Glivec, capsules 100 mg 120 pcs

Pharmacodynamics

Antitumor drug, proteinutyrosine kinase inhibitor.

. Imatinib has a selective inhibitory effect on the enzyme Bcr-Abl-tyrosine kinase, which is formed at the fusion of the Bcr gene site (breakpoint cluster region) and Abl (Abelson) protooncogene, at the cellular level, selectively inhibits proliferation and causes apoptosis of cell lines, expressing Bcr-Abl tyrosine kinase, including immature leukemia cells produced by patients with Philadelphia chromosome-positive chronic myeloleukemia and acute lymphoblastic leukemia.

Imatinib selectively inhibits Bcr-Abl-positive colonies derived from blood cells of patients with chronic myeloleukemia.

Imatinib inhibits proliferation and induces apoptosis of GI stromal tumor cells expressing tyrosine kinase with a c-Kit receptor mutation.

The activation of receptors to platelet-derived growth factor or Abl-fragment tyrosine kinase may be the cause of both myelodysplastic/myeloproliferative diseases and hypereosinophilic syndrome and chronic eosinophilic leukemia and bulging dermatofibrosarcoma.

The activation of c-Kit receptor tyrosine kinase and receptors to platelet-derived growth factors may underlie the pathogenesis of systemic mastocytosis. Imatinib inhibits cell signaling and cell proliferation resulting from the dysregulation of platelet and stem cell growth factor activity, c-Kit receptor and Abl-fragment tyrosine kinase.

The use of imatinib in patients with inoperable and/or metastatic malignant gastrointestinal stromal tumors showed a significant increase in overall patient survival (48.8 months) and symptom-free survival (21 months).

Adjuvant therapy with gastrointestinal stromal tumors reduced the risk of recurrence by 89% and increased survival without evidence of disease (38 months imatinib versus 20 months placebo).

Adjuvant therapy with gastrointestinal stromal tumors for 3 years results in significantly increased overall survival and progression-free survival compared to therapy for 1 year.

Pharmacokinetics

The pharmacokinetic parameters of Glivec were evaluated over a dose range of 25 mg to 1,000 mg. Pharmacokinetic profiles were analyzed on day 1 of administration and when equilibrium plasma concentrations of imatinib were reached on day 7 or day 28.

Eabsorption

After oral administration, the bioavailability of the drug averages 98%. The coefficient of variation for AUC is 40-60%. In the dose range from 25 to 1000 mg a direct linear dependence of AUC value on the value of the dose is noted.

When the drug is taken with a high-fat meal, compared to an empty stomach, a slight decrease in the degree of absorption is noted (decrease in C_max of imatinib in plasma by 11%, AUC by 7.4%) and delayed absorption rate (increase in T_max of imatinib in plasma by 1.5 h).

Distribution

The binding of imatinib to plasma proteins is about 95% (mainly to albumin and acidic α-glycoproteins, to a small extent to lipoproteins).

Metabolism

Imatinib is metabolized mainly in the liver to form the main metabolite (N-demethylated piperazine derivative) circulating in the systemic blood stream. In vitro metabolite of imatinib has pharmacological activity similar to that of the parent substance. The AUC of the metabolite is 16% of the AUC of imatinib.

The metabolite’s binding to plasma proteins is similar to that of imatinib.

The drug is excreted from the body within 7 days after a single dose, mainly as metabolites (68% – in the feces and 13% – in the urine). About 25% of the dose is excreted unchanged (20% – with feces and 5% – in the urine). T_1/2 of imatinib is about 18 h.

The pharmacokinetic parameters do not change with repeated doses of the drug 1 time/day, and the C_ss of imatinib is 1.5-2.5 times higher than the initial dose.

Pharmacokinetics in Special Clinical Cases

In patients over 65 years of age, V_d increases slightly (by 12%).

In patients with a body weight of 50 kg, the average clearance of imatinib is 8.5 l/h, and in patients with a body weight of 100 kg it is 11.8 l/h. However, these differences are not significant and do not require adjusting the drug dose according to the patient’s body weight.

The pharmacokinetics of imatinib are independent of gender.

Changes in clearance and V_d of imatinib when used concomitantly with other drugs are not significant and do not require dose adjustments.

In children and adolescents under 18 years of age, as in adults, imatinib is rapidly absorbed after oral administration. The AUC in the dose range of 260 and 340 mg/m² is similar to that in adults in the dose range of 400 mg and 600 mg, respectively.

