Glivec 100mg Novartis medicine for chronic marrow leukemia (6 blisters x 10 tablets)

Dosage form Box of 6 blisters x 10 tablets
Specifications Imatinib

Ingredient

Composition information	Content
Imatinib	100mg

Uses

Indications

Glivec drug indicated in the following cases:

Treatment of adult patients and children over 2 years of age with chronic medulla with Philadelphia chromosomes (pH + CML) has been diagnosed (for use for children to see the dosage and usage). Chronic after failing with Interferon-alpha treatment. Single therapy. Treatment of adult patients with eosinophilia syndrome (HES) and//or chronic leukemia (CEL). Adults Sarcom convex fiber (DFSP) cannot be removed, recurrent or metastatic. This compound selectively inhibits proliferation and promotes cell death according to the program (Apoptosis) in the cell line with positive BCR-ML as well as new cellules of leukemia of patients with CML with positive Philadelphia chromosomes and patients with acute lymphocytes (All). In the tests that change the form of peripheral blood samples and bone marrow Ex vivo, Imatinib shows the selective inhibition of positive BCR-Ml cell lines in patients with chronic leukemia.

In vivo this compound shows the anti-tumor effect as a single substance in the animal models using tumor cells with BCR-Ml positive.

Imatinib is also a tyrosin kinase receptor inhibitor for platelet-derived growth factors (PDGF) and germ cell factors (SCF), C-KIT, and inhibitors of PDGF and SCF intermediaries. In vitro, Imatinib inhibit proliferation and promote cell death under the program in the gastric gastric tumor cell (GIST), indicating a mutant C-KIT active. The basic activation of PDGFR or ABL Protein Tyrosin Kinase as a result of a combination of different proteins or the production of components of PDGF shows the pathological association of MDS/MPD, HES/CEL and DFSP. Moreover, the basic activation of C-KIT or PDRFG shows the pathological relevance of systemic cell tumor (SM). Imatinib inhibits signal transmission and cell proliferation due to activity adjustment disorders of PDGFR, C-KIT and ABL Kinase.

Dynamic pharmacokinetics

Glivec pharmacokinetics are assessed at a dose of 25 to 1,000 mg. Plasma pharmacokinetics charts are analyzed on the first and 7th day or 28th day that at that time the concentration in plasma achieved stable state.

absorption

Absolute average bioavailability for imatinib capsules is 98%. The variable coefficient under the concentration curve (AUC) of imatinib in plasma is 40% to 60% after taking a dose of oral. When eating high -fat meals, the maximum absorption rate of imatinib (down 11% in plasma (CMAX) and extends the time reaches the highest concentration in plasma (TMAX) to 1.5 hours), reducing the area under the concentration curve (7.4%) compared to hunger.

distribution

In clinical imatinib concentrations, the ratio is attached to plasma proteins about 95% on the basis of in vitro experiments, mostly attached to albumin and alpha-acid-glycoprotein, which is low with lipoprotein.

transformation

The main metabolite circulating in humans is the Piperazine N-Methyl (CGP71588) derivatives that In Vitro shows the same effect as the original substance. The area below the concentration curve in the relatively bloody blood of this metabolite is only 16% of the area below the concentration curve of the imatinib. The attachment to plasma proteins of metabolic metabolites is similar to the original substance.

Elimination

Based on finding the compounds after taking an imatinib dose of 14C radioactive, about 81% of the dose is eliminated within 7 days in the feces (68% of the dose) and urine (13% dose). The constant amount of imatinib accounts for 25% of the dose (5% in urine, 20% in feces), the rest are metabolites.

Before taking Glivec 100mg Novartis medicine for chronic marrow leukemia (6 blisters x 10 tablets)

How to use

Glivec drug treatment should be started when suitable by a doctor who has experience in treating patients with malignant tumors and malignant sarcoms.

Oral drugs with meals and a glass of water to minimize the risk of digestive disorders.

For patients who cannot swallow film bags, can mix tablets into a glass of water or apple juice. The number of tablets to be used should be added to an appropriate amount of drink (about 50 ml for 1 tablet of 100 mg and 200 ml for 1 tablet of 400 mg) and stir with a spoon.

The mixture must be used immediately after the tablet has completely disintegrated.

It is necessary to continue treatment as well as the patient.

Monitoring response to Glivec in patients with PH+CML should be conducted regularly and when the treatment is adjusted, to determine the response below the optimal level, the loss of response to treatment, the patient's poor compliance, or drug interaction. The monitoring results will guide the appropriate management of CML.

Take the prescribed dose of 400 mg or 600 mg once/day while the dose of 800 mg/day should be used 400 mg, 2 times/day, in the morning and evening.

