Composition, form of production and packaging
Capsules hard gelatinous, size No. 0, body and lid of white color, with black ink "ibr 140 mg" on the lid; the contents of the capsules are white or almost white powder.
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 capsule shell: titanium dioxide, gelatin, Opacode В® inks S-1-17822 and Opacode В® S-1-17823.
Ink composition: pharmaceutical glaze (shellac solution in ethanol), iron oxide black, n-butanol, 2-propanol, ammonium hydroxide 28%, propylene glycol.
90 pcs. - bottles of high-density polyethylene (1) - packs of cardboard.
120 pcs. - bottles of high-density polyethylene (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2017.
Mechanism of action
Ibrutinib is a potent low-molecular-weight inhibitor of Bruton tyrosine kinase (TKB). Ibrutinib forms a covalent bond with the cysteine вЂ‹вЂ‹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 signaling molecule of antigenic B-cell receptors (BCRs) and cytokine receptors. The BCR signaling pathway 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, ibrothinib inhibits proliferation and survival of malignant B cells in vivo, as well as migration of cells and their adhesion to substrates in vitro.
At the beginning of the therapy, a reversible increase in the number of lymphocytes (ie, 50% or more of the baseline with absolute values вЂ‹вЂ‹of 5000 / Ојl or more) was observed in the majority of patients (75%) with chronic lymphocytic leukemia receiving Imbruvic preparation, often accompanied by a decrease 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 / Ојl).
Lymphocytosis was not observed in patients with Waldenstrom macroglobulinemia who received Imbruvic's drug.
Ibrutinib is rapidly absorbed after oral administration with a median time to reach a maximum concentration (T max ) of 1-2 hours. Absolute fasting bioavailability (n = 8) was 2.9% (90% confidence interval for values вЂ‹вЂ‹from 2.1% to 3.9%) and this value doubled when taken with food. In patients with different B-cell malignancies, there are no significant differences in the pharmacokinetics of ibru- tinib. The concentration of Ibrutinib in the blood plasma increases proportionally with increasing dose to 840 mg. The equilibrium value of AUC in patients at a dose of 560 mg is 953 В± 705 ng В· h / ml (mean В± standard deviation). Admission of fasting ibrotinib reduced its concentration (AUC last ) to 60% of the concentration at reception 30 minutes before meals, 30 minutes after meals or 2 hours after breakfast with a high fat content.
The reversible binding of ibru- tinib to human plasma proteins in vitro was 97.3%, with no concentration dependence in the concentration range of 50-1000 ng / ml.The volume of distribution in the equilibrium state (V d, ss ) was 683 liters, and the apparent volume of the distribution in the equilibrium state (V d, ss / F) is about 10,000 liters.
Ibrutinib is metabolized predominantly by the CYP3A4 / 5 cytochrome P450 isoform 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 C ss of the dihydrodial metabolite is comparable to that of the parent drug.
According to the results of in vitro studies, the participation of the CYP2D6 isoenzyme 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 a weak and high activity of the isoenzyme CYP2D6 (according to genotyping data) was similar. Thus, no precautions are required in patients with different genotypes of the CYP2D6 isoenzyme.
Clearance with IV introduction 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.
T 1/2 ibrotinib is 4-6 hours.
The observed clearance (Cl / F) is about 1000 l / h. T 1/2 ibrotinib is 4-6 hours.
After a single oral intake of [ 14 C] -Ibrutinib (radioactive labeled) in healthy volunteers, approximately 90% of the radioactive substances were excreted within 168 hours, most (80%) were excreted through the intestine, and less than 10% by the kidneys.
Unchanged Ibrutinib accounted for about 1% of fecal excretion products and was absent in urine, the remainder being metabolites.
Special patient groups
Patients of advanced age (from 65 years and older)
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.
