Imbruvica® [Ibrutinib]

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Clinical Pharmacology

Pharmacological group: Antineoplastic drug. Protein tyrosine kinase inhibitor.
Pharmaceutical action: Ibrutinib is a potent low molecular weight inhibitor of Bruton tyrosine kinase (TKB). Ibrutinib forms a covalent bond with a cysteine residue (Cys481) in the TCB active center, resulting in a persistent inhibition of enzyme activity. TKB, which is a member of the Shc kinase family, acts as an important signaling molecule in the metabolic pathways associated with the signal activity of B cell antigenic receptors (BCR) and cytokine receptors. The BCR signaling pathway is involved in the pathogenesis of a number of B-cell malignant neoplasms, including mantle cell lymphoma, diffuse large-cell B-cell lymphoma, follicular lymphoma, and B-cell chronic lymphocytic leukemia. The key role of TKB in the signaling activity of B cell surface receptors leads to the activation of signaling pathways necessary for B cell migration, 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 cell migration and their adhesion to substrates in vitro.
Lymphocytosis.
At the beginning of therapy, the majority of patients (75%) with chronic lymphocytic leukemia who received the Imbruvica drug showed a reversible increase in the number of lymphocytes (ie, 50% or more from baseline with absolute values above 5000 / μl), often accompanied by a decrease in lymphadenopathy . This effect was also observed in some patients (35%) with recurrent or refractory lymphoma from the cells of the mantle zone who received the Imbruvica preparation. The observed lymphocytosis is a reflection of the pharmacodynamic effect, and should not be regarded as a 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 the Imbruvica drug (median - 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 mantle cell cells and chronic lymphocytic leukemia respectively.
Some patients had a significant increase in the number of circulating lymphocytes (i.e., over 400,000 / μl).
Pharmacokinetics: Absorption.
Ibrutinib is rapidly absorbed after oral administration with a median time to reach the maximum concentration (Tmax) for 1-2 hours. In patients with various B-cell malignant neoplasms, there are no significant differences in the pharmacokinetics of Ibrutinib. The concentration of ibrutinib in plasma increases proportionally with increasing doses to 840 mg. The equilibrium area under the concentration-time curve (AUC) in patients at a dose of 560 mg is 953 ± 705 ng × h / ml (mean ± standard deviation). Eating with food leads to an increase in the concentration of ibrutinib by about 2 times compared with fasting (without eating the previous evening).
Distribution.
Reversible binding of ibrutinib to human plasma proteins in vitro amounted to 97.3%, while in the concentration range from 50 to 1000 pg / ml there was no dependence on the concentration. The apparent volume of distribution in the equilibrium state (Vd, ss / F) is about 10,000 liters.
Metabolism.
Ibrutinib is metabolized predominantly by the CYP3A4 / 5 isoform of cytochrome P450 to form a predominantly dihydrodiol metabolite, the inhibitory activity of which in relation to TKB is approximately 15 times lower than that of ibrutinib. The systemic equilibrium concentration of the dihydrodiol metabolite is comparable to that of the original preparation. According to the results of in vitro studies, the participation of CYP2D6 isoenzyme in ibrutinib oxidative metabolism is less than 2%. In addition, according to a study of the mass balance in humans, the pharmacokinetic profile in patients with weak and high activity of the CYP2D6 isoenzyme (according to genotyping) was similar.Thus, in patients with different genotypes of the CYP2D6 isoenzyme, no precautions are required.
Derivation.
The observed clearance (CL / F) is about 1000 l / h. The half-life of ibrutinib is 4-6 hours.
After a single oral administration of [14C] ibrutinib (with a radioactive label) in healthy volunteers, about 90% of the radioactive substances were excreted for 168 hours, most (80%) were eliminated through the intestines, and less than 10% by the kidneys.
Unchanged ibrutinib accounted for about 1% of excretion products in the feces and was absent in the urine, the remainder being metabolites.
Special patient groups:
Elderly patients (aged 65 and over).
According to the results of the population analysis of pharmacokipetics, age does not have a significant effect on the clearance of ibrutinib from the bloodstream.
Children (18 years and under).
The pharmacokipetics of the drug Imbruvica were not studied in patients under 18 years of age.
Floor.
The results of a population-based pharmacokinetic analysis indicate the absence of a 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 special clinical studies in patients with impaired renal function have so far been conducted. In patients with impaired renal mild or moderate (creatinine clearance more than 30 ml / min) no dose adjustment is required. Currently there are no data on patients with severe renal impairment or on dialysis.
Patients with impaired liver function.
Ibrutinib is metabolized in the liver. In a study in patients with impaired liver function, but without malignant neoplasms, with the use of the drug Imbruvica at a dose of 140 mg, preliminary data show an increase in blood ibrutinib concentration of 4, 8 and 9 times in mild, moderate and severe liver dysfunction respectively. Concentration of the free fraction of Ibrutinib also increases with an increase in the degree of liver dysfunction 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%. The concentration of unbound ibrutinib increases by about 4.9 and 13 times in patients with mild, moderate and severe liver dysfunction, respectively.

