Ibrutinib - instructions for use, reviews, analogs and forms of release (capsules or tablets 140 mg) drugs for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia in adults, children and pregnancy. Composition

In this article, you can read the instructions for using the drug Ibrutinib. There are reviews of visitors to the site - consumers of this medication, as well as opinions of doctors of specialists on the use of Ibrutinib in their practice. A big request is to actively add their feedback on the drug: the medicine helped or did not help get rid of the disease, which were observed complications and side effects, possibly not declared by the manufacturer in the annotation. Analogues of Ibrutinib in the presence of existing structural analogs. The use for the treatment of mantle cell lymphoma,macroglobulinemia Valdenstrem and chronic lymphocytic leukemia in adults, children, as well as during pregnancy and breast-feeding. Composition of the preparation.

Ibrutinib - a powerful low-molecular inhibitor of tyrosine kinase Bruton (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 signaling molecule of antigenic B-cell receptors (BCR) 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 surface B-cell receptors is in 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.

Composition

Ibrutinib + auxiliary substances.

Pharmacokinetics

Ibrutinib is rapidly absorbed after oral administration. Absolute bioavailability on an empty stomach was 2.9%, and this value doubled when taken with food. The concentration of Ibrutinib in the blood plasma increases proportionally with increasing dose to 840 mg. Admission of ibrotinib on an empty stomach resulted in a decrease in its concentration to a level of 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 Ibrutinib to human plasma proteins in vitro was 97.3%. 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. After a single oral intake of ibrotinib with a radioactive label in healthy volunteers, approximately 90% of 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.

Indications

• treatment of adult patients with recurrent or refractory mantle cell lymphoma;
• treatment of adult patients with chronic lymphocytic leukemia (lymphocytic leukemia);
• 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.

Forms of release

Capsules 140 mg (sometimes mistakenly called pills).

Instructions for use and dosing regimen

The drug Ibrutinib is taken orally, once a day, at about the same time every day. Capsules must be swallowed whole, with a glass of water; Do not open, break, or chew capsules. Do not drink grapefruit juice.

The drug Ibrutinib should be continued 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 the drug Ibrutinib for the treatment of recurrent or refractory lymphoma from the cells of the mantle zone is 560 mg (4 capsules of 140 mg) once a day.

Chronic lymphocytic leukemia and Waldenstrom macroglobulinemia

The recommended dose Ibrutinib preparation for the treatment of chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia and 420 mg (3 capsules of 140 mg), 1 time per day.

Ibrutinib recommended dose for the treatment of chronic lymphocytic leukemia when used in combination with bendamustine and rituximab (which are taken every 28 days duration of up to 6 cycles) is 420 mg (3 capsules of 140 mg), 1 time per day. Further information on bendamustine and rituximab can be found in the respective instructions for use.

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 the patient needs combined use Ibrutinib and potent inhibitor of isoenzyme CYP3A (e.g., ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole), and possible benefit outweighs probable risk, reduce the dose Ibrutinib drug to 140 mg or temporarily suspend treatment (for a period of not more than 7 days).If necessary, concomitant use Ibrutinib and moderate inhibitor isoenzyme CYP3A (e.g., voriconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, krizotiniba, combinations darunavir / ritonavir, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil) should reduce the dose Ibrutinib preparation 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 or higher, neutropenia of grade 3 or higher with infection or fever, or hematologic toxicity of the 4th degree, therapy with Ibrutinib should be stopped.

After the clinical manifestations of toxicity decrease to a power of 1 or to the initial value (that is, the restoration of the initial value will be achieved), resumption of the intake of ibro- tinib 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 per day). If necessary, a second dose reduction of another 140 mg may be considered. In the case of persistent manifestations of toxicity or recurrence after two doses of Ibrutinib, the drug should be discontinued.

Dose skip

If the next dose of the 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.

Side effect

• pneumonia;
• upper respiratory tract infection;
• urinary tract infections;
• sinusitis (inflammation of the paranasal sinuses);
• skin infections;
• sepsis;
• neutropenia, thrombocytopenia, anemia, leukocytosis, lymphocytosis;
• leukostasis (accumulation of myeloblasts in microvessels, which leads to organ dysfunction);
• dehydration (dehydration);
• Hyperuricemia (high uric acid in the blood);
• dizziness, headache;
• blurred image;
• atrial fibrillation;
• bruising, petechiae, bleeding, including nasal;
• subdural hematoma (limited intracranial accumulation of blood localized between the hard and soft medulla);
• constipation, diarrhea;
• nausea, vomiting;
• stomatitis (inflammation of the oral mucosa);
• dry mouth;
• skin rash;
• urticaria, angioedema;
• arthralgia (joint pain), musculoskeletal pain;
• fever;
• peripheral edema.