The results of the 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 (QC 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 received Imbruvik's drug on an empty stomach at a dose of 140 mg. AUC last Ibrutinib increased 2.7, 8.2 and 9.8 times in patients with impaired hepatic function (n = 6, Child-Pugh class A), mean (n = 10, Child-Pugh class B) and severe (n = 8 , class C by Child-Pugh) degree, respectively. The concentration of the free fraction of ibrutinib also increases with an increase in the degree of disturbance of the liver function of 3.0%, 3.8%, and 4.8% in patients with impaired liver function of mild, moderate and severe degree, respectively. In healthy volunteers, the free fraction is 3.3%. The 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.
- for the treatment of adult patients with recurrent or refractory mantle cell lymphoma;
- for the treatment of adult patients with chronic lymphocytic leukemia;
- 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 unfit for chemotherapy.
The drug Imbruvik should be taken 1 time / day, washed down 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. It is not allowed to drink imbruwic with 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 (4 capsules to 140 mg) 1 time / day.
Chronic lymphocytic leukemia and Waldenstrom macroglobulinemia
The recommended dose of Imbruvic for the treatment of chronic lymphocytic leukemia and Waldenstrom's macroglobulinemia is 420 mg (3 capsules to 140 mg) 1 time / day.
Correction of dose
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 the combined use of Ibrutinib and a potent inhibitor of the isoenzyme CYP3A (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole) and the potential benefit outweighs the probable risk, then Imbruvik should be reduced 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 inhibitor of the isoenzyme CYP3A (eg, voriconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, cryotinib, darunavir / ritonavir, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil), the Imbruvic drug dose should be reduced to 140 mg at the time of combined use with a moderate inhibitor of the 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, it is necessary to reduce the dose per 1 capsule (by 140 mg / 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 Imbruvic
Dose of toxicity Dose modification after restoration of the initial value in patients with recurrent or refractory lymphoma from the cells of the mantle zoneDose 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 / day Resume therapy at a dose of 420 mg / day
Second Renew therapy at a dose of 420 mg / day Resume therapy at a dose of 280 mg / day
Third Renew therapy at a dose of 280 mg / day Resume therapy at a dose of 140 mg / day
Fourth Cancel the drug Imbruik
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.
Children (18 years and under)
The safety and efficacy of Imbruvic in children was not assessed.
Patients with impaired renal function
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 (QC 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 (class A according to Child-Pugh), the recommended dose is 280 mg / day (2 capsules). For patients with a moderate liver function disorder (Child-Pugh class B), the recommended dose is 140 mg / day (1 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).
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 side effects of degrees 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 incidence 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 frequency unknown (impossible to estimate 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 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
System-Organ Class Frequency
Infections and invasions Very often Pneumonia * Upper respiratory tract infections Urinary tract infections Sinusitis * Skin infections *
Disorders from the blood and lymphatic system Very often Neutropenia Thrombocytopenia Anemia
Often Febrile Neutropenia Leukocytosis Lymphocytosis
Metabolism and Nutrition Disorders Often Dehydration Hyperuricemia
Infrequent Tumor Lysis Syndrome
Disturbances from the nervous system Very often Vertigo Headache
Impaired vision of the body Often Image blurriness
Heart Failure Often Atrial Fibrillation
Vascular abnormalities Very often Bleeding * Nasal bleeding Bruising * Petechiae
Often Subdural hematoma
Disorders from the gastrointestinal tract Very often Diarrhea Vomiting Stomatitis * Constipation Nausea
Often Dryness in the mouth
Disturbances from the skin and subcutaneous tissue Very often Rash *
Infrequent Angioedema Edema Urticaria
Frequency unknown Erythema
Disorders from the musculoskeletal system and connective tissue Very often Arthralgia Musculoskeletal pain *
General disorders and reactions at the injection site Very 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.
Of the patients receiving Imbruvic, 59% were 65 years of age or 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.
- known hypersensitivity (for example, with anaphylactic and anaphylactoid reactions) on ibrotinib or auxiliary components contained in the dosage form;
- the period of breastfeeding;
- children's and adolescents under 18 years of age (effectiveness and safety not confirmed);
- severe renal dysfunction;
- severe violations of the liver (class C by Child-Pugh);
- Patients on dialysis;
- combined use with potent inducers isoenzyme CYP3A (e.g., carbamazepine, rifampin, phenytoin and preparations containing the extract of Hypericum perforatum (Hypericum perforatum));
- combined use of warfarin and other vitamin K antagonists, fish oil and vitamin E preparations
With caution should be used in patients requiring anticoagulant (except warfarin and other vitamin K-antagonists joint method which is to be excluded) or drugs that inhibit platelet function.