Indications

- treatment of adult patients with recurrent or refractory mantle cell lymphoma;
- treatment of adult patients with chronic lymphocytic leukemia who have received at least one line of therapy, or as the first line of therapy in patients with a 17p deletion or TP53 mutation in the presence of contraindications to chemoimmunotherapy.

Composition

Imbruvica capsules, solid gelatin, size No. 0, body and cap white, with an inscription in black ink "ibr 140 mg" on the cap; The contents of the capsules are white or almost white.
1 caps:
- Ibrutinib 140 mg
Excipients: microcrystalline cellulose 151.4 mg, croscarmellose sodium 23 mg, sodium lauryl sulfate 14 mg, magnesium stearate 1.6 mg.
The composition of the shell of capsules: titanium dioxide, gelatin.
Ink Composition: Opacode® S-1-17823 (pharmaceutical glaze (shellac solution in ethanol), ferric oxide black, n-butanol, 2-propanol, ammonium hydroxide 28%, propylene glycol).

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Dosage and Administration

For oral use.
Imbruvica drug 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; opening, breaking or chewing capsules is prohibited. Imbruvica drug is not allowed to drink grapefruit juice.
Imbruvica's drug should be continued until the disease progresses or until the patient can tolerate therapy anymore.
Recurrent or refractory lymphoma from the cells of the mantle zone:
The recommended dose of the drug Imbruvica for the treatment of recurrent or refractory lymphoma from the cells of the mantle zone is 560 mg (four 140 mg capsules) 1 time per day.
Chronic lymphocytic leukemia:
The recommended dose of Imbruvica for the treatment of chronic lymphocytic leukemia is 420 mg (three 140 mg capsules) 1 time per day.

Dose adjustment:
In the case of combined use with moderate or potent inhibitors of the CYP3A isoenzyme, dose adjustment is required, since the concentration of ibrutinib may increase. If a patient needs combination administration of ibrutinib and a potent inhibitor of the CYP3A isoenzyme (for example, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole), and the possible benefit outweighs the likely risk, you should reduce the speedy, too, to get to the one, too, to get to the one, too, would be too much to get it too. suspend treatment (for a period not exceeding 7 days). If necessary, concomitant use Ibrutinib and moderate inhibitor isoenzyme CYP3A (e.g., voriconazole, erythromycin, amprenavir, aprspitant, atazanavir, ciprofloxacin, krizotinib combination darunavir / ritonavir, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil) should reduce the dose Imbruvica® preparation 140 mg at the time of joint use with a moderate inhibitor of the isoenzyme CYP3A.
In the case of the development or enhancement of non-hematological toxicity of grade 3 and higher, neutropenia of grade 3 and higher with infection or fever or hematological toxicity grade 4, therapy with Imbruvica should be suspended.
After the clinical manifestations of toxicity are reduced to degree 1 or to the initial value (that is, the initial value will be restored), it is allowed to resume taking the drug Imbruvica in the initial dose. In the case of re-development of the phenomena of toxicity, it is necessary to reduce the dose by one capsule (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 of the dose, Imbruvica should be discontinued. Recommended dose adjustments for these toxic effects are described in Table 1.
Table 1. Recommended dose adjustment of the drug Imbruvica® with the development of toxicity.

Toxicity episode	Dose modification after restoration of the initial value in patients with recurrent or refractory lymphoma from the cells of the mantle zone	Dose modification after restoration of the initial value in patients with chronic lymphocytic leukemia
The 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
Third	Resume therapy at a dose of 280 mg per day	Resume therapy at a dose of 140 mg per day.
Fourth	Cancel drug Imbruvica®

Skip dose:
If the next dose of Imbruvica is not taken at the scheduled time, it is allowed to take it as soon as possible on the same day, returning to the usual schedule of taking the drug from the next day. It is not allowed to take additional capsules to replenish the missed doses.
Children (18 years and under):
The safety and effectiveness of the drug Imbruvica in children has not been evaluated.
Patients with impaired renal function:
Ibrutinib is characterized by minimal renal clearance. Separate clinical studies in patients with impaired renal function was not conducted. However, in clinical trials of the drug Imbruvica participated patients with impaired mild to moderate renal function. In patients with impaired mild to moderate renal function (creatinine clearance more than 30 ml / min), dose adjustment is not required. Information on patients with impaired severe renal function, as well as on patients on dialysis, is not available.
Patients with impaired liver function:
Ibrutinib is metabolized in the liver. Patients with serum activity of aspartate transaminases (AST / SGOT) or alanine transaminases (ALT / SGTPT) 3 or more times the upper limit of normal were excluded from clinical studies. According to preliminary data from a clinical study in patients with impaired liver function, for non-malignant tumors, an increase in the concentration of ibrutinib in the blood has been shown. In patients with mild or moderately impaired liver function (Child-Pugh class A and B), it is necessary to begin therapy with a dose of 280 mg and 140 mg, respectively. Patients should be carefully monitored for signs of toxicity, and, if necessary, dose adjustment. It is not recommended to use the drug Imbruvica in patients with severe liver dysfunction (Child-Pugh class C).

Adverse reactions

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

System organ class	Frequency	Side effect
Infections and invasions	Often	Pneumonia Sinusitis Upper respiratory tract infections Bacterial, viral and fungal infections
Infections and invasions	Often	Urinary tract infections Skin infections Sepsis
Violations of the blood and lymphatic system	Often	Neutropenia Thrombocytopenia Anemia
Violations of the blood and lymphatic system	Often	Febrile neutropenia Leukocytosis Lymphocytosis
Metabolic and nutritional disorders	Often	Reduced appetite
Metabolic and nutritional disorders	Often	Dehydration Hyperuricemia
Benign, malignant and malignant neoplasms	Often	Primary malignant neoplasms (skin cancer)
Nervous system disorders	Often	Dizziness Headache
Violations by the organ of vision	Often	Image Blurry
Heart disorders	Often	Atrial fibrillation
Vascular disorders	Often	Bleeding petechiae bruising Blood pressure increase
Vascular disorders	Often	Subdural hematoma
Kidney and urinary tract disorders	Often	Acute renal failure
Disorders of the respiratory system, chest and mediastinum	Often	Dyspnea Nosebleeds Cough
Gastrointestinal disorders	Often	Diarrhea Abdominal pain Vomiting Stomatitis Constipation Nausea Dyspepsia
Gastrointestinal disorders	Often	Dry mouth
Violations of the skin and subcutaneous tissue	Often	Rash
Violations of the skin and subcutaneous tissue	Often	Panniculitis
Violations of the musculoskeletal system and connective tissue	Often	Muscle spasms Myalgia Arthralgia Backache Pain in limbs
General disorders and reactions at the injection site	Often	Fever Fatigue Asthenia Peripheral edema
Injuries, poisoning and complications of procedures	Often	Tendency to hematomas with bruises

Serious side effects:
Serious side effects were observed in 60.4% of patients (occurring during the course of treatment). Serious side effects 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 are isolated cases of leucostasis.
Cases of discontinuation of therapy and dose reduction due to the occurrence of side effects
The most common side effect that led to the cancellation of treatment was subdural hematoma (1.7%).
Side effects that led to a decrease in dose were observed in 13.5% of patients.
Elderly patients:
Among patients who received therapy for recurrent or refractory lymphoma from the cells of the mantle zone, 63% were 65 years of age or older. In this group of patients, side effects from the side of the heart (atrial fibrillation and increased blood pressure), infections (pneumonia and panniculitis), as well as phenomena from the gastrointestinal tract (diarrhea and dehydration) were more common.

2. Chronic lymphocytic leukemia.
The most common non-hematological side effects (registered with a frequency of 20% or more) in patients with relapsed / refractory disease who received ibrutinib at 420 or 840 mg included diarrhea, upper respiratory tract infections, fatigue, fever, peripheral edema, arthralgia, constipation and tendency to hematomas with bruises (see table 3).
The most commonly reported hematologic side effects included neutropenia, thrombocytopenia, and anemia (see Table 3).
The most frequent adverse events of grade 3/4 (> 5%) included neutropenia, pneumonia, thrombocytopenia, increased blood pressure, febrile neutropenia, dehydration, atrial fibrillation, fatigue, asthenia, panniculitis and sinusitis.
Table 3 presents the side effects that have arisen during the treatment with Imbruvica, used once a day at a dose of 420 mg, and which were recorded with a frequency of at least 10.0% (frequency during treatment) in all previously treated patients with chronic lymphocytic leukemia.
Table 3. Side effects that occurred during treatment, and were observed in at least 10% of patients with recurrent or refractory chronic lymphocytic leukemia during ibrutinib therapy in a dose of 420 mg.

System organ class		Unwanted reaction
Infections and invasions	Often	Pneumonia Sinusitis Upper respiratory tract infections Bacterial, viral and fungal infections
Infections and invasions	Often	Urinary tract infections Bacteremia Sepsis Clostridial infection
Violations of the blood and lymphatic system	Often	Sunpening Thrombocytopenia Anemia
	Often	Febrile neutropenia Leukocytosis Lymphocytosis
	Infrequently	Leukostasis
Metabolic and nutritional disorders	Often	Reduced appetite
Benign, malignant and unspecified neoplasms	Often	Primary malignant neoplasms (skin cancer)
Nervous system disorders	Often	Dizziness Headache
Violations by the organ of vision	Often	Image Blurry
Heart disorders	Often	Atrial fibrillation
Vascular disorders	Often	Blood pressure increase Bleeding Bruising
Vascular disorders	Often	Subdural hematoma
Disorders of the respiratory system, chest and mediastinum	Often	Cough Pain in the oropharynx
Gastrointestinal disorders	Often	Diarrhea Vomiting Stomatitis Constipation Nausea Dyspepsia
Gastrointestinal disorders	Often	Dry mouth
Violations of the skin and subcutaneous tissue	Often	Increased tendency to form bruising Petechiae
Violations of the skin and subcutaneous tissue	Often	Panniculitis
Violations of the musculoskeletal system and connective tissue	Often	Muscle spasms Arthralgia
General disorders and reactions at the injection site	Often	Fever Chills Fatigue Asthenia Peripheral edema
Injuries, poisoning and complications of procedures	Often	Tendency to hematomas with bruises

Serious side effects:
Serious side effects were noted in 52.9% of patients (frequency for events during treatment). Serious side effects recorded in more than 2% of patients included pneumonia (7.8%), atrial fibrillation (5.9%), panniculitis (5.9%), sinusitis (5.9%), bacteremia (3, 9%), clostridial infection (3.9%), febrile neutropenia (3.9%) and subdural hematoma (3.9%).
Leukostasis.
There are isolated cases of leucostasis.
Cases of discontinuation of therapy and dose reduction due to the occurrence of side effects.
Side effects that led to a decrease in dose were observed in 11.8% of patients.
Elderly patients.
Among patients treated for recurrent / refractory chronic lymphocytic leukemia, 53% were 65 years old or older. The safety profile in this group of patients was comparable to the safety profile in younger patients.

- known hypersensitivity (for example, with anaphylactic and anaphylactoid reactions) to ibrutinib or auxiliary components contained in the dosage form;
- pregnancy and breastfeeding;
- children's age up to 18 years (efficiency and safety are not confirmed);
- Severe renal dysfunction;
- severe violations of the liver (class C on Child-Pyo);
- patients on dialysis;
- combined use with powerful inducers of CYP3A isoenzyme (for example, with carbamazepine, rifampin, phenytoin and preparations containing extract of Hypericum perforatum) (Hypericum perforatum);
- combined use with warfarin, other vitamin K antagonists, fish oil and preparations of vitamin E.
Caution should be used in patients who require the appointment of anticoagulants (except warfarin and other vitamin K antagonists, a joint reception with which should be excluded) or drugs that inhibit platelet function.
Imbruvica drug should be used with caution in the case of combined use with potent and mild inhibitors of the CYP3A isoenzyme.

Drug interactions

The metabolism of Ibrutinib is mainly involved CYP3A isoenzyme.
Drugs that can increase the concentration of ibrutinib in plasma
Joint use of the drug Imbruvica and potent or mild inhibitors of the CYP3A isoenzyme should be avoided, as these drugs can increase the concentration of ibrutinib.
As a result of the combined use of ketoconazole (a potent inhibitor of the CYP3A isoenzyme) with ibrutinib, 18 healthy volunteers showed an increase in ibrutinib concentration (Cmax and AUCo-last) by 29 and 24 times, respectively. The maximum observed ibrutinib concentration (AUC) in 37 patients who received mild and / or mild inhibitors of CYP3A isoenzyme had a maximum 2 times higher than the corresponding concentration in 76 patients who did not receive concomitant therapy with inhibitors of CYP3A isoenzyme.According to the results of clinical safety data, 66 patients who received moderate (n = 47) or potent (n = 19) inhibitors of the CYP3A isoenzyme did not show a significant increase in toxicity. It is necessary to avoid the use of a jar. chrysotinib, combination darunavir / ritonavir, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil). If a patient needs the combined use of ibrutinib and a potent inhibitor of the CYP3A isoenzyme, and the possible benefit outweighs the likely risk, reduce the dose of Imbruvica to 140 mg or temporarily suspend treatment (for a period not exceeding 7 days). If necessary, the joint use of Ibrutinib and a moderate inhibitor of the CYP3A isoenzyme should be reduced to a dose of Imbruvica to 140 mg for the time of joint use with a moderate inhibitor of the isoenzyme CYP3A. Dose adjustment is not required when Ibrutinib is used together with a weak inhibitor of the CYP3A isoenzyme. Careful monitoring of the toxicity of patients should be ensured, and, if necessary, dose adjustment should be carried out according to the instructions. During therapy with Imbruvica, eating grapefruits and pomeranians should be avoided, as these fruits contain mild inhibitors of the CYP3A isoenzyme.
Drugs that can reduce the concentration of ibrutinib in plasma
As a result of the combined use of the drug Imbruvica with powerful inducers of the CYP3A isoenzyme, a decrease in the concentration of ibrutinib in plasma is observed by about 90%.
Ibrutinib co-administration with potent inducers of CYP3A isoenzyme (for example, carbamazepine, rifampin, phenytoin, and preparations containing Hypericum perforatum extract) should be avoided.
Drugs whose concentration in plasma may change under the action of ibrutinib
According to the results of in vitro studies, ibrutinib is a weak inhibitor of isoenzymes CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 / 5. Ibrutinib dihydrodiol metabolite is a weak inhibitor of CYP2B6, CYP2C8, CYP2C9 and CYP2D6 isoforments. In vitro, both ibrutinib and its dihydrodiol metabolite had no more than a weak inducing effect on the activity of CYP450 isoenzymes. Thus, the clinically significant interaction of the drug Imbruvica with other drugs, the metabolism of which may be involved CYP450 isozymes, is unlikely.
According to the results of research, invitroibrutinib is not a substrate of P-glycoprotsin, but acts as its weak inhibitor. Systemic interaction of ibrutinib with drugs that are substrates of P-glycoprotein, is not expected. However, the possibility of ibrutinib inhibition of the intestinal form of P-glycoprotein after taking the drug in therapeutic doses cannot be excluded. Currently there are no clinical data. In order to prevent potential interactions in the gastrointestinal tract, P-glycoprotein substrates with a narrow therapeutic index (eg, digoxin) should be taken at least 6 hours apart before or after taking Imbruvica.

Pregnancy and Lactation

Pregnancy.
To date, there are no controlled studies of the drug Imbruvica in pregnant women. According to the results of research in animals, the drug Imbruvica® can cause harm to the fetus in the case of use in pregnant women.
Imbruvica drug should not be used during pregnancy. Women capable of childbirth should use highly effective methods of contraception while taking Imbruvica. Women using the hormonal contraceptive method should start using the second barrier method of contraception. It is necessary to avoid the onset of pregnancy during therapy with Imbruvica, as well as within 1 month after the end of therapy. If this drug is used during pregnancy, or the patient has become pregnant during therapy, it should be warned about the possible harm to the fetus. The period of time after completion of therapy with Imbruvica, after the passage of which a woman can become pregnant without any harm to the fetus, is currently unknown.
The effects of ibrutinib on the development of the embryo and fetus were studied in pregnant rats treated orally at doses of 10, 40 and 80 mg / kg / day. The use of ibrutinib at a dose of 80 mg / kg / day (approximately 14 times higher than the AUC vibrutinib and 9.5 times higher than the AUC of the 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 in the number of post-implantation fetal losses and an increase in the number of pathologies of the development of internal organs (heart and large vessels). Ibrutinib at a dose of 40 mg / kg / day and higher (approximately> 5.6 times higher than the IUC of Ibrutinib and about 4 times higher than the AUC of the dihydrodiol metabolite compared with patients receiving treatment at a dose of 560 mg per day) caused a decrease in fetal weight .
Breastfeeding period.
It is currently unknown whether ibrutinib or its metabolites in human breast milk is excreted. Since many drugs are excreted in breast milk in humans, and because of the possibility of serious adverse reactions in breastfed babies, breastfeeding should be stopped during Imbruvica therapy.
Fertility
Studies of the effect of Ibrutinib on fertility has not been conducted.
Men need to avoid conceiving a child during therapy with Imbruvica and for 3 months after its completion.

Special instructions

Hemorrhagic complications.
There are reports of hemorrhagic complications in patients receiving Imbruvica's drug, with and without thrombocytopenia. These included both minor hemorrhagic episodes, such as bleeding from bruises, nosebleeds 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 studies of phase II and phase III of Imbruvica. Warfarin and other vitamin K antagonists should not be used in combination with Imbruvica. Dietary supplements such as fish oil and vitamin E supplements should be avoided. When using Imbruvica for patients who need other anticoagulants or platelet-inhibiting drugs, the risk of bleeding may increase. The studies did not include patients with congenital hemorrhagic diathesis.
Imbruvica therapy should be suspended for a period of 3 to 7 days before and after surgery, depending on the type of surgery and the risk of bleeding.
Leukostasis.
In patients taking the drug Imbruvica, isolated cases of leucostasis. A high number of circulating lymphocytes (> 400,000 / µL) may increase the risk of leukostasis. In such cases, the possibility of a temporary suspension of therapy with Imbruvica should be considered. It is necessary to carefully monitor the condition of patients.According to the testimony should be maintenance therapy, including hydration and / or cytoreduction.
Infections.
Patients taking the drug Imbruvica®, there have been cases of infections (including sepsis, bacterial, viral or fungal infections). Some of these infections required hospitalization or resulted in death. It is necessary to monitor the condition of patients in order to identify fever and infections, as well as conduct appropriate anti-infective therapy if indicated.
Cytopenia.
In patients taking the drug Imbruvica®, there were cases of cytopenia (neutropenia, thrombocytopeia and anemia). It is necessary to conduct a detailed blood test every month.
Cardiac events.
Atrial fibrillation and flutter were observed in patients taking the Imbruvica drug, especially in patients with acute infections, with the presence of risk factors for the occurrence of cardiac events and with atrial fibrillation in history. It is necessary to conduct periodic monitoring of patients for the presence of atrial fibrillation. It is necessary to assess the health status of patients (including ECG for indications), who develop arrhythmic symptoms (for example, a sensation of heartbeat, dysfunctional dizziness) or first time shortness of breath is detected. In the case of continuing atrial fibrillation, it is necessary to assess the ratio of benefit / risk of therapy with Imbruvica, and, if necessary, adjust the dose.
Effects on the QT interval.
In clinical studies, the drug Imbruvica® caused a slight shortening of the QTcF interval (an average of 7.5 ms). The mechanism underlying this phenomenon and its significance for the safety of the drug are unknown. When considering the possibility of prescribing Ibrutinib to patients with a risk of a more pronounced shortening of the QTc interval (for example, congenital syndrome of a shortened QT interval or a family history of this syndrome), one should be guided by the results of a clinical assessment of the patient's health status.
Primary malignant neoplasms.
In patients taking the drug Imbruvica®, there were isolated cases of primary malignant tumors, mainly - skin cancer.
Impact on the ability to drive vehicles and mechanisms.
Patients taking the drug Imbruvica®, noted fatigue, dizziness and asthenia. This should be taken into account when assessing the patient's ability to drive vehicles and machinery.

Overdosage

Data on drug overdose Imbruvica® limited. In a phase I study in which patients received this drug at a dose of up to 12.5 mg / kg / day (1,400 mg), the maximum tolerated dose was not reached.
There is no specific antidote for Imbruvica. Careful monitoring of patients who have taken the dose higher than recommended, as well as proper maintenance therapy is necessary.