Glivec - Package Leaflet

- If you are being treated for Ph + ALL:

The starting dose is 600 mg to be taken as 12 capsules once a day.

- If you are being treated for MSD / MPD:

The starting dose is 400 mg, to be taken as 8 capsules once a day.

- If you are being treated for HES / CLE:

The starting dose is 100 mg, to be taken as 2 capsules once a day. Your doctor may decide to increase the dosage to 400 mg, to be taken as 8 capsules once a day based on your response to treatment.

- If you are being treated for DFSP:

The dose is 800 mg per day (16 capsules), to be taken as 8 capsules in the morning and 8 capsules in the evening.

Use in children and adolescents

Your doctor will tell you how many Glivec capsules to give to your child. The amount of Glivec administered will depend on the condition of the child, his weight and height. The total daily dose should not exceed 800 mg in children with CML and 600 mg in children with Ph + ALL. The treatment can be given to the child as a single daily dose or, alternatively, the daily dose can be divided into two administrations (half in the morning and half in the evening).

When and how to take Glivec

• Take Glivec with a meal. This will help protect your stomach when taking Glivec.
• Swallow the capsules whole with a large glass of water. Do not open or break the capsules unless you have difficulty swallowing (eg in children).
• If you are unable to swallow the capsules, you can open them and pour the powder into a glass of still water or apple juice.
• If you are pregnant or could become pregnant and are trying to open the capsules, you should handle the contents with caution to avoid skin and eye contact or inhalation. You should wash your hands immediately after opening the capsules.

How long to take Glivec

Keep taking Glivec every day for as long as your doctor tells you.

Overdose What to do if you have taken too much Glivec

If you take more Glivec than you should

If you have accidentally taken too many capsules, contact your doctor immediately. You may need medical attention. Take the medicine box with you.

If you forget to take Glivec

• If you forget a dose, take it as soon as you remember. However, if it is almost time for your next dose, skip the missed dose.
• Then continue with your normal dosage.
• Do not take a double dose to make up for a forgotten dose.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

Side Effects What are the side effects of Glivec

Like all medicines, this medicine can cause side effects, although not everybody gets them. These are generally mild to moderate.

Some side effects can be serious. Tell your doctor immediately if you experience any of the following:

Very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people):

• Rapid weight gain. Glivec can cause your body to retain water (severe fluid retention).
• Signs of infection such as fever, severe chills, pharyngitis or mouth ulceration.Glivec can reduce the number of white blood cells so you may get infections more easily.
• Unexpected bleeding or bruising (when it didn't hurt itself).

Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people):

• Chest pain, irregular heart rhythm (signs of heart problems).
• Cough, difficulty breathing or painful breathing (signs of lung problems).
• Light-headedness, lightheadedness or fainting (signs of low blood pressure).
• Feeling sick (nausea), with loss of appetite, dark colored urine, yellowing of the skin or eyes (signs of liver problems).
• Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or purple patches on the skin, itching, burning sensation, pustular rash (signs of skin problems).
• Severe abdominal pain, blood in vomit, stool or urine, black stools (signs of gastrointestinal disturbances).
• Significant decrease in the amount of urine, feeling thirsty (signs of kidney problems).
• Feeling sick (nausea) with diarrhea and vomiting, abdominal pain or fever (signs of bowel problems).
• Severe headache, weakness or paralysis of the limbs or face, slurred speech, sudden loss of consciousness (signs of nervous system problems such as bleeding or swelling in the skull / brain).
• Paleness, feeling tired and wheezing and dark colored urine (signs of low red blood cell values).
• Eye pain or deterioration of vision, bleeding in the eye.
• Hip pain or difficulty walking.
• Numb or cold fingers or toes (signs of Raynaud's syndrome).
• Sudden swelling and redness of the skin (signs of a skin infection called cellulitis).
• Hearing problems.
• Muscle weakness and muscle spasms with an abnormal heart rhythm (signs of changes in the amount of potassium in the blood). ? Bruising (bruising).
• Stomach pain with feeling sick (nausea).
• Muscle spasms with fever, red brown urine, muscle pain or weakness (signs of muscle problems).
• Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling dizzy or fainting due to low blood pressure (signs of problems with the ovaries and uterus).
• Nausea, shortness of breath, irregular heartbeat, cloudy urine, tiredness and / or joint discomfort associated with abnormal laboratory test results (e.g. high levels of potassium, uric acid and calcium and low levels of phosphorus in the blood).

Not known (frequency cannot be estimated from the available data):

• Combination of a severe widespread skin reaction, feeling sick, fever, increased number of certain types of white blood cells or yellowing of the skin or eyes (signs of jaundice i.e. a liver problem) with shortness of breath, chest pain / discomfort, significant decrease in urine production and feeling of thirst, etc. (signs of a treatment-related allergic reaction).

If you experience any of the effects described above, please tell your doctor immediately.

Other side effects can include:

Very common (may affect more than 1 in 10 people):

• Headache or tired feeling.
• Feeling sick (nausea), vomiting, diarrhea or indigestion.
• Rash.
• Muscle cramps or pains in joints, muscles or bones.
• Swelling for example around the ankles or puffy eyes.
• Weight gain.

If any of these affects you severely, tell your doctor.

Common (may affect up to 1 in 10 people):

• Anorexia, weight loss or a disturbed sense of taste.
• Feeling light-headed or weak.
• Sleep disturbances (insomnia).
• Discharge from the eyes with itching, redness and swelling (conjunctivitis), increased tearing or blurred vision.
• Nose bleeding.
• Abdominal pain or bloating, flatulence, heartburn or constipation.
• Itching.
• Unusual hair loss or thinning.
• Numbness of the hands or feet.
• Mouth ulcerations.
• Joint pain with swelling.
• Dry mouth, dry skin or dry eyes.
• Reduction or increase in skin sensitivity.
• Hot flashes, chills, or night sweats.

If any of these affects you severely, tell your doctor.

Not known (frequency cannot be estimated from the available data):

• Redness and / or swelling of the palms of the hands and soles of the feet which may be accompanied by a tingling sensation and painful burning.
• Slowing of growth in children and adolescents. If any of these affects you severely, tell your doctor.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

• Keep this medicine out of the sight and reach of children.
• Do not use this medicine after the expiry date which is stated on the carton.
• Do not store above 30 ° C.
• Store in the original package to protect the medicine from moisture.
• Do not use if package is damaged or shows signs of tampering.
• Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

What Glivec contains

• The active substance is imatinib mesylate. Each capsule of Glivec contains 50 mg of imatinib (as mesylate).
• The other ingredients are microcrystalline cellulose, crospovidone, magnesium stearate and anhydrous colloidal silica. The capsule shell consists of gelatin, yellow iron oxide (E172) and titanium dioxide (E171). The printing ink consists of red iron oxide (E172), shellac, soy lecithin.

Description of the appearance of Glivec and contents of the pack

Glivec 50 mg capsules are light yellow to yellow-orange in color and marked "NVR SH". They contain a white to yellow powder.

They are supplied in packs of 30 capsules.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

01.0 NAME OF THE MEDICINAL PRODUCT

GLIVEC 50 MG HARD CAPSULES

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 50 mg of imatinib (as mesylate).

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Hard capsule

White to yellow powder in a light yellow to yellow-orange opaque capsule, imprinted with "NVR SH".

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Glivec is indicated for the treatment of

• adult and pediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph +) chronic myeloid leukemia (CML) for whom bone marrow transplant is not considered a first-line treatment.

• adult and pediatric patients with chronic phase Ph + CML after failure of interferon-alpha therapy, or accelerated phase or blast crisis.

• adult and pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL) supplemented with chemotherapy.

• adult patients with relapsed or refractory Ph + ALL as monotherapy.

• adult patients with myelodysplastic / myeloproliferative diseases (MDS / MPD) associated with rearrangements of the platelet-derived growth factor receptor (PDGFR) gene.

• adult patients with advanced hypereosinophilic syndrome (HES) and / or chronic eosinophilic leukemia (CEL) with FIP1L1-PDGFRa rearrangement.

The effect of Glivec on bone marrow transplant outcome has not been determined.

Glivec is indicated for

• the treatment of adult patients with unresectable and / or metastatic malignant gastrointestinal stromal tumors (GIST), Kit positive (CD 117).

• the adjuvant treatment of adult patients with a significant risk of relapse after resection of Kit positive GISTs (CD 117). Patients with a low or very low risk of relapse should not receive adjuvant treatment.

• the treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with relapsed and / or metastatic DFSP who are not eligible for surgery.

In adult and pediatric patients, the efficacy of Glivec is based on overall haematological and cytogenetic response and progression-free survival values ​​in CML, on haematological and cytogenetic response values ​​in Ph + ALL, MDS / MPD, on haematological response values in HES / CLE and on objective response values ​​in adult patients with unresectable and / or metastatic GIST and DFSP and relapse-free survival in adjuvant treatment of GIST. The experience with Glivec in patients with MDS / MPD associated with PDGFR gene is very limited (see section 5.1). There are no controlled clinical trials demonstrating clinical benefit or increased survival for these conditions, except those conducted in newly diagnosed chronic phase CML.

04.2 Posology and method of administration

Therapy should be initiated by a physician experienced in the treatment of patients with haematological tumors and malignant sarcomas, as appropriate.