Imbruvika The drug should be used with caution in the case of joint use with powerful and moderate inhibitors isoenzyme CYP3A.
PREGNANCY AND LACTATION
To date, there are no controlled studies of the drug in pregnant women Imbruvika. According to the results of studies in animals Imbruvika drug can cause harm to the fetus in the case of pregnant women.
Imbruvika The drug should not be used during pregnancy. Fertility women should use highly effective methods of contraception while taking the drug Imbruvika. Women using hormonal method of contraception, must begin to additionally use a barrier method of contraception. You should avoid becoming pregnant during therapy with Imbruvika and within 1 month after the end of therapy. If this drug is used during pregnancy, or if the patient became pregnant during therapy, it is necessary to warn of the possible harm to the fetus. The period of time after completion of therapy with Imbruvika, after the passage of which a woman can become pregnant without any harm to the fetus, is currently unknown.
Men should avoid conception during therapy with Imbruvika and for 3 months after its completion.
Ibrutinib effects on embryo-fetal development were studied in pregnant rats treated with the drug orally in doses of 10, 40 and 80 mg / kg / day. Application Ibrutinib at a dose of 80 mg / kg / day (approximately 14-fold higher AUC Ibrutinib and 9.5-fold higher AUC digidrodiolnogo metabolite compared to the corresponding values вЂ‹вЂ‹in patients receiving the drug in a dose of 560 mg / day) was accompanied by an increase in the number of post-implantation losses fetus and increase the number of pathologies of internal organs (heart and great vessels). Ibrutinib at a dose of 40 mg / kg / day and higher (about? 5.6-fold higher AUC Ibrutinib and approximately 4-fold higher AUC digidrodiolnogo metabolite compared to patients treated at a dose of 560 mg / day) caused a reduction in fetal weight.
Ibrutinib also used orally in pregnant rabbits during the period of organogenesis at dosages of 5, 15 and 45 mg / kg / day. When used in doses of 15 mg / kg / day and above Ibrutinib caused skeletal malformations (fusion sternal segments), and for application in a dose of 45 mg / kg / day Ibrutinib increased incidence of post-implantation fetal death. Ibrutinib induced fetal malformations in rabbits by applying a dose of 15 mg / kg / day (the concentration in blood Ibrutinib about 2 times higher than that in patients with mantle cell lymphoma, host Ibrutinib at a dose of 560 mg / day, and about 2.8 times Ibrutinib higher concentration in the blood of patients with chronic lymphocytic leukemia or Waldenstrom's macroglobulinemia, Ibrutinib receiving a dose of 420 mg / day).
Whether Ibrutinib or its metabolites in breast milk in humans is currently unknown, is released. Because many drugs are excreted in breast milk in humans, and therefore the potential for serious adverse reactions in breastfed infants, breastfeeding should be discontinued during therapy with Imbruvika.
APPLICATION FOR FUNCTIONS OF THE LIVER
Patients with impaired mild and moderate renal function (creatinine clearance of more than 30 ml / min) a dose adjustment is required.
Use of the drug is contraindicated in severe renal impairment, in patients on dialysis.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
In patients with impaired liver mild to moderate function (class A and B Child-Pugh) need to begin therapy at a dose of 280 mg and 140 mg, respectively. Patients should be monitored closely for signs of toxicity, and, if necessary, to carry out the dose adjustment.
Not use this drug in severe hepatic dysfunction (class C Child-Pugh).
APPLICATION FOR CHILDREN
The safety and efficacy Imbruvika drug in children has not been evaluated. Use of the drug is contraindicated in children and adolescents up to 18 years.
have been reported bleeding events in patients receiving the drug Imbruvika, thrombocytopenia with or without it. They included both minor bleeding episodes, such as bleeding in bruises, nosebleeds, and petechiae, and significant bleeding complications (some of which were fatal), including gastrointestinal bleeding, intracranial hemorrhage and hematuria.