When comparing AUC_(0-24) values in children and adolescents on days 1 and 8 after repeated doses of the drug at 340 mg/m² once daily, there was a 1.7-fold increase in this value, indicating cumulation of imatinib.

In patients with varying degrees of hepatic impairment the average AUC values are not increased.

In patients with mild to moderate renal impairment (CK > 30 ml/min), an increase of 1.5-2.0-fold in plasma exposure of imatinib is noted, corresponding to an increase in the concentration of acidic α-glycoproteins (major plasma proteins that bind to imatinib).

As the drug is slightly excreted by the kidneys, the clearance of free imatinib was similar in healthy volunteers and patients with impaired renal function. No correlation was found between drug exposure and severity of renal impairment.

Indications

Cancer

• First-time Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in children and adults;
• Ph+ CML in the chronic phase with failure of prior interferon alpha therapy or in the acceleration phase or blast crisis in children and adults;
• relapsed or refractory Ph+ ALL in adult patients as monotherapy;
• myelodysplastic/myeloproliferative diseases associated with platelet growth factor receptor gene rearrangements in adult patients;
• systemic mastocytosis in adult patients with no D816V c-Kit mutation or unknown c-Kit mutation status;
• Inoperable and/or metastatic malignant gastrointestinal stromal tumors positive for c-Kit (CD 117) in adult patients;
• Adjuvant therapy for gastrointestinal stromal tumors positive for c-Kit (CD 117) in adult patients;
• inoperable, recurrent, and/or metastatic bulging dermatofibrosarcoma in adult patients.

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Active ingredient

Imatinib

Composition

1 capsule contains:

Active ingredients:

• imatinib mesylate 119.5 mg, corresponding to 100 mg of imatinib.

Associates:

• Microcrystalline cellulose – 92 mg,

• Crospovidone – 15 mg, <

• colloidal anhydrous silica – 2 mg,

• magnesium stearate – 1.5 mg,

• titanium dioxide – 600 µg,

• gelatin – 74.81 mg,

iron oxide yellow dye – 30 micrograms,

• iron oxide red dye – 560 micrograms.

Ink composition:

• Red iron oxide dye (E172),
  .

• shellac,

• soy lecithin.

.

How to take, the dosage

The drug should be taken with a meal with a full glass of water to reduce the risk of gastrointestinal distress. Doses of 400 mg and 600 mg/day should be taken as a single dose; the daily dose of 800 mg should be divided into 2 doses of 400 mg in the morning and in the evening.

Patients who cannot swallow the whole tablet or capsule, e.g., children, may take the drug diluted; the tablets or capsule contents are diluted with water or apple juice.

The desired amount of tablets or put in a glass, pour the liquid (about 50 ml of liquid for 100 mg tablets and 100 ml for 400 mg tablets) and stir with a spoon to form a suspension. The resulting suspension should be taken orally immediately after preparation.

In chronic myeloid leukemia (CML), the recommended dose of Glivec® depends on the phase of the disease. In chronic phase of CML the dose is 400 mg/day; in the phase of acceleration and at blast crisis it is 600 mg/day. The drug should be taken once daily.

The drug is treated as long as there is clinical effect.

In the absence of marked side effects and neutropenia or thrombocytopenia unrelated to leukemia, increase of dose from 400 mg to 600 mg or up to 800 mg/day in patients in chronic phase of disease, and from 600 mg to 800 mg/day in patients in acceleration phase and in blast crisis.

This dose increase may be necessary if CML progresses (at any stage), if there is no satisfactory hematologic response after 3 months of treatment, no cytogenetic response after 12 months of therapy, or if there is a loss of previously achieved hematologic and/or cytogenetic response.

The dosing regimen in children over 2 years of age is based on body surface area. Doses of 340 mg/m²/day are recommended in children with chronic phase CML and acceleration phase. The total daily dose in children should not exceed 600 mg.

The daily dose of the drug can be taken all at once or divided into 2 equal doses in the morning and in the evening.

In Ph+ acute lymphoblastic leukemia, the recommended dose of Glivec is 600 mg/day.

In myelodysplastic/myeloproliferative diseases, the recommended dose of Glivec is 400 mg/day.

In inoperable and/or metastatic malignant stromal tumors of the GI tract, the recommended dose of Glivek is 400 mg/day. If there are no side effects of the drug and insufficient response, it is possible to increase the daily dose of Glivec from 400 mg to 600 mg or up to 800 mg.