The prescribed dose should be administered orally, with a meal and with a large glass of water to reduce the risk of gastrointestinal irritation. 800 mg daily should be administered as 400 mg twice daily, in the morning and in the evening. For patients (children) who cannot swallow the capsules, the contents can be diluted in a glass of still water or apple juice. As studies in animals have shown signs of reproductive toxicity and the potential risk to the human fetus is unknown, women of childbearing potential who open the capsules should handle the contents with care and avoid contact with eyes or inhalation (see section 4.6) Hands should be washed immediately after handling the opened capsules.

Posology for CML in adult patients

For adult patients with chronic phase CML, the recommended dosage of Glivec is 400 mg / day. CML is defined as chronic when all of the following criteria are met: blood and bone marrow blasts peripheral blood basophils platelets> 100 x 109 / l.

For adult patients in accelerated phase the recommended dosage of Glivec is 600 mg / day. The accelerated phase is defined by the presence of any of the following: blasts in the blood or bone marrow ≥15% but

For adult patients in blast crisis the recommended dosage of Glivec is 600 mg / day. Blast crisis is defined by the presence of blood or bone marrow blasts ≥30% or by extramedullary disease other than hepatosplenomegaly.

Duration of treatment: In clinical studies, Glivec treatment continued until disease progression. The effect of stopping treatment after achieving a complete cytogenetic response has not been studied.

Doses can be increased from 400 mg to 600 mg or 800 mg in patients with chronic phase disease or from 600 mg to a maximum of 800 mg (given as 400 mg twice daily) in patients with chronic phase disease. accelerated or blast crisis in the absence of severe adverse drug reactions and severe neutropenia or thrombocytopenia not associated with leukemia in the following conditions:

disease progression (at any time); failure to obtain a satisfactory haematological response after at least 3 months of treatment; failure to obtain a cytogenetic response after 12 months of treatment; or loss of a previously obtained haematological and / or cytogenetic response. Patients should be closely monitored for dose escalation given the potential for increased incidence of adverse reactions at higher doses.

Posology for CML in pediatric patients

Dosage for pediatric patients should be calculated on the basis of body surface area (mg / m2).

A daily dose of 340 mg / m2 is recommended for children with chronic and advanced phase CML (not to exceed the total dose of 800 mg). The total daily dose can be taken as a single dose or divided into two administrations, one in the morning and one in the evening. Dosing recommendations are currently based on a limited number of pediatric patients (see sections 5.1 and 5.2). There are no data in the treatment of children under 2 years of age.

It is possible to increase the daily dose from 340 mg / m2 to 570 mg / m2 (not to exceed the total dose of 800 mg) in the pediatric population in the absence of severe adverse drug reactions and severe neutropenia or thrombocytopenia not associated with leukemia in the following circumstances : disease progression (at any time); failure to achieve a satisfactory haematological response after at least 3 months of treatment, failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously obtained haematological and / or cytogenetic response. Patients should be closely monitored after dose escalation, given the potential increased incidence of adverse reactions at higher doses.

Posology for Ph + ALL in adult patients

For adult patients with Ph + ALL the recommended dosage of Glivec is 600 mg / day.

Hematologists

experts in the management of this disease must supervise therapy at all stages of treatment. Treatment schedule: Based on existing data, Glivec has been shown to be effective and safe when administered at 600 mg / day in combination with chemotherapy in the induction, consolidation and maintenance phases (see section 5.1) used in the treatment of adult patients. with newly diagnosed Ph + ALL The duration of Glivec therapy may vary depending on the treatment regimen chosen, but generally better results have been achieved with longer exposure to Glivec.

For adult patients with relapsed or refractory Ph + ALL, Glivec monotherapy at 600 mg / day is safe, effective and can be administered until disease progression.

Posology for Ph + ALL in pediatric patients

Dosage for pediatric patients should be calculated on the basis of body surface area (mg / m2).

For children with Ph + ALL the recommended daily dose is 340 mg / m2 (not to exceed the total dose of 600 mg).

Dosage for MDS / MPD

For adult patients with MDS / MPD the recommended dosage of Glivec is 400 mg / day.

Duration of treatment: In the only clinical study conducted to date, treatment with Glivec was continued until disease progression (see section 5.1). At the time of analysis, the median duration of treatment was 47 months (24 days - 60 months).

Posology for HES / CLE

For adult patients with HES / CEL the recommended dosage of Glivec is 100 mg / day.

A dose increase from 100 mg to 400 mg may be considered in the absence of adverse drug reactions if evaluations demonstrate insufficient therapeutic response.

Treatment should be continued as long as the patient continues to benefit from it.

Posology for GISTs

For adult patients with unresectable and / or metastatic malignant GIST the recommended dosage of Glivec is 400 mg / day.

There are limited data on the effect of dose increases from 400 mg to 600 mg or 800 mg in patients progressing to the lower dose (see section 5.1).

Duration of treatment: In clinical trials in GIST patients, Glivec treatment was continued until disease progression.At the time of analysis, the duration of treatment was on average 7 months (7 days to 13 months). The effect of stopping treatment after response has been achieved has not been studied.

For adult patients with GIST, after resection, the recommended dosage of Glivec for adjuvant treatment is 400 mg / day. The optimal duration of adjuvant treatment has not yet been determined. The duration of treatment in the clinical study supporting this indication was 36 months (see section 5.1).

Dosage for DFSP

For adult patients with DFSP the recommended dosage of Glivec is 800 mg / day.

Dose adjustment in case of adverse reactions

Non-haematological adverse reactions

Should a non-haematological adverse reaction occur with the use of Glivec, treatment should be suspended until the event is resolved. Thereafter, treatment can be resumed as appropriate, depending on the initial severity of the event.

If elevations of bilirubin levels greater than 3 times the "Institutional upper limit of normal" IULN or liver transaminase levels greater than 5 times the IULN limit occur, Glivec should be suspended for as long as the bilirubin have returned to values ​​below 1.5 times the IULN limit and transaminase levels below 2.5 times the IULN limit. Glivec treatment can be continued with a reduced daily dosage.

In adults the dose should be reduced from 400 to 300 mg or from 600 to 400 mg, or from 800 mg to 600 mg and in children from 340 to 260 mg / m2 / day.

Haematological adverse reactions

A dose reduction or discontinuation of treatment is recommended for severe neutropenia and thrombocytopenia as indicated in the table below.

Dose adjustments for neutropenia and thrombocytopenia:

Special categories of patients

Pediatric use: there is no experience in children with CML less than 2 years of age and in children with Ph + ALL less than 1 year of age (see section 5.1). Experience in children with MDS / MPD, DFSP, GIST and with HES / LEC is very limited.

The safety and efficacy of imatinib in children with MDS / MPD, DFSP, GIST and HES / CEL below the age of 18 have not been established in clinical studies. Currently available published data are summarized in section 5.1 but cannot be made no recommendations regarding posology.

Liver failure: imatinib is primarily metabolised by the liver. Patients with mild, moderate or severe hepatic dysfunction should be given the minimum recommended dose of 400 mg per day. The dose can be reduced if not tolerated (see sections 4.4, 4.8 and 5.2).

Hepatic dysfunction classification:

ULN = upper limit of normal for the institution

AST = aspartate aminotransferase

Kidney failure: Patients with renal dysfunction or undergoing dialysis should be given the minimum recommended dose of 400 mg per day as a starting dose. However, caution is recommended in these patients. The dose can be reduced if not tolerated. If tolerated, the dose may be increased due to lack of efficacy (see sections 4.4 and 5.2).

Older people: the pharmacokinetics of imatinib in elderly people have not been specifically studied. In adult patients, no significant age-related pharmacokinetic differences were observed in clinical trials involving more than 20% of patients aged 65 years or older.

No specific dose recommendation is needed in older people.

04.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

04.4 Special warnings and appropriate precautions for use

When Glivec is given together with other medicines, drug interactions are possible.

Caution should be exercised when administering Glivec with protease inhibitors, azole antifungals, some macrolides (see section 4.5), CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil , terfenadine, bortezomib, docetaxel, quinidine) or warfarin and other coumarin derivatives (see section 4.5).

The concomitant use of imatinib and medicinal products that induce CYP3A4 (eg dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital orHypericum perforatum, also known as St. John's Wort) can significantly reduce exposure to Glivec, potentially increasing the risk of treatment failure. Therefore, concomitant use of strong CYP3A4 inducers and imatinib should be avoided (see section 4.5).

Hypothyroidism

Clinical cases of hypothyroidism have been reported in thyroidectomised patients receiving levothyroxine replacement during therapy with Glivec (see section 4.5). Thyroid stimulating hormone (TSH) levels should be closely monitored in such patients.

Hepatotoxicity

The metabolism of Glivec is mainly hepatic, and only 13% of excretion occurs via the kidneys. In patients with hepatic dysfunction (mild, moderate or severe), peripheral blood tests and liver enzymes should be closely monitored (see sections 4.2, 4.8 and 5.2). It has been found that patients with GIST may have liver metastases which could cause hepatic impairment.

Cases of hepatic injury, including hepatic failure and hepatic necrosis, have been observed with imatinib. When imatinib is combined with high-dose chemotherapy regimens, an increase in severe hepatic reactions has been reported. Hepatic function should be closely monitored in situations where imatinib is combined with chemotherapy regimens, also known to be associated with hepatic dysfunction (see sections 4.5 and 4.8).