Contraindications

• increased sensitivity (for example, with anaphylactic and anaphylactoid reactions) to ibortinib or auxiliary components of the drug;
• pregnancy;
• the period of breastfeeding;
• children and adolescents under 18 years of age (efficacy and safety not confirmed);
• severe renal dysfunction;
• severe liver function disorders (Child-Pugh class C);
• patients on dialysis;
• joint application with powerful inducers of the isoenzyme CYP3A (for example, with carbamazepine, rifampicin, phenytoin and preparations containing Hypericum perforatum extract);
• joint use with warfarin, other vitamin K antagonists, fish oil and vitamin E preparations.

Application in pregnancy and lactation

Pregnancy

To date, there are no controlled studies of the drug Ibrutinib in pregnant women. According to the results of studies in animals, he is able to cause harm to the fetus in case of use in pregnant women.

The drug Ibrutinib should not be used during pregnancy.Women capable of giving birth should use highly effective methods of contraception during the intake of ibro- tinib. 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 the treatment with the drug Ibrutinib, 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 the completion of therapy with the drug Ibrutinib, 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 the drug Ibrutinib and within 3 months after its completion.

Breastfeeding period

At present, it is not known whether Ibrutinib or its metabolites are excreted in human breast milk. Because many drugs are excreted in human milk and because of the risk of serious adverse reactions in breastfeedinginfants, breastfeeding should be discontinued during therapy with Ibrutinib.

Use in children

The use of the drug Ibrutinib is contraindicated in children and adolescents under 18 years.

Application in elderly patients

The need for dose adjustment in relation to age is not confirmed.

special instructions

Hemorrhagic complications

There are reports of hemorrhagic complications in patients who received the drug Ibrutinib, 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 studies 2 and 3 phases of the drug Ibrutinib, patients who required therapy with Warfarin or other vitamin K antagonists were excluded. Warfarin and other vitamin K antagonists should not be used in combination with the Ibrutinib drug. It is necessary to avoid the use of such food additives as fish oil and preparations of vitamin E.When using the drug Ibrutinib 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.

Therapy with the drug Ibrutinib should be suspended for a period of 3 to 7 days before and after surgery depending on the type of operation and the risk of bleeding.

Leukostasis

In patients who took the drug Ibrutinib, isolated cases of leukostasis were noted. A high number of circulating lymphocytes (more than 400,000 in 1 μl) may increase the risk of leukostasis. In such cases, the possibility of temporary suspension of therapy 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 the drug Ibrutinib, there were cases of infections (including sepsis, bacterial, viral or fungal infections). Some of these infections required hospitalization or resulted in death.In patients receiving therapy with the drug Ibrutinib, there were 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.

Cytopenia

There were cases of cytopenia (neutropenia, thrombocytopenia and anemia). It is necessary to conduct a detailed blood test every month.

Interstitial lung diseases (LES)

Cases of IZL were noted in patients taking the drug Ibrutinib. It is necessary to observe for the appearance of pulmonary symptoms in patients with pulmonary tuberculosis. With the development of such symptoms, it is necessary to suspend therapy and conduct appropriate therapy. In case of persistence of symptoms of IZL, it is necessary to evaluate the benefits and risks of therapy with the drug Ibrutinib and follow the instructions for correcting its dose.

Atrial fibrillation

Atrial fibrillation and flutter were noted in patients taking the drug Ibrutinib, especially in patients with acute infections, with the presence of 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 electrocardiography (ECG) according to indications) who have arrhythmic symptoms (for example, palpitations, pre-fainting dizziness) or for the first time shows dyspnea. In the case of ongoing atrial fibrillation, it is necessary to assess the benefit / risk ratio of therapy with Ibrutinib, and if necessary, adjust the dose.

Effects on the QT interval

In clinical trials, the preparation of Ibrutinib caused an insignificant shortening of the QTcF interval. The mechanism underlying this phenomenon and its significance for drug safety are unknown. When considering the possibility of prescribing ibrotinib to patients at risk of a more pronounced shortening of the QTc interval (for example, with a congenital syndrome of a truncated QT interval or in the presence of a family history of this syndrome), it is necessary to be guided by the results of a clinical assessment of patients' health status.

Tumor lysis syndrome

Tumor lysis syndrome was noted during therapy with the drug Ibrutinib.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.