From studies of phase II and III preparation Imbruvika excluded patients who required therapy with warfarin or other vitamin K antagonist warfarin and other vitamin K antagonists should not be used in combination with a preparation Imbruvika. It should avoid the use of dietary supplements such as fish oil and vitamin E preparations Imbruvika In applying the drug in patients who require administration of other anticoagulants or agents that inhibit platelet function, may increase the risk of bleeding. The study did not include patients with congenital bleeding diathesis.
Therapy with Imbruvika should be suspended for a period of 3 to 7 days before and after surgical intervention, depending on the type of surgery and the risk of bleeding.
Patients taking the drug Imbruvika, noted isolated cases leukostasis. The high number of circulating lymphocytes (> 400,000 / ul) can increase the risk of leukostasis. In such cases, you should consider the possibility of a temporary suspension of therapy with Imbruvika. It is necessary to closely monitor the patient's condition. By indications should be supportive therapy comprising the hydration and / or cytoreduction.
Patients taking the drug Imbruvika, there have been cases of infections (including sepsis, bacterial, viral or fungal infections). Some of these infections requiring hospitalization or resulted in death. Patients receiving therapy with Imbruvika, observed cases of progressive multifocal leukoencephalopathy of unknown origin. It is necessary to monitor the status of patients in order to identify the symptoms (fever, chills, weakness, confusion), as well as to pursue appropriate therapy when indicated.
in patients treated with the drug Imbruvika, there have been cases of occurrence of cytopenias (neutropenia, thrombocytopenia and anemia). It is necessary to carry out a detailed analysis of blood every month.
Fibrillation and atrial flutter were observed in patients taking the drug Imbruvika, particularly in patients with acute infection, the presence of risk factors for cardiac phenomena and with a history of atrial fibrillation. It is necessary to carry out periodic monitoring of patients for the presence of atrial fibrillation. It is necessary to assess the state of health of the patient (including ECG readings), who appear arrhythmic symptoms (such as palpitations, dizziness, lightheadedness) or shortness of breath for the first time revealed. In the case of the ongoing atrial fibrillation is necessary to evaluate the benefit / risk ratio of therapy with Imbruvika, and spend a dose adjustment if necessary.
Effects on QT interval
In clinical studies Imbruvika drug caused a slight shortening of the interval QTcF (an average of 7.5 msec). The mechanism underlying this phenomenon and its importance for the safety of the drug is unknown. When considering the destination Ibrutinib patients with a risk of more pronounced shortening of QTc interval (e.g., congenital QT interval syndrome truncated or having a family history of this syndrome) must be guided by the results of the clinical evaluation of patients health.
The second primary malignancy
in patients taking the drug Imbruvika, marked individual occurrences of the second primary malignancies, preferably - skin cancer.
Tumor lysis syndrome
tumor lysis syndrome was observed during therapy with Imbruvika. The risk of tumor lysis syndrome is present in patients who had a large tumor burden prior to treatment. It is necessary to carefully monitor the patient's condition and take appropriate precautions.
Impact on the ability to drive vehicles and mechanisms
Patients taking the drug Imbruvika, marked fatigue, dizziness, and asthenia. This must be taken into account when assessing a patient's ability to drive vehicles and mechanisms.
Instructions for recycling
unused product should be disposed of in accordance with local regulations for the destruction of such waste.
Data on drug overdose Imbruvika limited. In phase I study in which patients received the drug at a dose of 12.5 mg / kg / day (1400 mg), the maximum tolerated dose was not achieved. A specific antidote for Imbruvika no drug. Careful monitoring of the patient, take the dose recommended above, as well as carrying out proper maintenance therapy.
The metabolism Ibrutinib involved primarily isozyme CYP3A.
Drugs that can increase the concentration in plasma Ibrutinib
Avoid joint use drug Imbruvika and powerful inhibitors or moderate isoenzyme CYP3A, since these drugs are capable of increasing the concentration Ibrutinib.