Fluid retention

Cases of severe fluid retention (pleural effusion, edema, pulmonary edema, ascites, superficial edema) have been reported in approximately 2.5% of newly diagnosed CML patients treated with Glivec. Therefore it is highly recommended to weigh patients regularly. Unexpected rapid weight gain should be carefully investigated and appropriate supportive care and therapeutic measures taken if necessary. In clinical trials, there is an increased incidence of these events in elderly people and in those with a prior history of heart disease. Therefore, caution should be exercised in patients with cardiac dysfunction.

Patients with heart disease

Patients with heart disease, risk factors for heart failure or a history of renal failure should be monitored closely and all patients with signs or symptoms related to heart or renal failure should be evaluated and treated.

In patients with hypereosinophilic syndrome (HES) with occult infiltration of HES cells within the myocardium, isolated cases of cardiogenic shock / left ventricular dysfunction have been associated with HES cell degranulation soon after initiation of imatinib therapy. The condition has been reported as reversible with systemic steroid administration, haemodynamic supportive measures, and with temporary discontinuation of imatinib. As adverse cardiac events have been reported uncommonly with imatinib, the benefit / risk balance of imatinib therapy in the HES / CEL patient population should be carefully considered before initiating treatment.

Myelodysplastic / myeloproliferative diseases with PDGFR gene rearrangements may be associated with elevated eosinophil levels. Therefore, in patients with HES / CEL and in patients with MDS / MPD associated with elevated levels of eosinophils, evaluation by a cardiologist, performing an echocardiogram and determination of serum troponin should be considered prior to administration of imatinib. one of the two is out of the norm, at the beginning of therapy, periodic control by a cardiologist and the prophylactic use of systemic steroids (1-2 mg / kg) should be considered for one to two weeks concurrently with "start of therapy.

Gastrointestinal bleeding

In the study in patients with unresectable and / or metastatic GIST, both gastrointestinal and intra-tumor haemorrhages were reported (see section 4.8). Based on the available data, no predisposing factors (eg tumor size, tumor location, coagulation alterations) have been identified that place patients with GIST at a higher risk for both types of bleeding. Because increased vascularity and propensity to bleed are part of the nature and clinical course of GISTs, common medical practices and procedures for monitoring and treating bleeding should be adopted for all patients.

Tumor lysis syndrome

Due to the possible occurrence of Tumor Lysis Syndrome (TLS), correction of clinically significant dehydration and treatment of high uric acid levels is recommended before initiating Glivec (see section 4.8).

Laboratory analysis

During therapy with Glivec, carry out a complete blood count on a regular basis. Treatment of CML patients with Glivec has been associated with neutropenia or thrombocytopenia. However, the occurrence of these cytopenias is probably related to the stage of the disease treated and was more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. Treatment with Glivec can be stopped or the dose reduced as recommended in section 4.2.

Liver function (transaminase, bilirubin, alkaline phosphatase) should be monitored regularly in patients treated with Glivec.

In patients with impaired renal function, the plasma exposure of imatinib appears to be higher than that observed in patients with normal renal function, possibly due to elevated plasma levels of alpha acid glycoprotein (AGP), a protein to which imatinib binds, in These patients. Patients with renal impairment should be given the lowest starting dose. Patients with severe renal impairment should be treated with caution. The dose may be reduced if not tolerated (see sections 4.2 and 5.2).

Pediatric population

Cases of growth retardation have been reported in children and pre-adolescents treated with imatinib. The long-term effects of prolonged treatment with imatinib on growth in children are unknown. Therefore, careful monitoring of growth in children receiving imatinib is recommended (see section 4.8).

04.5 Interactions with other medicinal products and other forms of interaction

Active substances that may increase imatinib plasma concentrations:

Substances that inhibit the activity of the cytochrome P450 isoenzyme CYP3A4 (eg protease inhibitors such as indinavir, lopinavir / ritonavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir; azole antifungals including ketoconazole, itolidraconazole, some macricon, some posriconazole; such as erythromycin, clarithromycin and telithromycin) could reduce metabolism and increase imatinib concentrations. There was a significant increase in imatinib exposure (mean Cmax and AUC values ​​of imatinib increased by 26% and 40% respectively) in healthy subjects when co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution is required when administering Glivec with the CYP3A4 family of inhibitors.

Active substances that may reduce imatinib plasma concentrations:

Substances that stimulate CYP3A4 activity (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, fosphenytoin, primidone orHypericum perforatum, also known as St. John's Wort) can significantly reduce exposure to Glivec, potentially increasing the risk of treatment failure. Pretreatment with multiple doses of 600 mg rifampicin followed by a single 400 mg dose of Glivec resulted in a decrease of Cmax, and AUC (0-∞) of at least 54% and 74% relative to their values ​​without rifampicin treatment. Similar results were observed in patients with malignant gliomas treated with Glivec while taking enzyme-inducing antiepileptic drugs (EIAED ) such as carbamazepine, oxcarbazepine and phenytoin. Imatinib plasma AUC was reduced by 73% compared to patients not treated with EIAED. Concomitant use of rifampicin or strong CYP3A4 inducers and imatinib should be avoided.

Active substances whose plasma concentration can be altered by Glivec

Imatinib increases the mean Cmax and AUC values ​​of simvastatin (CYP3A4 substrate) by 2- and 3.5-fold, respectively, indicating an "inhibition of CYP3A4 by imatinib. Therefore caution is recommended when administering Glivec with CYP3A4 substrates with close therapeutic window (eg cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel and quinidine). Glivec may increase the plasma concentrations of other drugs metabolised by CYP3A4 (eg benzidodiazole-triazole) , calcium channel blockers, some HMG-CoA reductase inhibitors, e.g. statins etc.).

Because of the known increased risk of bleeding in conjunction with the use of imatinib (eg haemorrhage), patients requiring anticoagulants should receive standard or low molecular weight heparin instead of coumarin derivatives such as warfarin.

In vitro Glivec inhibits the activity of the cytochrome P450 isoenzyme CYP2D6 at concentrations similar to those affecting CYP3A4 activity. Imatinib 400 mg twice daily had an inhibitory effect on the CYP2D6 mediated metabolism of metoprolol, with an increase in Cmaxe of the AUC by approximately 23% (90% CI [1.16-1.30]). Dose adjustments do not appear to be necessary when imatinib is co-administered with CYP2D6 substrates, however caution is advised for CYP2D6 substrates with a narrow therapeutic window such as metoprolol.

Clinical monitoring should be considered in patients treated with metoprolol.

In vitro, Glivec inhibits the O-glucuronidation of paracetamol with a Ki value of 58.5 micromol / l.

This inhibition was not observed in vivo after the administration of 400 mg of Glivec and 1000 mg of paracetamol. Higher doses of Glivec and paracetamol have not been studied.

Therefore, caution should be exercised when high doses of Glivec and paracetamol are used concomitantly.

In thyroidectomised patients receiving levothyroxine, plasma exposure to levothyroxine may be decreased when co-administered with Glivec (see section 4.4). Caution is therefore recommended. The mechanism of the observed interaction is, however, currently unknown.

There is clinical experience of Glivec administered concomitantly with chemotherapy in patients with Ph + ALL (see section 5.1), but the drug interactions between imatinib and chemotherapy regimens have not been fully characterized.Adverse events of imatinib, such as hepatotoxicity, myelosuppression or others, may be increased and it has been reported that concomitant use with L-asparaginase may be associated with increased hepatotoxicity (see section 4.8). Therefore the use of Glivec in combination requires special precaution.

04.6 Pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should be advised of the need to use effective contraception during treatment.

Pregnancy

There are limited data from the use of imatinib in pregnant women. However, animal studies have shown reproductive toxicity (see section 5.3) and the potential risk to the fetus is unknown. Glivec should not be used during pregnancy. unless absolutely necessary If administered during pregnancy, inform the patient of the potential risk to the fetus.

Feeding time

There is limited information regarding the distribution of imatinib in breast milk. Evaluations in two nursing women showed that both imatinib and its active metabolite can be distributed into breast milk. The milk / plasma ratio, evaluated in a single patient, was determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite in milk. Taking into account the combined concentration of imatinib and the metabolite and the maximum daily milk intake of infants, the total exposure would appear to be low (approximately 10% of a therapeutic dose). However, as the effects of low exposure doses in infants are not known, women taking imatinib should not breastfeed.

Fertility

In non-clinical studies, the fertility of male and female rats was not affected (see section 5.3). No studies have been conducted in patients treated with Glivec to evaluate its effect on fertility and spermatogenesis. Patients who are concerned about their fertility while being treated with Glivec should consult their doctor.

04.7 Effects on ability to drive and use machines

Patients should be advised that undesirable effects such as dizziness, blurred vision or somnolence may occur during treatment with imatinib. Therefore caution is recommended while driving vehicles and using machines.

04.8 Undesirable effects

Patients with advanced cancers may have a number of unclear clinical conditions that make it difficult to assess the cause of adverse reactions given the variety of symptoms related to the underlying disease, its progression, and the concomitant administration of numerous medications.

In CML clinical studies, drug discontinuation due to drug-associated adverse reactions was observed in 2.4% of newly diagnosed patients, in 4% of patients in advanced chronic phase after failure of interferon therapy, in 4% of patients in advanced chronic phase. patients in accelerated phase after failure of interferon therapy and in 5% of patients with blast crisis after failure of interferon therapy. In the GIST studies, drug administration was discontinued in 4% of patients due to drug-related adverse reactions.

