoagulants, or thrombolytics may increase the risk of bleeding. Patients receiving antiplatelet agents, anticoagulants, or thrombolytics should be monitored for signs of bleeding. Zanubrutinib should be discontinued if intracranial hemorrhage of any grade occurs. The benefit-risk ratio of temporarily interrupting zanubrutinib for 3-7 days before and after surgery should be considered, depending on the type of surgery and the risk of bleeding.

In patients at increased risk of opportunistic infections, prophylaxis for herpes simplex virus, pneumocystis pneumonia, and other infections should be considered according to standard of care for patients at increased risk of infections. Patients should be carefully monitored for signs and symptoms of infection and treated appropriately according to established practice.

Complete blood count parameters should be monitored according to established procedures.

Second primary malignancies, including non-skin carcinoma, occurred in 9% of patients receiving zanubrutinib monotherapy. The most frequent second primary malignancy was skin cancer (basal cell carcinoma and squamous cell carcinoma of the skin), reported in 6% of patients. Patients are advised to use sun protection.

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.

Effect on ability to drive and use machines

Fatigue and dizziness may occur during therapy with zanubrutinib, and if these symptoms are present, patients should exercise caution when driving or operating machinery.

Drug Interactions

Concomitant administration of multiple doses of CYP3A inhibitors increases the C_max and AUC of zanubrutinib. Patients taking strong CYP3A inhibitors concomitantly with zanubrutinib should be closely monitored for possible adverse reactions.

When co-administered with itraconazole, the C_max and AUC of zanubrutinib increased by 157% and 278%, respectively. A similar reaction is expected with concomitant use of clarithromycin, diazepam, erythromycin, fluconazole.

Concomitant administration of multiple doses of rifampicin (a strong CYP3A inducer) decreased the C_max of zanubrutinib by 92% and the AUC by 93%.

Concomitant administration of multiple doses of efavirenz (a moderate CYP3A inducer) is estimated to decrease the C_max of zanubrutinib by 58% and the AUC by 60%.

No clinically significant differences in the pharmacokinetics of zanubrutinib were observed when co-administered with gastric acid-reducing agents (proton pump inhibitors, H₂-receptor blockers).

Concomitant administration of multiple doses of zanubrutinib decreased the C_max of midazolam (a CYP3A substrate) by 30% and the AUC by 47%.

Concomitant administration of multiple doses of zanubrutinib decreased the C_max of omeprazole (a CYP2C19 substrate) by 20% and the AUC by 36%.

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.