In case of signs of disease progression, therapy with Glivec should be stopped.

When using the drug as adjuvant therapy in patients with gastrointestinal stromal tumors, the recommended dose is 400 mg/day. The minimum duration of treatment is 3 years. The optimal duration of adjuvant therapy has not been established.

In inoperable, recurrent and/or metastatic bulging dermatofibrosarcoma, the recommended dose of Glivec is 800 mg/day.

In systemic mastocytosis in the absence of a D816V c-Kit mutation, the recommended dose of Glivek is 400 mg/day. If mutation status is unknown and previous therapy has not been sufficiently effective, the recommended dose is 400 mg/day.

In systemic mastocytosis caused by the abnormal FIP1L1-PDGFR α-tyrosine kinase formed by fusion of the Fip like1 and PDGFR genes, the recommended starting dose is 100 mg/day.

In case of insufficient efficacy and absence of pronounced 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 patients with HES/CHL caused by abnormal FIP1L1-PDGFR α-tyrosine kinase, 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.

The drug is treated as long as the clinical effect persists.

Because imatinib is metabolized primarily in the liver, patients with mild, moderate or severe hepatic impairment should be given the minimum daily dose of Gleevec® 400 mg.

In case of development of undesirable toxic effects, the drug dose should be reduced. Caution should be exercised when prescribing the drug in patients with severe hepatic insufficiency.

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 systematic hemodialysis, treatment with Glivec® should be started at the lowest effective dose of 400 mg once daily and should be started with caution.

While there is limited experience with Glivec® in patients with severe renal impairment or who undergo regular hemodialysis, therapy with Glivec® may also be initiated at 400 mg once daily in this population.

In case of intolerance to Glivec, the initial dose of the drug may be decreased; if it is not effective, the dose may be increased.

In elderly patients there is no need to adjust the dosing regimen of the drug.

Correcting the dosing regimen if non-hematologic side effects of the drug develop

If any serious non-hematologic side effect associated with taking the drug develops, therapy should be interrupted until the situation resolves. Treatment may then be resumed at a dose depending on the severity of the observed side effect.

If bilirubin concentration and liver transaminase activity in serum increase 3 and 5 times of BHN, respectively, therapy with the drug should be temporarily suspended until bilirubin concentration decreases to less than 1.5×BHN and liver transaminase activity to less than 2.5×BHN.

Therapy with Glivec is resumed with a reduced daily dose: in adults, the dose is reduced from 400 mg to 300 mg/day or from 600 mg to 400 mg/day, or from 800 mg to 600 mg/day; in children, from 340 to 260 mg/m²/day.

Mode of dosing adjustment in case of serious adverse effects of the hematopoietic system (severe thrombocytopenia, neutropenia)

In case of neutropenia and thrombocytopenia a temporary withdrawal of the drug or dose reduction is required, depending on the degree of these adverse events.

In systemic mastocytosis (SM) and hypereosinophilic syndrome and/or chronic eosinophilic leukemia (HES/CHL) caused by abnormal FIP1L1-PDGFR α-tyrosine kinase (starting dose of Gleevec 100 mg), in case of decrease of absolute neutrophil number < 1,000/μL and/or platelet count < 50,000/μL is recommended:

• cancel Glivec® until the absolute neutrophil count is ≥ 1,500/μL and platelet count ≥ 75,000/μL;
• resume treatment with Glivec at the dose used before interruption of therapy.

In chronic phase CML in children and adults, malignant GI stromal tumors, myelodysplastic/myeloproliferative diseases, CM and HES/CHL in adult patients (starting dose for adults is 400 mg, for children is 340 mg/msup>2) when absolute neutrophil count < 1,000/μL and/or platelet count < 50,000/μL are recommended:

• cancel Glivec® until the absolute neutrophil count is ≥1,500/µL and platelet count ≥75,000/µL;
• resume treatment with Glivec at the dose used before interruption of therapy.

In case of a repeated decrease in neutrophil count < 1000/μl and/or platelet count < 50,000/µl, Gleevec® should be discontinued again until the absolute neutrophil count is ≥1,500/µl and platelet count ≥75,000/µl, and then resume treatment with Gleevec at a reduced dose of 300 mg (in children, 260 mg/m²).

In the phase of acceleration and blastic crisis of CML in children and adults and in PH+ acute lymphoblastic leukemia in adult patients (initial dose for adults is 400 mg, in children 340 mg/m²).sup>2) in case of decreased absolute neutrophil count < 500/μL and/or platelet count < 10,000/μL after one or more months of treatment is recommended:

• check whether the cytopenia is due to leukemia (bone marrow study); -if the cytopenia is not due to leukemia, reduce the Gleevec dose to 400 mg (in children, 260 mg/msup>2);
• if cytopenia persists for 2 weeks, reduce the dose to 300 mg (in children, 200 mg/msup>2);
• If cytopenia persists for 4 weeks and its association with leukemia is not confirmed, discontinue Glivec® until the absolute neutrophil count is ≥1000/μL and platelets ≥20,000/μL; then resume treatment with Glivec® at a dose of 300 mg (in children, 260 mg/m2).

In inoperable, recurrent and/or metastatic bulging dermatofibrosarcoma (starting dose of Glivek 800 mg), if absolute neutrophil count < 1000/μL and/or platelet count < 50,000/μL decrease is recommended:

• cancel Glivec® until the absolute neutrophil count is ≥1,500/μL and platelet count ≥75,000/μL;
• resume treatment with Glivec at the 600 mg dose.

If the neutrophil count < 1000/µL and/or platelet count < 50,000/µL decrease again, discontinue Glivec® until the absolute neutrophil count is ≥1500/µL and platelet count ≥75,000/µL and then resume treatment with Glivec at a reduced dose of 400 mg.

Interaction

In concomitant use of Glivec with drugs that inhibit CYP3A4 isoenzyme (including ketoconazole, itraconazole, erythromycin, clarithromycin), metabolism of imatinib may be slowed and its concentration in blood plasma may be increased. Caution is required when combining Gleevec with drugs – CYP3A4 isoenzyme inhibitors.

On the contrary, concomitant use of drugs that are inducers of CYP3A4 isoenzymes (e.g., dexamethasone, phenytoin, fosphenytoin, rifampicin, phenobarbital or St John’s wort, carbamazepine, oxcarbazepine, primidone) may lead to increased metabolism of imatinib and a decrease in its plasma concentration.

In concomitant use of imatinib and simvastatin it is observed that C_max and AUC of simvastatin are increased 2 and 3.5 times, respectively, which is due to inhibition of CYP3A4 isoenzyme by imatinib.

Precaution is recommended when concomitant use of Glivec and drugs which are substrates of CYP3A4 isoenzyme and have narrow range of therapeutic concentration (for example, cyclosporine, pimozide).

Gleevec® can increase serum concentrations of other drugs metabolized by CYP3A4 isoenzyme (triazole benzodiazepines, dihydropyridine, calcium channel blockers, most HMG-CoA reductase inhibitors, including statins).

Imatinib also inhibits the CYP2C9 and CYP2C19 isoenzymes in vitro.

Longening of prothrombin time was observed when used in combination with warfarin. When concomitant use with coumarin derivatives, short-term monitoring of prothrombin time at the beginning and end of therapy with Glivec, as well as when changing the dosing regimen of Glivec.

The use of low molecular weight heparin derivatives should be considered as an alternative.

In combination of Glivec® with chemotherapeutic agents at high doses, transient hepatic toxicity in the form of increased liver transaminase activity and hyperbilirubinemia may occur.

When imatinib is combined with chemotherapy regimens that have the potential to cause hepatic dysfunction, liver function monitoring should be considered.

In vitro Gleevec® inhibits the CYP2D6 isoenzyme at the same concentrations that it inhibits CYP3A4.

When Glivec® is used at a dose of 400 mg 2 times daily with metoprolol, a substrate of the CYP2D6 isoenzyme, there is a moderate decrease in metabolism of metoprolol accompanied by an increase in C_max and AUC of approximately 21%.

In view of moderate enhancement of the effects of the drugs which are substrates of CYP2D6 isoenzyme (e.g. metoprolol) when used together with Glivec, no change in dosing regimen is required.

Special Instructions

Treatment with Glivek should only be done under the supervision of a physician experienced in working with antitumor drugs.

Avoid contact with skin and eyes and inhalation of the drug powder when handling the drug.

When using Glivek, regular clinical peripheral blood tests and monitoring of liver function (transaminases, bilirubin, ALP) are recommended.

Patients with heart disease should be closely monitored.

Due to the fact that during the use of Glivek in 1-2% of cases there is marked fluid retention, it is recommended to monitor the body weight of patients regularly.

In case of rapid unexpected weight gain the patient should be examined and if necessary Glivec therapy should be temporarily stopped and/or diuretics should be prescribed. The highest incidence of fluid retention occurs in elderly patients with cardiovascular disease.

In some cases, severe fluid retention may have a severe course with a fatal outcome. When using the drug, death of a patient with blastic crisis and complex symptoms: pleural effusion, chronic cardiac and renal failure has been noted.

When prescribing the drug to patients with liver disease, peripheral blood and liver enzymes clinical studies should be performed regularly.

While there are reports of hypothyroidism with Glivec in patients who have undergone thyroidectomy and are receiving levothyroxine replacement therapy, TTG concentrations should be determined regularly in this patient population.

In patients with hypereosinophilia syndrome and cardiac disease, there have been isolated cases of cardiogenic shock/left ventricular failure at the start of therapy with imatinib.

These adverse events resolve after administration of systemic GCS, circulatory support measures, and temporary withdrawal of Glivec®.

In patients with MDS/MPD and high eosinophil counts, an ECG study should be performed and serum cardiac-specific troponin concentrations should be determined.

If abnormalities are detected, prophylactic use of systemic GCS (1-2 mg/kg) for 1-2 weeks concurrently with imatinib should be considered at the start of therapy.

In patients with inoperable and/or metastatic malignant gastrointestinal stromal tumors in phase III clinical trials, bleeding of various localizations was observed in 12.9% of cases; in phase II trials, gastrointestinal bleeding was observed in 8 patients (5.4%) and bleeding from tumor foci in 4 patients (2.7%).

Patients should use reliable contraception during therapy with Glivec and for at least 3 months thereafter.

A marked increase in transaminases or bilirubin levels has been reported in less than 3% of patients with CML and was usually controlled by reducing the dose of the drug or temporarily interrupting treatment (mean duration of these episodes was about 1 week).

Because of the risk of tumor lysis syndrome, clinically significant dehydration and elevated uric acid levels in patients should be corrected as necessary before administration of Glivec®.

Pediatric use

The experience with Glivec® in children younger than 2 years of age with CML is limited, and experience with other indications is limited in patients younger than 18 years.

The long-term effects of long-term effects of Glivec® on growth in children are unknown. But since there have been reports of growth retardation, close monitoring of growth in children receiving Glivec® is recommended.

Impact on ability to drive vehicles and other mechanisms requiring increased concentration

Some adverse reactions of the drug, such as dizziness and blurred vision, may adversely affect the ability to drive and perform potentially hazardous activities requiring increased concentration and rapid psychomotor reactions.

As a result, patients receiving Glivec® should use extra caution and attention when driving vehicles and performing potentially hazardous activities.

Contraindications

• Pregnancy
• lactation period (breastfeeding)
• children under 2 years of age (efficacy and safety has not yet been established)
• high sensitivity to the drug components.

Cautions: Gleevec® should be used with caution in patients with severe hepatic impairment, severe renal impairment, cardiovascular disease, or if there are risk factors for heart failure or if regular hemodialysis is performed.

Side effects

The safety profile of Glivec® has been well studied.

The majority of patients experience some form of adverse events while using the drug. The most common adverse events (>10%) associated with taking the drug were: neutropenia, thrombocytopenia, anemia, headache, dyspepsia, edema, weight gain, nausea, vomiting, diarrhea, myalgia, muscle cramps, rash, weakness, abdominal pain.

For the most part, these adverse events were mild to moderately severe. Only 2-5% of patients discontinued therapy with Glivec® because of the development of adverse events.

Myelosuppression, gastrointestinal adverse events, edema and rash occur with imatinib in both CML and malignant stromal gastrointestinal tumors.

CML patients are more likely to develop myelosuppression, and gastrointestinal and intratumoral bleeding is more common in patients with malignant gastrointestinal stromal tumors.

Other gastrointestinal disorders, such as gastrointestinal obstruction, perforation and ulceration, are more common in gastrointestinal stromal tumors.

Other serious adverse events with imatinib use are hepatotoxicity, acute renal failure, hypophosphatemia, respiratory system disorders, tumor lysis syndrome and growth retardation in children.

The drug dose can be corrected depending on the degree of adverse reactions up to discontinuation of the drug.

In clinical trials in patients with CML and inoperable and/or metastatic malignant stromal tumors of the GIT, the following adverse events were noted, listed below by organs and systems with indication of their frequency:

• very frequently (≥1/10);
• frequently (≥1/100, < 1/10);
• infrequently (≥1/1000, < 1/100);
• frequently (≥1/10,000, < 1/1000);
• very rarely ( < 1/10,000), including.
• very rarely ( < 1/10,000),

including individual reports.

Infectious diseases: infrequent – herpes simplex, herpes shingles, nasopharyngitis, pneumonia¹, sinusitis, subcutaneous tissue inflammation, upper respiratory tract infections, influenza, urinary tract infections, gastroenteritis, sepsis; rare – mycoses.

Benign, malignant and unspecified neoplasms (including polyps and cysts): rarely – tumor lysis syndrome.

Hematopoietic system: very frequently – neutropenia, thrombocytopenia, anemia; frequently – pancytopenia, febrile neutropenia; infrequently – thrombocythemia, lymphopenia, suppression of medullar hemopoiesis, eosinophilia, lymphoadenopathy; rarely – hemolytic anemia.

Metabolism: frequently – anorexia; infrequently – hypokalemia, increased appetite or decreased appetite, hypophosphatemia, dehydration, hyperuricemia, gout, hypercalcemia, hyperglycemia, hyponatremia; rarely – hyperkalemia, hypomagnesemia.

Nervous system disorders: very common – headache²; common – dizziness, impaired taste, paresthesia, hypoesthesia, insomnia; infrequent – hemorrhagic stroke, syncope, peripheral neuropathy, somnolence, migraine, memory impairment, sciatica, restless legs syndrome, tremor, depression, anxiety, decreased libido; rare – increased intracranial pressure, seizures, optic neuritis, confusion.

VIight organ disorders: frequent – eyelid edema, increased lacrimation, conjunctival hemorrhage, conjunctivitis, dry eye syndrome, blurred vision; infrequent – eye irritation, eye pain, orbital edema, sclera hemorrhage, retinal hemorrhages, blepharitis, macular edema; rare – cataract, optic disc edema, glaucoma.

Hearing organ and labyrinth disorders: infrequent – vertigo, tinnitus, decreased hearing.

Cardiovascular system disorders: infrequent – palpitations, congestive heart failure³, pulmonary edema, tachycardia, flushes⁴, hemorrhages⁴; rare – arrhythmias, atrial fibrillation, sudden cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion, arterial hypertension, hematomas, cold extremities, arterial hypotension, Raynaud’s syndrome, BP decrease.

Respiratory system: frequently – nasal bleeding, shortness of breath, cough; infrequently – pleural effusion⁵, 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 pain⁶; common – abdominal bloating, flatulence, constipation, gastroesophageal reflux, dry mouth, gastritis, increased activity of liver transaminases; infrequent – stomatitis, ulceration of the oral mucosa, gastrointestinal bleeding⁷, belching, melena, esophagitis, ascites, gastric ulcer, vomiting blood, cheilitis, dysphagia, pancreatitis, hyperbilirubinemia, jaundice, hepatitis; Rarely, colitis, paralytic/obturative intestinal obstruction, intestinal inflammation, liver failure⁹, liver necrosis⁹.

Dermatological reactions: very common – periorbital edema, dermatitis, eczema, skin rash; common – facial swelling, itching, erythema, dry skin, erythema, alopecia, night sweats, photosensitization reactions; infrequent – pustular rash, bruises, increased sweating, urticaria, ecchymoses, increased susceptibility to hematoma formation, hypotrichosis, hyperpigmentation/hypopigmentation of the skin, exfoliative dermatitis, nail damage, folliculitis, petechiae, psoriasis, purpura, bullous rash; rarely – discoloration of nails, acute febrile neutrophilic dermatosis (Sweet’s syndrome), angioedema, erythema multiforme, leukoclastic vasculitis, Stevens-Johnson syndrome, acute generalized pustular exanthema.

Muscular system disorders: very common – muscle spasms and cramps, musculoskeletal pain (including Myalgia, arthralgia, bone pain⁸); common – swelling of joints; infrequent – stiffness of muscles and joints; rare – muscle weakness, arthritis; common unknown – growth retardation in children.

Urinary system disorders: 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.

General reactions: very common – fluid retention, edema, increased fatigue, weight gain; common – weakness, increased body temperature, anasarca, chills, shivering, weight loss; infrequent – chest pain, general malaise.

Laboratory measures: infrequent – increase of ALP, CPK, LDH and creatinine activity in blood serum; rare – increase of amylase activity in blood plasma.

¹ – Pneumonia was most commonly seen in patients with CML in the acceleration phase, blast crisis and with inoperable and/or metastatic malignant gastrointestinal stromal tumors of the GI tract.

² – Headache was most commonly reported in patients with inoperable and/or metastatic malignant gastrointestinal stromal tumors.

³ – Adverse cardiac events, including congestive heart failure, were more frequently noted in patients with CML in the acceleration phase and at blast crisis compared with patients with CML in the chronic phase (duration of follow-up – 1 year).

⁴ – Tides were most common in patients with inoperable and/or metastatic GI malignancies; bleeding (hematomas, hemorrhages) was most common in patients with CML in the acceleration phase, blast crisis and with inoperable and/or metastatic GI malignancies.

⁵ – Pleural effusion was more frequent in patients with CML in the acceleration phase and in blast crisis compared with CML in the chronic phase (duration of follow-up, 1 year).

^6/7 – Abdominal pain and gastrointestinal bleeding were most commonly reported in patients with inoperable and/or metastatic GI malignancies.

⁸ – Muscle-skeletal pain (including myalgia, arthralgia, bone pain) was more frequently noted in patients with CML compared to patients with inoperable and/or metastatic GI malignancies.

⁹ – Individual cases of hepatic failure and hepatic necrosis have been reported.

The following adverse reactions, listed by organs and systems with indication of the frequency of occurrence, have been noted in clinical practice and in additional clinical trials with Glivec®:

• very frequently (≥1/10);
• frequently (≥1/100, < 1/10);
• infrequently (≥1/1000, < 1/100);
• frequently (≥1/10,000, < 1/1000);
• very rarely ( < 1/10,000), including.

The relationship between the use of the drug and these adverse reactions has not been established (patient population size unknown).

Nervous system disorders: infrequent cerebral edema.

An organ of vision: rarely – vitreous hemorrhage.

Cardiovascular system: infrequent thrombosis/embolism; rarely – pericarditis, cardiac tamponade; very rare – anaphylactic shock.

Respiratory system disorders: infrequent – acute respiratory failure¹, interstitial pneumonia.

Gastrointestinal system disorders: infrequent – paralytic/obturative intestinal obstruction, bleeding from a GI tumor, GI tumor necrosis, GI perforation²; rarely – diverticulitis.

Muscular system disorders: rare – avascular necrosis/necrosis of the femoral head, rhabdomyolysis/myopathy.

Perior genital system disorders: very rare in women – bleeding from the corpus luteum/ovarian cysts.

Dermatological reactions: infrequent – palmar and plantar erythrodysesthesia; rare – lichenoid keratosis, red squamous lichen, toxic epidermal necrolysis.

Allergic reactions: very rare – anaphylactic shock.

¹ – There have been isolated reports of the development of severe acute respiratory failure with fatal outcome in patients with severe infectious diseases, marked neutropenia and other serious comorbidities.

² – Individual cases of fatal gastrointestinal perforations have been reported.

Overdose

The experience of using Glivec in doses exceeding the therapeutic ones is limited. Cases of drug overdose have been observed in clinical practice. In general, the outcome of cases of Glivec® overdose was favorable (improvement of patients’ condition was noted).

The symptoms of overdose in adults:

In 1-10 days, nausea, vomiting, diarrhea, rash, erythema, edema, swelling (mostly of the face), increased fatigue, muscle cramps, thrombocytopenia, pancytopenia, abdominal pain, headache, reduced appetite were observed when taking Glivec® in doses of 1200-1600 mg.

When taking the drug at a dose of 1800-3200 mg (the highest dose was 3200 mg/day for 6 days) weakness, myalgia, increased blood CPK, bilirubin, gastrointestinal pain were observed.

When Glivec® was administered once in dose of 6400 mg (information from the published source) the patient developed nausea, vomiting, abdominal pain, hyperthermia, facial edema, decrease of neutrophil number and increase of liver transaminases activity.

In a single dose of 8-10 g, vomiting and gastrointestinal pain were reported.

In a child aged 3 years, vomiting, diarrhea and anorexia were reported when a single dose of 400 mg was taken. In another case, a child aged 3 years had decreased white blood cell count and diarrhea when Glivek was taken once at a dose of 980 mg.

Treatment: Medical monitoring and symptomatic therapy are recommended. The antidote to Glivec is unknown.