Adverse reactions were similar in all indications, with two exceptions. There was more myelosuppression observed in CML patients than in GIST patients, which is likely due to the underlying disease. In the study in patients with unresectable and / or metastatic GIST, 7 patients (5%) experienced CTC grade 3/4 GI bleeding (3 patients), intra-tumor bleeding (3 patients), or both (1 patient) . Location of GI tumors may have been the cause of GI bleeding (see section 4.4). GI bleeding and tumor bleeding could be serious and sometimes fatal. The most commonly (≥10%) drug-associated adverse reactions reported in both disorders were mild nausea, vomiting, diarrhea, abdominal pain, fatigue, myalgia, muscle cramps and rash. Superficial edema, described primarily as periorbital or lower limb edema, was commonly found in all studies. However, these edemas were rarely severe and can be managed with diuretics, other supportive measures or by reducing the dose of Glivec.

When imatinib was combined with high-dose chemotherapy in patients with Ph + ALL, transient hepatic toxicity in terms of elevated transaminases and hyperbilirubinaemia was observed.

Considering the limited safety information, adverse events reported so far in children are consistent with the safety profile established in adult Ph + ALL patients. Safety information for children with Ph + ALL is very limited, however no new safety concerns have been identified.

Various adverse reactions such as pleural effusion, ascites, pulmonary edema and rapid weight gain with or without superficial edema can be collectively described as "fluid retention". These reactions can usually be managed by temporarily withholding Glivec and diuretics and other appropriate supportive therapeutic measures. Some of these reactions, however, can be serious or life-threatening, and several patients with blast crisis have died with a complex clinical picture of pleural effusion, congestive heart failure, and renal failure. No particular safety aspect emerged from the clinical studies conducted in pediatric patients.

Adverse reactions

Adverse reactions reported as more than one isolated case are listed below by system organ class and frequency. Frequency categories are defined using the following convention: very common (≥1 / 10), common (≥1 / 100,

Within each frequency class, undesirable effects are listed in order of frequency, the most frequent first.

The adverse reactions and their frequencies reported in Table 1 are based on the main pivotal studies.

Table 1 Adverse reactions in clinical studies

1 Pneumonia was most commonly reported in patients with advanced CML and in patients with GIST.

2 Headache was more common in GIST patients.

3 On a patient-year basis, cardiac events including congestive heart failure were observed more commonly in patients with advanced CML than in patients with chronic CML.

4 Flushing was more common in patients with GIST and bleeding (hematoma, haemorrhage) was more common in patients with GIST and advanced CML (CML-AP and CMLBC).

5 Pleural effusion was reported more commonly in patients with GIST and in patients with advanced CML (CML-AP and CML-BC) than in patients with chronic CML.

6 + 7 Abdominal pain and gastrointestinal bleeding were most commonly observed in patients with GIST.

8 Some fatal cases of hepatic failure and hepatic necrosis have been reported.

9 Musculoskeletal pain and related events were observed more commonly in CML patients than in GIST patients.

The following types of reactions have mainly been reported from post-marketing experience with Glivec. They include spontaneous reports and serious adverse events reported in ongoing studies, extended access programs, clinical pharmacology studies and exploratory studies in unapproved indications. reactions are reported in a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship with imatinib exposure.

Table 2 Adverse reactions from post-marketing reports

1 Fatal cases have been reported in patients with advanced disease, severe infections, severe neutropenia and other serious concomitant conditions.

Abnormalities in laboratory analyzes:

Hematology

In CML, cytopenias, and in particular neutropenia and thrombocytopenia, were common in all studies, with an indication of a higher frequency at high doses ≥750 mg (phase I study). However, the occurrence of cytopenia was also found to clearly depend on the stage of the disease, the frequency of neutropenia (ANC

In newly diagnosed chronic phase CML, neutropenia (ANC

However in rare cases they can lead to a permanent suspension of treatment. In pediatric patients with CML, the most frequently observed toxicities were grade 3 or 4 cytopenias including neutropenia, thrombocytopenia and anemia. They usually occurred within the first few months of therapy.

In the study in patients with unresectable and / or metastatic GIST, grade 3 and 4 anemia was reported in 5.4% and 0.7% of patients, respectively, which could be related to gastrointestinal or intra-tumor bleeding at least in some of these patients. Grade 3 and 4 neutropenia were observed in 7.5% and 2.7% of patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. No patient developed grade 4 thrombocytopenia. leukocytes (WBCs) and neutrophil counts occurred mostly during the first six weeks of therapy, with values ​​remaining relatively stable thereafter.

Biochemistry

Severe elevation of grade 3 or 4 transaminases (alanine aminotransferase) and 4.8% elevation of grade 3 or 4 aspartate aminotransferase (AST) was observed in CML patients. 3%.

There have been cases of cytolytic and cholestatic hepatitis and liver failure; in some of which the outcome was fatal, including one patient being treated with high doses of paracetamol.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

04.9 Overdose

Experience with doses higher than the recommended therapeutic dose is limited. Isolated cases of overdose with Glivec have been reported spontaneously and in the literature. In the event of overdose, the patient should be observed and given appropriate symptomatic treatment. Typically the outcome reported in these cases has been "improved" or "fixed". The following events have been reported at different dose intervals:

Adult population

1200-1600 mg (duration of treatment ranging from 1 to 10 days): Nausea, vomiting, diarrhea, rash, erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.

1800-3200 mg (up to 3200 mg per day for 6 days): Weakness, myalgia, increased creatine phosphokinase, increased bilirubin, gastrointestinal pain.

6400 mg (single dose): A case was reported in the literature of a patient presenting with nausea, vomiting, abdominal pain, fever, swelling of the face, decreased neutrophil count, increased transaminases.

8-10 g (single dose): Vomiting and gastrointestinal pain have been reported.

Pediatric population

One 3-year-old child exposed to a single dose of 400 mg had vomiting, diarrhea and anorexia and another 3-year-old child exposed to a single dose of 980 mg had decreased white blood cell counts and diarrhea.

In the event of an overdose, the patient should be observed and given appropriate supportive treatment.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: protein tyrosine kinase inhibitor, ATC code: L01XE01

Mechanism of action

Imatinib is a small protein-tyrosine kinase inhibitor molecule that potently inhibits the activity of the Bcr-Abl tyrosine kinase, as well as several tyrosine kinase receptors: Kit, the stem cell factor (SCF) receptor encoded by the proto - oncogene c-Kit, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the alpha and beta receptors for platelet-derived growth factor (PDGFR-alpha and PDGFR -beta).

Imatinib may also inhibit cellular events mediated by the activation of these kinase receptors.

Pharmacodynamic effects

Imatinib is a protein-tyrosine kinase inhibitor that potently inhibits the Bcr-Abl tyrosine kinase at levels in vitro, at the cellular level e in vivo. The compound selectively inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines and fresh leukemia cells from Philadelphia chromosome positive CML and acute lymphoblastic leukemia (ALL) patients.

In vivo the compound exhibits antitumor activity as a single agent in animal models with Bcr-Abl positive tumor cells.

Imatinib is also a tyrosine kinase receptor inhibitor for platelet-derived growth factor (PDGF), PDGF-R, and stem cell factor (SCF), c-Kit, and inhibits cellular events mediated by PDGF and SCF. In vitro, imatinib inhibits proliferation and induces apoptosis in gastrointestinal tract stromal tumor (GIST) cells, which express an active mutation of kit. Constitutive activation of the PDGF receptor or Abl protein tyrosine kinase as a consequence of fusion of different partner proteins or constitutive production of PDGF have been involved in the pathogenesis of MDS / MPD, HES / CLE and DFSP. Imatinib inhibits signaling. and cell proliferation driven by PDGFR deregulation and Abl kinase activity.

Clinical studies in chronic myeloid leukemia

The efficacy of Glivec is based on overall values ​​of haematological and cytogenetic response and progression-free survival of the disease. With the exception of newly diagnosed chronic phase CML, there are no controlled clinical trials demonstrating a clinical benefit, intended as improvement of the disease-related symptoms or increased survival. Three large, open, uncontrolled, Phase II international studies have been conducted in Philadelphia chromosome positive (Ph +) CML patients with advanced, accelerated, or blast crisis disease. other Ph + leukemias or with chronic phase CML, but which did not benefit from prior interferon-alpha (IFN) therapy. A large, randomized, open-label, Phase III international study was conducted in patients with Ph + CML newly diagnosed. In addition, pediatric patients were treated in two phase I and one phase II studies.

In all clinical studies, 38-40% of patients were ≥60 years of age and 10-12% of patients were ≥70 years of age.

Chronic phase, new diagnosis: This phase III study in adult patients compared treatment with Glivec alone and the combination of interferon-alpha (IFN) and cytarabine (Ara-C). Patients who did not respond (no complete haematological response (REC) at 6 months, increase in white blood cell count (WBC), no major cytogenetic response (MCR) at 24 months), who experienced a loss of response (loss of of the REC and MCR) or severe intolerance to treatment, was allowed to switch to the alternative treatment. In the Glivec arm, patients were treated with 400 mg daily doses. In the IFN arm, patients were administered subcutaneously with IFN doses of 5 MIU / m2 / day in combination with Ara-C at a dose of 20 mg / m2 / day for 10 days per month.

