Imbruvica (Capsules) Instructions for Use

Marketing Authorization Holder

Johnson & Johnson, LLC (Russia)

Manufactured By

Catalent CTS LLC (USA)

Or

Cilag, AG (Switzerland)

Primary Packaging

CILAG, AG (Switzerland)

Packaging and Quality Control Release

CILAG, AG (Switzerland)

Or

PHARMSTANDARD-UfaVITA, JSC (Russia)

Contact Information

JANSSEN, pharmaceutical division of Johnson & Johnson LLC

ATC Code

L01EL01 (Ibrutinib)

Active Substance

Ibrutinib (Rec.INN registered by WHO)

Dosage Form

Imbruvica

Capsules 140 mg: 90 or 120 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size No. 0, white body and cap with black ink inscription “ibr 140 mg” on the cap; capsule contents – powder from white to almost white.

Excipients: microcrystalline cellulose – 151.4 mg, croscarmellose sodium – 23 mg, sodium lauryl sulfate – 14 mg, magnesium stearate – 1.6 mg; capsule: titanium dioxide, gelatin, Opacode^® S-1-17822 and Opacode^® S-1-17823 ink; ink composition: pharmaceutical glaze (shellac solution in ethanol), black iron oxide dye, n-butanol, 2-propanol, ammonium hydroxide 28%, propylene glycol.

90 pcs. – high-density polyethylene bottles (1) – cardboard packs.
120 pcs. – high-density polyethylene bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agents, protein kinase inhibitors

Pharmacological Action

Mechanism of action

Ibrutinib is a potent 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.

Inhibition of BTK by ibrutinib increases the dependence of CLL cells on BCL-2, a cell survival signaling pathway, while venetoclax inhibits BCL-2, leading to apoptosis. In preclinical tumor models, the combination of ibrutinib and venetoclax resulted in enhanced cellular apoptosis and antitumor activity compared to either drug used as monotherapy.

Lymphocytosis

At the beginning of therapy, most patients (66%) with chronic lymphocytic leukemia/small lymphocytic lymphoma receiving Imbruvica monotherapy experienced a reversible increase in lymphocyte count (i.e., by 50% or more from baseline with absolute values of 5000/µL or more), often accompanied by a decrease in lymphadenopathy. This effect was also observed in some patients (35%) with mantle cell lymphoma receiving Imbruvica. The observed lymphocytosis is a reflection of the pharmacodynamic effect and should not be considered as disease progression in the absence of other clinical manifestations. In both diseases, lymphocytosis usually develops within the first months of treatment with Imbruvica and usually resolves with a median of 8 and 14 weeks in patients with relapsed or refractory mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, respectively (lymphocytosis resolution time values ranged from 0.1 to 104 weeks).

When using Imbruvica in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma as part of combination therapy with bendamustine and rituximab or with obinutuzumab, lymphocytosis was rare (in 7% of patients in the Imbruvica + bendamustine + rituximab group compared to 6% of patients in the placebo + bendamustine + rituximab group; and in 7% of patients in the Imbruvica + obinutuzumab group compared to 1% of patients in the chlorambucil and obinutuzumab group). When using Imbruvica in combination with bendamustine and rituximab in patients with previously untreated mantle cell lymphoma, lymphocytosis was noted in 5% of patients in the Imbruvica + bendamustine + rituximab group compared to 4% in the placebo + bendamustine + rituximab group.

Lymphocytosis was not observed in patients with Waldenström’s macroglobulinemia receiving Imbruvica.

Platelet aggregation in vitro

In an in vitro study, Ibrutinib inhibited collagen-induced platelet aggregation in samples from a group of subjects with impaired renal function or receiving warfarin and from a group of healthy subjects. The magnitude of inhibition of collagen-induced platelet aggregation in the group of subjects taking aspirin was lower, as collagen-induced platelet aggregation was decreased in this group without the participation of ibrutinib. Ibrutinib did not demonstrate significant inhibition of platelet aggregation associated with 4 agonists: adenosine diphosphate (ADP), arachidonic acid, ristocetin, and thrombin receptor-activating peptide 6 (TRAP-6) in these subject groups and in healthy subjects.

