Imatinib-TL, 100 mg capsules 120 pcs
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ATC: L.01.X.E.01 Imatinib
Pharmacodynamics:
Proteintyrosine kinase inhibitor. Inhibits the enzyme Bcr-Abl-tyrosine kinase at the cellular level, in vitro and in vivo. It selectively suppresses proliferation and causes apoptosis of Bcr-Abl positive cell lines as well as young leukemia cells in Philadelphia chromosome positive chronic myeloleukemia and in acute lymphoblastic leukemia.
In colony transformation studies performed on peripheral blood and bone marrow samples, imatinib was shown to selectively inhibit Bcr-Abl-positive colonies obtained from chronic myeloleukemia patients.
In in vivo studies in animal models using Bcr-Abl-positive tumor cells, imatinib was shown to have antitumor activity with monotherapy.
In addition, imatinib is a tyrosine kinase receptor inhibitor for platelet-derived growth factor and stem cell factor and inhibits cellular responses mediated by these factors.
In vitro imatinib inhibits proliferation and induces apoptosis of GI stromal tumor cells expressing kit mutations.
Pharmacokinetics
Indications
First-time Philadelphia chromosome (Ph+)-positive chronic myeloid leukemia (CML) in pediatric and adult patients;
– Ph+ CML in the chronic phase with failure of prior interferon alfa therapy or in the phase of acceleration or blast crisis in pediatric and adult patients;
– Newly diagnosed Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) in adult patients in combination with chemotherapy;
– Recurrent or refractory Ph+ ALL in adult patients as monotherapy;
– Myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet growth factor receptor gene rearrangements in adult patients;
– Systemic mastocytosis (SM) in adult patients with no D816V c-Kit mutation or unknown c-Kit mutation status;
– Hypereosinophilic syndrome and/or chronic eosinophilic leukemia (HES/CHL) in adult patients with positive or negative abnormal FIP1L1-PDGFR alpha-tyrosine kinase;
– Inoperable, recurrent and/or metastatic bulging dermatofibrosarcoma in adult patients.
Active ingredient
Imatinib
Composition
Active ingredient:
Imatinib mesylate – 119.50 mg in terms of imatinib base 100.00 mg,
Excipients:
Microcrystalline cellulose 91.00 mg
Crospovidone 15.00 mg
Colloidal silica (Aerosil) 2.00 mg
Magnesium stearate 1.5 mg
Capsule shell:
Solid gelatin capsule #3:
[body: titanium dioxide -2%, gelatin – to 100%; 48.00 mg cap: azorubin dye (E122) – 0.0328%, sunset yellow dye (E110) – 0.219%, titanium dioxide -2%, gelatin – to 100%]
[body: titanium dioxide – 1 %, iron dye №1,yellow oxide – 0.5 %, gelatin – up to 100 %; 75.00 mg cap: titanium dioxide – 1 %, iron oxide yellow dye – 0.5 %, gelatin – up to 100 %]
How to take, the dosage
Orally, with meals, with a full glass of water. Doses of 400 and 600 mg/day should be taken in 1 dose; the daily dose of 800 mg should be divided into 2 doses – 400 mg in the morning and in the evening.
For patients who have no ability to swallow the whole capsule, such as children, the drug may be taken in diluted form, the contents of capsules diluted with water or apple juice. Place a glass with the required quantity of capsule contents, pour in liquid (approximately 50 ml of liquid for 100 mg capsules) and stir with a spoon; this will form a suspension. The resulting suspension should be taken orally immediately after preparation.
In chronic myeloid leukemia (CML), the recommended dose of imatinib depends on the phase of the disease. In chronic phase of CML the dose is 400 mg/day; in the acceleration phase and at blast crisis it is 600 mg/day. The drug should be taken once daily. Treatment with the drug is carried out as long as there is a clinical effect. In absence of marked side effects, neutropenia or thrombocytopenia unrelated to leukemia the dose can be increased from 400 to 600 or 800 mg/day in patients in chronic phase of disease and from 600 to 800 mg/day in patients in acceleration phase and at blast crisis.