A total of 1,106 patients were randomized, 553 for each arm. The baseline characteristics of the two groups were similar. Median age was 51 years (range 18-70 years), with 21.9% of patients aged ≥60 years. 59% were male and 41% female; 89.9% were Caucasian and 4.7% black. Seven years after the last patient was enrolled, the median duration of first-line treatment was 82 and 8 months in the Glivec arm and the IFN arm, respectively.

The median duration of second-line treatment with Glivec was 64 months. Overall, in patients on first-line treatment with Glivec, the mean daily dose administered was 406 ± 76 mg. The main efficacy endpoint of the study is progression-free survival. Progression was defined as one of the following: progression to an accelerated phase or blast crisis, death, loss of complete haematological response (REC) or major cytogenetic response (MCR) or, in patients who do not achieve REC, an increase in the number of white blood cells despite appropriate therapeutic management. The main secondary endpoints are major cytogenetic response, haematological response, molecular response (disease assessment residual minimum), time to accelerated phase and blast crisis and survival The results are shown in Table 3.

Table 3 Response in newly diagnosed CML study (84-month data)

* p

** Molecular response rates are based on available samples

Hematological response criteria (all responses must be confirmed after at least 4 weeks):

WBC

Cytogenetic response criteria: complete (0% Ph + metaphases), partial (1-35%), minor (36-65%) or minimal (66-95%). The major response (0-35%) combines both complete and partial responses.

Major molecular response criteria: in peripheral blood ≥ 3 log reduction in Bcr-Abl transcript (measured by quantitative reverse transcriptase RT-PCR) from standardized baseline.

The rates of complete haematological response, major cytogenetic response, and complete cytogenetic response in first-line treatment were calculated according to the Kaplan-Meier method, whereby non-responses were truncated at the date of the last evaluation. With this method, cumulative response rates, estimated for first-line treatment with Glivec, were better from 12 months to 84 months of therapy as follows: CHR from 96.4% to 98.4%, respectively, and CCyR from 69, respectively , 5% to 87.2%.

After 7 years of follow-up there were 93 (16.8%) progression events in the Glivec arm: 37 (6.7%) accelerated phase progression / blast crisis, 31 (5.6%) loss of MCyR, 15 (2.7%) loss of CHR or increase in white blood cells, and 10 cases (1.8%) of non-CML-related death. There were 165 events (29.8%) in the IFN + Ara-C treatment, of which 130 occurred during first-line treatment with IFN + Ara-C.

The estimated rate of progression-free patients to accelerated phase or blast crisis at 84 months was significantly higher in the Glivec arm than in the IFN arm (92.5% vs 85.1%, p

There were 71 (12.8%) and 85 (15.4%) deaths in the Glivec and IFN + Ara-C arms, respectively.

The estimated overall survival at 84 months is 86.4% in the Glivec randomization arm and 83.3% in the IFN + Ara-C arm, respectively (log-rank test p = 0.073). The "time to event" end point is highly influenced by the "high percentage of cross-over from the IFN + Ara-C arm to the Glivec arm. The effect of Glivec treatment on survival in newly diagnosed chronic phase CML was further assessed by a "retrospective analysis of the Glivec data reported above and the primary data from another Phase III study using IFN + Ara-C (n = 325) with an identical dosing regimen. Superiority was demonstrated in this retrospective analysis. of Glivec against IFN + Ara-C in terms of overall survival (p

The degree of cytogenetic and molecular response had an evident effect on long-term outcomes in patients receiving Glivec. While an estimated 96% (93%) of patients with CCyR (PCyR) at 12 months were progression-free accelerated phase / blast crisis at 84 months, only 81% of patients without MCyR at 12 months were progression-free to CML in advanced stage at 84 months (global p

In this study, the authorized dose increases were from 400 mg per day to 600 mg per day, then from 600 mg per day to 800 mg per day. After 42 months of follow-up, 11 patients experienced a confirmed loss (over 4 weeks) of their cytogenetic response. Of these 11 patients, 4 patients had a dose increase up to 800 mg per day, 2 of these with recovery of the cytogenetic response (1 partial and 1 complete, the latter also reaching the molecular response), while of the 7 patients who they had not had the dose increase, only one had recovered the complete cytogenetic response. The rate of some adverse reactions was higher in the 40 patients in whom the daily dose was increased to 800 mg than in the patient population prior to dose escalation (n = 551). The most frequent adverse reactions included gastrointestinal bleeding , conjunctivitis and elevations of transaminases or bilirubin Other adverse reactions have been reported with equal or lesser frequency.

Chronic phase, failure of interferon therapy: 532 adult patients were treated with a starting dose of 400 mg. Patients were divided into three main categories: haematological insufficiency (29%), cytogenetic insufficiency (35%) or interferon intolerance (36%). Patients had previously received a median of 14 months of IFN therapy at doses ≥ 25 x 106 IU / week and were all in the chronic advanced phase, with a mean time of 32 months from diagnosis. The primary efficacy variable of the study was the rate of major cytogenetic response (complete plus partial response, Ph + metaphases from 0 to 35% in the bone marrow).

In this study, 65% of patients achieved a major cytogenetic response that was complete in 53% of patients (confirmed for 43%) (Table 4). A complete haematological response was achieved in 95% of patients.

Accelerated phase: 235 adult patients with accelerated phase disease were enrolled in the study. The first 77 patients started treatment at 400 mg, later the protocol was adjusted to allow for higher doses and the remaining 158 patients started treatment at 600 mg.

The primary efficacy variable was haematological response rate, reported as complete haematological response, no evidence of leukemia (i.e. clearance of blasts from marrow and blood but without full peripheral blood recovery as is the case for complete responses). , or return to chronic phase CML. A confirmed haematological response was achieved in 71.5% of patients (Table 4). Importantly, a relevant cytogenetic response was also achieved in 27.7% of patients, which was complete in 20.4% of patients (confirmed for 16%).

For patients treated at 600 mg, current median progression-free survival and overall survival estimates were 22.9 and 42.5 months, respectively.

Myeloid blast crisis: 260 patients with myeloid blast crisis were enrolled. 95 (37%) had previously undergone chemotherapy for the treatment of accelerated phase disease or blast crisis ("pretreated patients"), while 165 (63%) had not been treated ("untreated patients"). The first 37 patients started treatment with 400 mg, later the protocol was adjusted to allow for higher doses and the remaining 223 patients started treatment with 600 mg. The primary efficacy variable was haematological response rate, reported as complete haematological response, no evidence of leukemia, or return to chronic phase CML, using the same criteria as in the accelerated phase study. In this study, 31% of patients achieved a haematological response (36% in previously untreated patients and 22% in previously treated patients). The response rate was therefore higher in patients treated with 600 mg (33%) than in patients treated with 400 mg (16%, p = 0.0220). The mean survival estimate of previously untreated and treated patients was 7.7 and 4.7 months, respectively.

Lymphoid blast crisis: a limited number of patients were enrolled in the phase I studies (n = 10). The value of the haematological response was 70%, with a duration of 2-3 months.

Table 4 Response in adult CML studies

Pediatric patients: A total of 26 aged pediatric patients

Patients were treated at Glivec doses of 260 mg / m2 / day (n = 5), 340 mg / m2 / day (n = 9), 440 mg / m2 / day (n = 7) and 570 mg / m2 / day. die (n = 5). Among the 9 patients with chronic phase CML for whom cytogenetic data were available, 4 (44%) and 3 (33%) achieved complete and partial cytogenetic response, respectively, for a higher rate of cytogenetic response (MCR) than 77%.

A total of 51 pediatric patients with newly diagnosed, untreated chronic phase CML were enrolled in an open-label, single-arm, multicenter, phase II study. Patients were treated with Glivec 340 mg / m2 / day, with no interruptions in the absence of dose-limiting toxicity. In pediatric patients with newly diagnosed CML, treatment with Glivec induced a rapid response with a complete haematological response (REC) of 78% after 8 weeks of therapy. The high rate of REC was associated with the development of a complete cytogenetic response (CCyR) of 65%, comparable to the results observed in adults. In addition, a partial cytogenetic response (PCyR) was observed in 16% of cases for a response. greater (MCyR) than 81%. In the majority of patients who achieved a complete cytogenetic response (CCyR), CCyR occurred between month 3 and month 10 with a median time to response, based on the Kaplan-Meier estimate, of 5.6 months.

The European Medicines Agency has waived the obligation to submit the results of studies with Glivec in all subsets of the pediatric population in Philadelphia chromosome positive chronic myeloid leukemia (bcr-abl translocation) (see section 4.2 for information on pediatric use).

Clinical studies in Ph + ALL

Newly diagnosed Ph + ALL: In a controlled study (ADE10) of imatinib versus induction chemotherapy in 55 newly diagnosed patients 55 years of age and older, imatinib used as a single agent induced a significantly higher rate of complete haematological responses than chemotherapy ( 96.3% vs 50%; p = 0.0001) When rescue therapy with imatinib was given to patients who were unresponsive or insufficiently responsive to chemotherapy, 9 patients (81.8%) were observed out of 11 had achieved a complete haematological response. This clinical effect was associated with a greater reduction in bcr-abl transcript in patients treated with imatinib than in patients treated with chemotherapy after 2 weeks of therapy (p = 0.02). All patients had received imatinib and consolidation chemotherapy (see Table 5) after the induction phase and the bcr-abl transcript levels at week 8 were identical in both arms. As predicted by the study design, no difference was observed in the duration of remission, disease-free survival, or overall survival, although patients with complete molecular response and remaining with minimal residual disease had a better outcome in terms of both duration. remission (p = 0.01) and disease-free survival (p = 0.02).