Non-malignant malignant neoplasm of the skin

In patients receiving therapy with the drug Ibrutinib, non-malignant malignant tumors of the skin were noted. It is necessary to carefully monitor patients for non-malignant malignant skin lesions.

Disposal instruction

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

Impact on the ability to drive vehicles and manage mechanisms

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

Drug Interactions

In the metabolism of Ibrutinib, the predominantly isozyme CYP3A is involved.

Drugs that can increase the concentration of ibrotinib in plasma

It is necessary to avoid the combined use of Ibrutinib with potent inhibitors of the CYP3A isoenzyme (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazodone and cobicystate) and with moderate inhibitors of the CYP3A isoenzyme (eg, voriconazole, erythromycin, amprenavir, atazanavir, ciprofloxacin, krizotinibom, the combination of darunavir / ritonavir, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil, amiodarone, dronedarone) ecause these drugs are capable of increasing the concentration Ibrutinib.

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 Ibrutinib 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 Ibrutinib to 140 mg per joint application time with a moderate inhibitor isoenzyme CYP3A.No dose adjustment is required when combined with Ibrutinib with a weak inhibitor of the CYP3A isoenzyme. Care should be taken to monitor the manifestations of toxicity in patients, and if necessary, adjust the dose according to the instructions. During the treatment with Ibrutinib, grapefruit and orange should be avoided, since these fruits contain moderate inhibitors of the CYP3A isoenzyme.

Drugs that can reduce the concentration of ibrotinib in plasma

As a result of the combined use of the drug Ibrutinib with powerful inducers of the CYP3A isoenzyme, a decrease in the concentration of ibrutinib in plasma by about 90% is observed.

Avoid joint use of Ibrutinib with powerful inducers of the CYP3A isoenzyme (eg, carbamazepine, rifampin, phenytoin and preparations containing Hypericum perforatum extract). Consider using alternatives with a lower inducing activity against the CYP3A isoenzyme.

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

Both Ibrutinib and its dihydrodiol metabolite had in vitro no more than a weak inducing effect on the activity of the CYP450 isoenzymes. Thus, the clinically significant interaction of the drug Ibrutinib with other drugs, in the metabolism of which can participate in the isozymes CYP450, is unlikely.

Systemic interaction of Ibrutinib with drugs that are substrates of P-glycoprotein is not expected. However, the possibility of inhibition of the intestinal form of the P-glycoprotein and the breast cancer resistance protein (BCRP) by the administration of Ibrutinib at therapeutic doses can not be ruled out. There are currently no clinical data available. To reduce the possibility of interaction in the gastrointestinal tract (GIT), 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 Ibrutinib. Ibrutinib can also systemically inhibit BCRP and increase the concentration of drugs that undergo BCRP-mediated hepatic efflux (for example, rosuvastatin).

Analogues of the drug Ibrutinib

Structural analogs for the active substance:

• Imbruwick.

Analogues of the drug Ibrutinib by pharmacological group (antitumor agents - inhibitors of protein kinases):

• Albitinib;
• The Athlete;
• Bosulif;
• Vargatef;
• Votrient;
• Genfatinib;
• Gefitinib;
• Giotrip;
• Histamel;
• Gleihib;
• Glivec;
• Dasatinib;
• Djakavi;
• Zelborough;
• Zikadiya;
• Ibrans;
• Iglib;
• Imagliv;
• Imatib;
• Imatinib;
• Imbruvik;
• Imvek;
• Inlita;
• Iressa;
• Capresa;
• Kiskaly;
• Cotellus;
• Xalqori;
• Lenwima;
• Mechinist;
• Nexavar;
• Neopax;
• Nilotinib;
• Ninlaro;
• Sorafenib;
• Sprysel;
• Steiverg;
• Sunitinib;
• Sutent;
• Tagrisso;
• Tayverb;
• Tarlenib;
• Tarceva;
• Taxis;
• Tafinlar;
• Tafinlar;
• Thorizel;
• Filachromine;
• Everolimus;
• Erlotinib.

Review of a hematologist

Patients suffering from chronic lymphocytic leukemia are sometimes forced to take Ibrutinib. I would describe this drug as very hard for the body. Because of the high incidence of side effects, usually manifested in the form of bleeding and infections of the respiratory and urinary tract, you have to constantly adjust the dose of the drug (reduce and then re-increase it).In the case of severe adverse reactions, Ibrutinib must be discontinued. Therefore, if the patient can appoint an analogue of this medicine, I try to do just that.

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