This dose increase may be necessary in CML progression (at any stage), in the absence of a satisfactory hematological response after 3 months of treatment, cytogenetic response after 12 months of therapy or in the loss of previously achieved hematological and/or cytogenetic response. In children over 2 years of age, the dosing regimen is based on body surface area. A dose of 340 mg/m/day is recommended for children with chronic phase XMJI and acceleration phase. The total daily dose in children should not exceed 600 mg. The daily dose of the drug can be taken simultaneously or divided into 2 equal doses – morning and evening.
In Ph+ acute lymphoblastic leukemia (ALL) the recommended dose of the drug is 600 mg/day.
In myelodysplastic/myeloproliferative (MDS/MPD) diseases the recommended dose of imatinib is 400 mg/day.
In case of signs of disease progression, imatinib therapy should be discontinued.
In inoperable, recurrent and/or metastatic bulging dermatofibrosarcoma, the recommended dose of the drug is 800 mg/day.
In systemic mastocytosis (SM) in the absence of a D816V c-Kit mutation, the recommended dose of imatinib is 400 mg/day. With unknown mutational status and insufficient efficacy of previous therapy, the recommended dose is 400 mg/day.
In systemic mastocytosis (SM) due to the abnormal FIP1L1-PDGFR a-tyrosine kinase resulting from the fusion of the Fip likel and PDGFR genes, the recommended starting dose is 100 mg/day. If efficacy is insufficient and there are no significant side effects, the dose may be increased to 400 mg/day. In hypereosinophilic syndrome and/or chronic eosinophilic leukemia (HES/CHL) in adult patients, the recommended dose is 400 mg/day. In adult patients with HES/HEL caused by abnormal FIP1L1-PDGFR a-tyrosine kinase, the recommended starting dose is 100 mg/day. In case of insufficient effectiveness and in absence of marked side effects the dose may be increased up to 400 mg/day.
Dosage regimen correction
Patients with hepatic impairment
Since imatinib is metabolized primarily in the liver, patients with mild, moderate or severe hepatic impairment should be prescribed imatinib in the minimum daily dose of 400 mg. If undesirable toxic effects develop, the drug dose should be reduced. Caution should be exercised when prescribing the drug in patients with severe hepatic impairment.
Patients with impaired renal function
The kidneys do not play a significant role in excretion of imatinib and its metabolites. In patients with impaired renal function or in patients who require systemic hemodialysis, treatment with imatinib should be started with the lowest effective dose of 400 mg once daily, exercising caution. In case of intolerance to imatinib the initial dose of the drug may be reduced, in case of insufficient efficacy – increased.
Elderly patients
In elderly patients no adjustment of the drug dosage regimen is required.
Dosing regimen correction in the development of non-hematologic side effects of the drug
In the development of any serious non-hematologic side effect associated with taking the drug, therapy should be interrupted until the situation is resolved. Treatment may then be resumed at a dose depending on the severity of the side effect observed.
In case of bilirubin concentration increase and increase of “liver” transaminases activity in blood serum 3 and 5 times higher than the upper limit of norm (ULN) correspondingly, the drug treatment should be temporarily suspended until bilirubin concentration decreases to values less than 1.5 x ULN and “liver” transaminases activity to values less than 2.5 x ULN.
Imatinib therapy is resumed with a reduced daily dose: in adult patients the dose is reduced from 400 to 300 mg/day or from 600 to 400 mg/day or from 800 to 600 mg/day; in children – from 340 to 260 mg/m2/day.
