Ibrutinib (Capsules) Instructions for Use

ATC Code

L01EL01 (Ibrutinib)

Active Substance

Ibrutinib (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

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

Pharmacological Action

Antitumor agent, a low-molecular-weight inhibitor of Bruton’s tyrosine kinase (BTK). Ibrutinib forms a covalent bond with a cysteine residue (Cys 481) in the active site of BTK, leading to sustained inhibition of enzymatic activity.

BTK, a member of the Tec kinase family, acts as an important signaling molecule for B-cell antigen receptors (BCR) and cytokine receptors. The BCR signaling pathway is involved in the pathogenesis of a number of B-cell malignancies, including mantle cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, and B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma.

The key role of BTK in the signaling activity of B-cell surface receptors leads to the activation of signaling pathways necessary for B-cell migration, chemotaxis, and adhesion. According to preclinical studies, Ibrutinib inhibits the proliferation and survival of malignant B-cells in vivo, as well as cell migration and their adhesion to substrates in vitro.

Pharmacokinetics

After oral administration, Ibrutinib is rapidly absorbed with a median T_max of 1-2 hours. The absolute bioavailability in the fasted state (n=8) was 2.9% (90% confidence interval from 2.1% to 3.9%) and this value doubled when taken with food. In patients with various B-cell malignancies, there are no significant differences in the pharmacokinetics of ibrutinib.

The plasma concentration of ibrutinib increases proportionally with increasing dose up to 840 mg. The steady-state AUC in patients at a dose of 560 mg is 953±705 ng×h/ml (mean ± standard deviation); at a dose of 420 mg in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma – 732±521 ng×h/ml (680±517 ng×h/ml in the subgroup with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma) and in patients with chronic graft-versus-host disease – 1159±583 ng×h/ml.

Taking ibrutinib on an empty stomach led to a decrease in its concentration (AUC_last) to a level of 60% of the concentration when taken 30 minutes before meals, 30 minutes after meals, or 2 hours after a high-fat breakfast.

Reversible binding of ibrutinib to human plasma proteins in vitro was 97.3%, with no concentration dependence in the concentration range from 50 to 1000 ng/ml. V_d was 683 L, and V_d,ss is about 10000 L.

Ibrutinib is metabolized primarily by the cytochrome P450 isoform CYP3A4/5 to form mainly a dihydrodiol metabolite, whose inhibitory activity against BTK is approximately 15 times lower than that of ibrutinib. The systemic C_ss of the dihydrodiol metabolite is comparable to that of the original active substance.

Clearance after intravenous administration was 62 and 76 L/h, in the fasted and fed state, respectively. Due to a strong first-pass effect, the apparent clearance after oral administration is 2000 and 1000 L/h, in the fasted and fed state, respectively.

The T_1/2 of ibrutinib is 4-6 hours. After a single oral dose of [¹⁴C]-ibrutinib (radiolabeled) in healthy volunteers, approximately 90% of the radioactive substances were excreted within 168 hours, most (80%) was eliminated through the intestine, and less than 10% through the kidneys.

Unchanged Ibrutinib accounted for about 1% of the excretion products in feces and was absent in urine, the remainder consisted of metabolites.

Indications

Relapsed or refractory mantle cell lymphoma; chronic lymphocytic leukemia/small lymphocytic lymphoma; Waldenström’s macroglobulinemia; marginal zone lymphoma requiring systemic therapy and who have received at least one prior anti-CD20-directed therapy.

Treatment of patients with chronic graft-versus-host disease who have received at least one prior systemic therapy.

ICD codes

Dosage Regimen

Take orally, once daily at approximately the same time each day. Swallow capsules whole with a glass of water; do not open, break, or chew.

Administer with food to improve bioavailability. Avoid grapefruit, Seville oranges, and their juices during treatment.

The standard adult dose for mantle cell lymphoma and marginal zone lymphoma is 560 mg (four 140 mg capsules) once daily.