The results observed in a population of 211 newly diagnosed Ph + ALL patients in four uncontrolled clinical trials (AAU02, ADE04, AJP01 and AUS01) are consistent with the results described above. Imatinib in combination with induction chemotherapy (see Table 5) achieved a complete haematological response rate of 93% (147 out of 158 evaluable patients) and a cytogenetic response rate greater than 90% (19 out of 21 evaluable patients). molecular complete response rate was 48% (49 out of 102 evaluable patients). In the two studies (AJP01 and AUS01) the duration of disease-free survival (DFS) and overall survival (OS) consistently exceeded 1 year and was superior to historical controls (p DFS

Table 5 Chemotherapy regimens used in combination with Glivec

Pediatric patients: A total of 93 pediatric, adolescent and young adult patients with Ph + ALL (aged 1 to 22 years) were enrolled in the Phase III I2301, multicentre, open-label, non-randomized, sequential cohort study and were treated with Glivec (340 mg / m2 / day) in combination with intensive chemotherapy after induction therapy. Glivec was given intermittently in cohorts 1-5, with increasing duration and earlier onset of Glivec from cohort to cohort; cohort 1 received the lowest dose intensity of Glivec and cohort 5 received the highest dose intensity (the longest duration in days of treatment with Glivec administered continuously daily during the first courses of chemotherapy treatment). In patients in cohort 5 (n = 50), continuous daily exposure of Glivec at the start of the course of treatment in combination with chemotherapy improved 4-year event-free survival (EFS). compared to historical controls (n = 120), who had received standard chemotherapy without

Glivec (respectively 69.6% versus 31.6%). The estimated 4-year OS in cohort 5 was 83.6% versus 44.8% in historical controls. 20 of the 50 patients (40%) in cohort 5 received hematopoietic stem cell transplantation.

Table 6 Chemotherapy regimens used in combination with Glivec in study I2301

G-CSF = granulocyte growth factor, VP-16 = etoposide, MTX = methotrexate, IV = intravenous, SC = subcutaneous, IT = intrathecal, PO = oral, IM = intramuscular, ARA-C = cytarabine, CPM = cyclophosphamide, VCR = vincristine, DEX = dexamethasone, DAUN = daunorubicin, 6-MP = 6- mercaptopurine, E.Coli L-ASP = L-asparaginase, PEG-ASP = pegylated asparaginase, MESNA = sodium-2-mercaptoethane sulfonate, iii = or up when the level of MTX is

Study AIT07 was a Phase II / III, multicenter, open-label, randomized study enrolling 128 patients (1 to

Ph + relapsed / refractory ALL: When imatinib was used as a single agent in patients with relapsed / refractory Ph + ALL there was a 30% (9% complete) haematological response rate and a 23% higher cytogenetic response rate in 53 patients, out of 411 evaluable for the answer. (More precisely, out of 411 patients 353 were treated in the "context of an expanded access program that did not provide for the collection of data on primary response.) In the whole population of 411 patients with relapsed / refractory Ph + ALL, the median time to progression ranged from 2.6 to 3.1 months and, in the 401 evaluable patients, the median overall survival ranged from 4.9 to 9 months. Data were similar when retested to include only patients 55 years of age and older .

Clinical studies in MDS / MPD

Experience with Glivec in this indication is very limited and is based on haematological and cytogenetic response rates. There are no controlled clinical studies demonstrating clinical benefit or increased survival. An open-label, multicenter Phase II clinical study (study B2225) was conducted to evaluate Glivec in different patient populations with at-risk diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. 7 patients were included in this study. with MDS / MPD who had been treated with Glivec 400 mg daily. Three patients had had a complete haematological response (CHR) and one patient had had a haematological partial response (PHR). At the time of the original analysis, three of the four patients with detection of the PDGFR gene rearrangement they had developed a haematological response (2 CHR and 1 PHR). The age of these patients ranged from 20 to 72 years. In addition, an additional 24 patients with MDS / MPD were reported in 13 publications. 21 patients were treated with Glivec 400 mg daily, while the other 3 patients received lower doses. . In eleven patients PDGFR gene rearrangement was found, 9 of these had achieved CHR and 1 PHR. The age of these patients ranged from 2 to 79 years. In a recent publication, updated information on 6 of these 11 patients revealed that all patients remained in cytogenetic remission (range 32-38 months).

The same publication reported long-term follow-up data from 12 patients (including 5 patients from study B2225) with MDS / MPD with PDGFR gene rearrangements. These patients had received Glivec for a median of 47 months (range 24 days - 60 months). In 6 of these patients, the follow-up now exceeds 4 years. Eleven patients rapidly achieved CHR, ten had complete resolution of cytogenetic abnormalities and decreased or disappearance of fusion transcripts measured by RT-PCR. Hematological and cytogenetic responses were maintained for a median of 49 months (range 19-60) and 47 months (range 16-59), respectively. Overall survival is 65 months from diagnosis (range 25-234). Administration of Glivec to patients without a genetic translocation does not generally lead to improvement.

There are no controlled studies in pediatric patients with MDS / MPD. Five patients with MDS / MPD associated with PDGFR gene rearrangement have been reported in 4 publications. The ages of these patients ranged from 3 months to 4 years, and imatinib was administered at a dose of 50 mg per day or at doses ranging from 92.5 to 340 mg / m2 daily. All patients had achieved a complete haematological response, a cytogenetic response and / or a clinical response.

Clinical studies in HES / CLE

An open-label, multicenter Phase II clinical study (study B2225) was conducted to evaluate Glivec in different patient populations with severe disease associated with Abl, Kit or PDGFR protein tyrosine kinases. In this study, 14 patients with HES / CEL were treated with daily doses of Glivec from 100 mg to 1,000 mg. Additional 162 patients with HES / CEL, reported in 35 case reports and published case series, received Glivec at daily doses from 75 mg to 800 mg. They were Cytogenetic abnormalities were evaluated in 117 patients of the total population of 176 patients. In 61 of these 117 patients, fusion kinase FIP1L1-PDGFRα was identified. In another 3 published papers, an additional four patients with HES tested positive for FIP1L1 fusion kinase -PDGFRα. All 65 patients, positive for FIP1L1-PDGFRα fusion kinase, had achieved a CHR maintained for months (range 1+ to 44+ months truncated at the time of reporting). and reported in a recent publication, 21 of these 65 patients had also achieved complete molecular remission with a median follow-up of 28 months (range 13-67 months). The ages of these patients ranged from 25 to 72 years. In addition, clinical cases of symptom improvement and other functional organ abnormalities were reported by investigators. Improvements in the cardiac, nervous system, skin / subcutaneous tissue, respiratory / thoracic / mediastinal tract, musculoskeletal / connective / vascular and gastrointestinal tract have been reported.

There are no controlled studies in pediatric patients with HES / CEL. Three patients with HES and CLE associated with PDGFR gene rearrangement were reported in 3 publications. The ages of these patients ranged from 2 to 16 years and imatinib was administered at a dose of 300 mg / m2 per day or at doses of 200 to 400 mg daily. All patients had achieved haematological response, complete cytogenetic response, and / or a complete molecular response.

Clinical studies in inoperable and / or metastatic GIST

An international, randomized, uncontrolled, phase II, open-label study was conducted in patients with unresectable or metastatic malignant gastrointestinal stromal tumors (GIST). In this study, 147 patients were enrolled and randomized. received, orally, 400 mg or 600 mg once daily for up to 36 months. These patients were aged 18 to 83 years and had a pathological diagnosis of unresectable and / or metastatic malignant GISTs positive for kit. Immunohistochemical tests were periodically conducted with Kit antibody (A-4502, polycloned rabbit antiserum, 1: 100; DAKO Corporation, Carpinteria, CA) in accordance with the analysis with the avidin-biotin-peroxidase complex method after recovery of the antigen. .

Primary evidence of efficacy was based on objective response values. Tumors needed to be measurable at at least one point in the disease, and response characterization was based on Southwestern Oncology Group (SWOG) criteria. Results are reported in Table 7.

Table 7 Best tumor response in study STIB2222 (GIST)

There were no differences in the response rate between the two treatment groups. A significant number of patients who had disease stabilization at the time of the interim analysis achieved partial response with longer treatment (median follow-up of 31 months). Median time to response was 13 weeks ( 95% CI 12-23) .The median time to treatment failure in responding patients was 122 weeks (95% CI 106-147) while in the overall study population it was 84 weeks (95% CI 71- 109) The median overall survival was not reached The Kaplan-Meir estimate for survival after 36 months of follow-up is 68%.

In the two clinical studies (study B2222 and intergroup study S0033) the daily dose of Glivec was increased up to 800 mg in patients progressing to lower daily doses of 400 mg or 600 mg. The daily dose was increased to 800 mg in a total of 103 patients; 6 patients achieved partial response and 21 stabilized disease after dose escalation for an overall clinical benefit of 26%.From the available safety data, the safety profile of Glivec does not appear to be affected by increasing the daily dose to 800 mg in patients progressing to lower daily doses of 400 mg or 600 mg.