As a result, the joint use of ketoconazole (a potent inhibitor of isoenzyme CYP3A) with Ibrutinib in 18 healthy volunteers showed an increase Ibrutinib concentration (C max and AUC 0-last) At 29 and 24 times, respectively. Maximum observed concentration Ibrutinib (AUC) in 37 patients treated with light and / or moderate inhibitors isoenzyme CYP3A, it has a maximum of 2 times higher than corresponding concentrations in 76 patients who did not receive concomitant therapy with inhibitors isoenzyme CYP3A. Upon review of clinical safety data from 66 patients treated with moderate (n = 47) or strong (n = 19) isoenzyme CYP3A inhibitors showed no significant increase in toxicity. It is necessary to avoid concomitant use Ibrutinib with potent inhibitors isoenzyme CYP3A (e.g., ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazodone and kobitsistat) and with moderate inhibitors isoenzyme CYP3A (e.g., voriconazole, erythromycin, amprenavir, aprenitant,atazanavir, ciprofloxacin, krizotinib, the combination of darunavir / ritonavir, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil, amiodarone, dronedarone). If the patient needs combined use Ibrutinib and potent inhibitor of isoenzyme CYP3A, and possible benefit outweighs probable risk, it should be to reduce the dose of the drug Imbruvika to 140 mg or temporarily suspend treatment (for not more than 7 days). If necessary, concomitant use Ibrutinib and moderate CYP3A isoenzyme inhibitor should reduce the dose of the drug Imbruvika to 140 mg per joint application time with a moderate inhibitor isoenzyme CYP3A. No dose adjustment is required when used together with a weak inhibitor Ibrutinib isoenzyme CYP3A. There should be closely monitored for signs of toxicity in patientsand if necessary to conduct correction of the dose according to the instruction. During therapy with Imbruvika should avoid eating grapefruits and oranges, because these fruits contain moderate inhibitors of CYP3A isoenzyme.
Drugs that can reduce the concentration of plasma Ibrutinib
As a result, the joint use of the drug with potent inducers Imbruvika isoenzyme CYP3A Ibrutinib a decrease in the plasma concentration of about 90%.
Avoid joint application Ibrutinib with potent inducers isoenzyme CYP3A (e.g., carbamazepine, rifampin, phenytoin and preparations containing the extract of Hypericum perforatum (Hypericum perforatum). It is necessary to consider the use of alternative medications with less inducing activity regarding isoenzyme CYP3A.
Drugs concentration in plasma can vary under the influence Ibrutinib
According to studies in vitro Ibrutinib is a weak inhibitor of isoenzymes CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 / 5, and shows time-dependent inhibition of CYP450. Digidrodiolny Ibrutinib metabolite is a weak inhibitor of isoenzymes CYP2B6, CYP2C8, CYP2C9 and CYP2D6. As Ibrutinib and its metabolite digidrodiolny in in vitro conditions had no more than a weaker inducing effect on the activity of the isoenzymes CYP450. Thus, clinically significant drug interactions Imbruvika with other drugs, in the metabolism which may participate isoenzymes CYP450, is unlikely.
According to the results of in vitro studies Ibrutinib not a substrate of P-glycoprotein or other primary conveyor, except OCT2. Digidrodiolny metabolite and other metabolites are substrates of P-glycoprotein. Ibrutinib is a weak inhibitor of P-glycoprotein and resistance protein of breast cancer (BCRP). Ibrutinib system interaction with drugs that are substrates of P-glycoprotein, is not expected. Nevertheless, we can not exclude the possibility of inhibiting intestinal Ibrutinib form P-glycoprotein, and BCRP after taking the drug at therapeutic doses. There is currently no clinical evidence. To reduce the possibility of interaction in the gastrointestinal tract, substrates of P-glycoprotein or BCRP with a narrow therapeutic index (e.g.digoxin or methotrexate) to be taken with an interval of at least 6 hours before or after taking the drug Imbruvika. Ibrutinib may also systemically inhibit BCRP and increase the concentrations of drugs that undergo hepatic BCRP-mediated efflux (e.g., rosuvastatin).