Dosage

recommended dose

Dosage for CML disease

recommended dose of Glivec is 400 mg/day for adult patients with chronic CML disease and 600 mg/day for patients during acceleration or sperm attacks.

It is possible to consider increasing the dose from 400 mg to 600 mg or 800 mg in patients with chronic diseases, or from 600 mg to up to 800 mg/day in patients during accelerating phase or sperm attack when there is no severe side effect with medication and neutropenia or severe platelet reduction does not related to leukemia in the following conditions: Progressive disease (any time) cell genetics after 12 months of treatment, or loss of hematology and/or cell genetics have been achieved before.

Dosage for children over 2 years: Dosage for children should be based on the body surface area (mg/m2). The dose of 340 mg/m2/day is recommended for children with a chronic and progressive period of CML (not exceeding the total dose of 600 mg/day). It is possible to treat one dose 1 time/day or another way is the daily dose that can be divided into 2 use: once in the morning and once in the evening.

Dosage for PH+ All

Dosage Glivec recommends 600 mg/day for adult patients with pH+ All.

Dosage for children: Dosage for children should be based on the body surface area (mg/m2). The dose of 340 mg/m2/day is recommended for children with PH+ All (not exceeding the total dose of 600 mg/day). Can treat one dose 1 time/day.

Dosage for MDS/MPD disease

The recommended dose of Glivec is 400 mg/day for adult patients with MDS/MPD.

Dosage for SM

The recommended dose of Glivec is 400 mg/day for an adult patient with SM without D816V C-Kit or an unknown mutation or non-response to other therapies.

For patients with SM combined with eosin leukemia, a line of hematology related to FIP1L1L1-PDGFR-ALPHA Fip1-PDGFR-ALPHA, the starting dose of 100 mg/day is recommended. Increasing the dose from 100 mg to 400 mg for these patients may be considered without the side effects of the drug, if the assessment shows that response to treatment is incomplete.

Dosage for HES/CEL

recommended dose of gluvec is 400 mg/day for adult patients with Hes/Cel.

For patients with HES/CEL with FIP1L1-PDGFR-Alpha Fusion Kinase has been proven, the starting dose of 100 mg/day is recommended. Increasing the dose from 100 mg to 400 mg for these patients may be considered without the side effects of the drug, if the assessment shows that response to treatment is incomplete.

Dosage for gist

recommended dose of Glivec is 400 mg/day for adult patients with malignant gist that cannot be removed or metastatic.

It is possible to consider increasing the dose from 400 mg to 600 mg or 800 mg for patients when there are no side effects with the drug if the assessments see inadequate treatment.

recommended dose of Glivec is 400 mg/day for complementary treatment for adult patients after gust removal surgery. The minimum treatment time is recommended for 36 months.

Optimal treatment time with Glivec for complementary treatment is not clear.

Dosage for DFSP

The recommended dose of Glivec is 800 mg/day for adult patients with DFSP.

Adjust the dose for side effects of drugs

Auxiliary reactions of non -hematoma

If a side reaction of non -hematoma is severe when using Glivec, it is necessary to stop treating until this event is resolved. Then can be treated again when appropriate depending on the initial weight of that side effect.

If the bilirubin level increases more than 3 times the upper limit of normal level (IULN) or liver transaminase increases more than 5 times Iuln, it is necessary to stop glivec until the concentration of bilirubin returns

Adjust the dose for neutropenia and thrombocytopenia

SM is combined with eosin cells and hes/cells with FIP1L1-PDGFR-Alpha Fusion Kinase (starting dose 400 mg):

ANC

stop using Glivec until ANC ≥ 1.5 x 109/l and platelets ≥ 75 x 109/l. Mg):
ANC
1. stop using Glivec until ANC ≥ 1.5 x 109/l and platelets ≥ 75 x 109L. The dose has dropped to 300 mg.
  ANC
  1. stop using Glivec until ANC ≥ 1.5 x 109/l and platelets ≥ 75 x 109/l. Glivec with the dose has decreased to 260 mg/m2.
    aanc
    1. Check if blood cell reduction is related to leukemia or not (bone marrow detection or biopsy). Stop using Glivec until ANC ≥ 1 x 109/l and platelets ≥ 20 x 109/l, then treat back at a dose of 300 mg.
      ANC
      1. stop using glivec until anC ≥ 1.5 x 109/l and platelets ≥ 75 x 109/l. mg.
      2. ANC = Absolute number of neutrophils.
      3. A occurs after at least 1 month of treatment.
        Children
        Inexperienced in using glivec for children under 2 years old with CML and children under 1 year of age with PH+ All. There is very little to no experience in using Glivec for children in other indications.
        Dosage for children should be based on the body surface area (mg/m2). The dose of 340 mg/m2/day is recommended for children with CML and pH+ All phase of chronic and progressive phase (do not exceed the total dose of 600 mg/day). It is possible to treat one dose 1 time/day in the indication of CML and pH+ All. For the daily dose Idental Distance, it can be divided into 2 times: Once in the morning and once in the evening.
        Patients with liver failure
        Imatinib is metabolized mainly by the liver. Patients with mild, medium or severe liver dysfunction should be used for the lowest doses recommended by 400 mg/day. This dose may be reduced if not tolerated.
        Reduce kidney function
        Imatinib and its metabolites are insignificant excretion through the kidneys. Patients with kidney dysfunction or are in feces may be recommended by the lowest starting dose of 400 mg/day (see pharmacological part). However, caution recommends for these patients. This dose may be reduced if not tolerated. If tolerated, the dose may increase if ineffective.
        Elderly patients
        Not observing a significant difference in pharmacokinetics related to adult patients in clinical trials including over 20% of patients aged 65 and over. No special recommended dose for elderly patients.
        Note: The above dose is for reference only. Specific dosage depends on the condition and level of progression of the disease. For a suitable dose, you need to consult a doctor or medical specialist.
        
        What to do when using overdose? The individually overdose of Glivec has been spontaneously reported and in literature. In the general, these cases are reported to be improved or recovered. In case of overdose, patients must be monitored and have appropriate symptomatic treatments.
        The events are reported at different doses as follows:
        Adults
        Dosage from 1,200 to 1,600 mg (with a period of change between 1 to 10 days): symptoms of nausea, vomiting, diarrhea, rash, erythema, edema, swelling, fatigue, muscle spasms, platelet reduction, reduced hemorrhage, abdominal pain, headache, decreased appetite.
        Dosage from 1,800 to 3,200 mg (equivalent to 3,200 mg/day for 6 days): weak body, muscle pain, increased CPK, increased bilirubin, stomach pain.
        The dose of 6,400 mg (single dose): A case in the literature is reported, patients with nausea, vomiting, abdominal pain, fever, face swelling, reduced neutropenia, increased transaminase.
        Dosage from 8 to 10 g (single dose): Vomiting and stomach pain have been reported.
        Children
        A 3 -year -old boy with a single dose of 400 mg has vomiting, diarrhea and anorexia and another 3 -year -old boy using a single dose of 980 mg is reduced leukocytes and diarrhea.
        In an emergency, call the 115 emergency center immediately or go to the nearest local health station.
        
        What to do when forgetting 1 dose? However, if the time to relax with the next dose is too short, skip the dose and continue the calendar of the drug. Do not use double dose to compensate for missed dose.

Side Effects

Summary of safety

The general characteristics of Glivec's safety in humans are clearly described over 12 years of experience using Glivec. In the process of clinical development, most patients undergo side effects at some time. The most common side effects of the drug (> 10%) are reported: neutropenia, thrombocytopenia, anemia, headache, digestive disorders, edema, weight gain, nausea, vomiting, cramps, muscle aches, diarrhea, rash, fatigue, and abdominal pain. Mild to medium reactions, and only 2 to 5% of patients have to stop permanent treatment due to drug -related reactions.

Glivec safety in adult patients and children with leukemia pH+ is similar.

Differences in safety characteristics between pH leukemia and concentrated tumor are higher bone marrow inhibitor ratio and more seriousness in pH leukemia, and gastrointestinal bleeding and hemorrhage in tumors in Gist patients and almost certainly due to factors related to the disease. Inhibiting bone marrow, side effects in the gastrointestinal tract, edema and common rash in these two groups of patients. The pathological condition of other gastrointestinal tract, such as gastrointestinal obstruction, perforation and ulcers, seems to appear specially as prescribed. Other outstanding side effects have been observed after using glivec, and may have causal relationships, including liver toxicity, acute renal failure, hypoglycemia, serious adverse response reactions, tumor solving syndrome and child growth slowly.

may need to adjust the dose, depending on the severity of the reaction. Very few cases have to stop drugs due to side effects of the drug.

The adverse reactions are listed according to the title of frequency, first is the most common, using the following convention: Very common (≥1/10), common (≥1/100,

Disadvantages in clinical research for CML and Gist

Infections and parasites:

Uncommon: shingles (herpes zoster), herpes simplex, nasopharyngitis, pneumonia, sinusitis, cellular inflammation. Upper respiratory tract infections, influenza, urinary tract infections, gastritis, blood infections

Very common: neutropenia, thrombocytopenia, anemia Nursing:

Common: Anorexia.

Common: Insomnia

Very common: headache 2.

Eye disorders:

Common: eyelid edema, increased tear secretion, conjunctival bleeding, conjunctivitis, dry eyes, blurred vision.

Less: dizziness, tinnitus, deafness.

Heart disorders:

Uncommon: beating the chest, heart beating, heart failure, hemorrhage 3, pulmonary edema.

Common: Flushing, hemorrhage

Less: Hypertension, Hematoma, Hematoma under the endomology, cold limb, hypotension, Raynaud phenomenon.

Common: Difficulty breathing, nosebleeds, cough.

Very common: nausea, diarrhea, vomiting, indigestion, abdominal pain 6.

Rare: colitis, bowel obstruction, Inflammation.

Hepatic disorders:

Common: Increasing liver enzymes

Uncommon: increased blood bilirubin, hepatitis, jaundice.

Very common: edema around the eye sockets, ductzema/ban inflammation. Bleeding spots, psoriasis, hemorrhage, hyperpigmentation, water balls

Musculoskeletal and connective tissue disorders:

Very common: muscle spasm and muscle spasm, musculoskeletal pain including muscle pain, joint pain, bone pain 8.

Less: kidney pain, blood urination, kidney failure, increase the number of urination.

Reproductive and breast disorders:

Less: Big breasts in men, erectile dysfunction, menstrual period, irregular menstruation, genital dysfunction, nipple pain, enlarged breast, scrotum.

Very common: fluid and edema, fatigue

Very common: weight gain.

Common weight loss.

1 pneumonia is most commonly reported in patients with CML in the form and in gist patients.
2 The most common headache in patients with gist. Gist patients and patients with CML transfer form (CML-AP and CML-BC)
5 Pleural effusion are commonly reported in Gist patients and patients with CML transfer (CML-AP and CML-BC) rather than in chronic CML patients. More in patients with Gist.

The following forms of side effects are reported from after -sales experience and from added clinical studies with Glivec. These side effects include spontaneous reports as well as serious side effects of drugs from smaller clinical studies or conducted studies and expanded approaches. Because the reactions of this drug are reported from a population with unknown population, it is not reliable in a reliability of their frequency or establishing causal relationships with the use of Glivec.

Disadvantages from after -sales reports

Infections and parasites:

Unknown: Activation of hepatitis b.

Nervous system disorders:

Uncommon: Brain edema.

Eye disorders:

Rare: Glass epidemic hemorrhage (crystal).

Heart disorders:

Rare: pericarditis, heart compression.

Uncommon: thrombosis/embolism.

Rare: Anaphylaxis.

Uncommon: Level 1 respiratory failure, interstitial pneumonia.

Gastrointestinal disorders:

Uncommon: intestinal obstruction, tumor hemorrhage/necrotic tumor, gastrointestinal puncture 2.

Uncommon: Hand and feet redness syndrome. Body.

Rare: Votoric necrosis/hip necrosis, muscle -muscular globin/muscle disease.

Very rare: Hemorrhage/Ovarian cysts

benign, malignant and uncertain (including cysts and polyps):

Rare: Tumor solving syndrome.

2 In some cases of death from the gastrointestinal perforation.

Describe the selective side effects of the drug

bone marrow inhibition

Bone marrow inhibitor is very common in cancer patients with Glivec treatment. Inhibiting bone marrow, thrombocytopenia, neutropenia, and anemia are 3 and 4 abnormalities on the most common tests that have been reported. Overall, bone marrow inhibition in patients with CML used Glivec often recovers and in most patients without interrupting dosage or reducing the dose. A few patients need to stop the drug. Other reactions such as reduced hemorrhage, reduced lymphocytes and bone marrow inhibitors have also been reported.

Hemoclasses reduction can appear most at the highest dose and appear depending on the stage of CML disease, neutral neutropenemia and platelet reduction of 3 or 4 platelets at 4 to 6 times higher than the cell and acceleration period (44% for neutrophils and 63% for platelet reduction) when compared with patients with chronic medulla, diagnosis of chronic microscopic reduction (neutral hypocopulation platelets). These events can usually handle by reducing the dose or stopping treatment, but rarely need to stop treatment with Glivec. The rate of hematology toxicity in patients with concentrated tumors (for example, gist) is lower than patients with leukemia with Piladelphia chromosomes, about 10% of neutropenia reduction in 3 or 4 and 1% reduction of platelets 3 or 4.

Bleeding

The central nervous system hemorrhage and gastrointestinal bleeding are not uncommon in patients with chronic marrow leukemia with the injured marrow function from the beginning. Hemorrhage is a recognizable sign of complications in the group of subjects with acute leukemia, which may be the result of platelet reduction, or less common than platelet dysfunction. However, not all patients with central nervous system hemorrhage and gastrointestinal bleeding during the treatment of imatinib have platelets.

The most common manifestation of clinical bleeding is gastrointestinal bleeding, the most common occurrence in patients with chronic marrow leukemia and in metastatic gist patients, in which bleeding may occur as part of the main disease due to tumor bleeding due to tumor hemorrhage/necrosis of tumor. Observed the lowest frequency of gastrointestinal bleeding in the context of a one -cm step treatment and a supplementary treatment. It is also rare for after -sales reports on vasodilation (GAVE) when treated with Glivec.

edema and fluid

edema is a common toxicity of imatinib appearing over 50% of patients of all indications. Edema is related to the dose and the correlation between the appearance of edema and the concentration of drugs in plasma. The most common manifestation is edema around the eyes and less common than the lower chi. Usually there is no need for specific treatment. Other congestion events are less common, but because in anatomical position, it may be serious. The most common stasis of pleural fluid is the most common in patients with chronic marrow leukemia and metastatic gist. The frequency of heart failure is often low in patients with edema and fluid. This frequency is higher in patients with chronic medulla, compared to other groups. This is explained by health condition in patients with malicious marrow leukemia. Also notice the same trend of renal failure in patients with edema and fluids.

In a clinical study, the frequency of hemorrhagic heart failure events is 1.5% in the imatinib group compared to 1.1% of the group using ifn-alpha in patients with chronic medulla. The higher frequency is significantly higher in patients with chronic medullary white blood cells (accelerated or higher age), or with hemoglobin at the beginning less than 8g/dl. Hemorrhagic heart failure and left ventricular dysfunction are continued to monitor in periodic alignment reports (PSUR: Periodic Safety Update Report). In all indications, it is found that patients with chronic medulla have a higher frequency of congestive heart failure than the Gist patient, which may indicate the difference of some risk factors associated with the disease. In addition, a particularly announced safety analysis of the heart events in EorttC research on 942 patients with Gist can not be removed or metastatic gist concludes that imatinib does not lead to left ventricular failure in Gist patients with an observation rate of about 0.2% while it can be up to 2% of the subjects already suffering from heart disease.

Serious skin and adverse reactions

There have been reports on the whole body, lumpy, itchy rash may disappear even though it continues to be treated. Some patients may be itchy without accompanying the board, and sometimes a part of the skin is peeling. Some patients reappear the skin when taking the drug again, but not in all patients. These skin rashes are often responded to antihistamines and topical steroids. Sometimes it is necessary to use systemic steroids.

Observed a skin rash in 1/3 of patients treated with imatinib for all indications. The most common and most common itching is to the pink, lumpy or peeling skin on the arm, body or face or manifestation of the whole body. Skin biopsy shows a reaction to drug toxicity with mixed cell contamination. Although most rashes are mild and self-limited, severe severe cases such as Stevens-Johnson poisoning epidermis, diverse roses or dress may need interrupting or stopping treatment. It is not surprising that skin reactions are observed at a higher percentage than a placebo in the Gist supplementary treatment test.

Liver poisoning

Liver poisoning, sometimes serious, may occur, which has been clinical and clinical. Liver function abnormalities usually include a slight increase in transaminase, although a small number of patients increases bilirubin. The attack is usually within the first two months of treatment, but it also occurs late after 6 to 12 months after the beginning of the treatment. The concentration returns to normal after stopping treatment for 1 to 4 weeks.

Hemorrhage reduction

Low serum phosphate and hypoglycemia (up to level 3 or 4) have been observed relatively common in all indications, but it does not prove the origin and clinical significance of this finding. Imatinib has manifested inhibiting solid leukemia into cancellation of the cell. This decline is accompanied by reducing the ability to destroy bones in these cells. Observed the decrease of the dose dependence of Rank-L in the cell cancel in the presence of imatinib. The maintenance of the activity of the cell cancel can lead to reverse air conditioning response, resulting in an increase in the concentration of PTH. The clinical relevance of preclinical findings is unclear and the combination of adverse reactions on the bone such as unproven fractures.

In clinical development programs, serum phosphate is not measured in all studies. Mặc dù bước đầu đã có giả thuyết rằng giảm phosphat huyết có thể phụ thuộc liều, nhưng kết quả 24 tháng phân tích được từ nghiên cứu pha III TOPS được thiết kế để khảo sát sự phụ thuộc liều của các kết cục về an toàn trên bệnh nhân CML mới được chẩn đoán đã cho thấy rằng phosphat huyết thanh giảm độ 3 hoặc 4 là 19,1% so với 15,5% và calci huyết thanh giảm độ 3 hoặc 4 là 5,1% so với 0,9% lần lượt ở bệnh nhân dùng 400 mg và 800 mg.

Tacuats, perforation or gastrointestinal ulcers

Gastrointestinal ulcer, which can be considered as representing cases of excessive local irritation due to the use of imatinib, has been observed on a small percentage of patients in all indications. Tumor hemorrhage/necrotic hemorrhage and gastrointestinal perforation are considered as related to the disease and occur only or more often in Gist patients. In the case of metastatic gist, tumor necrosis may occur as a reaction of the tumor, rarely leading to perforation. Gastrointestinal/gastrointestinal obstruction occurs in the Gist patients, then the cause may be due to metastatic gust tumor blockage and in case of supportive treatment due to intestinal adhesion from the previous gastrointestinal surgery.

Tumor solving syndrome

There may be causal relationships between tumor solving syndrome and Glivec treatment, although some cases are interfered with simultaneous medications and other non -dependent risks.

Growth in children

Glivec seems to affect the stature of children, especially in children before puberty. It is impossible to eliminate the causal relationship between growth slowly in children and Glivec treatment, although the information is limited to some cases of slow growth in CML patients (see the warning section).

Side -severe response of heavy respiratory tract

The respiratory response, sometimes fatal, has been observed with Glivec treatment, including acute respiratory failure, pulmonary hypertension, interstitial lung disease and pulmonary fibrosis. Heart or lung diseases may be related to severe respiratory events that have been reported in many cases.

Testing abnormalities

Hematology

Reducing CML blood cells, especially neutropenia and thrombocytopenia, is a sign that always encountered in all studies, with higher frequency at high doses ≥ 750mg (phase I research). However, the appearance of blood cells also depends clearly on the stage of the disease. In patients with newly diagnosed chronic leukemia, reducing blood cells is less common than patients with other chronic medullary leukemia. The frequency of neutropenia decreased at 3 or 4 (ANC

In patients with malignant gist that cannot be removed or metastatic (B2222 research), anemia 3 has been reported in 5.4% of patients and 4them of anemia in 0.7% of patients and may be associated with stomach bleeding or bleeding within the tumor at least some of these patients. Neutral leukocytes have been encountered at 7.5% and level 4 at 2.7% of patients, and platelet reduction in 3rd level at 0.7% of patients. No patients with thrombocytopenia at level 4. Reducing leukocytes and neutrophils mainly occurred in the first 6 weeks of treatment, then the values kept relatively stable.

biochemistry

Seriously increased the transaminase (

Notify the physician the unwanted effects when using the drug.

Warnings

Before using the drug you need to read the instructions carefully and refer to the information below.

Contraindicated

Glivec drugs contraindicated in the following cases:

Patients with hypersensitivity to active ingredients or any ingredients of excipients.

Precautions when using

This drug is only used as prescribed by a doctor.

When used in combination with glivec with other drugs, there is a possibility of drug interactions. Caution should be used when using Glivec along with rifampicin or other strong CYP3A4 stimulants, ketoconazole or strong CYP3A4 inhibitors, CYP3A4 substrates with narrow treatment windows (eg cyclosporin or pimozide) or CYP2C9 have narrow treatment windows (for example, Warfarin and other Coumarin derivatives).

Hypothyroidism

There have been reports on clinical hypothyroidism cases in patients with thyroid cutting levothyroxine instead of treatment with glivec. It is necessary to closely monitor the concentration of thyroid stimulating hormones (TSH) in these patients.

Liver poisoning

In patients with liver dysfunction (mild, medium or severe), closely monitor peripheral blood formula and liver enzymes.

When glivec is combined with high -dose therapy, it has observed a transient liver toxicity in the form of transaminase increased and hyperlirubin blood bilirubin. Moreover, there have been non -common reports on acute liver failure. The recommendation for monitoring liver function in the case of glivec is combined with known chemotherapy regimens is associated with liver dysfunction.

Translation

There have been reports on severe fluid retention (pleural effusion, edema, pulmonary edema, ascites and surface edema) in about 2.5% of patients with chronic medullary leukemia are diagnosed with glivec. Therefore, patients should be weighed regularly. Carefully check the phenomenon of abnormal rapid weight gain and if needed should take appropriate support and treatment care measures. In clinical trials, the proportion of these events increased in elderly patients and people with a history of heart disease.

Patients with heart disease or kidney failure

Patients with heart disease, with risk factors for heart failure or a history of renal failure must be strictly controlled and any patient shows signs or symptoms suitable for heart failure or renal failure must be assessed and treated.

In patients with eosinophilia syndrome (HES) with hidden contamination of HES cells into the heart muscle, individual cases suffering from cardiac shock/left ventricular dysfunction is associated with Hes cell loss at the beginning of glivec treatment. This condition is reported as recovery with systemic steroid treatment, circulatory support and temporary gluel stops. Bone marrow dysplasia (MDS)/Bone marrow proliferation disorder (MPD) and system cell tumor can be combined with high levels of eosinophilia. Therefore, serum troponin ultrasound must be considered in patients with HES/CEL, and patients with MDS/MPD or SM in combination with high levels of eosinophilia. If any abnormalities, consideration of systemic steroid reserve (1-2 mg/kg) should be considered for 1-2 weeks simultaneously with Glivec at the beginning of treatment.

Gastrointestinal bleeding

In phase III studies on gist in patients with malignant gist that cannot be removed or metastatic has 211 patients (12.9%) are reported with 3/4 bleeding at any position. In phase II studies in patients with malignant gist that cannot be removed or metastatic (research B2222), eight patients (5.4%) suffer from gastrointestinal bleeding and four patients (2.7%) of tumor bleeding. Depending on the anatomical position of tumor lesions, tumor bleeding is the bleeding in the abdomen or in the liver. The positions in the gastrointestinal tract of the tumor may contribute to reports on gastrointestinal bleeding in this patient group. In addition, vascular vasodilation (GAVE), a rare cause of gastrointestinal bleeding, has been reported in after -sales experience with patients with CML, All and some other diseases. Therefore, patients need to be tested for symptoms of the gastrointestinal tract at the beginning and during the treatment with Glivec. When needed, it is possible to consider stopping using Glivec.

Tumor solving syndrome

Cases of tumor syndrome (TLS) have been reported in patients treated with Glivec. Because TLS may appear, it is recommended to treat dehydration of clinical significance and treatment of high uric acid levels before starting Glivec treatment.

Activation of hepatitis B

The activity of hepatitis B can occur in patients with chronic viruses after using a Tyrosin Kinase inhibitor (TKI) BCR-ABL, such as imatinib. Some cases are related to the use of BCR-MLL TKI drugs leading to acute liver failure or acute hepatitis leading to liver transplant or death.

Patients should be tested for hepatitis B virus infection before starting with imatinib treatment. The current patients who are using imatinib should be initially tested for hepatitis B virus infection to identify chronic virus infections. Experts should consult with liver disease and treat hepatitis B before the beginning of treatment in patients with a positive serum with hepatitis B virus (including people with hepatitis active) and patients with positive tests with hepatitis B virus during therapy. People with hepatitis B virus should be treated with imatinib should be closely monitored to detect symptoms and signs of hepatitis B virus infection that works during the therapy and a few months after the termination of therapy.

Testing

Must conduct a regular total blood formula during the glivec treatment. The treatment of patients with chronic marrow leukemia with Glivec is associated with neutropenia or thrombocytopenia. However, this hypoglycemia depends on the stage of treatment and is more common in patients with chronic marrow leukemia at the stage of accelerating stage or a cellular attack compared to patients with chronic chronic leukemia. Can stop treatment with Glivec or reduce the dose.

Monitor regular liver function (transaminase, bilirubin, alkaline phosphatase) in patients using glivec. As recommended for these tests to be treated by stopping and/or reducing the glivec treatment dose.

Glivec and its metabolites are not excreted through the kidney at a significant level. Creatinine clearance coefficient (CrCl) is known to be reduced with age, but age does not significantly affect the kinetics of Glivec. In patients with impaired renal function, the imatinib resent in plasma seems to be higher than that patients with normal renal function, probably due to the concentration of alpha-acid glycoprotein (AGP) in plasma is a protein associated with imatinib, increasing in these patients. There is no correlation between imatinib concentration and the degree of impaired renal function of classification by measuring the creatinine clearance (CrCl), between patients with mild renal function (CrCl: 40-59ml/min) and severe (CrCl:

Children and teenagers

There have been cases of disease -slow growth occurring in children and teenagers using Glivec. It is unknown for long -term effects when long -term treatment with Glivec on children's growth. Therefore, it is recommended to closely monitor the growth of children when treated with Glivec.

Using drugs for women during pregnancy and lactation

Women are likely to be pregnant

Pregnant women must be recommended to use a highly effective method of contraception during the treatment period of Glivec. Highly effective contraceptive method is a method of contraception for low failure results (for example, less than 1%/year) when used steadily and correctly.

Pregnant women

Animal research shows toxicity on the reproductive system. There is no clinical trial on pregnant women using Glivec. There has been a after -sales report on spontaneous miscarriage and birth defects in children with Glivec. Glivec should only be used during pregnancy when the expected benefits surpassing the potential risk to the fetus. Patients must be notified of hidden risks for the fetus if the drug is used during pregnancy.

breastfeeding women

both imatinib and its active metabolites can be excreted into breast milk. The ratio of plasma milk is determined by 0.5 with imatinib and 0.9 with metabolites, showing that the metabolite of imatinib is more excreted into the breast milk. Considering the combined concentration of imatinib and metabolites and maximum amount of milk daily babies feeding, the total amount of exposure is considered low (about 10% of the treatment dose). However, women who are using glivec should not breastfeed due to the effects of imatinib exposure in low doses in unknown children.

fertility

Studies in male patients use Glivec and its effects on male fertility and sperm production have not been done. Male patients are concerned about their fertility when treating with Glivec should consult a doctor.

The effect of the drug on the ability to drive and operate machinery

There have been reports on accidents when driving in patients using Glivec. While most of these reports are not suspected by Glivec, patients should be recommended that they may have unwanted effects such as dizziness, blurred vision, or chicken sleep while using Glivec. Therefore, it is necessary to be cautious when driving or operating machinery.

Drug interaction

Observations are indicated, resulting in not recommended use of simultaneously

Drugs that can reduce imatinib concentration in plasma

The substances that promote the activity of CYP3A4 (e.g. Dexamethasone, Phenytoin, Carbamazepine, Rifampicin, Phenobarbital or Hypericum Perforatum - also known as St. John’s World) can significantly reduce Glivec's background.

Pre-treatment for 14 healthy volunteers with many doses of rifampicin 600 mg/day for 8 days, then using a single dose of 400 mg Glivec, the clearance when using Glivec oral doses increased by 3.8 times (90% of trust = 3.5 to 4.3 times), which indicates the average CMAX reduction of 54%, AUC (0-24) is 68% and AUC (0-∞) is 74%) Rifampicin.

The same results are observed in patients with malignant nerve tumors treated with glivec while taking anti -epilepsy drugs that cause enzyme (EIAED) such as carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital and primidone.The plasma AUC of Imatinib decreased by 73% compared to those who do not use Eiaed. In the two published studies, simultaneously used Glivec and a product containing St. John’s World leads to a 30 to 32% reduction of AUC of Glivec. In patients specified to use rifampicin or other CYP3A4 promotion substances, it is recommended to consider changing the low -treatment drug that can cause enzyme induction.

Other interactions that can affect the existence of Glivec or other drugs

Medications can increase the level of imatinib in plasma

The active inhibitors of Cytochrome P450 Isoenzyme CYP3A4 (for example ketoconazole, iTraconazole, erythromycin, Clarithromycin) can reduce metabolism and increase imatinib concentration. There is a significant increase in imatinib resent (the highest concentration in plasma (CMAX) of the average increase of 26% and the area under the concentration curve (AUC) of IMATINIB increases 40%) in healthy people when the drug is used simultaneously with a single dose of Ketoconazole (a CYP3A4 inhibitor). Should be cautious when using Glivec with CYP3A4 inhibitors.

Drugs may be changed in plasma concentrations by Glivec:

Glivec increases the average CMAX and the AUC of Simvastatin (CYP3A4 substrate) is twice as high as the CYP3A4 inhibitor by Glivec. Therefore, it is recommended to be careful when using glivec with CYP3A4 substrates with narrow treatment windows (eg cyclosporin or pimozide). Glivec may increase the plasma concentration of drugs metabolized by other CYP3A4 (eg triazolo-benzodiazepine, calcium channel blockers dihydropyridine group, some HMG-CAA Reductase inhibitors are statins, etc.).

Glivec also inhibits CYP2C9 and CYP2C19 in vitro. Observed prothrombin (PT) time after use simultaneously with warfarin. So when using Coumarin, prothrombin should be monitored for a short time at the beginning and at the end of the Glivec treatment and when the dose changes. Another way is to consider using low molecular weight heparin.

In vitro, Glivec inhibit the activity of Cytochrome P450 Isoenzyme CYP2D6 at concentrations similar to the concentration that affects the operation of CYP3A4. Glivec 400 mg twice a day has a weak inhibition effect on metoprolol metabolism through CYP2D6 intermediaries, with CMAX and AUC of Metoprolol increased by about 23%. Simultaneous use of Glivec with CYP2D6 substrates such as Metoprolol does not seem to be a risk factor for drug-drug interaction and the adjustment of the dose may be unnecessary.

In vitro, Glivec inhibit the metabolic path of acetaminophen o-glucuronidate (KI 58.5microm).

Self -use Glivec (400 mg/day for 8 days) with acetaminophen/paracetamol (1000 mg single dose on the 8th day) in patients with CML does not lead to any pharmacokinetic changes of acetaminophen/paracetamol.

The pharmacokinetics of glivec are not changed when using acetaminophen/paracetamol.

There is no data on safety and pharmacokinetics when using simultaneously gleac at a dose greater than 400 mg/day or long -term use with acetaminophen/paracetamol.

Storage

Do not store at temperatures over 30 ° C, avoid moisture. Keep the medicine in the original packaging.

Other drugs

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