Dosage regimen correction in case of serious adverse effects of blood and lymphatic system (severe thrombocytopenia, neutropenia)
In case of neutropenia and thrombocytopenia a temporary drug withdrawal or dose reduction is required, depending on the degree of these adverse events. In CM and HES/HEL caused by abnormal FIP1L1-PDGFR a-tyrosine kinase (initial dose of imatinib is 100 mg) in case of decrease of absolute neutrophil number <1*109/l and/or platelet number <50*109/l is recommended:
– discontinue imatinib until the absolute neutrophil count is >1.5* 109/l and platelet count is >75*109/l ;
– resume imatinib treatment at the dose used before interruption of therapy.
In the chronic phase of CML in pediatric and adult patients, MDS/MPH, CM and HES/CHEL in adult patients (starting dose for adult patients is 400 mg, for children is 340 mg/m2) in case of a decrease in absolute neutrophil count <1*109/l and/or platelet count <50*109/l is recommended:
-continue imatinib until the absolute neutrophil count is >1.5*109/L and platelet count is >75* 109/L;
– resume imatinib treatment at the dose used prior to interruption of therapy.
If the neutrophil count <1*109/L and/or platelet count <50*10/L decrease again, imatinib should be discontinued until the absolute neutrophil count becomes >1.5*10% and platelet counts >75*109/L, and then resume treatment with imatinib at a reduced dose of 300 mg (260 mg/m in children).
In the phase of acceleration and power crisis of CML in children and adults and in Ph+ acute lymphoblastic leukemia in adult patients (initial dose for adults – 600 mg, for children – 340 mg/m2) in case of absolute neutrophil count <0.5*109/l and/or platelet count <1*109/l decrease after one or more months of treatment is recommended:
– check whether the cytopenia is due to leukemia (bone marrow study);
– If cytopenia is not associated with leukemia, reduce the dose of imatinib to 400 mg (in children – 260 mg/m2);
– if ditopenia persists for 2 weeks, reduce the dose to 300 mg (in children – 200 mg/m2);
– if cytopenia persists for 4 weeks and its association with leukemia is not confirmed, discontinue imatinib until the absolute neutrophil count is >1*109/l and platelet count is >20*109/l; then resume treatment with imatinib at a dose of 300 mg (in children – 260 mg/m2).
In inoperable, recurrent and/or metastatic bulging dermatofibrosarcoma (starting dose of imatinib is 800 mg), if the absolute neutrophil count <1*109/L and/or platelet count <50* 109/L decrease is recommended:
– Discontinue imatinib until the absolute neutrophil count is >1.5*109/L and platelet count is >75*10/L;
– Resume treatment with imatinib at a dose of 600 mg.
If the neutrophil count <1*109/l and/or platelet count <50*10/l, imatinib should be discontinued again until the absolute neutrophil count is >1.5*109/l and platelet count is >75*109/l, and then resume treatment with imatinib at the reduced dose of 400 mg.
Interaction
In concomitant use of imanitib with drugs that inhibit the CYP3A4 isoenzyme of cytochrome P450, such as viral protease inhibitors (indinavir, lopinavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir), antifungal drugs of the azole group (including ketoconazole, itraconazole, voriconazole).including ketoconazole, itraconazole, posaconazole, voriconazole), some macrolide antibiotics (erythromycin, clarithromycin, telithromycin), metabolism of imatinib may be slowed and its concentration in blood plasma may increase. Caution is required when using imatinib concomitantly with drugs with CYP3A4 isoenzyme inhibitors.
In concomitant use of imatinib and simvastatin, there is a 2 and 3.5-fold increase in Cmax and AUC of simvastatin, respectively, which is due to inhibition of CYP3A4 by imatinib. Caution is recommended when concomitant use of imatinib and drugs that are substrates of CYP3A4 and have a narrow range of therapeutic concentration (e.g., cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, fentanyl, terfenadine, bortezomib, docetaxel, quinidine). Imatinib may increase serum concentrations of other drugs metabolized by CYP3A4 isoenzyme (triazolobenzodpaseppines, dihydropyridine, “slow” calcium channel blockers, most HMG-CoA reductase inhibitors, including statins).
Imatinib also inhibits CYP2C9 isoenzyme and CYP2C19 isoenzyme in vitro. When concomitant use with warfarin, prolongation of prothrombin time was observed. Concomitant use with coumarin derivatives requires short-term monitoring of prothrombin time at the beginning and end of therapy, as well as when changing the dosing regimen. As an alternative to warfarin, the use of low molecular weight heparins should be considered.
The issue of drug interactions between imatinib and chemotherapy drugs in patients with Ph+ OLL is poorly understood. Caution should be exercised when concomitant use of imatinib and chemotherapy drugs due to possible increased risk of drug complications, such as hepatotoxicity, myelosuppression and others.
When combining imatinib with chemotherapeutic agents at high doses, transient hepatic toxicity as increased liver transaminase activity and hyperbilirubinemia may develop. When combining imatinib and chemotherapy regimens that have the potential to cause liver dysfunction, liver function monitoring should be considered.
Invitroimatinib inhibits the CYP2D6 isoenzyme of cytochrome P450 at the same concentrations at which it inhibits the CYP3A4 isoenzyme.
In patients after thyroidectomy receiving levothyroxine sodium hormone replacement therapy, its concentrations may decrease when used simultaneously with imatinib.
There have been reports of liver damage with concomitant use of imatinib and asparaginase.
Cases of fatal liver failure have been reported when imatinib is taken concomitantly with paracetamol.
Special Instructions
The treatment with imatinib should only be performed under the supervision of a physician experienced in the use of antitumor drugs.
In cases of marked fluid retention have been reported with imatinib, regular monitoring of body weight is recommended. If there is a sudden rapid increase in body weight, an examination should be performed and, if necessary, imatinib therapy should be temporarily discontinued and/or diuretics should be started.
The development of neutropenia or thrombocytopenia has been noted with imatinib; these events have a clear relationship to the stage of the disease, with a higher incidence in patients with CML in the blast crisis or acceleration phase compared to patients with CML in the chronic phase. Temporary suspension of therapy or reduction of imatinib dose may be necessary.
When using imatinib it is recommended to perform regular clinical blood tests and monitor liver function (transaminases, bilirubin, ALP). When using in patients with liver disease, regular clinical blood tests should be performed and liver enzyme activity should be determined.
Imatinib and its metabolites are excreted by the kidneys to a small extent. Creatinine clearance decreases with age, and age has no significant effect on the pharmacokinetic parameters of imatinib. There is no correlation between imatinib exposure and renal function impairment in patients with renal impairment from mild (creatinine clearance 40-59 ml/min) to severe (creatinine clearance <20 ml/min) degrees of severity. However, the initial dose of imatinib should be reduced if intolerance is present in patients in this category.
There have been reports of hypothyroidism with imatinib in patients who have undergone thyroidectomy and are receiving levothyroxine sodium replacement therapy. Regular determination of thyrotropic hormone concentration in this category of patients should be performed.
Patients with cardiovascular diseases, risk factors for heart failure, and patients with a history of renal failure should be closely monitored. If signs or symptoms suggestive of these conditions are identified, the patient should be evaluated and appropriate treatment initiated.
In patients with myelodysplastic/myeloproliferative diseases and high eosinophil counts, serum cardiac-specific troponin concentrations should be measured. Prophylactic use of systemic GCS for 1-2 weeks concomitantly with imatinib should be considered if deviations from normal values are detected at the beginning of therapy.
There have been anecdotal reports of vascular ectasia of the gastric antrum (GAVE syndrome), a rare cause of gastrointestinal bleeding, reported in patients with CML and OLL and other conditions.
Gastrointestinal conditions in patients with metastatic malignant GVHD (abdominal pain, gastrointestinal bleeding, constipation and others) should be monitored at baseline and throughout therapy with imatinib. Discontinuation of imatinib therapy should be considered if necessary.
Because of the risk of tumor lysis syndrome, clinically significant dehydration and elevated uric acid concentrations should be corrected before use of imatinib, if necessary.
In patients who are carriers of hepatitis B virus, reactivation of this virus after therapy with BCR-ABL tyrosine kinase inhibitors such as imatinib is possible. In some cases during the use of this class of medications development of acute hepatic failure or fulminant hepatitis has been noted, leading to liver transplantation or death.
Before starting therapy with imatinib, all patients should be screened for hepatitis B virus. Patients who are carriers of hepatitis B virus should be closely monitored for signs and symptoms of active infection both during treatment with imatinib and for several months after therapy with imatinib.
Impact on driving and operating machinery
Some side effects, such as dizziness and blurred vision, may adversely affect the ability to drive and perform other potentially hazardous activities that require increased concentration and rapid psychomotor reactions. Therefore, patients should refrain from performing the above mentioned activities in case of manifestation of the described adverse effects.
Contraindications
Hypersensitivity to the active ingredient or any other component of the drug, pregnancy, breastfeeding, children under 2 years of age (safety and efficacy not currently established).
With caution:
Caution should be exercised when prescribing imatinib in patients with severe hepatic impairment, severe renal impairment, cardiovascular
disease and/or if there are risk factors for heart failure, and if regular hemodialysis is performed.
Side effects
Infectious and parasitic diseases: infrequent – herpes zoster, herpes simplex, nasopharyngitis, pneumonia, sinusitis, subcutaneous tissue inflammation, upper respiratory tract infections, flu, urinary tract infections, gastroenteritis, sepsis; rarely – mycosis.
Hematopoietic system disorders: very common – neutropenia, thrombocytopenia, anemia; common – pancytopenia, febrile neutropenia; infrequent – thrombocythemia, lymphopenia, suppression of medullar hemopoiesis, eosinophilia, lymphadenopathy; rare – hemolytic anemia
Metabolism: very often – weight gain; often – anorexia, weight loss; infrequent – hypokalemia, increased appetite, hypophosphatemia, decreased appetite, dehydration, hyperuricemia, gout, hypercalcemia, hyperglycemia, hyponatremia; rarely – hyperkalemia, hypomagnesemia.
Psychiatric disorders: frequently – insomnia; infrequently – depression, decreased libido, anxiety; rarely – mental confusion.
Nervous system disorders: very commonly – headache; frequently – dizziness, paresthesia, taste disorder, hypoesthesia; infrequently – migraine, somnolence, syncope, peripheral neuropathy, memory disorders, sciatica, restless legs syndrome, tremor, hemorrhagic stroke; rarely – increased intracranial pressure, seizures, optic neuritis.
VIight organ disorders: often – eyelid edema, increased lacrimation, conjunctival hemorrhages, conjunctivitis, “dry eye” syndrome, blurred (hazy) vision; infrequent – eye irritation, eye pain, orbital edema, sclera hemorrhages, retinal hemorrhages, blepharitis, macular edema; rarely – cataract, optic disc edema, glaucoma.
Hearing and vestibular disorders: infrequent – vertigo, tinnitus, decreased hearing.
Cardiovascular system disorders: frequent – flushes, hemorrhage; infrequent – palpitations, tachycardia, chronic heart failure, pulmonary edema, increased or decreased BP, hematoma, subdural hematoma, cold extremities, Raynaud’s syndrome; rare – arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion.
Respiratory system: frequently – nasal bleeding, dyspnea, cough; infrequently – pleural effusion, pain in the pharynx or larynx, pharyngitis; rarely – pleural pain, pulmonary fibrosis, pulmonary hypertension, pulmonary hemorrhage.
Digestive system disorders: very common – nausea, vomiting, diarrhea, dyspepsia, abdominal pain; common – abdominal bloating, flatulence, constipation, gastroesophageal reflux, dry mouth, gastritis; infrequent – stomatitis, ulceration of the oral mucosa, gastrointestinal bleeding, belching, melena, esophagitis, ascites, stomach ulcer, vomiting blood, cheilitis, dysphagia, pancreatitis; rare – colitis, paralytic/obstructive intestinal obstruction, inflammation of the colon.
Hepatic and biliary tract disorders: often – increased activity of liver transaminases; infrequent – jaundice, hepatitis, hyperbilirubinemia; rare – hepatic failure, liver necrosis.
Skin and subcutaneous tissue disorders: very common – periorbital edema, dermatitis, eczema, skin rash; common – skin itching, facial swelling, dry skin, erythema, alopecia, night sweating, photosensitization reactions; infrequent – pustular rash, petechiae, increased sweating, urticaria, ecchymosis, predisposition to formation of hematomas, hypotrichosis, hyperpigmentation/hypopigmentation of the skin, exfoliative dermatitis, nail damage, folliculitis, petechiae, psoriasis, purpura, bullous rash; rare – acute febrile neutrophilic dermatosis (Sweet’s syndrome), discoloration of nails, angioedema, vesicular rash, erythema multiforme, leukoplastic vasculitis, Stevens-Johnson syndrome, acute generalized pustular exanthema.
Muscular system disorders: very frequently – muscle spasms and cramps, musculoskeletal pain, including myalgia and arthralgia, bone pain; frequently – swelling of joints; infrequently – stiffness of muscles and joints; rarely – muscle weakness, arthritis.
Urinary system: infrequent – renal pain, hematuria, acute renal failure, frequent urination.
Reproductive system disorders: infrequent – gynecomastia, erectile dysfunction, menorrhagia, menstrual cycle disorders, sexual dysfunction, nipple pain, breast enlargement, scrotal edema.
Actually: very often – fluid retention, edema, increased fatigue; often – weakness, increased body temperature, anasarca, chills, shivering; infrequently – pain in the chest, general malaise.
Laboratory measures: infrequent – increase of creatinine concentration in blood, increased CPK activity in blood, increased ALP activity, LDH; rare – increase of amylase activity in plasma.
Overdose
There are reports of individual cases of imatinib overdose.
Overdose in adults
In one case, when imatinib was taken at a dose of 1200-1600 mg for 1-10 days, patients experienced: nausea, vomiting, diarrhea, rash, erythema, edema, facial swelling, increased fatigue, muscle cramps, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.
When taking the drug in a dose of 1800-3200 mg weakness, myalgia, increased blood creatine phosphokinase activity, bilirubin concentration, gastrointestinal pain were noted.
When the drug was administered in a single dose of 6400 mg (information from the published source) the patient developed nausea, vomiting, abdominal pain, hyperthermia, facial edema, decreased platelet count and increased liver transaminase activity. When taking the drug in dose of 8-10 g once vomiting and gastrointestinal pain were noted.
Overdose in children and adolescents
When taking the drug in dose 400 mg once in children aged 3 years vomiting, anorexia, diarrhea were noted, and in dose 980 mg – decrease of leukocyte count and diarrhea. Treatment: medical observation and symptomatic therapy are recommended. The antidote for imatinib is not known.
Pregnancy use
There are currently no data on the use of imatinib in pregnant women. Animal studies have shown toxic effects on reproductive function, but the potential risk to the fetus is not yet known. Imatinib use is contraindicated during pregnancy. Women of childbearing age should use effective contraception during imatinib therapy and for at least 3 months after treatment.
It is currently unknown whether imatinib is excreted with breast milk in breastfeeding women. Studies in animals have shown that unchanged drug and/or its metabolites are excreted in significant amounts with milk. Women taking imatinib should avoid breastfeeding.
Weight | 0.084 kg |
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Shelf life | 2 years. Do not use after the expiration date. |
Conditions of storage | Store in a dark place at a temperature not exceeding 25 °С. Keep out of reach of children. |
Manufacturer | Drug Technology, Russia |
Medication form | capsules |
Brand | Drug Technology |
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