Effects on QT/QT_c interval and cardiac electrophysiology

The effects of ibrutinib on the QT_c interval were evaluated in 20 healthy volunteers. At supratherapeutic doses (1680 mg), Ibrutinib did not increase the QT_c interval to a clinically significant extent. The highest value of the upper bound of the two-sided 90% confidence interval for the mean difference between ibrutinib and placebo was less than 10 ms. A concentration-dependent decrease in the QT_c interval was also observed (-5.3 ms; 90% CI from -9.4 ms to -1.1 ms at C_max 719 ng/mL after taking a supratherapeutic dose of 1680 mg), which was not clinically significant.

Pharmacokinetics

Absorption

Ibrutinib is rapidly absorbed after oral administration with a median time to maximum concentration (T_max) of 1-2 hours. The absolute bioavailability on an empty stomach (n=8) was 2.9% (90% CI for values 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 exposure of ibrutinib in plasma increases with increasing dose up to 840 mg. The equilibrium AUC value 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 reaction – 1159±583 ng×h/mL. Taking ibrutinib on an empty stomach led to a decrease in its exposure (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.

Distribution

Reversible binding of ibrutinib to human plasma proteins in vitro was 97.3%, with no concentration dependence in the range from 50 to 1000 ng/mL. V_d was 683 L, and the apparent volume of distribution at steady state (V_d,ss/F) is about 10000 L.

Metabolism

Ibrutinib is metabolized primarily by the CYP3A4/5 isoform of cytochrome P450 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 parent drug.

According to in vitro studies, the participation of the CYP2D6 isoenzyme in the oxidative metabolism of ibrutinib is less than 2%. Furthermore, according to a human mass balance study, the pharmacokinetic profile in patients with low and high activity of the CYP2D6 isoenzyme (based on genotyping) was similar. Thus, no precautions are required in patients with different CYP2D6 isoenzyme genotypes.

Excretion

Clearance after intravenous administration was 62 and 76 L/h, on an empty stomach and after meals, respectively. Due to a strong first-pass effect, the apparent clearance after oral administration is 2000 and 1000 L/h, on an empty stomach and after meals, respectively.

T_1/2 of ibrutinib is 4-6 hours.

After a single oral dose of [¹⁴C]-ibrutinib (radiolabeled) in healthy volunteers, approximately 90% of radioactive substances were excreted within 168 hours, most (80%) were eliminated through the intestine, and less than 10% – by the kidneys. Unchanged Ibrutinib accounted for about 1% of excretion products in feces and was absent in urine, the remainder being metabolites.

Pharmacokinetics in special patient groups

Elderly patients (65 years and older). According to the results of a population pharmacokinetic analysis, an increase in ibrutinib exposure of 14% is expected in elderly patients (from 67 to 81 years). The need for dose adjustment depending on age has not been confirmed.

Children and adolescents (18 years and younger). No pharmacokinetic studies of Imbruvica have been conducted in patients under 18 years of age.

Gender. The results of population pharmacokinetic analysis indicate no significant effect of gender on the clearance of ibrutinib from the bloodstream.

Patients with impaired renal function. Renal clearance of ibrutinib is minimal; excretion of metabolites in urine is less than 10% of the dose. No specific clinical studies have been conducted to date in patients with impaired renal function. In patients with mild or moderate renal impairment (creatinine clearance greater than 30 mL/min), dose adjustment is not required. There are currently no data for patients with severe renal impairment or on dialysis.

Patients with impaired hepatic function. Ibrutinib is metabolized in the liver. A study was conducted in patients with impaired hepatic function without malignancies taking Imbruvica on an empty stomach at a dose of 140 mg. The AUC_last of ibrutinib increased by 2.7, 8.2, and 9.8 times in patients with mild (n=6, Child-Pugh class A), moderate (n=10, Child-Pugh class B), and severe (n=8, Child-Pugh class C) hepatic impairment, respectively. The exposure of the free fraction of ibrutinib also increases with increasing degree of hepatic impairment, amounting to 3.0%, 3.8%, and 4.8% in patients with mild, moderate, and severe hepatic impairment, respectively. In healthy volunteers, the free fraction is 3.3%. The exposure of unbound ibrutinib (AUC_unbound,last) increases approximately 4.1, 9.8, and 13 times in patients with mild, moderate, and severe hepatic impairment, respectively.

Indications

• For the treatment of adult patients with relapsed or refractory mantle cell lymphoma;
• For the treatment of adult patients with chronic lymphocytic leukemia/small lymphocytic lymphoma;
• For the treatment of adult patients with Waldenström’s macroglobulinemia;
• For the treatment of patients with marginal zone lymphoma who require systemic therapy and who have received at least one prior anti-CD20-directed therapy;
• For the treatment of patients with chronic graft-versus-host reaction who have received at least 1 prior line of systemic therapy.

ICD codes

Dosage Regimen

Orally.

Imbruvica should be taken once daily with a glass of water, at approximately the same time each day. Capsules must be swallowed whole with water. Do not open, break, or chew the capsules. Imbruvica should not be taken with grapefruit juice.

Imbruvica should be continued until disease progression or until the patient can no longer tolerate therapy.

Patients with relapsed or refractory mantle cell lymphoma or patients with marginal zone lymphoma who require systemic therapy

The recommended dose of Imbruvica for the treatment of patients with relapsed or refractory mantle cell lymphoma or patients with marginal zone lymphoma who require systemic therapy is 560 mg (4 capsules of 140 mg) once daily until disease progression or until the patient can no longer tolerate therapy. In mantle cell lymphoma, Imbruvica can be prescribed in combination with bendamustine and rituximab in patients with previously untreated mantle cell lymphoma, or as monotherapy in patients with relapsed or refractory mantle cell lymphoma. Additional information on bendamustine and rituximab can be found in the respective prescribing information.

Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma or patients with Waldenström’s macroglobulinemia

The recommended dose of Imbruvica for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma is 420 mg (3 capsules of 140 mg) once daily. In chronic lymphocytic leukemia/small lymphocytic lymphoma (as monotherapy or in combination with anti-CD20-directed therapy (with rituximab or with obinutuzumab) or in combination with bendamustine and rituximab) in patients with relapsed or refractory lymphocytic leukemia/small lymphocytic lymphoma and Waldenström’s macroglobulinemia (as monotherapy or in combination with rituximab), Imbruvica can be prescribed until disease progression or until the patient can no longer tolerate therapy. In combination with venetoclax, Imbruvica should be prescribed as monotherapy for 3 cycles (1 cycle is 28 days), followed by 12 cycles of therapy with Imbruvica in combination with venetoclax.

Additional information on bendamustine, rituximab, obinutuzumab, and venetoclax can be found in the respective prescribing information.

When used in combination with anti-CD20-directed therapy, it is recommended to take Imbruvica before anti-CD20-directed therapy if they are administered on the same day.

Chronic graft-versus-host reaction

The recommended dose of Imbruvica for the treatment of chronic graft-versus-host reaction is 420 mg (3 capsules of 140 mg) once daily until disease progression, relapse of the underlying malignancy, or until the patient can no longer tolerate therapy.

When the patient no longer requires therapy for chronic graft-versus-host reaction, Imbruvica should be discontinued based on clinical assessment of the patient’s condition.

Dose adjustment

Dose adjustment is required when co-administered with moderate or potent inhibitors of the CYP3A isoenzyme, as exposure to ibrutinib may increase (see section “Drug Interactions”).

In case of development or worsening of toxicities associated with heart failure of grade 2 or cardiac arrhythmia of grade 3, non-hematological toxicity of grade 3 and above, neutropenia of grade 3 and above with infection or fever, or hematological toxicity of grade 4, therapy with Imbruvica should be interrupted.

After the clinical manifestations of toxicity have decreased to grade 1 or to the baseline value (i.e., resolution is achieved), therapy with Imbruvica should be resumed at the recommended dose as indicated in the tables below. Recommended dose adjustments for toxicities not associated with heart failure are described in Table 1.

Table 1. Recommendations for dose adjustment of Imbruvica (toxicities not associated with heart failure)

* The risk-benefit ratio should be assessed before resuming therapy.

Missed Dose

If a dose of Imbruvica is missed on the scheduled day, it can be taken as soon as possible on the same day, with a return to the regular dosing schedule the following day. Do not take additional capsules to make up for missed doses.

Special Patient Groups

Children and adolescents (18 years and younger). The safety and efficacy of Imbruvica in children have not been evaluated.

Patients with renal impairment. Ibrutinib is characterized by minimal renal clearance. Separate clinical studies in patients with renal impairment have not been conducted. However, patients with mild and moderate renal impairment were included in the clinical studies of Imbruvica. For patients with mild and moderate renal impairment (CrCl >30 ml/min), no dose adjustment is required. Adequate hydration should be ensured, and serum creatinine levels should be measured regularly. Data are not available for patients with severe renal impairment or for patients on dialysis.

Patients with hepatic impairment. Ibrutinib is metabolized in the liver. According to a clinical study, patients with hepatic impairment showed increased blood concentrations of ibrutinib. For patients with mild hepatic impairment (Child-Pugh class A), the recommended dose is 280 mg/day (2 capsules). For patients with moderate hepatic impairment (Child-Pugh class B), the recommended dose is 140 mg/day (1 capsule). Patients should be closely monitored for signs of toxicity, and dose adjustments should be made if necessary. The use of Imbruvica is not recommended in patients with severe hepatic impairment (Child-Pugh class C).

Adverse Reactions

Data on adverse effects are based on data obtained during clinical studies and in the post-marketing period.

The most frequently observed adverse effects (≥20%) are: diarrhea, neutropenia, rash, musculoskeletal pain, bleeding (e.g., bruising), nausea, thrombocytopenia, arthralgia, upper respiratory tract infections, and pyrexia. The most frequently observed Grade 3 and 4 adverse effects (≥5%) are: neutropenia, lymphocytosis, thrombocytopenia, pneumonia, arterial hypertension, and rash.

Treatment-emergent adverse reactions in patients with B-cell malignancies and adverse reactions noted in the post-marketing period are presented in the table below according to the system organ class and frequency of occurrence. The frequency of adverse effects is defined as follows: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), and frequency not known (cannot be estimated from the available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Table 3. Treatment-emergent adverse reactions in patients with B-cell malignancies and adverse reactions noted in the post-marketing period

¹– includes multiple adverse reaction terms
² – includes fatal outcomes
³ – low-level term selected
⁴ – spontaneous reports during the post-marketing period
⁵ – frequency calculated using monotherapy clinical trial data

Table 4. Adverse reactions reported at a frequency of ≥10% in clinical studies in patients with chronic graft-versus-host disease

* – includes multiple adverse reaction terms

Discontinuation of therapy and dose reduction due to adverse effects

Among patients receiving Imbruvica therapy for B-cell malignancies, approximately 8% discontinued therapy due to adverse effects. These adverse effects included pneumonia, rash, atrial fibrillation, neutropenia, thrombocytopenia, bleeding, and diarrhea.

Adverse effects leading to dose reduction were observed in approximately 10% of patients.

Elderly patients

Among patients receiving Imbruvica therapy, 55% were 65 years of age and older. In this patient group, Grade 3 and higher pneumonia (14% of patients aged 65 and older compared to 4% of younger patients) and thrombocytopenia (12% of patients aged 65 and older compared to 5% of younger patients) were more frequently reported.

Contraindications

• Hypersensitivity (e.g., with anaphylactic and anaphylactoid reactions) to ibrutinib or to any of the excipients of the drug;
• 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 (Hypericum perforatum) extract);
• Concomitant use with warfarin, other vitamin K antagonists, fish oil, and vitamin E preparations;
• Pregnancy;
• Breastfeeding period;
• Children and adolescents under 18 years of age (efficacy and safety have not been established).

With caution

Imbruvica should be used with caution in patients requiring anticoagulants (except for warfarin and other vitamin K antagonists, concomitant use of which should be avoided) or drugs that inhibit platelet function.

Imbruvica should be used with caution in case of concomitant use with potent and moderate inhibitors of the CYP3A isoenzyme.

Use in Pregnancy and Lactation

Pregnancy

There are no controlled studies of Imbruvica in pregnant women to date. Based on animal studies, Imbruvica may cause harm to the fetus when administered to pregnant women.

Imbruvica is contraindicated for use during pregnancy. Women of childbearing potential should use highly effective methods of contraception while taking Imbruvica. Pregnancy should be avoided during Imbruvica therapy and for 1 month after the end of therapy. If a patient becomes pregnant during therapy, she should be warned of the potential risk to the fetus. The period of time after completion of Imbruvica therapy after which a woman can become pregnant without any harm to the fetus is currently unknown.

Men should avoid fathering a child and donating sperm during Imbruvica therapy and for 3 months after its completion.

The effects of ibrutinib on embryo-fetal development were studied in pregnant rats given the drug orally at doses of 10, 40, and 80 mg/kg/day. Administration of ibrutinib at a dose of 80 mg/kg/day (approximately 14 times the AUC of ibrutinib and 9.5 times the AUC of the dihydrodiol metabolite compared to the corresponding values in patients receiving the drug at a dose of 560 mg/day) was accompanied by an increase in post-implantation fetal loss and an increase in the number of internal organ (heart and great vessels) developmental abnormalities. Ibrutinib at doses of 40 mg/kg/day and higher (approximately ≥5.6 times the AUC of ibrutinib and approximately 4 times the AUC of the dihydrodiol metabolite compared to patients receiving treatment at a dose of 560 mg/day) caused a decrease in fetal weight.

Ibrutinib was also administered orally to pregnant rabbits during the period of organogenesis at doses of 5, 15, and 45 mg/kg/day. When administered at doses of 15 mg/kg/day and higher, Ibrutinib caused skeletal malformations (fusion of sternal segments), and when administered at a dose of 45 mg/kg/day, Ibrutinib increased the incidence of post-implantation fetal death. Ibrutinib caused fetal malformations in rabbits when administered at a dose of 15 mg/kg/day (with blood concentrations of ibrutinib approximately 2 times higher than those in patients with mantle cell lymphoma or marginal zone lymphoma taking Ibrutinib at a dose of 560 mg/day, and approximately 2.8 times higher than the blood concentrations of ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma or Waldenström’s macroglobulinemia taking Ibrutinib at a dose of 420 mg/day).

Breastfeeding period

It is currently unknown whether Ibrutinib or its metabolites are excreted in human breast milk. Since many drugs are excreted in human breast milk and due to the potential for serious adverse reactions in breastfed infants, breastfeeding should be discontinued during Imbruvica therapy.

Use in Hepatic Impairment

Patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment should be closely monitored for signs of toxicity and, if necessary, the dose should be adjusted.

The use of the drug is contraindicated in severe hepatic impairment (Child-Pugh class C).

Use in Renal Impairment

In patients with mild and moderate renal impairment (CrCl greater than 30 ml/min), no dose adjustment is required.

The use of the drug is contraindicated in severe renal impairment and in patients on dialysis.

Pediatric Use

The use of the drug is contraindicated 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

Hemorrhagic complications

There have been reports of hemorrhagic complications in patients receiving Imbruvica, with and without thrombocytopenia. They included both minor bleeding, such as bruising, epistaxis, and petechiae, and major bleeding (some of which were fatal), including gastrointestinal bleeding, intracranial hemorrhage, and hematuria.

In an in vitro platelet function study, Ibrutinib inhibited collagen-induced platelet aggregation. The use of anticoagulants or antiplatelet agents concomitantly with Imbruvica increases the risk of major bleeding. The risk is higher with concomitant use of anticoagulants than with antiplatelet agents. The risk and benefit of using anticoagulants or antiplatelet agents concomitantly with Imbruvica should be assessed. Signs and symptoms of bleeding should be monitored.

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

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

Patients with congenital hemorrhagic diathesis were not included in the studies.

Leukostasis

Isolated cases of leukostasis have been reported in patients taking Imbruvica. A high number of circulating lymphocytes (>400,000/µl) may increase the risk of leukostasis. In such cases, temporary interruption of Imbruvica therapy should be considered. Patients should be closely monitored. Supportive care, including hydration and/or cytoreduction, should be provided as indicated.

Infections

Cases of infections (including sepsis, bacterial, viral, or fungal infections) have been reported in patients taking Imbruvica. Some of these infections required hospitalization or were fatal. Prophylaxis against infections should be considered according to standard of care in patients at increased risk of opportunistic infections. Cases of progressive multifocal leukoencephalopathy and reactivation of hepatitis B of unknown origin have been reported in patients receiving Imbruvica therapy.

Cases of hepatitis E, which can be chronic, have also been observed.

Patients should be monitored for signs and symptoms of infection (such as fever, chills, weakness, confusion, vomiting, jaundice, and abnormal liver function biochemistry), and appropriate therapy should be initiated as indicated.

Cytopenias

Cases of cytopenias (neutropenia, thrombocytopenia, and anemia) have been reported in patients taking Imbruvica. A complete blood count should be performed monthly.

Interstitial lung disease (ILD)

Cases of ILD have been reported in patients taking Imbruvica. Patients should be monitored for pulmonary symptoms suggestive of ILD. If such symptoms develop, Imbruvica therapy should be interrupted and appropriate therapy for ILD should be initiated. If ILD symptoms persist, the benefit and risks of Imbruvica therapy should be assessed and the dose adjustment instructions should be followed.

Cardiac arrhythmias and heart failure

Fatal and serious arrhythmias or heart failure have been observed in patients taking Imbruvica. Patients with significant pre-existing cardiac conditions may be at greater risk for adverse events, including fatal sudden cardiac events. Atrial fibrillation, atrial flutter, ventricular tachyarrhythmias, and heart failure have been reported, particularly in patients with acute infections or with risk factors for cardiac events, including hypertension, diabetes, and a history of cardiac arrhythmias. Before starting Imbruvica, an appropriate clinical assessment of medical history and cardiac function should be performed. Patients should be closely monitored during treatment for signs of clinical deterioration of cardiac function and should be under clinical supervision. Further evaluation (e.g., ECG, echocardiogram) should be considered as indicated for patients with cardiovascular problems. For signs and symptoms that persist, the benefit/risk ratio of Imbruvica therapy should be assessed, and the dose should be adjusted if necessary.

Effects on QT interval

In clinical studies, Imbruvica caused a slight shortening of the QTcF interval (on average by 7.5 msec). The mechanism underlying this phenomenon and its significance for drug safety are unknown. When considering the possibility of prescribing ibrutinib to patients at risk of more pronounced QTc shortening (e.g., congenital short QT syndrome or a family history of this syndrome), the results of the clinical assessment of the patient’s health should be taken into account.

Tumor lysis syndrome

Tumor lysis syndrome has been reported during Imbruvica therapy. The risk of tumor lysis syndrome is present in patients who had a high tumor burden prior to initiation of therapy. Patients should be closely monitored and appropriate precautions should be taken.

Non-melanoma skin cancers

Non-melanoma skin cancers have been reported in patients receiving Imbruvica therapy. Patients should be closely monitored for the occurrence of non-melanoma skin cancers.

Hypertension

Hypertension has been reported in patients receiving Imbruvica therapy. Blood pressure should be measured regularly in patients during Imbruvica therapy, and antihypertensive therapy should be initiated or adjusted as necessary.

Effect on ability to drive and use machines

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

Overdose

Data on overdose with Imbruvica are limited. In a Phase I study in which patients received the drug at doses up to 12.5 mg/kg/day (1400 mg), the maximum tolerated dose was not reached.

There is no specific antidote for Imbruvica. Close monitoring of patients who have taken a dose higher than recommended and appropriate supportive care are necessary.

Drug Interactions

Ibrutinib metabolism primarily involves the CYP3A4 isoenzyme.

Drugs That Can Increase Ibrutinib Plasma Concentration

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

Potent CYP3A4 Isoenzyme Inhibitors

Concomitant administration of ketoconazole (a potent CYP3A4 isoenzyme inhibitor) with ibrutinib in 18 healthy volunteers resulted in an increase in ibrutinib exposure (C_max and AUC_0-last) by 29-fold and 24-fold, respectively. In a drug-drug interaction study in patients with B-cell malignancies, concomitant use with voriconazole increased the C_max and AUC of ibrutinib by 6.7-fold and 5.7-fold, respectively. In clinical studies, the maximum observed concentration (AUC) of ibrutinib in 37 patients receiving mild and/or moderate CYP3A4 isoenzyme inhibitors was at most 2 times higher than the corresponding concentration in 76 patients who did not receive concomitant CYP3A4 isoenzyme inhibitor therapy. Based on a review of clinical safety data in 66 patients receiving moderate (n=47) or potent (n=19) CYP3A4 isoenzyme inhibitors, no significant increase in toxicity was detected. Voriconazole and posaconazole may be used concomitantly with Imbruvica, provided the dosing recommendations specified in Table 5 are followed. Concomitant use of ibrutinib with all other potent CYP3A4 isoenzyme inhibitors (e.g., ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazodone, and cobicistat) should be avoided, and the use of alternative drugs with less CYP3A4 isoenzyme inhibitory potential should be considered. If the potential benefit outweighs the possible risk and the use of a potent CYP3A4 isoenzyme inhibitor is necessary, the dose adjustment recommendations provided in Table 5 should be followed.

