Imatinib

When ATH:
L01XX28

Characteristic.

The antitumor agent, an inhibitor of protein tyrosine kinase (Bcr-Abl тирозинкиназы) — abnormal enzyme, produced by the Philadelphia chromosome in chronic myeloid leukemia.

Imatinib mesylate is a white or nearly white with brownish or yellowish white crystalline powder. Soluble in aqueous buffer solutions at pH≤5,5; very slightly soluble or insoluble in neutral / alkaline aqueous solutions. The solubility in non-aqueous solvents ranging from insignificant to very unlimited in dimethylsulfoxide, methanol and ethanol; нерастворим в n-октаноле, acetone and acetonitrile. Molecular weight 589,7.

Pharmacological action.
Antitumor.

Application.

Chronic myelogenous leukemia (blastnыy crisis, acute phase and the chronic phase) if unsuccessful previous treatment with interferon alpha.

Age to 18 years (Safety and efficacy have not been established).

Can be given to pregnant women only if, if the benefits of treatment outweigh the potential risk to the fetus (adequate and well-controlled studies in pregnant women have not performed). In the case of pregnancy or during planned pregnancy must notify the patient of the potential risk to the fetus. Women of childbearing age during therapy must use effective methods of contraception.

Category actions result in FDA - D. (There is evidence of the risk of adverse effects of drugs on the human fetus, obtained in research or practice, However, the potential benefits, associated with drugs in pregnant, may justify its use, in spite of the possible risk, if the drug is needed in life-threatening situations or severe disease, when safer agents should not be used or are ineffective.)

Imatinib mesylate has teratogenic effects in rats at doses ≥ 100 mg/kg (roughly equivalent to the maximum clinical dose 800 mg / day, based on body surface area). Teratogenic effects included: èkzencefaliâ or encephalocele, the lack of decrease in frontal and parietal bones lack. Female rats at doses of ≥ 45 mg/kg (about 1/2 MRDC — 800 mg / day, based on body surface area) also there were significant losses postimplantacionnye (or early fetal resorption, or stillbirth), the birth of viable pups, the premature death of calves, between 0-4 days after delivery. At doses above 100 mg/kg fetal losses were noted in all animals, whereas at doses <30 mg / kg (about 1/3 MRDC — 800 mg / day) they have not been observed.

Females and males rats were exposed to Imatinib mesylate in dose 45 mg/kg during fetal development, starting from day 6 of pregnancy and until the end of lactation. Then these animals did not receive Imatinib about 2 Months. These rats was reduced body weight at birth and until the end of the observation. Although violations of fertility in animals were observed, experienced fetal loss after mating these males and females.

In animal experiments show, that Imatinib mesylate and its metabolites infiltrating breast milk of rats. So, with the introduction of lactating females rats at a dose of 100 mg/kg of Imatinib and its metabolites in breast milk this is extensively. Concentration in milk was approximately 3 times higher, than in plasma. Established, roughly 1,5% maternal dose of èkskretirovalos′ in milk, the equivalent dose for baby, of equal 30% maternal dose, based on body surface area. Unknown, Imatinib mesylate Lee stands out and/or its metabolites in breast milk among women. However, taking into account the possibility of the development of potentially serious side effects in the child in the case of HP in the body, Imatinib mesilate do not give nursing mothers.

In patients with chronic myelogenous leukemia was observed in most cases sideeffects of mild to moderate severity. However, the abolition of Imatinib mesylate in connection with the development of undesirable effects, associated with the acquisition of HP, was held at the 4% patients with chronic phase of the disease, in 5% patients in the acute phase and 5% patients with blastnom krize.

The most common side effects, therapy-related imatinibom, were swelling, nausea and vomiting, myalgia and muscle spasm, diarrhea, rash. Peripheral edema were observed mainly in the periorbital area and lower extremities, they were in therapy dioretikami or at the same time reducing the dose Imatinib mesylate. Expressed by peripheral edema were observed with a frequency of 0.9-6%. Side effects, associated with water retention, including pleural effusion, ascites, pulmonary edema, and rapid weight gain with peripheral edema or without them, doses were, more often observed in studies in blastnom krize and in acute phase (patients in these studies, the dose was 600 mg / day), and in elderly patients. These adverse effects are also usually removed after discontinuation of HP, When taking diuretics. However, in some cases, these complications can be serious or life-threatening. One case of death in a patient with blastnym crisis and the appearance of pleural effusion, congestive heart failure and renal failure.

The table below shows adverse effects, noted in clinical trials in patients, treated with Imatinib mesylate, and observed at ≥ 10% of patients.

