Imbruvica capsules 140 mg, 90 pcs.

Pharmgroup: Antitumor drug. Protein tyrosine kinase inhibitor.
Pharmacological effect: Ibrutinib is a potent low molecular weight inhibitor of Bruton tyrosine kinase (TKB). Ibrutinib forms a covalent bond with the cysteine residue (Cys481) in the active center of TKB, resulting in persistent inhibition of enzymatic activity. TKB, which is a member of the Tss kinase family, acts as an important signaling molecule in metabolic pathways related to the signaling activity of B-cell antigen receptors (BCRs) and cytokine receptors. The BCR signaling pathway has been implicated in the pathogenesis of several B-cell malignancies, including mantle cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, and B-cell chronic lymphocytic leukemia. The key role of TCB 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 the results of preclinical studies ibrutinib inhibits proliferation and survival of malignant B-cells in vivo, as well as cell migration and adhesion to substrates in vitro.
Lymphocytosis.
At the beginning of therapy, the majority of patients (75%) with chronic lymphocytic leukemia treated with Imbruvik showed a reversible increase in lymphocyte count (i.e., by 50% or more from baseline with absolute values above 5000/μL), often accompanied by a reduction in lymphadenopathy. This effect was also observed in some patients (35%) with relapsed or refractory mantle cell lymphoma treated with Imbruvic. The observed lymphocytosis is a reflection of the pharmacodynamic effect and should not be regarded as disease progression in the absence of other clinical manifestations. In both diseases, lymphocytosis usually develops within the first few weeks of treatment with Imbruvic (median 1.1 weeks) and usually resolves with median 8.0 and 18.7 weeks in patients with relapsed or refractory mantle cell lymphoma and chronic lymphocytic leukemia, respectively.
A significant increase in the number of circulating lymphocytes (i.e. over 400,000/μL) was observed in some patients.
Pharmacokinetics: Absorption.
Ibrutinib is rapidly absorbed after oral administration with a median time to maximum concentration (Tmax) of 1-2 hours. There are no significant differences in the pharmacokinetics of ibrutinib in patients with various B-cell malignancies. The plasma concentration of ibrutinib increases proportionally with increasing dose up to 840 mg. The equilibrium value of the area under the concentration-time curve (AUC) in patients at a dose of 560 mg is 953±705 ng×h/mL (mean ± standard deviation). Administration with food leads to an increase in ibrutinib concentration by approximately 2-fold compared to fasting (without food from the previous evening).
Distribution.
Reversible binding of ibrutinib to human plasma proteins was 97.3%, with no concentration dependence in the concentration range of 50 to 1000 pg/ml. The apparent equilibrium volume of distribution (Vd,ss/F) is approximately 10,000 l.
Metabolism.
Ibrutinib is metabolized primarily by the CYP3A4/5 cytochrome P450 isoform to form primarily a dihydrodiol metabolite, whose inhibitory activity against TKB is approximately 15 times lower than that of ibrutinib. The systemic equilibrium concentration of the dihydrodiol metabolite is comparable to that of the parent drug. According to the results of in vitro studies, the participation of CYP2D6 isoenzyme in oxidative metabolism of ibrutinib is less than 2%. In addition, according to human mass balance studies, the pharmacokinetic profile in patients with weak and high CYP2D6 isoenzyme activity (according to genotyping data) was similar. Thus, no precautions are required in patients with different CYP2D6 isoenzyme genotypes.
Excretion.
Observed clearance (CL/F) is approximately 1000 l/h. The half-life of ibrutinib is 4-6 hours.
After a single oral administration of [14C]-ibrutinib (radioactively labeled) in healthy volunteers, approximately 90% of the radioactivity was excreted within 168 hours, with most (80%) excreted through the intestine and less than 10% through the kidneys.
Unexcreted ibrutinib accounted for about 1% of the excretion products in the feces and was absent in the urine, the remainder being metabolites.
Special patient groups:
Elderly patients (65 years and older).
According to population pharmacokinetics analysis, age has no significant effect on the clearance of ibrutinib from the bloodstream.
Children (18 years and younger).
No studies of the pharmacokinetics of Imbruvic in patients younger than 18 years have been conducted.
Gender.
Results of a population-based pharmacokuetic analysis indicate no significant effect of sex on the clearance of ibrutinib from the bloodstream.
Patients with impaired renal function.
Renal clearance of ibrutinib is minimal; excretion of metabolites in the urine is less than 10% of the dose. No specific clinical studies in patients with impaired renal function have been conducted to date. No dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance greater than 30 ml/min). There are currently no data on patients with severe renal dysfunction or on dialysis.
Patients with impaired hepatic function.
Ibrutinib is metabolized in the liver. In a study in patients with impaired liver function but without malignancies, when Imbruvic was administered at a dose of 140 mg, preliminary data show a 4, 8 and 9-fold increase in ibrutinib blood concentrations in mild, moderate and severe hepatic impairment, respectively. The free fraction concentration of ibrutinib is also increased with increasing degree of hepatic impairment and is 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 concentration of unbound ibrutinib increases approximately 4.9 and 13-fold in patients with mild, moderate and severe liver dysfunction, respectively.

Indications

– Treatment of adult patients with relapsed or refractory mantle cell lymphoma;
– Treatment of adult patients with chronic lymphocytic leukemia who have received at least one line of therapy, or as first-line therapy in patients with a 17p deletion or TR53 mutation if contraindications to chemoimmunotherapy exist.

Active ingredient

Composition

Capsules Imbruvica, hard gelatin, size 0, body and cap white, with the inscription in black ink “ibr 140 mg” on the cap; capsule contents – powder of white or almost white.
1 capsule:
– ibrutinib 140 mg
Excipients: microcrystalline cellulose 151.4 mg, croscarmellose sodium 23 mg, sodium lauryl sulfate 14 mg, magnesium stearate 1.6 mg.
Capsule shell composition: titanium dioxide, gelatin.
Ink composition: Opacode® S-1-17823 (pharmaceutical glaze (shellac solution in ethanol), iron oxide black, n-butanol, 2-propanol, ammonium hydroxide 28%, propylene glycol).

How to take, the dosage

Imbruvica should be taken once a day with a glass of water at approximately the same time each day. The capsules should be swallowed whole with water; it is prohibited to open, break or chew the capsules. Imbruvica should not be drunk with grapefruit juice.
Imbruvica should be continued until the disease progresses or until the patient can no longer tolerate the therapy.
Recurrent or refractory mantle cell lymphoma:
The recommended dose of Imbruvic for therapy of recurrent or refractory mantle cell lymphoma is 560 mg (four 140 mg capsules) once daily.
Chronic lymphocytic leukemia:
The recommended dose of Imbruvic for the treatment of chronic lymphocytic leukemia is 420 mg (three 140 mg capsules) once daily.

Dose adjustment:
In case of co-administration with moderate or potent CYP3A isoenzyme inhibitors, dose adjustment is required because the concentration of ibrutinib may increase. If a patient needs to use ibrutinib together with a potent CYP3A isoenzyme inhibitor (e.g., ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole) and the possible benefits outweigh the possible risks, then the dose of Imbruvic should be reduced to 140 mg or temporarily suspended (for not more than 7 days). If co-administration of ibrutinib and a moderate CYP3A isoenzyme inhibitor (e.g., voriconazole, erythromycin, amprenavir, aprespitant, atazanavir, ciprofloxacin, crizotinib darunavir/ritonavir combination, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil) the dose of Imbruvic should be reduced to 140 mg during co-administration with a moderate CYP3A isoenzyme inhibitor.
In case of development or worsening of non-hematologic toxicity of grade 3 or higher, neutropenia of grade 3 or higher with infection or fever or hematologic toxicity of grade 4, therapy with Imbruvic should be suspended.
After clinical manifestations of toxicity decrease to grade 1 or to baseline (that is, the baseline value is achieved), resumption of Imbruvic at the original dose is allowed. In the event of a recurrence of toxicity, the dose should be reduced by one capsule (140 mg per day). If necessary, a second dose reduction of another 140 mg may be considered. In case of persistent manifestations of toxicity or their recurrence after two dose reductions, Imbruvic should be discontinued. Recommended dose adjustments for these toxicities are described in Table 1.
Table 1. Recommended dose adjustments for Imbruvic in the development of toxicity.

Skip a dose:
If the next dose of Imbruvic is not taken at the scheduled time, it is allowed to be taken as soon as possible on the same day with a return to the normal schedule of taking the drug from the next day. Additional capsules should not be taken to make up for missed doses.
Children (18 years and younger):
The safety and efficacy of Imbruvic in children has not been evaluated.
Patients with impaired renal function:
Ibrutinib has minimal renal clearance. No separate clinical studies have been conducted in patients with impaired renal function. However, patients with mild to moderate renal dysfunction participated in clinical trials of Imbruvic. No dose adjustment is required in patients with mild to moderate renal dysfunction (creatinine clearance more than 30 ml/min). There are no data on patients with severe renal dysfunction and patients on dialysis.
Patients with impaired hepatic function:
Ibrutinib is metabolized in the liver. Patients with serum aspartate transaminase (AST/CGTT) or alanine transaminase (ALT/CGTT) activity 3 or more times the upper limit of normal were excluded from clinical trials. Preliminary data from a clinical trial in patients with impaired liver function, but without malignancy, show increased blood concentrations of ibrutinib. In patients with mild to moderate hepatic impairment (Child-Pugh grades A and B) therapy should be started at 280 mg and 140 mg, respectively. Patients should be closely monitored for signs of toxicity and, if necessary, the dose should be adjusted. It is not recommended to use Imbruvica in patients with severe hepatic impairment (Child-Pugh class C).

Interaction

Drugs that may increase the plasma concentration of ibrutinib
The co-administration of Imbruvic with potent or moderate CYP3A isoenzyme inhibitors should be avoided, since these drugs may increase the concentration of ibrutinib.
Co-administration of ketoconazole (a potent CYP3A isoenzyme inhibitor) with ibrutinib in 18 healthy volunteers resulted in an increase in ibrutinib concentration (Cmax and AUCo-last) of 29 and 24 times, respectively. The maximum observed concentration of ibrutinib (AUC) in 37 patients receiving mild and/or moderate CYP3A isoenzyme inhibitors was at most 2-fold higher than the corresponding concentration in 76 patients who did not receive concomitant therapy with CYP3A isoenzyme inhibitors. According to the results of review of data on clinical safety in 66 patients who received moderate (n=47) or potent (n=19) CYP3A isoenzyme inhibitors no significant increase in toxicity was found. Co-administration of ibrutinib with potent CYP3A inhibitors (e.g., ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole) and with moderate CYP3A isoenzyme inhibitors (e.g., voriconazole, erythromycin, ampreiavir, aprenitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir combination, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil). If co-administration of ibrutinib and a potent CYP3A isoenzyme inhibitor is necessary in a patient and the possible benefit outweighs the likely risk, the dose of Imbruvic should be reduced to 140 mg or treatment should be temporarily suspended (for not more than 7 days). If co-administration of ibrutinib and a moderate CYP3A isoenzyme inhibitor is required, the dose of Imbruvic should be reduced to 140 mg while co-administration with a moderate CYP3A isoenzyme inhibitor. No dose adjustment is required when co-administering imbrutinib with a mild CYP3A isoenzyme inhibitor. Careful monitoring of toxicity in patients should be ensured, and if necessary, the dose should be adjusted according to the instructions. During therapy with Imbruvica, consumption of grapefruit and orange should be avoided because these fruits contain moderate inhibitors of CYP3A isoenzyme.
Drugs that can decrease the plasma concentration of ibrutinib
Co-administration of Imbruvica with potent CYP3A inducers has resulted in a plasma concentration decrease of about 90% of ibrutinib.
Co-administration of imbrutinib with potent CYP3A inducers (e.g. carbamazepine, rifampin, phenytoin and preparations containing Hypericum perforatum extract) should be avoided. Alternative preparations with less inducing activity against CYP3A isoenzyme should be considered.
Drugs whose plasma concentrations may be changed by ibrutinib
According to the results of in vitro studies ibrutinib is a weak inhibitor of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 isoenzymes. The dihydrodiol metabolite of ibrutinib is a weak inhibitor of the CYP2B6, CYP2C8, CYP2C9, and CYP2D6 isoenzymes. Both ibrutinib and its dihydrodiol metabolite under in vitro conditions had no more than a weak inducing effect on the activity of CYP450 isoenzymes. Thus, clinically significant interaction of Imbruvic with other drugs, metabolism of which may involve CYP450 isoenzymes, is unlikely.
According to the results of studies, imbruvitinib is not a substrate of P-glycoprotensin, but acts as its weak inhibitor. Systemic interaction of ibrutinib with drugs that are substrates of P-glycoprotein is not expected. Nevertheless, the possibility of inhibition of the intestinal form of P-glycoprotein by ibrutinib after administration of the drug at therapeutic doses cannot be excluded. No clinical data are currently available. In order to prevent potential gastrointestinal interactions, P-glycoprotein substrates with a narrow therapeutic index (e.g., digoxin) should be taken at least 6 hours before or after administration of Imbruvic.

Special Instructions

Hemorrhagic complications.
There have been reports of hemorrhagic complications in patients treated with Imbruvic with and without thrombocytopenia. These have included both minor hemorrhagic episodes, such as bruise bleeding, nasal bleeding and petechiae, and significant hemorrhagic complications, including gastrointestinal bleeding, intracranial hemorrhage and hematuria.
Patients who required therapy with warfarin or other vitamin K antagonists were excluded from phase II and III studies of Imbruvic. Warfarin and other vitamin K antagonists should not be used in combination with Imbruvic. Nutritional supplements such as fish oil and vitamin E preparations should be avoided. When using Imbruvic in patients who require the administration of other anticoagulants or drugs that inhibit platelet function, the risk of bleeding may increase. Studies did not include patients with congenital hemorrhagic diathesis.
Therapy with Imbruvica should be suspended for 3 to 7 days before and after surgery depending on the type of surgery and risk of bleeding.
Leukostasis.
In patients taking Imbruvica drug, there were isolated cases of leukostasis. A high number of circulating lymphocytes (>400000/μl) may increase the risk of leukostasis. In such cases, temporary suspension of therapy with Imbruvic should be considered. Patients should be closely monitored. Supportive therapy including hydration and/or cytoreduction should be given when indicated.
Infections.
There have been cases of infections (including sepsis, bacterial, viral or fungal infections) in patients taking Imbruvica. Some of these infections have required hospitalization or resulted in death. Patients should be monitored for fever and infections and appropriate anti-infective therapy should be given as indicated.
Cytopenias.
There have been cases of cytopenias (neutropenia, thrombocytopenia and anemia) in patients taking Imbruvic. It is necessary to conduct monthly detailed blood tests.
Cardiac phenomena.
Atrial fibrillation and flutter have been reported in patients taking Imbruvica, especially in patients with acute infections, with the presence of risk factors for cardiac phenomena and with atrial fibrillation in the anamnesis. Patients should be monitored periodically for atrial fibrillation. Patients should be evaluated (including ECG if indicated) who present with arrhythmic symptoms (e.g., palpitations, preconscious dizziness) or who are first diagnosed with dyspnea. In cases of ongoing atrial fibrillation, the benefit/risk ratio of therapy with Imbruvic should be evaluated, and if necessary, the dose should be adjusted.
Effects on the QT interval.
In clinical trials, Imbruvic caused a slight shortening of the QTcF interval (on average, by 7.5 ms). The mechanism underlying this phenomenon and its relevance to drug safety is unknown. Patients at risk of more severe QTc interval shortening (e.g., congenital short QT interval syndrome or a family history of this syndrome) should be considered for administration of ibrutinib according to the results of a clinical evaluation of their health status.
Primary malignant neoplasms.
In patients taking Imbruvic, there have been isolated cases of primary malignancies, mainly skin cancer.
Effect on the ability to drive and operate vehicles.
In patients taking Imbruvic, fatigue, dizziness and asthenia have been reported. This should be taken into account when assessing the patient’s ability to drive vehicles and mechanisms.

Contraindications

– known hypersensitivity (e.g., with anaphylactic and anaphylactoid reactions) to ibrutinib or excipients contained in the dosage form;
– pregnancy and breastfeeding period;
– childhood under 18 years (effectiveness and safety not confirmed);
– severe renal function impairment;
– severe hepatic function impairment (class C by Child-Pyo);
– patients on dialysis;
– co-administration with potent inducers of CYP3A isoenzyme (e.g., carbamazepine, rifampin, phenytoin and preparations containing Hypericum perforatum extract);
– co-administration with warfarin, other vitamin K antagonists, fish oil and vitamin E preparations.
Caution should be used in patients who require administration of anticoagulants (except warfarin and other vitamin K antagonists, coadministration with which should be excluded) or drugs that inhibit platelet function.
Imbruvica drug should be used with caution in case of co-administration with potent and moderate CYP3A isoenzyme inhibitors.

Side effects

This section lists adverse events considered to be related to ibrutinib based on a review of available information. In some cases, a causal relationship with ibrutinib cannot be reliably established. Because clinical trials are conducted in patients with a fairly wide range of conditions, the frequencies of adverse events in clinical trials of one drug cannot be directly compared with the frequencies in trials of another drug; moreover, they may not match the frequencies in actual clinical practice.
The adverse events listed below were reported regardless of the presence of a causal relationship.
The frequency of side effects is defined as follows: very common (≥1/10 cases), common (≥1/100 and
1. Recurrent or refractory mantle cell lymphoma
The most common non-hematologic side effects (≥20%) included diarrhea, fatigue, nausea, peripheral edema, shortness of breath, constipation, upper respiratory infections, vomiting and decreased appetite. The most commonly reported hematologic adverse events included neutropenia, thrombocytopenia, and anemia (see Table 2).
The most common grade 3/4 adverse events (observed with a frequency of 5% or more) included neutropenia, thrombocytopenia, anemia, pneumonia, diarrhea, abdominal pain, and atrial fibrillation.
Table 2 Adverse events that occurred during treatment and were observed in 10% or more of patients with relapsed or refractory mantle cell lymphoma on treatment with ibrutinib at a dose of 560 mg.

Serious side effects:
Serious adverse events were noted in 60.4% of patients (occurring during treatment). Serious adverse events observed in more than 2% of patients included atrial fibrillation (6.3%), pneumonia (5.4%), urinary tract infections (3.6%), abdominal pain (2.7%), subdural hematoma (2.7%), febrile neutropenia (2.7%), acute renal failure (2.7%), peripheral edema (2.7%) and fever (2.7%). There were single cases of leukostasis.
Cases of therapy discontinuation and dose reduction due to side effects
The most common side effect leading to treatment withdrawal was subdural hematoma (1.7%).
Side effects leading to dose reduction were reported in 13.5% of patients.
Elderly patients:
Among patients treated for recurrent or refractory mantle cell lymphoma, 63% were 65 years of age or older. Adverse cardiac events (atrial fibrillation and increased blood pressure), infections (pneumonia and panniculitis), and gastrointestinal events (diarrhea and dehydration) were more common in this group of patients.

2. Chronic lymphocytic leukemia.
The most common non-hematologic adverse events (reported at a frequency of 20% or more) in patients with relapsed/refractory disease who received ibrutinib at a dose of 420 or 840 mg included diarrhea, upper respiratory tract infections, fatigue, fever, peripheral edema, arthralgia, constipation and a tendency to bruise hematomas (see Table 3).
The most commonly reported hematologic adverse events included neutropenia, thrombocytopenia, and anemia (see Table 3). Table 3).
The most frequent Grade 3/4 adverse events (>5%) included neutropenia, pneumonia, thrombocytopenia, increased blood pressure, febrile neutropenia, dehydration, atrial fibrillation, fatigue, asthenia, panniculitis, and sinusitis.
Table 3 summarizes adverse events that occurred during treatment with Imbruvic, administered once daily at a dose of 420 mg, and which were reported at a frequency of at least 10.0% (frequency during treatment) in all previously treated patients with chronic lymphocytic leukemia.
Table 3: Treatment-emergent adverse events reported in at least 10% of patients with relapsed or refractory chronic lymphocytic leukemia on therapy with ibrutinib at a dose of 420 mg.

Overdose

There are limited data on overdose with Imbruvic. In a phase I study in which patients received this drug at a dose of up to 12.5 mg/kg/day (1400 mg), the maximum tolerated dose was not reached.
There is no specific antidote for Imbruvic. Careful monitoring of patients who have taken a dose higher than the recommended dose is necessary, as well as appropriate maintenance therapy.