Moderate and Weak CYP3A4 Isoenzyme Inhibitors

In patients with B-cell malignancies, concomitant use with the CYP3A4 isoenzyme inhibitor erythromycin increased the C_max and AUC of ibrutinib by 3.4-fold and 3.0-fold, respectively. If the use of a moderate CYP3A4 isoenzyme inhibitor is indicated (e.g., fluconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, diltiazem, fosamprenavir, imatinib, verapamil, amiodarone, dronedarone), the dose of Imbruvica should be reduced according to the dose adjustment recommendations provided in Table 5.

No dose adjustment is required when ibrutinib is used concomitantly with a weak CYP3A4 isoenzyme inhibitor. Patients should be closely monitored for manifestations of toxicity, and dose adjustment should be performed as needed according to the instructions. During therapy with Imbruvica, consumption of grapefruit and Seville oranges should be avoided, as these fruits contain moderate inhibitors of the CYP3A4 isoenzyme.

Table 5. Dose Adjustment Recommendations

* Patients should be monitored for adverse reactions to Imbruvica and therapy should be interrupted or dose adjusted if necessary.

** Posaconazole at a dose of 200 mg oral suspension three times daily or 400 mg oral suspension twice daily; 300 mg as intravenous injections once daily; 300 mg oral extended-release tablets once daily.

After discontinuation of the CYP3A4 isoenzyme inhibitor, Imbruvica therapy is continued at the original dose.

Drugs That Can Decrease Ibrutinib Plasma Concentration

As a result of concomitant use of Imbruvica 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 (Hypericum perforatum) extract) should be avoided. The use of alternative drugs with less inducing activity on the CYP3A4 isoenzyme should be considered.

Drugs Whose Plasma Concentration May Be Altered by Ibrutinib

Based on in vitro studies, Ibrutinib is a weak reversible inhibitor of the CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 isoenzymes and does not show time-dependent inhibition of CYP450. The dihydrodiol metabolite of ibrutinib is a weak inhibitor of the CYP2B6, CYP2C8, CYP2C9, and CYP2D6 isoenzymes. Both Ibrutinib and its dihydrodiol metabolite exhibited no more than a weak inducing effect on CYP450 isoenzyme activity in vitro. However, in a drug interaction study in patients with B-cell malignancies, a single 560 mg dose of Ibrutinib did not have a clinically significant effect on the concentration of the CYP3A4 isoenzyme substrate midazolam. In the same study, therapy with ibrutinib at a dose of 560 mg daily for 2 weeks did not have a clinically significant effect on the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel), the CYP3A4 isoenzyme substrate midazolam, and the CYP2B6 substrate bupropion.

Based on in vitro studies, Ibrutinib is not a substrate of P-glycoprotein or other major transporters, except for OCT2. The dihydrodiol metabolite and other metabolites are substrates of P-glycoprotein. Ibrutinib is a weak inhibitor of P-glycoprotein and the breast cancer resistance protein (BCRP). Systemic interaction of ibrutinib with drugs that are substrates of P-glycoprotein is not expected. However, the possibility of ibrutinib inhibiting the intestinal form of P-glycoprotein and BCRP after administration of the drug at therapeutic doses cannot be excluded. Currently, there are no clinical data. To reduce the possibility of gastrointestinal interaction, 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 Imbruvica. Ibrutinib may also systemically inhibit BCRP and increase the concentration of drugs that undergo BCRP-mediated hepatic efflux (e.g., rosuvastatin).

Storage Conditions

The drug does not require special storage conditions. Keep out of reach of children.

Shelf Life

The shelf life is 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

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.