The standard adult dose for chronic lymphocytic leukemia, small lymphocytic lymphoma, and Waldenström’s macroglobulinemia is 420 mg (three 140 mg capsules) once daily.

The standard adult dose for chronic graft-versus-host disease is 420 mg once daily.

Continue treatment until disease progression or unacceptable toxicity occurs.

For moderate or severe hepatic impairment (Child-Pugh class B or C), reduce the dose. Do not use in severe hepatic impairment (Child-Pugh class C).

For patients taking concomitant moderate CYP3A inhibitors, reduce the dose. Avoid concomitant use with strong CYP3A inhibitors.

Manage toxicity using dose interruptions and/or dose reductions. For non-hematologic toxicities, interrupt dosing until resolution; may restart at the same or reduced dose. For hematologic toxicities, interrupt dosing; may restart at the same or reduced dose, or consider blood product support.

Suspend therapy for 3 to 7 days before and after surgical procedures, depending on the type of surgery and bleeding risk.

Adverse Reactions

Infections and infestations : very common – pneumonia, upper respiratory tract infections, sinusitis, skin infections; common – sepsis, urinary tract infections; uncommon – reactivation of hepatitis B.

Benign and malignant neoplasms (including cysts and polyps): common – non-melanoma skin cancer, basal cell carcinoma, squamous cell carcinoma.

Blood and lymphatic system disorders: very common – neutropenia, thrombocytopenia; common – febrile neutropenia, leukocytosis, lymphocytosis; uncommon – leukostasis.

Immune system disorders: common – interstitial lung disease.

Metabolism and nutrition disorders: common – tumor lysis syndrome, hyperuricemia; possible – hypokalemia.

Nervous system disorders: very common – headache; common – peripheral neuropathy, dizziness.

Eye disorders: common – blurred vision.

Cardiac disorders: very common – bleeding, bruising; common – atrial fibrillation, ventricular tachyarrhythmia, arterial hypertension.

Vascular disorders: common – subdural hematoma, epistaxis, petechiae.

Gastrointestinal disorders: very common – diarrhea, vomiting, stomatitis, nausea, constipation; common – dry mouth.

Hepatobiliary disorders: frequency unknown – hepatic failure.

Skin and subcutaneous tissue disorders: common – urticaria, erythema, onychoclasis; uncommon – angioedema; frequency unknown – Stevens-Johnson syndrome.

Respiratory, thoracic and mediastinal disorders: possible – cough, dyspnea.

Musculoskeletal and connective tissue disorders: very common – arthralgia, muscle spasms, musculoskeletal pain.

Contraindications

Hypersensitivity (e.g., with anaphylactic and anaphylactoid reactions) to ibrutinib; severe renal impairment; severe hepatic impairment (Child-Pugh class C); patients on dialysis; concomitant use with potent inducers of the CYP3A isoenzyme (e.g., carbamazepine, rifampicin, phenytoin and preparations containing St. John’s wort extract); concomitant use with warfarin, other vitamin K antagonists, fish oil and vitamin E preparations; pregnancy; breastfeeding; children and adolescents under 18 years of age.

With caution

Patients requiring anticoagulants (except warfarin and other vitamin K antagonists, concomitant use of which should be excluded) or drugs that inhibit platelet function.

Concomitant use with potent and moderate inhibitors of the CYP3A isoenzyme.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindication: severe renal impairment; severe hepatic impairment (Child-Pugh class C).

Use in Renal Impairment

In patients with mild or moderate renal impairment (creatinine clearance more than 30 ml/min), dose adjustment is not required. Currently, there are no data for patients with severe renal impairment or on dialysis.

Contraindication: severe renal impairment, patients on dialysis.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

The need for dose adjustment depending on age has not been confirmed.

Special Precautions

The risk is higher with concomitant use of anticoagulants than with antiplatelet agents. The risk and benefit of using anticoagulants or antiplatelet agents in combination with Imbruvica should be assessed.

During treatment, it is necessary to promptly monitor for symptoms of bleeding, infections (fever, chills, weakness, confusion, vomiting and jaundice), and provide appropriate therapy as indicated; perform a complete blood count monthly; manifestations of tumor lysis syndrome; consider the risk of developing non-melanoma skin malignancies.

Cases of interstitial lung disease have been reported in patients receiving Ibrutinib. Patients should be monitored for pulmonary symptoms suggestive of interstitial lung disease. If such symptoms develop, ibrutinib therapy should be suspended and appropriate treatment initiated. If symptoms of this disease persist, the benefit and risk of ibrutinib therapy should be assessed and the instructions for its dose adjustment should be followed.

The use of dietary supplements such as fish oil and vitamin E is contraindicated.

Ibrutinib therapy should be suspended for 3 to 7 days before and after surgery, depending on the type of surgery and the risk of bleeding.

Isolated cases of leukostasis have been reported in patients taking Ibrutinib. A high number of circulating lymphocytes (>400000/µl) may increase the risk of leukostasis. In such cases, temporary suspension of therapy should be considered. Patients should be closely monitored. Supportive care, including hydration and/or cytoreduction, should be provided as indicated.

Patients should be periodically monitored for cardiac arrhythmias. The health status of patients who develop arrhythmic symptoms (e.g., palpitations, presyncopal dizziness, syncope, chest discomfort, or new-onset dyspnea) should be assessed (including ECG as indicated). In case of persistent cardiac arrhythmia, the benefit/risk ratio of ibrutinib therapy should be assessed, and the dose should be adjusted if necessary.

When considering the use of ibrutinib in patients at risk of more pronounced shortening of the QTc interval (e.g., congenital short QT syndrome or a family history of this syndrome), the results of the clinical assessment of the patient’s health status should be followed.

Effect on ability to drive and operate machinery

Fatigue, dizziness, and asthenia have been reported in patients receiving Ibrutinib. This should be taken into account when assessing the patient’s ability to drive vehicles and operate machinery.

Drug Interactions

Concomitant use of ibrutinib and potent inhibitors of the CYP3A4 isoenzyme should be avoided, as these drugs can increase the concentration of ibrutinib.

If a moderate inhibitor of the CYP3A4 isoenzyme (e.g., fluconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, diltiazem, fosamprenavir, imatinib, verapamil, amiodarone, dronedarone) is indicated, the dose of ibrutinib should be reduced according to the dose adjustment recommendations.

No dose adjustment is required when ibrutinib is co-administered with a weak inhibitor of the CYP3A4 isoenzyme. Careful monitoring for manifestations of toxicity in patients should be ensured, and its dose should be adjusted if necessary.

During ibrutinib therapy, consumption of grapefruit and Seville oranges should be avoided, as these fruits contain moderate inhibitors of the CYP3A4 isoenzyme.

As a result of concomitant use of ibrutinib with potent inducers of the CYP3A4 isoenzyme, the decrease in ibrutinib plasma concentration can be up to 90%.

Concomitant use of ibrutinib with potent inducers of the CYP3A4 isoenzyme (e.g., carbamazepine, rifampicin, phenytoin and preparations containing St. John’s wort extract) should be avoided. The possibility of using alternative drugs with less inducing activity on the CYP3A4 isoenzyme should be considered.

Systemic interaction of ibrutinib with drugs that are substrates of P-glycoprotein is not expected. However, the possibility of inhibition of the intestinal form of P-glycoprotein and BCRP by ibrutinib after oral administration at therapeutic doses cannot be ruled out. Currently, there are no clinical data. To reduce the possibility of interaction in the gastrointestinal tract, substrates of P-glycoprotein or BCRP with a narrow therapeutic index (e.g., digoxin or methotrexate) should be taken at least 6 hours before or after taking ibrutinib.

Ibrutinib may also systemically inhibit BCRP and increase the concentration of drugs that undergo BCRP-mediated hepatic efflux (e.g., rosuvastatin).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°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.