Clinical studies for the adjuvant treatment of GIST

Adjuvant treatment with Glivec was evaluated in a multi-center, double-blind, long-term, placebo-controlled phase III study (Z9001) involving 773 patients. The age of these patients ranged from 18 to 91 years. The patients included in the study had a histological diagnosis, by immunohistochemistry, of primary GIST with Kit protein expression and a tumor diameter greater than 3 cm, with complete resection of the primary GIST. within 14-70 days prior to enrollment. After resection of the primary GIST, patients were randomized into one of two treatment groups: Glivec 400 mg / day or placebo for one year.

The primary efficacy end point of the study was relapse-free survival (RFS), defined as the time from the date of randomization to the date of relapse or death from any cause.

Glivec significantly prolonged RFS, with 75% of patients relapse free at 38 months in the Glivec group versus 20 months in the placebo group (95% CI, respectively [30 - not estimable]; [14 - not estimable) ]); (hazard ratio = 0.398 [0.259-0.610], p

The risk of recurrence in patients after resection of the primary GIST was retrospectively assessed on the basis of the following prognostic factors: tumor size, mitotic index, tumor location. Mitotic index data were available for 556 of 713 patients [intention-to-treat (ITT) population]. Results of subgroup analyzes, in accordance with US National Institutes of Health (NIH) risk classifications and the Armed Forces Institute of Pathology (AFIP), are shown in Table 8. No benefit was observed in the low and very low risk groups No overall survival benefit was observed.

Table 8 Summary of RFS analyzes from study Z9001 according to NIH and AFIP risk classifications

* full follow-up period; NS - Not estimable

A second phase III, open-label, multicenter study (SSG XVIII / AIO) compared 12 months of treatment with Glivec 400 mg / day versus 36 months of treatment in patients after surgical resection of the GIST and with one of the following factors: tumor> 5 cm and mitotic count> 5/50 high-power fields (HPF); o tumor diameter> 10 cm and any mitotic count or tumor of any size with mitotic count> 10/50 HPF or tumor rupture in the peritoneal cavity. In total, 397 patients agreed and were randomized in the study (199 patients in the 12-month arm and 198 patients in the 36-month arm), the median age was 61 years (range 22-84 years). The median time to follow-up was 54 months (from the date of randomization to the data cut-off date), with a total of 83 months between the first randomized patient and the cut-off date.

The primary endpoint of the study was recurrence-free survival (RFS), defined as the time from the date of randomization to the date of relapse or death from any cause.

Treatment with Glivec for thirty-six months significantly prolonged RFS compared to treatment with Glivec for 12 months (with overall Hazard Ratio (HR) = 0.46 [0.32; 0.65], p

Furthermore, treatment with Glivec for thirty-six months significantly prolonged overall survival (OS) compared to treatment with Glivec for 12 months (HR = 0.45 [0.22; 0.89], p = 0.0187 ) (Table 9).

A longer duration of treatment (> 36 months) may delay the onset of further relapses; however, the impact of this evidence on overall survival remains unknown. The total number of deaths was 25 in the 12-month treatment arm and 12 in the 36-month treatment arm.

In the ITT analysis, ie including all study population, treatment with imatinib for 36 months was superior to treatment for 12 months. In a planned subgroup analysis by mutation type, in patients with exon 11 related mutation, HR for RFS for 36 months of treatment was 0.35 [95% CI: 0.22; 0.56]. No conclusions can be drawn for other less common subgroups of mutations due to the low number of observed events .

Table 9 Treatment with Glivec for 12 months and 36 months (Study SSGXVIII / AIO)

There are no controlled studies in pediatric patients with c-Kit positive GISTs. Seventeen patients with GIST (with or without Kit and PDGFR mutations) have been reported in 7 publications.

The ages of these patients ranged from 8 to 18 years and imatinib had been administered in both adjuvant and metastatic forms at daily doses ranging from 300 to 800 mg.

The majority of pediatric patients treated for GIST lacked confirmatory data for c-kit or PDGFR mutations which may have led to conflicting clinical results.

Clinical studies in the DFSP

An open-label, multicenter Phase II clinical study (study B2225) was conducted which included 12 patients with DFSP treated with Glivec 800 mg daily. The age of patients with DFSP ranged from 23 to 75 years; the DFSP was metastatic, with local recurrence after initial surgical resection and considered not further resectable at study entry. Primary evidence of efficacy was based on objective response rates. Out of 12 enrolled patients, 9 had a response, one of which was complete and 8 were partial. Three of the partial response patients were subsequently rendered disease free by surgery. The median duration of therapy in study B2225 was 6.2 months, with a maximum duration of 24.3 months. An additional 6 patients with DFSP treated with Glivec were reported in 5 published clinical cases, their ages ranged from 18 months to 49 years. Adult patients described in the published literature were treated with Glivec 400 mg (4 cases) or 800 mg per day (1 case). Five patients had a response, 3 of which were complete and 2 were partial. The median duration of therapy in the published literature ranged from 4 weeks to more than 20 months. Translocation t (17:22) [(q22: q13)] or its gene product was present in nearly all responding patients to Glivec treatment.

There are no controlled studies in pediatric patients with DFSP. Five patients with DFSP and PDGFR gene rearrangement were reported in 3 publications. The ages of these patients ranged from neonate to 14 years and imatinib was administered at a dose of 50 mg per day or at doses ranging from 400 to 520 mg / m2 daily. All patients achieved partial and / or complete response.

05.2 "Pharmacokinetic properties

Glivec Pharmacokinetics

Glivec pharmacokinetics were evaluated over a dose range of 25 to 1,000 mg. Plasma pharmacokinetic profiles were analyzed on day 1 and day 7 or day 28, by which time plasma concentrations had reached steady state.

Absorption

The mean absolute bioavailability for the capsule formulation is 98%. There is high inter-patient variability in imatinib plasma AUC levels following an oral dose. When given with a high-fat meal, the absorption rate of imatinib was minimally reduced (11% reduction in Cmax and prolongation of Tmax by 1.5 h), with a slight decrease in AUC (7.4%) in relation to fasting conditions. The effect of previous surgery on drug absorption has not been studied.

Distribution

At clinically relevant concentrations of imatinib, plasma protein binding, based on experiments in vitro, was approximately 95%, mainly albumin and alpha-acid glycoproteins, with minimal binding to lipoproteins.

Biotransformation

The major circulating metabolite in humans is the N-demethylated derivative of piperazine which exhibits in vitro activity similar to the molecule from which it derives. The plasma AUC of this metabolite was found to be only 16% of the AUC of imatinib. The plasma protein binding of the N-desmethyl metabolite is similar to that of the parent compound.

Imatinib and the N-desmethyl metabolite together accounted for approximately 65% ​​of the circulating radioactivity (AUC (0-48h)). The rest of the circulating radioactivity was due to a number of minor metabolites.

The results in vitro showed that CYP3A4 was the major human P450 enzyme that catalyzes the biotransformation of imatinib. Of a whole group of potential comedications (paracetamol, aciclovir, allopurinol, amphotericin, cytarabine, erythromycin, fluconazole, hydroxyurea, norfloxacin, penicillin V), only erythromycin (IC50 50 mcM) and fluconazole (IC50 118 mcM inhibition) showed metabolism of imatinib which could be clinically relevant.

Imatinib in vitro proved to be a competitive inhibitor of substrates labeled for CYP2C9, CYP2D6 and CYP3A4 / 5. Ki values ​​in human liver microsomes were 27, 7.5 and 7.9 μmol / L, respectively. The maximum plasma concentrations of imatinib in patients are 2-4 μmol / l, and therefore CYP2D6 and / or CYP3A4 / 5 mediated metabolic inhibition of the concomitant drugs is possible. Imatinib did not interfere in the biotransformation of 5-fluorouracil. but it inhibited the metabolism of paclitaxel, as a consequence of the competitive inhibition of CYP2C8 (Ki = 34.7 mcM). This Ki value is much higher than the plasma levels of imatinib expected in patients and therefore no interaction is expected with the concomitant administration of 5-fluorouracil or paclitaxel and imatinib.

Elimination

Based on recovery of compound (s) following an oral dose of 14C-labeled imatinib, approximately 81% of the dose was recovered within 7 days in faeces (68% of dose) and urine (13% of dose). 25% of the dose consisted of unchanged imatinib (5% urine, 20% faeces), the remainder being metabolites.

Plasma pharmacokinetics Following oral administration in healthy volunteers, t½ was approximately 18 hours, suggesting that once daily dosing is appropriate. The mean AUC increase following dose escalation was linear and dose proportional over the range of 25-1,000 mg imatinib following oral administration. accumulation was 1.5-2.5 times that occurring at steady-state after once daily dosing.

Pharmacokinetics in patients with GIST

In GIST patients, steady-state exposure was 1.5 times higher than that observed for CML patients at the same dose (400 mg per day). Based on preliminary population pharmacokinetic analyzes in GIST patients , there were three variables (albumin, WBC and bilirubin) that were shown to have a statistically significant correlation with imatinib pharmacokinetics. A decrease in albumin values ​​caused a reduction in clearance (CL / f); and higher WBC levels. have led to a reduction in CL / f. However, these correlations are not sufficiently marked to warrant a dose adjustment. In this patient population, the presence of liver metastases could potentially lead to hepatic failure and impaired metabolism.

