Imbruvik - instructions for use, dose, side effects, contraindications

Active substanceIbrutinibIbrutinib

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capsules inwards

Dosage form: & nbspcapsules

Composition:

1 capsule contains: active ingredient: ibrutinib - 140.0 mg; auxiliary substances: microcrystalline cellulose - 151.4 mg, croscarmellose sodium - 23.0 mg, sodium lauryl sulfate - 14.0 mg, magnesium stearate - 1.6 mg; capsule: titanium dioxide, gelatin, ink Opacode® S-1-17822 and Opacode® S-1-17823; composition of ink: pharmaceutical glaze (shellac solution in ethanol), iron oxide black, n-butanol, 2-propanol, ammonium hydroxide 28%, propylene glycol.

Description:

Hard gelatin capsules No. 0, body and cap of white color with the inscription in black ink "ibr 140 mg" on the lid. The contents of capsules are white or almost white powder.

Pharmacotherapeutic group:Antineoplastic agents, protein kinase inhibitors

ATX: & nbsp

L.01.X.E.27 Ibrutinib

Pharmacodynamics:

Mechanism of action

Ibrutinib is a potent low-molecular-weight inhibitor of Bruton tyrosine kinase (TKB). Ibrutinib forms a covalent bond with the cysteine residue (Cys 481) in the active center of TKB, leading to persistent inhibition of enzymatic activity. TKB, which is a member of the Tes family of kinases, acts as an important signal molecule of antigenic B-cell receptors (BCR) and cytokine receptors. Signal path BCR is involved in the pathogenesis of a number of B-cell malignancies, including lymphoma from the cells of the mantle zone, diffuse large-cell B-cell lymphoma, follicular lymphoma and B-cell chronic lymphocytic leukemia. The key role of TKB in the signal activity of B-cell surface receptors leads to the activation of signaling pathways necessary for migration of B cells, their chemotaxis and adhesion. According to the results of preclinical studies Ibrutinib inhibits proliferation and survival of malignant B cells in vivo, as well as migration of cells and their adhesion to substrates in vitro.

Lymphocytosis

At the beginning of the therapy, a reversible increase in the number of lymphocytes (ie, 50% or more of the baseline level and with absolute values of 5000 / μL or more) was observed in the majority of patients (75%) with chronic lymphocytic leukemia receiving Imbruvic preparation, often accompanied by decreased lymphadenopathy. This effect was also observed in some patients (35%) with lymphoma from the cells of the mantle zone, who received the Imbruvic preparation. The observed lymphocytosis is a reflection of the pharmacodynamic effect, and it should not be regarded as the progression of the disease in the absence of other clinical manifestations.In both diseases, lymphocytosis usually develops during the first few weeks of treatment with Imbruvic (median is 1.1 weeks), and is usually resolved with a median of 8.0 and 18.7 weeks in patients with recurrent or refractory lymphoma from the cells of the mantle zone and chronic lymphocytic leukemia, respectively. In some patients, there was a significant increase in the number of circulating lymphocytes (ie, over 400,000 / μl).

Lymphocytosis was not observed in patients with Waldenstrom macroglobulinemia who received Imbruvic's drug.

Pharmacokinetics:

Suction

Ibrutinib is rapidly absorbed after oral administration with the median time to reach the maximum concentration (T_m_Oh) 1-2 hours. Absolute bioavailability on an empty stomach (n= 8) was 2.9% (90% confidence interval for values from 2.1% to 3.9%) and this value doubled when taken with food. Patients with different B-cell malignancies are absent significant differences in the pharmacokinetics of ibrotinib.

The concentration of Ibrutinib in the blood plasma increases proportionally with increasing dose to 840 mg. The equilibrium value of the area under the "concentration-time" curve (AUC) in patients with a dose of 560 mg is 953 ± 705 ng * h / ml (mean ± standard deviation).Reception of ibrutinib on an empty stomach resulted in a decrease in its concentration (AUC_last) to the level of 60% of the concentration at the reception 30 minutes before meals, 30 minutes after meals or 2 hours after breakfast with a high fat content.

Distribution

Reversible binding of Ibrutinib to human plasma proteins in vitro was 97.3%, while in the concentration range from 50 to 1000 ng / ml there was no dependence on the concentration. The volume of distribution in the equilibrium state (V_d_,_ss) was 683 liters, and the apparent volume of distribution in the equilibrium state (V_d_,_ss/F) is about 10,000 liters.

Metabolism

Ibrutinib is metabolized predominantly by isoform CYP3A4/5 cytochrome P450 with the formation of a predominantly dihydrodiol metabolite whose inhibitory activity against TKB is approximately 15 times lower than that of ibru- tinib. The systemic equilibrium concentration of the dihydrodial metabolite is comparable to that of the parent drug.

Based on research results in vitro isoenzymatic participation CYP2D6 in the oxidative metabolism of ibrotinib is less than 2%. In addition, according to the study of mass balance in humans, the pharmacokinetic profile in patients with weak and high isoenzyme activity CYP2D6 (according to genotyping data) was similar.Thus, in patients with different isoenzyme genotypes CYP2D6 no precautions are required.

Excretion

The clearance for intravenous administration was 62 and 76 l / h, on an empty stomach and after meals, respectively. Due to the strong effect of the first pass, the apparent clearance after ingestion is 2000 and 1000 l / h, on an empty stomach and after eating, respectively.

The half-life of ibbrutinib is 4-6 hours.

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

Special Groups patients

Elderly patients (65 years and over)

According to the results of the population analysis of pharmacokinetics, age does not have a significant effect on the clearance of ibrotinib from the bloodstream.

Children (18 years and under)

Studies of the pharmacokinetics of Imbruvic in patients under the age of 18 years have not been conducted.

Floor

The results of a population analysis of pharmacokinetics indicate that there is no significant effect of sex on the clearance of ibrotinib from the bloodstream.

Patients with impaired renal function

The renal clearance of Ibrutinib is minimal; excretion of metabolites with urine is less than 10% of the dose. No special clinical studies have been performed in patients with impaired renal function. In patients with impaired renal function of mild or moderate degree (creatinine clearance more than 30 ml / min) no dose adjustment is required. At present, there are no data on patients with impaired renal function of a serious degree or who are on dialysis.

Patients with impaired hepatic function

Ibrutinib is metabolized in the liver. A study was conducted in patients with impaired liver function without malignant neoplasms who took the drug

Imbruvik on an empty stomach in a dose of 140 mg. AUC_last Ibrutinib increased 2.7, 8.2 and 9.8 times in patients with impaired liver function of lung (n= 6, Child-Pugh class A), medium (n= 10, class B by Child-Pugh) and severe (n= 8, class C by Child-Pugh) degree, respectively.The concentration of the free fraction of ibrothinib also increases with an increase in the degree of impaired liver function and is 3.0%, 3.8% and 4.8% in patients with mild, moderate and severe liver dysfunction, respectively. In healthy volunteers, the free fraction is 3.3%. Concentration of unbound ibrutinib (AUC_unbound_,_last) increases approximately in 4,1, 9,8 and 13 times in patients with impaired liver function of mild, moderate and severe degree, respectively.

Indications:

The drug Imbruvic is indicated for the treatment of adult patients with recurrent or refractory mantle cell lymphoma. The drug Imbruvik is indicated for the treatment of adult patients with chronic lymphocytic leukemia.

Imbruvic preparation is indicated for the treatment of adult patients with Waldenstrom macroglobulinemia (MV) who received at least one course of therapy or as a first-line therapy in patients unsuitable for chemotherapy.

Contraindications:

- known hypersensitivity (for example, with anaphylactic and anaphylactoid reactions) on Ibrutinib or auxiliary components contained in the dosage form;

- pregnancy and the period of breastfeeding;

- children under 18 years of age (effectiveness and safety not confirmed);

- severe renal dysfunction;

- severe liver function disorders (Child-Pugh class C);

- patients on dialysis;

- joint application with powerful isoenzyme inducers CYP3A (E.g., carbamazepine, rifampin, phenytoin and preparations containing the extract of Hypericum perforatum (Hypericum perforatum));

- joint use with warfarin, other vitamin K antagonists, fish oil and vitamin E preparations.

Carefully:

Imbruvika The drug should be used with caution in patients requiring anticoagulant (except warfarin and other vitamin K-antagonists joint reception which should be deleted), or drugs that inhibit platelet function.

Imbruvic's drug should be used with caution in the case of combined use with potent and moderate isoenzyme inhibitors CYP3A.

Pregnancy and lactation:

Pregnancy

To date, there are no controlled studies of Imbruvic in pregnant women.According to the results of studies in animals, Imbruvic's drug can cause harm to the fetus in case of use in pregnant women.

The drug Imbruvic should not be used during pregnancy. Women capable of giving birth should use highly effective methods of contraception while taking Imbruvic. Women using the hormonal method of contraception need to start using the barrier method of contraception in addition. It is necessary to avoid pregnancy during treatment with Imbruvic and also within 1 month after the end of therapy. If this drug is used during pregnancy, or the patient has become pregnant during therapy, it must be warned about the possible harm to the fetus. The time period after completion of therapy with Imbruvic, after which a woman can conceive without any harm to the fetus, is currently unknown.

Men should avoid conception of the child during therapy with Imbruvic and within 3 months after its completion.

The effects of Ibrutinib on the development of the embryo and fetus have been studied in pregnant rats,who received this drug orally in doses of 10, 40 and 80 mg / kg / day. The use of Ibrutinib in a dose of 80 mg / kg / day (about 14 times higher AUC Ibrutinib and 9.5 times higher AUC dihydrodiol metabolite compared with the corresponding values in patients receiving the drug at a dose of 560 mg per day) was accompanied by an increase number of postimplantation losses of the fetus and an increase in the number of pathologies of the development of internal organs (heart and large vessels). Ibrutinib in a dose of 40 mg / kg / day and above (about ≥ 5.6 times higher AUC Ibrutinib and about 4 times higher AUC dihydrogenated metabolite by compared with patients receiving treatment at a dose of 560 mg per day) caused a decrease in the weight of the fetus.

Ibrutinib was also administered orally in pregnant rabbits during the period of organogenesis at doses of 5, 15 and 45 mg / kg / day. When used at doses of 15 mg / kg / day and above Ibrutinib caused malformations of the skeleton (fusion of segments of the sternum), and when applied at a dose of 45 mg / kg / day Ibrutinib increased the incidence of postimplantation death of the fetus. Ibrutinib caused fetal malformations in rabbits when applied at a dose of 15 mg / kg / day (with the concentration of ibrotinib in the blood approximately 2 times higher than that of patients with mantle cell lymphoma, taking Ibrutinib at a dose of 560 mg per day, and approximately 2.8 times higher than the concentration of ibrotinib in the blood in patients with chronic lymphocytic leukemia or Waldenstrom macroglobulinemia taking Ibrutinib in a dose of 420 mg per day).

Breastfeeding period

At present, it is not known whether Ibrutinib or its metabolites with breast milk rights. Since many drugs are excreted in human breast milk, and because of the possibility of serious adverse reactions in breastfed infants, breastfeeding should be stopped during Imbruvic treatment.

Dosing and Administration:

Inside.

The drug Imbruvik should be taken 1 time per day, with a glass of water, at about the same time every day. Capsules must be swallowed whole with water; Do not open, break, or chew capsules. The drug Imbruvic is not allowed to drink grapefruit juice.

The drug Imbruvik should continue to be taken until the disease progresses or until the patient can no longer tolerate therapy.

Recurrent or refractory lymphoma from cells of the mantle zone

The recommended dose of Imbruvic for the treatment of recurrent or refractory lymphoma from the cells of the mantle zone is 560 mg (four capsules of 140 mg) once a day.

Chronic lymphocytic leukemia and Waldenstrom macroglobulinemia

The recommended dose of Imbruvik for the treatment of chronic lymphocytic leukemia and Waldenstrom macroglobulinemia is 420 mg (three capsules of 140 mg) once a day.

Correction of dose

In the case of combined use with moderate or potent inhibitors of isoenzyme CYP3A a dose adjustment is required, since the concentration of ibrotinib may increase. If a patient needs the combined use of Ibrutinib and a potent inhibitor of isoenzyme CYP3A (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole), and the possible benefit outweighs the probable risk, it is necessary to reduce the dose of Imbruvik preparation to 140 mg or temporarily suspend treatment (for a period of not more than 7 days). If it is necessary to jointly use Ibrutinib and a moderate isoenzyme inhibitor CYP3A (eg, voriconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, cryotinib, a combination of darunavir / ritonavir, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil) should reduce the dose of Imbruvik preparation to 140 mg at the time of combined use with a moderate inhibitor of isoenzyme CYP3A.

In the case of development or enhancement of non-hematologic toxicity of grade 3 and higher, neutropenia of grade 3 or higher with infection or fever or hematological toxicity of the 4th degree, Imbruvic should be stopped.

After the clinical manifestations of toxicity decrease to 1 or to the initial value (that is, the restoration of the initial value will be achieved), resumption of the Imbruvic preparation in the initial dose is permissible. In the case of repeated development of toxicity, the dose per capsule should be reduced (by 140 mg per day). If necessary, a second dose reduction of another 140 mg may be considered. In the case of persistent manifestations of toxicity or their recurrence after two doses, Imbruvic should be discontinued. Recommended dose adjustments for these toxicity manifestations are described in Table 1.

Table 1. Recommendations for correcting the dose of Imbruvik.

Episode toxicity	Modification of the dose after restoration of the initial value in patients with recurrent or refractory lymphoma from cells of the mantle zone	Dose modification after restoration of the initial value in patients with chronic lymphocytic leukemia or Waldenstrom macroglobulinemia
First	Resume therapy at a dose of 560 mg per day	Resume therapy at a dose of 420 mg per day
Second	Resume therapy at a dose of 420 mg per day	Resume therapy at a dose of 280 mg per day
The third	Resume therapy at a dose of 280 mg per day	Resume therapy at a dose of 140 mg per day
Fourth	Cancel Imbruvic's drug

Dose skip

If the next dose of Imbruvic's drug is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the usual schedule of taking the drug from the next day. Do not take additional capsules to fill in the missed doses.

Special patient groups

Children (18 years and under)

The safety and efficacy of Imbruvic in children was not assessed.

Patients with impaired function of night

Ibrutinib is characterized by minimal renal clearance.There were no separate clinical studies in patients with impaired renal function. However, in clinical studies of the Imbruvic drug, patients with mild and moderate renal dysfunction participated. In patients with impaired renal function of mild and moderate degree (creatinine clearance more than 30 ml / min) dose adjustment is not required. It is necessary to provide an adequate level of hydration, and also to regularly measure the concentration of creatinine in the blood serum. Information on patients with impaired renal function of a serious degree, as well as on patients on dialysis, are absent.

Patients with impaired hepatic function

Ibrutinib is metabolized in the liver. According to the clinical study, patients with impaired liver function showed an increase in the concentration of ibrotinib in the blood. For patients with mild liver function disorder (Child-Pugh class A), the recommended dose is 280 mg per day (two capsules). For patients with impaired liver function of an average degree (class B by Child-Pugh), the recommended dose is 140 mg per day (one capsule).It is necessary to carefully monitor patients for signs of toxicity, and, if necessary, carry out dose adjustment. It is not recommended to use the Imbruvic preparation in patients with severe hepatic dysfunction (Child-Pugh class C).

Side effects:

Data on side effects are based on data obtained during clinical trials and post-marketing period.

The most frequently observed side effects (≥20%) are: neutropenia, anemia, diarrhea, musculoskeletal pain, upper respiratory tract infections, bruising, rash, vomiting and fever. The most commonly observed adverse effects of degree 3 and 4 (≥5 %) are: anemia, neutropenia, pneumonia and thrombocytopenia.

Side effects associated with therapy performed according to the indication of lymphoma from cells of the mantle zone, chronic lymphocytic leukemia or Waldenstrom's macroglobulinemia and side effects noted in the post-marketing period are given in the table below in accordance with the system-organ classification and the frequency distribution of occurrence. The frequency of side effects is defined as follows: very often (≥1 / 10 cases), often (≥1 / 100 and <1/10 cases),infrequently (≥1 / 1000 and <1/100 cases) and the frequency is unknown (it is impossible to estimate the frequency from the available data). In each frequency group, side effects are presented in order of decreasing severity.

Table 2. Side effects associated with therapy in patients who received ibrutinib therapy but showed lymphoma from cells of the mantle zone, chronic lymphocytic leukemia or Waldenstrom's macroglobulinemia and side effects, registered in the post-registration period

System-Organ Class	Frequency	Side effect
Infections and invasions	Often	Pneumonia* Upper respiratory tract infections Urinary tract infection Sinusitis * Skin infections *
	Often	Sepsis*
Violations of the blood and lymphatic system	Often	Neutropenia Thrombocytopenia Anemia
	Often	Febrile neutropenia Leukocytosis Lymphocytosis
	Infrequently	Leukostasis
Disorders from the metabolism and nutrition	Often	Dehydration Hyperuricemia
	Infrequently	Tumor lysis syndrome
Disturbances from the nervous system	Often	Dizziness Headache
Disturbances on the part of the organ of sight	Often	Image blurriness
Heart Disease	Often	Atrial fibrillation
Vascular disorders	Often	Bleeding * Nose bleed Bleeding * Petechia
	Often	Subdural hematoma
Disorders from the gastrointestinal tract	Often	Diarrhea Vomiting Stomatitis*
		Nausea Constipation
	Often	Dry mouth
Disturbances from the skin and subcutaneous tissue	Often	Rash*
	Infrequently	Angioedema Hives
	Frequency unknown	Erythema
Violations of the motor and connective tissue	Often	Arthralgia Musculoskeletal pain *
General disorders and reactions at the injection site	Often	Fever Peripheral edema

* - includes several terms of undesirable reactions

Termination of therapy and dose reduction due to side effects Among patients who received Imbruvic with lymphoma from mantle cells, chronic lymphocytic leukemia or Waldenstrom macroglobulinemia, about 4% discontinued therapy due to side effects. Such side effects included infections and subdural hematoma.

Side effects that led to a decrease in dose were observed in about 7% of patients.

Elderly patients

Among the patients receiving Imbruvik, 59 % were at the age of 65 years and older. In this group of patients, side effects of grade 3 and higher were more common (53% of patients aged 65 years and older compared with 42% of younger patients). Side effects of degree 3 and above, more often observed in elderly patients, are: pneumonia, atrial fibrillation and urinary tract infections.

Overdose:

Data on an overdose of Imbruvic is limited. In the Phase I study, in which patients received the drug at a dose of up to 12.5 mg / kg / day (1400 mg), the maximum tolerated dose was not achieved. A specific antidote for Imbruvic is not available. Careful monitoring of the condition of patients taking a dose higher than recommended is necessary, as well as proper maintenance therapy.

Interaction:

In the metabolism of Ibrutinib, predominantly isoenzyme CYP3A.

Drugs that can increase the concentration of ibrotinib in plasma

It should avoid joint use of Imbruvic and powerful or moderate inhibitors of isoenzyme CYP3A, because these drugs can increase the concentration of ibrotinib.

As a result of the combined use of ketoconazole (a potent inhibitor of isoenzyme CYP3A) with ibrutinib in 18 healthy volunteers, an increase in the concentration Ibrutinib (C_max and AUC_0-_last) at 29 and 24 times respectively. The maximum observed concentration of ibrutinib (AUC) the 37 patients who received lung and / or moderate isoenzyme inhibitors CYP3A, was the maximum in 2 times higher than the corresponding concentration in 76 patients who did not receive concomitant therapy with isoenzyme inhibitors CYP3A. Based on a review of clinical safety data, 66 patients receiving moderate (n=47) or powerful (n= 19) inhibitors of isoenzyme CYP3A there was no significant increase in toxicity. It is necessary to avoid the simultaneous use of Ibrutinib with potent inhibitors of isoenzyme CYP3A (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazodone and cobicystate) and with moderate isoenzyme inhibitors CYP3A (eg, voriconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, cryotinib, a combination of darunavir / ritonavir, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil, amiodarone, dronedaron). If a patient needs the combined use of Ibrutinib and a potent inhibitor of isoenzyme CYP3A, and the possible benefit outweighs the probable risk, it is necessary to reduce the dose of Imbruvic preparation to 140 mg or temporarily suspend treatment (for a period not exceeding 7 days). If it is necessary to jointly use Ibrutinib and a moderate isoenzyme inhibitor CYP3A should reduce the dose of Imbruvic 140 mg at the time of combined use with a moderate inhibitor of isoenzyme CYP3A. No dosage adjustment is required when combined with Ibrutinib with a weak isoenzyme inhibitor CYP3A. Care should be taken to monitor the manifestations of toxicity in patients, and if necessary, adjust the dose according to the instructions. During therapy with Imbruvic, grapefruit and orange should be avoided because these fruits contain mild inhibitors of the isoenzyme CYP3A.

Drugs that can reduce the concentration of ibrotinib in plasma

As a result of the joint use of Imbruvic with powerful isoenzyme inducers CYP3A a decrease in the concentration of ibrotinib in plasma can be up to 90%. It should avoid joint use of ibrotinib with powerful isoenzyme inducers CYP3A (for example, carbamazepine, rifampin, phenytoin and preparations containing St. John's wort extract of perforated (Hypericum perforatum). Consider the possibility of using alternative drugs with less inducing activity with respect to the isoenzyme CYP3A.

Drugs, the concentration of which in the plasma can change under the action of ibru- tinib

Based on research results in vitro Ibrutinib is a weak reversible inhibitor of isoenzymes CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5, and does not show time-dependent inhibition CYP450. The dihydroglobulin metabolite Ibrutinib is a weak inhibitor of isoenzymes CYP2B6, CYP2C8, CYP2C9 and CYP2D6. how Ibrutinib, and its dihydro-hydrolytic metabolite under conditions in vitro had no more than a weak inducing effect on the activity of isoenzymes CYP450. Thus, clinically significant interaction of Imbruvic with other drugs, in the metabolism of which isozymes can participate CYP450, unlikely.

Based on research results in vitro Ibrutinib is not a substrate of the P-glycoprotein or other major transporter, except for OCT2. Dihydrodiotic metabolite and other metabolites are substrates of P-glycoprotein. Ibrutinib is a weak P-glycoprotein inhibitor and breast cancer resistance protein (BCRP). Systemic interaction of Ibrutinib with drugs that are substrates of P-glycoprotein is not expected. Nevertheless, it can not be ruled out that ibrutinib inhibits the intestinal form of P-glycoprotein and BCRP after taking the drug in therapeutic doses. There are currently no clinical data available. In order to reduce the possibility of interaction in the gastrointestinal tract, substrates of P-glycoprotein or BCRP with a narrow therapeutic index (for example, digoxin or methotrexate) should be taken at intervals of at least 6 hours before or after taking Imbruvic. Ibrutinib can also systemically inhibit BCRP and increase the concentration of drugs that are exposed BCRP-mediated hepatic efflux (for example, rosuvastatin).

Special instructions:

Hemorrhagic complications

There are reports of hemorrhagic complications in patients treated with Imbruvic, with and without thrombocytopenia. They included minor haemorrhagic episodes, such as bleeding from bruises, nosebleeds and petechiae, and significant hemorrhagic complications (some of which were fatal), including gastrointestinal bleeding, intracranial hemorrhage, and hematuria.

From research II and III Phase Imbruvic drug excluded patients who required therapy with warfarin or other antagonists of vitamin K. Warfarin and other vitamin K antagonists should not be used in combination with Imbruvic's drug. It is necessary to avoid the use of food additives such as fish oil and vitamin E preparations. When using Imbruvic in patients who require the appointment of other anticoagulants or drugs that inhibit the function of platelets, the risk of bleeding may increase. The study did not include patients with congenital hemorrhagic diathesis.

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

Leukostasis

In patients who took the drug Imbruvik, isolated cases of leukostasis were noted. A high number of circulating lymphocytes (> 400000 / μl) may increase the risk of leukostasis. In such cases, the possibility of temporary suspension of therapy with Imbruvic should be considered. It is necessary to carefully monitor the condition of patients. According to the indications, supportive therapy, including hydration and / or cytoreduction, should be performed.

Infections

Patients taking Imbruvic's drug had cases of infection (including sepsis, bacterial, viral or fungal infections). Some of these infections required hospitalization or resulted in death. Patients treated with Imbruvik received cases of progressive multifocal leukoencephalopathy of unknown origin. It is necessary to observe the condition of patients with the purpose of revealing the symptoms (fever, chills, weakness, confusion), and also to conduct proper therapy according to the indications.

Cytopeniaand

Patients taking Imbruvic's preparation noted cases of cytopenia (neutropenia,thrombocytopenia and anemia). It is necessary to conduct a detailed blood test every month.

Atrial fibrillation

Atrial fibrillation and flutter were noted in patients taking Imbruvic's drug, especially in patients with acute infections, with risk factors for cardiac events and with atrial fibrillation in the anamnesis. Periodic monitoring of patients for atrial fibrillation should be performed. It is necessary to assess the health status of patients (including ECG according to indications) who have arrhythmic symptoms (for example, palpitation, pre-fainting dizziness), or for the first time, dyspnoea appears. In the case of ongoing atrial fibrillation, the benefit / risk ratio of Imbruvic should be assessed and, if necessary, dose adjustment should be performed.

Interval Effects QT

In clinical trials Imbruvic's preparation caused an insignificant shortening of the interval QTcF (an average of 7.5 msec). The mechanism underlying this phenomenon and its significance for drug safety are unknown.When considering the possibility of appointing ibrotinib to patients at risk of a more pronounced shortening of the interval QTc (for example, a congenital syndrome of a shortened interval QT or having a family history of this syndrome) should be guided by the results of a clinical assessment of patients' health status.

Second primary malignant neoplasms

In patients who took the drug Imbruvik, there were isolated cases of the emergence of second primary malignant neoplasms, mainly skin cancer.

Tumor lysis syndrome

Tumor lysis syndrome was noted during therapy with Imbruvic. The risk of tumor lysis syndrome is present in patients who had a large tumor burden prior to initiation of therapy. It is necessary to carefully monitor the condition of patients and take appropriate precautions.

Effect on the ability to drive transp. cf. and fur:

Patients taking Imbruvic's drug experienced fatigue, dizziness and asthenia. This should be taken into account when assessing the patient's ability to drive vehicles and mechanisms.

Form release / dosage:Capsules, 140 mg.

Packaging:

Capsules, 140 mg; 90 or 120 capsules per bottle of high-density polyethylene, covered with aluminum film, polypropylene lid, protected from accidental opening by children. 1 bottle per pack of cardboard along with instructions for use.

Storage conditions:

Store at a temperature of no higher than 25 ° C in a dark place.

Keep out of the reach of children.

Disposal instruction

The unused preparation must be disposed of in accordance with local requirements for the destruction of such waste.

Shelf life:

2 years

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002811

Date of registration:12.01.2015

Expiration Date:12.01.2020

The owner of the registration certificate:Johnson & Johnson, LLC Johnson & Johnson, LLC Russia

Manufacturer: & nbsp

CILAG, AG Switzerland

Information update date: & nbsp14.10.2016

Illustrated instructions

Instructions

Imbruwick (Imbruvica)