Side effects, observed when conducting clinical trials in patients with chronic lymphocytic leukemia

* Other effects, associated with water retention, include pleural effusion, ascites, pulmonary edema, pericardial effusion, common swelling subcutaneous tissue (anasarca), weighed down by swelling, nonspecific fluid retention

Hematologic toxicity. Zitopenia, neutropenia and thrombocytopenia are constantly observed in all studies, with greater frequency — when assigning high (≥ 750 mg) doses (study of phase I). However, in patients with CML zitopenia depended also on the stage of the disease. In patients with newly diagnosed CML zitopenia observed less often, than other patients. Frequency of 3-4 neutropenia degree (3 degree: число нейтрофилов ≥0,5–1,0·10⁹/l, 4 degree: the number of neutrophils <0,5In the treatment of severe infections in patients with a normal white blood cell count in adults - at a dose⁹/l) thrombocytopenia and (3 degree: число тромбоцитов ≥10–50·10⁹/l, 4 degree: the number of platelets <10In the treatment of severe infections in patients with a normal white blood cell count in adults - at a dose⁹/l) was 2-3 times higher in blastnom krize and in the phase of deterioration compared to the chronic phase CML. The median duration of episodes of neutropenia and thrombocytopenia, varied from 2 to 3 Ned and from 3 to 4 weeks respectively. Dose reduction, or temporary discontinuation of treatment have led to a reduction in manifestations gematotoksicnosti.

Gepatotoksichnostь. Expressed by raising transaminaz or bilirubin observed in 3-6% of cases and usually controlled by lower doses or interruption of treatment (the median duration of such episodes was about 1 Sun). Treatment was cancelled due to a change in laboratory indexes of the liver less than 1% patients. However, one case of death — one patient in the acute phase, taking paracetamol regularly in connection with fever, He died of acute hepatic failure.

Side effects in children. Adverse effects, observed at 39 children, treated with Imatinib mesylate, were similar to those recorded in adult patients, with the exception of bone and muscle pain, observed less (20,5%); also there were no peripheral edema.

Side effects in other patient populations. In patients ≥ 65 years, There were no differences in the frequency and severity of adverse effects, except for edema, that were observed more often. Neutropenia occurred more frequently among women, as well as peripheral edema, headache, nausea, chills, vomiting, rash, fatigue. There was no racial differences, but the sample was very small.

Cooperation.

Imatinib increases the concentration of substrates isoenzymes CYP3A4 (including triazolobenzodiazepiny, BPC series digidropiridinovogo, some inhibitors of HMG-CoA reductase inhibitors, incl. simvastatin, cyclosporine, pimozid), CYP2C9 (warfarin etc.), CYP2D6, CYP3A5.

Izofermenta CYP3A4 inhibitors (incl. ketoconazole, itraconazole, Erythromycin, clarithromycin) increase the concentration of Imatinib in plasma. Displaying, that in healthy volunteers when Imatinib and single dose ketoconazole values (C)_max and AUC increased in 26 and 40% respectively. Индукторы изофермента CYP3A4 (incl. phenytoin, Dexamethasone, Carbamazepine, rifampicin, phenobarbital) reduce concentration in plasma Imatinib.

Studies in vitro shows, that Imatinib inhibits the activity of CYP2D6 izofermenta zitohroma r450 in the same concentrations, where it has an effect on the activity of CYP3A4. In this regard, may increase the system impact of medicines-CYP2D6 substrates when coupled with the use of imatinibom; Special studies have been carried out, Caution should be exercised.

In vitro Imatinib inhibits the on-glûkuronidaciû of paracetamol (K_in= 58.5 µm) at therapeutic levels. Systemic effects of paracetamol when coupled with the use of imatinibom may increase; Special studies have been carried out, Caution should be exercised.

Overdose.

Experience of application of Imatinib in doses greater than 800 mg limited. In the case of an overdose patient monitoring and appropriate symptomatic therapy.

There is a message about increasing the level of serum creatinine (severity 1), development of ascites and raising transaminaz liver (severity 2), raising cium (severity 3) in a patient with mieloidnym crisis blastnym, receiving Imatinib dose 1200 mg for 6 days. Therapy has been temporarily suspended and all these figures are completely returned to baseline values within 1 Sun. Treatment was resumed in daily dose 400 mg, While repeated increase of these indicators not mentioned.

There is also a message about the development of strong muscle cramps after taking Imatinib dose 1600 mg / day for 6 days. After a temporary cessation of therapy imatinibom convulsions have stopped.

Dosing and Administration.

Inside (while eating, with a full glass of water), 1 once a day.

Adults, the recommended daily dose in remission — 400 mg, in the acute stage and when blastnom krize — 600 mg. With the progression of the disease, lack of hematological effects within 3 months of therapy and the lack of serious side effects may increase doses: in remission, until 600 mg / day, in the acute stage and when blastnom krize — to 800 mg / day (by 400 mg 2 once a day). Treatment is prolonged, with a view to achieving and maintaining clinical and Hematological remission.

In case of occurrence of neutropenia and thrombocytopenia treatment depends on the stage of the disease. В стадии ремиссии при снижении числа нейтрофилов до 1,0·10⁹/l, тромбоцитов — до 50·10⁹/l treatment ceased to normalize indicators (нейтрофилов — не менее 1,5·10⁹/l, тромбоцитов — не менее 75·10⁹/l), treatment then resume as usual (400 mg / day); If it happens again declines below the allowed values, treatment of resume after interruption (necessary for the reconstruction of the blood) in a reduced dose is 300 mg / day. In blastnom krize and in the acute stage (the dosage is 600 mg / day) в случае снижения числа нейтрофилов менее 0,5·10⁹/л и/или числа тромбоцитов — менее 10·10⁹/l treatment ceased. To differentiate the causes of, caused citopeniû, conduct a biopsy of bone marrow; If zitopenia not associated with leukemia, dose Imatinib mesylate reduced to 400 mg; If zitopenia persists over the next 2 Sun, the dose to 300 mg; If zitopenia continues until 4 Sun, treatment ceased before the restoration of the blood (нейтрофилов — не менее 1,0·10⁹/l, тромбоцитов — не менее 20,0·10⁹/l), and then resume at a reduced dose — 300 mg / day.

If abnormal liver function (increasing the concentration of bilirubin in 3 fold compared with the upper limit of normal, liver transaminaz — 5 times compared with the upper limit of normal) treatment should be stopped, While values falls under <1,5 and <2,5 respectively. In this case treatment resume, reducing doses 400 to 300 mg and with 600 to 400 mg.

Calculating doses for children are conducted on the basis of body surface area (mg / m²). Total daily dose for children should not exceed the equivalent dosage for adults (400 and 600 mg).

Precautions.

Use only under the supervision of hematologist or oncologist, with experience of such treatment.

Fluid retention and edema. Imatinib mesilate often causes swelling and fluid retention in the body (cm. Side effects). Therefore patients should regularly monitor the weighing and signs/symptoms of fluid retention. With a sudden increase in body weight, you should carefully investigate the cause and assign appropriate therapy. Patients older 65 years, the likelihood of swelling increases and increases the risk of pleural and perikardial′nogo effusion, pulmonary edema. Expressed by the superficial edema were observed in 0,9% cases in patients with newly diagnosed CML, treated with Imatinib mesylate, and 2-6% of other adult patients, on Imatinib therapy mezilatom. Swelling disappear when lower doses and appointment dioretikov or withdrawal.

Bleeding. In clinical trials at 0,7% patients with newly diagnosed CML observed bleeding 3/4 severity.

Hematologic toxicity. Imatinib treatment mezilatom associated with the development of anemia, neutropenia, thrombocytopenia. During therapy should be monitored picture peripheral blood downloads within the first month, 1 once every 2 weeks during the second month and every 2-3 months is beyond. If CML risk zitopenia depends on the stage of the disease is increasing in blastnom krize and in acute phase.

Gepatotoksichnostь. Gepatotoksichnostь, sometimes expressed, observed in the treatment of Imatinib mezilatom (cm. «Side effects of»). In order to avoid the development of liver failure before treatment, monthly or in the presence of clinical symptoms during treatment should monitor liver function (activity transaminaz liver and AP, the content of bilirubin in the blood). In patients with hepatic insufficiency shows a careful control of the concentration of the drug in plasma to avoid intoxication.

Toxicity in long-term care. It will be appreciated, that long-term therapy Imatinib mezilatom there is a potential risk of toxicity, particularly in relation to the liver and kidneys, as well as opportunistic infections (as a consequence of immunosuppression), Since these effects were observed in animals. So, in dogs, treated with HP for 2 Sun, There was a pronounced hepatotoxicity, manifested in increasing levels of liver enzymes, Hepatocellular necrosis, necrosis or bile duct hyperplasia. Nephrotoxicity has been featured in monkeys, treated with HP for 2 Sun; She manifested focal mineralization and renal tubular dilation and nefrozom. Several of these animals was observed an increase of urea nitrogen and creatinine blood. An increase in the frequency of opportunistic infections while constantly receiving Imatinib has been noted in studies on laboratory animals. In the 39-week study in monkeys receiving Imatinib resulted in aggravation of suppressed malaria effectively infections in these animals. Lymphopenia was observed in animals (like humans).

In the case of heavy non-hematological complications (such as hepatotoxicity or fluid retention) you want to cancel receiving medication before the disappearance of these side effects (cm. "Dosage and administration").

Imatinib may cause irritation of the DIGESTIVE TRACT, Therefore, it is recommended to take with food and drink a full glass of water.