Population pharmacokinetics

Population pharmacokinetic analysis in CML patients revealed a limited effect of age on volume of distribution (12% increase in patients> 65 years of age). This variation is not considered to be clinically significant. The effect of body weight on imatinib clearance is such that, for a 50 kg patient, the expected mean clearance is 8.5 l / h, while for a 100 kg weight patient, the clearance will increase up to at 11.8 l / h. These variations are not considered sufficient to allow for dose adjustment based on kilograms of body weight. Gender has no effect on imatinib kinetics.

Pharmacokinetics in children

As in adult patients, imatinib was rapidly absorbed in pediatric patients following oral administration in both phase I and phase II studies. By administering to children doses of 260 and 340 mg / m2 / day, exposure similar to that obtained in adults treated with doses of 400 mg and 600 mg, respectively, was achieved. Comparison of AUC (0-24) to day 8 and day 1 levels at a dose of 340 mg / m2 / day showed drug accumulation 1.7 times that occurring after repeated single-dose administration. daily.

Based on a combined population pharmacokinetic analysis in pediatric patients with haematological disorders (CML, Ph + ALL, or other haematological disorders treated with imatinib), the clearance of imatinib increases with increasing body surface area (BSA). ).

After correction for the effect of BSA, other demographic factors such as age, body weight and body mass index did not demonstrate clinically significant effects on imatinib exposure. The analysis confirmed that imatinib exposure in pediatric patients receiving 260 mg / m2 once daily (not exceeding 400 mg once daily) or 340 mg / m2 once daily (not exceeding 600 mg once daily) was similar to that in adult patients receiving imatinib 400 mg or 600 mg once daily.

Impaired organ function

Imatinib and its metabolites are not significantly excreted via the kidneys. Patients with mild and moderate renal impairment appear to have higher plasma exposure than observed in patients with normal renal function. The increase is approximately 1.5 to 2-fold, corresponding to a 1.5-fold increase in plasma AGP, to which imatinib binds strongly. The clearance of imatinib as a free drug is likely to be similar among patients with impaired renal function. and normal as renal excretion represents only a minor route of elimination for imatinib (see sections 4.2 and 4.4).

Although the results of the pharmacokinetic analyzes showed that there is considerable inter-subject variation, the mean exposure to imatinib did not increase in patients with varying degrees of hepatic dysfunction compared to patients with normal hepatic function (see sections 4.2, 4.4 and 4.8).

05.3 Preclinical safety data

The preclinical safety profile of imatinib was evaluated in mice, dogs, monkeys and rabbits.

Multiple dose toxicity studies revealed mild to moderate haematological changes in mice, dogs and monkeys, accompanied by bone marrow changes in mice and dogs.

The liver was a target organ in mice and dogs. Mild to moderate increases in transaminase levels and slight decreases in cholesterol, triglyceride, total protein, and albumin levels were observed in both species. No hepatic histopathological changes were observed in mice. severe level of hepatic toxicity in dogs treated for 2 weeks, with elevated liver enzyme values, hepatocellular necrosis, necrosis and hyperplasia of the bile ducts.

Renal toxicity phenomena were found in monkeys undergoing therapy for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephropathy. Increased levels of blood urea nitrogen (BUN) and creatinine were observed in several of these animals. Transitional epithelial hyperplasia in the renal papilla and urinary bladder was found in mice at doses ≥6 mg. / kg in a 13-week study, without reporting any changes in serum and urine parameters. With chronic treatment of imatinib, an increase in the rate of opportunistic infections is observed.

In a 39-week monkey study, no NOAEL (no observed adverse effect level) was established at the lowest dose of 15 mg / kg, which corresponds to approximately one third of the maximum human dose of 800 mg. calculated based on the body surface. Therapy carried out on these animals resulted in a worsening of normally suppressed malarial infections.

Imatinib was not considered genotoxic when tested in a bacterial cell assay I invite (Ames test), with a "mammalian cell analysis in vitro (mouse lymphoma) and with a mouse micronucleus test in vivo. Positive genotoxic effects were obtained for imatinib in a mammalian cell assay in vitro (Chinese hamster ovary) due to clastogenicity (chromosomal aberration) in the presence of metabolic activation. Two intermediate compounds of the preparation process, which are also present in the final product, proved positive for mutagenesis in the Ames test and one of these was also positive in the analysis of mouse lymphoma.

In a fertility study conducted in male mice, with doses corresponding approximately to the maximum daily clinical dose of 800 mg, determined on the basis of body surface area, administered for 70 days prior to mating, the weight of the testes, that of the epididymis and the percentage of motile sperm fell to 60 mg / kg. This phenomenon was not detected at doses ≤20 mg / kg. A mild to moderate reduction in spermatogenesis was also observed in the dog at oral doses ≥30 mg / kg. When female mice were dosed for 14 days, prior to mating and up to the sixth day of gestation, there was no effect on mating or number of pregnancies. At doses of 60 mg / kg, female mice exhibited significant post-implantation fetal loss and fewer live fetuses. This was not seen at doses ≤20 mg / kg.

In a pre- and postnatal developmental interference study conducted in rats, with oral administration, red vaginal discharge was observed in the 45 mg / kg / day group on day 14 or day 15 of gestation. At the same dose, the number of stillbirths and subjects dying between days 0 and 4 after delivery increased. At the same dose level, mean body weight from birth to terminal sacrifice decreased in F1 offspring, and the number of subjects meeting foreskin separation criteria was slightly reduced. The fertility of the F1 generation was not affected while an increase in the number of resorptions and a decrease in the number of viable fetuses was noted at the dose of 45 mg / kg / day. For both mothers and the F1 generation, the no observed effect level (NOEL) was 15 mg / kg / day (one quarter of the maximum human dose of 800 mg).

Imatinib was teratogenic in mice when administered during organogenesis at doses ≥100 mg / kg, which is approximately equivalent to the maximum clinical dose of 800 mg / day, as determined by body surface area. Teratogenic effects included exencephaly or encephalocele, absence / reduction of frontal bones and absence of parietal bones These effects were not observed at doses ≤30 mg / kg.

In a developmental toxicology study in juvenile rats (day 10 to day 70 post partum) no new target organs were identified compared to known target organs in adult rats. In the juvenile animal toxicology study, effects on growth, delay in vaginal opening and separation of the foreskin were observed at approximately 0.3-2 times the mean pediatric exposure at the maximum recommended dose of 340 mg / m2. In addition, mortality was observed in juvenile animals (around weaning) at approximately 2 times the mean pediatric exposure at the maximum recommended dose of 340 mg / m2.

A 2-year carcinogenicity study in rats treated with doses of 15, 30 and 60 mg / kg / day of imatinib showed a statistically significant reduction in longevity in males treated at 60 mg / kg / day and in females. treated at doses ≥30 mg / kg / day. Histopathological examination of cadavers revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and papilloma of the preputial gland as the main causes of death or sacrifice. The target organs for neoplastic changes were the kidneys. , the urinary bladder, the urethra, the preputial and clitoral glands, the small intestine, the parathyroid glands, the adrenal glands and the non-glandular part of the stomach.

Papillomas / carcinomas of the preputial and clitoral glands have been observed at doses from 30 mg / kg / day onwards which represent approximately 0.5 or 0.3 times the daily human exposure at 400 mg / day or 800 mg / day, respectively. day (based on AUC), and 0.4 times the daily exposure in children at 340 mg / m2 / day (based on AUC). The no observed effect level (NOEL) was 15 mg / kg / day. Renal adenoma / carcinoma, papilloma of the urinary bladder and urethra, adenocarcinomas of the small intestine, adenomas of the parotid glands, benign and malignant tumors of the medullary portion of the adrenal glands and papillomas / carcinomas of the non-glandular part of the stomach were observed at 60 mg / kg / day which represents approximately 1.7 or 1 times the daily human exposure at 400 mg / day or 800 mg / day, respectively (based on AUC). , and 1.2 times the daily exposure in children at 340 mg / m2 / day (based on AUC). no observed effect (NOEL) was 30 mg / kg / day.

For humans, the mechanism and relevance of these findings in the rat carcinogenesis study are not yet elucidated.

Non-neoplastic lesions not identified in previous preclinical studies involved the cardiovascular system, pancreas, endocrine organs and teeth. The most notable changes included cardiac hypertrophy and dilation that led to signs of heart failure in some animals.

The active substance imatinib shows an environmental risk for sediment organisms.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Capsule contents: Microcrystalline cellulose

Crospovidone

Magnesium stearate

Colloidal silica, anhydrous

Capsule shell: Gelatin

Yellow iron oxide (E172)

Titanium dioxide (E171)

Printing ink: Red iron oxide (E172)

Shellac

Soy lecithin

06.2 Incompatibility

Not relevant.

06.3 Period of validity

2 years

06.4 Special precautions for storage

Do not store above 30 ° C.

Store in the original package to protect the medicine from moisture.

06.5 Nature of the immediate packaging and contents of the package

PVC / aluminum blister

Packs of 30 capsules.

06.6 Instructions for use and handling

Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.

07.0 MARKETING AUTHORIZATION HOLDER

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

UK

08.0 MARKETING AUTHORIZATION NUMBER

EU / 1/01/198/001

035372010

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Date of first authorization: 07 November 2001

Date of most recent renewal: 07 November 2006

10.0 DATE OF REVISION OF THE TEXT

July 2014

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL