Imatinib

Imatinib

Capsules 100 mg

Hard gelatin capsules, number 0, white.

Active substance: imatinib 100 mg (as imatinib mesylate).
Auxiliary substances: crospovidone, colloidal anhydrous silicon dioxide, microcrystalline cellulose, magnesium stearate.
Coating composition: titanium dioxide (E171), gelatin.

Other anitumourals, protein kinase inhibitors.

L01ХE01

Anitumoural, tyrosine kinase inhibitor. Imatinib potently inhibits the Bcr-Abl tyrosine kinase at the in vitro, cellular and in vivo levels. Imatinib selectively inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as fresh leukaemic cells from Philadelphia chromosome positive (Ph+) CML and acute lymphoblastic leukaemia patients. In vivo the compound shows anti-tumour activity as a single agent in animal models using Bcr-Abl positive tumour cells. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF), and stem cell factor (SCF), c-Kit, and it also suppresses cellular events mediated by the above-mentioned factors. In vitro, imatinib inhibits proliferation and induces apoptosis in gastrointestinal stromal tumour (GIST) cells, which express an activating kit mutation.

• treatment of adult and paediatric patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myeloid leukaemia (CML) for whom bone marrow transplantation is not considered as the first line of treatment.
• treatment of adult and paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in accelerated phase or blast crisis.
• treatment of adult and paediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy.
• treatment of adult patients with relapsed or refractory Ph+ ALL as monotherapy.
• treatment of adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.
• treatment of adult patients with advanced hypereosinophilic syndrome and/or chronic eosinophilic leukaemia (HES/CEL) with FIP1L1-PDGFRα rearrangement.

The effect of Imatinib on the outcome of bone marrow transplantation has not been determined.

The medicinal product is also indicated for

• treatment of adult patients with Kit (CD 117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumours (GIST).
• adjuvant treatment of adult patients who are at significant risk of relapse following resection of Kit (CD117)-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.
• treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent or metastatic DFSP who are not eligible for surgery.

In adult and paediatric patients, the effectiveness of Imatinib is based on overall haematological and cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic response rates in Ph+ ALL, MDS/MPD, on haematological response rates in HES/CEL and on objective response rates in adult patients with unresectable and/or metastatic GIST and DFSP and on recurrence-free survival in adjuvant GIST. The experience with Imatinib in patients with MDS/MPD associated with PDGFR gene re-arrangements is very limited. Except in newly diagnosed chronic phase CML, there are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.

Therapy should be initiated by a physician experienced in the treatment of patients with haematological malignancies and malignant sarcomas, as appropriate. The prescribed dose should be administered orally with a meal and a large glass of water to minimize the risk of gastrointestinal irritations. Doses of 400 mg or 600 mg should be administered once daily, whereas a daily dose of 800 mg should be administered as 400 mg twice a day, in the morning and in the evening. For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of still water or apple juice. The suspension should be administered immediately after preparation. Since studies in animals have shown reproductive toxicity and the potential risk to the foetus is unknown, women of child bearing potential should be careful when opening capsules and handling the contents and avoid contact with skin, eyes or inhalation. After handling open capsules, wash your hands immediately.

Posology:

CML in adult patients
The recommended dosage of Imatinib is 400 mg/day for adult patients in chronic phase CML. Chronic phase CML is defined when all of the following criteria are met: blasts <15% in blood and bone marrow, peripheral blood basophils <20%, platelets> 100 x 109/l.

The recommended dosage of Imatinib is 600 mg/day for adult patients in accelerated phase. Accelerated phase is defined by the presence of any of the following: Blasts ≥ 15% but < 30% in blood or bone marrow, blasts plus promyelocytes≥ 30% in blood or bone marrow (providing < 30% blasts), peripheral blood basophils ≥ 20%, platelets <100 x 109/l unrelated to therapy.

The recommended dose of Imatinib is 600 mg/day for adult patients in blast crisis. Blast crisis is defined as blasts ≥ 30% in blood or bone marrow or extramedullary disease other than hepatosplenomegaly.

Treatment duration: in clinical trials, treatment with Imatinib was continued until disease progression. The effect of stopping treatment after the achievement of a complete cytogenetic response has not been investigated.

Dose increases 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 accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non- leukaemia-related neutropenia or thrombocytopenia. Such an increase in the dose may be necessary 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 achieved haematological and/or cytogenetic response. Patients should be monitored closely following dose escalation given the potential for an increased incidence of adverse reactions at higher dosages.

CML in children
Dosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily is recommended for children with chronic phase and advanced phase CML (not to exceed the total dose of 800 mg). Treatment can be given as a once daily dose or alternatively the daily dose may be split into two administrations – one in the morning and one in the evening. The dose recommendation is currently based on a small number of paediatric patients. There is no experience with the treatment of children below 2 years of age.

Dose increases from 340 mg/m² daily to 570 mg/m² daily (not to exceed the total dose of 800 mg) may be considered in children in the absence of severe adverse drug reaction and severe non-leukaemia-related neutropenia or thrombocytopenia 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 achieved haematological and/or cytogenetic response. Patients should be monitored closely following dose escalation given the potential for an increased incidence of adverse reactions at higher dosages.

Ph+ALL in adult patients
The recommended dose of Imatinib is 600 mg/day for adult patients with Ph+ ALL. Haematological experts in the management of this disease should supervise the therapy throughout all phases of care.

Treatment duration: On the basis of the existing data, Imatinib has been shown to be effective and safe when administered at 600 mg/day in combination with chemotherapy in the induction phase, the consolidation and maintenance phases of chemotherapy for adult patients with newly diagnosed Ph+ ALL. The duration of Imatinib therapy can vary with the treatment programme selected, but generally longer exposures to Imatinib have yielded better results.

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

Ph+ ALL in children
Dosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily is recommended for children with Ph+ ALL (not to exceed the total dose of 600 mg).

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

Treatment duration: In the only clinical trial performed up to now, treatment with Imatinib was continued until disease progression. At the time of analysis, the treatment duration was a median of 47 months (24 days – 60 months).

HES/CEL
The recommended dose of Imatinib is 100 mg/day for adult patients with HES/CEL. Dose increase from 100 mg to 400 mg may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
Treatment should be continued as long as the patient continues to benefit.

GIST
The recommended dose of Imatinib is 400 mg/day for adult patients with unresectable and/or metastatic malignant GIST. Limited data exist on the effect of dose increases from 400 mg to 600 mg or 800 mg in patients progressing at the lower dose.

Treatment duration: In clinical trials in GIST patients, treatment with imatinib was continued until disease progression. At the time of analysis, the treatment duration was a median of 7 months (7 days to 13 months). The effect of stopping treatment after achieving a response has not been investigated.

The recommended dose of imatinib is 400 mg/day for the adjuvant treatment of adult patients following resection of GIST. Optimal treatment duration is not yet established. Length of treatment in the clinical trial supporting this indication was 36 months.

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

Dose adjustment for adverse reactions

Non-haematological adverse reactions
If a severe non-haematological adverse reaction develops with Imatinib use, treatment must be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.
If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases > 5 x IULN occur, Imatinib should be withheld until bilirubin levels have returned to < 1.5 x IULN and transaminase levels to < 2.5 x IULN. Treatment with Imatinib may then be continued at a reduced daily dose. 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. In children the dose should be reduced from 340 to 260 mg/m²/day.

Haematological adverse reactions
Dose reduction or treatment interruption for severe neutropenia and thrombocytopenia are recommended as indicated in the table below.

Dose adjustments for neutropenia and thrombocytopenia:

Special populations

Paediatric population
There is no experience in children with CML below 2 years of age and with Ph+ALL below 1 year of age. There is limited experience in children with MDS/MPD, DFSP, GIST and HES/CEL.

The safety and efficacy of imatinib in children with MDS/MPD, DFSP, GIST and HES/CEL aged less than 18 years of age have not been established in clinical trials. According to the currently available published data no recommendation on a posology can be made.

Patients with hepatic impairment
Imatinib is mainly metabolised through the liver. Patients with mild, moderate or severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. The dose can be reduced if not tolerated.

Hepatic impairment classification:

ULN = upper limit of normal for the institution
AST = aspartate aminotransferase

Patients with renal impairment
Patients with renal dysfunction or on dialysis should be given the minimum recommended dose of 400 mg daily as starting dose. However, in these patients caution is recommended. The dose can be reduced if not tolerated. If tolerated, the dose can be increased for lack of efficacy.

Elderly patients
Imatinib pharmacokinetics have not been specifically studied in older people. No significant age-related pharmacokinetic differences have been observed in adult patients in clinical trials which included over 20% of patients age 65 and older. No specific dose recommendation is necessary in older people.

Patients with advanced stages of malignancies may have numerous confounding medical conditions that make causality of adverse reactions difficult to assess due to the variety of symptoms related to the underlying disease, its progression, and administration of numerous medicinal products.

In clinical trials in CML, medication discontinuation for drug-related adverse reactions was observed in 2.4% of newly diagnosed patients, 4% of patients in late chronic phase after failure of interferon therapy, 4% of patients in accelerated phase after failure of interferon therapy and 5% of blast crisis patients after failure of interferon therapy. In GIST the study medication was discontinued for drug-related adverse reactions in 4% of patients.

The adverse reactions were similar in all indications, with two exceptions. There was more myelosuppression seen in CML patients than in GIST, which is probably due to the underlying disease. In the clinical study in patients with unresectable and/or metastatic GIST, 7 (5%) patients experienced CTC grade 3/4 GI bleeds (3 patients), intra-tumoural bleeds (3 patients) or both (1 patient). GI tumour sites may have been the source of the GI bleeds. GI and tumoural bleeding may be serious and sometimes fatal. The most commonly reported (≥ 10%) drug-related adverse reactions in both settings were mild nausea, vomiting, diarrhoea, abdominal pain, fatigue, myalgia, muscle cramps and rash. Superficial oedemas were a common finding in all studies and were described primarily as periorbital or lower limb oedemas. However, these oedemas were rarely severe and may be managed with diuretics, other supportive measures, or by reducing the dose of Imatinib.
When imatinib was combined with high dose chemotherapy in Ph+ ALL patients, transient liver toxicity in the form of transaminase elevation and hyperbilirubinaemia were observed. Considering the limited safety database, the adverse events thus far reported in children are consistent with the known safety profile in adult patients with Ph+ ALL.

Miscellaneous adverse reactions such as pleural effusion, ascites, pulmonary oedema and rapid weight gain with or without superficial oedema may be collectively described as “fluid retention”. These reactions can usually be managed by withholding Imatinib temporarily and with diuretics and other appropriate supportive care measures. However, some of these reactions may be serious or life- threatening and several patients with blast crisis died with a complex clinical history of pleural effusion, congestive heart failure and renal failure. There were no special safety findings in paediatric clinical trials.

Adverse reactions
Adverse reactions are listed below, by system organ class and by frequency.

Frequency categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Infections and infestations: uncommon – herpes zoster, herpes simplex, nasopharyngitis, pneumonia1, sinusitis, cellulitis, upper respiratory tract infection, influenza, urinary tract infection, gastroenteritis, sepsis; rare – fungal infection; not known – hepatitis B reactivation*.

Neoplasm benign, malignant and unspecified (including cysts and polyps): rare – tumour lysis syndrome; not known – tumour haemorrhage/tumour necrosis*.

Blood and lymphatic system disorders: very common – neutropenia, thrombocytopenia, anaemia; common – pancytopenia, febrile neutropenia; uncommon – thrombocythaemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy; rare – haemolytic anaemia, thrombotic microangiopathy.

Immune system disorders: not known – anaphylactic shock*.

Metabolism and nutrition disorders: common – anorexia; uncommon – hypokalaemia, increased appetite, hypophosphataemia, decreased appetite, dehydration, gout, hyperuricaemia, hypercalcaemia, hyperglycaemia, hyponatraemia; rare – hyperkalaemia, hypomagnesaemia.

Psychiatric disorders: common – insomnia; uncommon – depression, libido decreased, anxiety; rare – confusional state.

Nervous system disorders: very common – headache2; common – dizziness, paraesthesia, taste disturbance, hypoaesthesia; uncommon – migraine, somnolence, syncope, peripheral neuropathy, memory impairment, sciatica, restless leg syndrome, tremor, cerebral haemorrhage; rare – increased intracranial pressure, convulsions, optic neuritis; not known – cerebral oedema*.

Eye disorders: common – eyelid oedema, lacrimation increased, conjunctival haemorrhage, conjunctivitis, dry eye, blurred vision; uncommon – eye irritation, eye pain, orbital oedema, scleral haemorrhage, retinal haemorrhage, blepharitis, macular oedema; rare – cataract, glaucoma, papilloedema; not known – vitreous haemorrhage*.

Ear and labyrinth disorders: uncommon – vertigo, tinnitus, hearing loss.

Cardiac disorders: uncommon – palpitations, tachycardia, cardiac failure congestive3, pulmonary oedema; rare – arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion; not known – pericarditis*, cardiac tamponade*.

Vascular disorders4: common – flushing, haemorrhage; uncommon – hypertension, haematoma, subdural haematoma, peripheral coldness, hypotension, Raynaud’s phenomenon; not known – thrombosis/embolism*.

Respiratory, thoracic and mediastinal disorders: common – dyspnoea, epistaxis, cough; uncommon – pleural effusion5, pharyngolaryngeal pain, pharyngitis; rare – pleuritic pain, pulmonary fibrosis, pulmonary hypertension, pulmonary haemorrhage; not known – acute respiratory failure10*, interstitial lung disease*.

Gastrointestinal disorders: very common – nausea, diarrhoea, vomiting, dyspepsia, abdominal pain6; common – flatulence, abdominal distension, gastro-oesophageal reflux, constipation, dry mouth, gastritis; uncommon – stomatitis, mouth ulceration, gastrointestinal haemorrhage7, eructation, melaena, oesophagitis, ascites, gastric ulcer, haematemesis, cheilitis, dysphagia, pancreatitis; rare – colitis, ileus, inflammatory bowel disease; not known – ileus/intestinal obstruction*, gastrointestinal perforation*, diverticulitis*, gastric antral vascular ectasia (GAVE)*.

Hepatobiliary disorders: common – increased hepatic enzymes; uncommon – hyperbilirubinaemia, hepatitis, jaundice; rare – hepatic failure8, hepatic necrosis.

Skin and subcutaneous tissue disorders: very common – periorbital oedema, dermatitis/eczema/rash; common – pruritus, face oedema, dry skin, erythema, alopecia, night sweats, photosensitivity reaction; uncommon – rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, dermatitis exfoliative, onychoclasis, folliculitis, petechiae, psoriasis, purpura, skin hyperpigmentation, bullous eruptions; rare – acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discolouration, angioneurotic oedema, rash vesicular, erythema multiforme, leucocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis (AGEP); not known – palmoplantar erythrodysesthesia syndrome*, lichenoid keratosis*, lichen planus*, toxic epidermal necrolysis*, drug rash with eosinophilia and systemic symptoms (DRESS)*, pseudoporphyria*.

1 Pneumonia was reported most commonly in patients with transformed CML and in patients with GIST.
2 Headache was the most common in GIST patients.
3 On a patient-year basis, cardiac events including congestive heart failure were more commonly observed in patients with transformed CML than in patients with chronic CML.
4 Flushing was most common in GIST patients and bleeding (haematoma, haemorrhage) was most common in patients with GIST and with transformed CML (CML-AP and CML-BC) compared to patients with chronic CML.
5 Pleural effusion was reported more commonly in patients with GIST and in patients with transformed CML (CML-AP and CML-BC) than in patients with chronic CML.
6+7 Abdominal pain and gastrointestinal haemorrhage were most commonly observed in GIST patients.
8 Some fatal cases of hepatic failure and of hepatic necrosis have been reported.
9 Musculoskeletal pain and related events were more commonly observed in patients with CML than in GIST patients.
10 Fatal cases have been reported in patients with advanced disease, severe infections, severe neutropenia and other serious concomitant conditions.
11 Reactivation of hepatitis B virus has been reported in connection with the intake of tyrosine kinase activity inhibitors Bcr-Abl. Several adverse cases were associated with the development of acute renal failure or fulminant hepatitis, which led to liver transplantation or death.
12 Musculoskeletal pain during treatment with imatinib or after discontinuation has been observed in post-marketing.

Laboratory test abnormalities

Haematology
In CML, cytopenias, particularly neutropenia and thrombocytopenia, have been a consistent finding in all clinical trials, with the suggestion of a higher frequency at high doses ≥ 750 mg (phase I study). However, the occurrence of cytopenias was also clearly dependent on the stage of the disease, the frequency of grade 3 or 4 neutropenias (ANC < 1.0 x 10⁹/l) and thrombocytopenias (platelet count < 50 x 10⁹/l) being between 4 and 6 times higher in blast crisis and accelerated phase (59–64% and 44–63% for neutropenia and thrombocytopenia, respectively) as compared to newly diagnosed patients in chronic phase CML (16.7% neutropenia and 8.9% thrombocytopenia). In newly diagnosed chronic phase CML grade 4 neutropenia (ANC < 0.5 x 10⁹/l) and thrombocytopenia (platelet count < 10 x 10⁹/l) were observed in 3.6% and < 1% of patients, respectively. The median duration of the neutropenic and thrombocytopenic episodes usually ranged from 2 to 3 weeks, and from 3 to 4 weeks, respectively. These events can usually be managed with either a reduction of the dose or an interruption of treatment with Imatinib, but can in rare cases lead to permanent discontinuation of treatment. In paediatric CML patients the most frequent toxicities observed were grade 3 or 4 cytopenias involving neutropenia, thrombocytopenia and anaemia. These generally occur within the first several months of therapy.

In the study in patients with unresectable and/or metastatic GIST, grade 3 and 4 anaemia was reported in 5.4% and 0.7% of patients, respectively, and may have been related to gastrointestinal or intra- tumoural bleeding. Grade 3 and 4 neutropenia was seen in 7.5% and 2.7% of patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. No patient developed grade 4 thrombocytopenia. The decreases in white blood cell (WBC) and neutrophil counts occurred mainly during the first six weeks of therapy, with values remaining relatively stable thereafter.

Biochemistry
Severe elevation of transaminases (< 5%) or bilirubin (< 1%) was seen in CML patients and was usually managed with dose reduction or interruption (the median duration of these episodes was approximately one week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1% of CML patients. In GIST patients, 6.8% of grade 3 or 4 ALT (alanine aminotransferase) elevations and 4.8% of grade 3 or 4 AST (aspartate aminotransferase) elevations were observed. Bilirubin elevation was observed in less than 3% of cases.

There have been cases of cytolytic and cholestatic hepatitis and hepatic failure; in some of them outcome was fatal, including 1 patient on high dose paracetamol.

Description of selected adverse reactions

Hepatitis B reactivation
Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see Section Special warnings and precautions for use).

Reporting of suspected adverse reactions
If you have any adverse reactions, consult your doctor. This recommendation applies to any possible adverse reactions, including those not listed in this patient information leaflet. By reporting side effects you help to gather more information on safety of this medication.

Hypersensitivity to Imatinib mesylate or to any other component of the medicinal product.
Children under 2 years of age.

Experience with doses higher than the recommended therapeutic dose is limited. Isolated cases of Imatinib overdose have been reported spontaneously and in the literature. As a rule, the consequences reported in such cases were reversible. In the event of overdose, the patient should be observed and appropriate symptomatic treatment given. Generally, the reported outcome in these cases was “improved” or “recovered”. Events that have been reported at different dose ranges are as follows:

Adults
1200 to 1600 mg (duration varying between 1 to 10 days): nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.
1800 to 3200 mg (as high as 3200 mg daily for 6 days): weakness, myalgia, increased creatine phosphokinase, increased bilirubin, gastrointestinal pain.
6400 mg (single dose): one case reported in the literature of one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, increased transaminases.
8 to 10 g (single dose): vomiting and gastrointestinal pain have been reported.

Paediatric population
400 mg (single dose): vomiting, diarrhoea and anorexia (1 case in a 3-year-old child).
980 mg (single dose): decreased white blood cell count and diarrhoea (1 case in a 3-year-old child).

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

Medicinal products that may increase imatinib plasma concentrations
Medications that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g., protease inhibitors such as indinavir, lopinavir/ritonavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir; azole antifungals including ketoconazole, itraconazole, posaconazole, voriconazole; certain macrolides such as erythromycin, clarithromycin and telithromycin) could decrease metabolism and increase imatinib concentrations. There was a significant increase in exposure to imatinib (the mean C_max and AUC of imatinib rose by 26% and 40%, respectively) in healthy subjects when it was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution should be taken when administering Imatinib with inhibitors of the CYP3A4 family.

Medicinal products that may decrease imatinib plasma concentrations
Medications that are inducers of CYP3A4 activity (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, fosphenytoin, primidone or Hypericum perforatum, also known as St. John’s Wort) may significantly reduce exposure to Imatinib, potentially increasing the risk of therapeutic failure. Pretreatment with multiple doses of rifampicin 600 mg followed by a single 400 mg dose of Imatinib resulted in decrease in C_max and AUC_(0-∞) by at least 54% and 74%, of the respective values without rifampicin treatment. Similar results were observed in patients with malignant gliomas treated with Imatinib while taking such as carbamazepine, oxcarbazepine and phenytoin. The plasma AUC for imatinib decreased by 73% compared to patients not on enzyme-inducing anti-epileptic drugs. Concomitant use of rifampicin or other strong CYP3A4 inducers and imatinib should be avoided.

Active substances that may have their plasma concentration altered by Imatinib
Imatinib increases the mean C_max and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, indicating an inhibition of the CYP3A4 by imatinib. Caution is recommended when administering Imatinib with CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel and quinidine). Imatinib may increase plasma concentration of other CYP3A4 metabolised drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, i.e., statins).

Because of known increased risks of bleeding in conjunction with the use of imatinib (e.g., haemorrhage), patients who require anticoagulation should receive low-molecular-weight or standard heparin, instead of coumarin derivatives such as warfarin.

In vitro Imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 activity at concentrations similar to those that affect CYP3A4 activity. Imatinib at 400 mg twice daily had an inhibitory effect on CYP2D6-mediated metoprolol metabolism, with metoprolol C_max and AUC being increased by approximately 23% (90%CI [1.16- 1.30]). Dose adjustments do not seem to be necessary when imatinib is co- administrated with CYP2D6 substrates, however caution is advised for CYP2D6 substrates with a narrow therapeutic window such as metoprolol. In patients treated with metoprolol clinical monitoring should be considered.

In vitro, Imatinib inhibits paracetamol O-glucuronidation with Ki value of 58.5 micromol/l. This inhibition has not been observed in vivo after the administration of Imatinib 400 mg and paracetamol 1000 mg. Higher doses of Imatinib and paracetamol have not been studied.

Caution should therefore be exercised when using high doses of Imatinib and paracetamol concomitantly.

In thyroidectomy patients receiving levothyroxine, the plasma exposure to levothyroxine may be decreased when Imatinib is co-administered. Caution is therefore recommended. However, the mechanism of the observed interaction is presently unknown.

In Ph+ ALL patients, there is clinical experience of co-administering Imatinib with chemotherapy, but drug-to-drug interactions between imatinib and chemotherapy regimens are not well characterized. Imatinib adverse events, i.e., hepatotoxicity, myelosuppression or others, may increase and it has been reported that concomitant use with L-asparaginase could be associated with increased hepatotoxicity. Therefore, the use of Imatinib in combination requires special precaution.

When Imatinib is co-administered with other medicinal products, there is a potential for drug-to-drug interactions. Caution should be used when taking Imatinib with protease inhibitors, azole antifungals, certain macrolides, 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 Drug-to-drug interactions).

Concomitant use of imatinib and medicinal products that induce CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum, also known as St. John’s Wort) may significantly reduce exposure to Imatinib, potentially increasing the risk of therapeutic failure. Therefore, concomitant use of strong CYP3A4 inducers and imatinib should be avoided.

Hypothyroidism
Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Imatinib. Thyroid-stimulating hormone levels should be closely monitored in such patients.

Hepatotoxicity
Metabolism of Imatinib is mainly hepatic, and only 13% of excretion is through the kidneys. In patients with hepatic dysfunction (mild, moderate or severe), peripheral blood counts and liver enzymes should be carefully monitored. It should be noted that GIST patients may have hepatic metastases which could lead to hepatic impairment.

Cases of liver injury, including hepatic failure and hepatic necrosis, have been observed with imatinib. When imatinib is combined with high dose chemotherapy regimens, an increase in serious hepatic reactions has been detected. Hepatic function should be carefully monitored in circumstances where imatinib is combined with chemotherapy regimens also known to be associated with hepatic dysfunction.

Fluid retention
Occurrences of severe fluid retention (pleural effusion, oedema, pulmonary oedema, ascites, superficial oedema) have been reported in approximately 2.5% of newly diagnosed CML patients taking Imatinib. Therefore, it is highly recommended that patients be weighed regularly. An unexpected rapid weight gain should be carefully investigated and if necessary appropriate supportive care and therapeutic measures should be undertaken. In clinical trials, there was an increased incidence of these events in older people and those with a prior history of cardiac disease. Therefore, caution should be exercised in patients with cardiac dysfunction.

Patients with cardiac diseases
Patients with cardiac disease, risk factors for cardiac failure or history of renal failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac 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 upon the initiation of imatinib therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding imatinib. As cardiac adverse events have been reported uncommonly with imatinib, a careful assessment of the benefit/risk of imatinib therapy should be considered in the HES/CEL population before treatment initiation.

Myelodysplastic/myeloproliferative diseases with PDGFR gene re-arrangements could be associated with high eosinophil levels. Evaluation by a cardiology specialist, performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD associated with high eosinophil levels before imatinib is administered. If either is abnormal, follow-up with a cardiology specialist and the prophylactic use of systemic steroids (1–2 mg/kg) for one to two weeks concomitantly with imatinib should be considered at the initiation of therapy.

Gastrointestinal haemorrhage
In the study in patients with unresectable and/or metastatic GIST, both gastrointestinal and intra- tumoural haemorrhages were reported. Based on the available data, no predisposing factors (e.g., tumour size, tumour location, coagulation disorders) have been identified that place patients with GIST at a higher risk of either type of haemorrhage. Since increased vascularity and propensity for bleeding is a part of the nature and clinical course of GIST, standard practices and procedures for the monitoring and management of haemorrhage in all patients should be applied.

In addition, gastric antral vascular ectasia (GAVE), a rare cause of gastrointestinal haemorrhage, has been reported in post-marketing experience in patients with CML, ALL and other diseases. When needed, discontinuation of Imatinib treatment may be considered.

Tumour lysis syndrome
Due to the possible occurrence of tumour lysis syndrome, correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of Imatinib.

Hepatitis B reactivation
Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome.

Patients should be tested for HBV infection before initiating treatment with Imatinib. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with Imatinib should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.

Phototoxicity
Exposure to direct sunlight should be avoided or minimized due to the risk of phototoxicity associated with imatinib treatment. Patients should be instructed to use measures such as protective clothing and sunscreen with high sun protection factor (SPF).

Thrombotic microangiopathy
BCR-ABL tyrosine kinase inhibitors have been associated with thrombotic microangiopathy (TMA), including individual case reports for Imatinib. If laboratory or clinical findings associated with TMA occur in a patient receiving Imatinib, treatment should be discontinued and thorough evaluation for TMA, including ADAMTS13 activity and anti-ADAMTS13-antibody determination, should be completed. If anti-ADAMTS13-antibody is elevated in conjunction with low ADAMTS13 activity, treatment with Imatinib should not be resumed.

Laboratory tests
Complete blood counts must be performed regularly during therapy with Imatinib. Treatment of CML patients with Imatinib has been associated with neutropenia or thrombocytopenia. However, the occurrence of these cytopenias is likely to be related to the stage of the disease. In patients with accelerated phase CML or blast crisis these adverse reactions were more frequent as compared to patients with chronic phase CML. When these undesirable phenomena occur, treatment with Imatinib may be interrupted or the dose may be reduced, as recommended in Section Dosage and administration.

Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in patients receiving Imatinib.

In patients with impaired renal function, imatinib plasma exposure seems to be higher than that in patients with normal renal function, probably due to an elevated plasma level of alpha-acid glycoprotein (an imatinib-binding protein) in these patients. Patients with renal impairment should be given the minimum starting dose. Patients with severe renal impairment should be treated with caution. The dose can be reduced if not tolerated (see Section Dosage and administration).

Long-term treatment with imatinib may be associated with a clinically significant decline in renal function. Renal function should, therefore, be evaluated prior to the start of imatinib therapy and closely monitored during therapy, with particular attention to those patients exhibiting risk factors for renal dysfunction. If renal dysfunction is observed, appropriate management and treatment should be prescribed in accordance with standard treatment guidelines.

Paediatric population
There have been case reports of growth retardation occurring in children and pre-adolescents receiving imatinib. In an observational study in the CML paediatric population, a statistically significant decrease (but of uncertain clinical relevance) in median height standard deviation scores after 12 and 24 months of treatment was reported in two small subsets irrespective of pubertal status or gender. Close monitoring of growth in children under imatinib treatment is recommended.

Women of childbearing potential must be advised to use effective contraception during treatment with imatinib.

Pregnancy
There are limited data on the use of imatinib in pregnant women. There have been post-marketing reports of spontaneous abortions and infant congenital anomalies from women who have taken Imatinib. Studies in animals have however shown reproductive toxicity and the potential risk for the foetus is unknown. Imatinib should not be used during pregnancy unless the potential benefits outweigh the potential risks to the foetus. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.

Breast-feeding
There is limited information on imatinib distribution on human milk. Studies in two breast-feeding women revealed that both imatinib and its active metabolite can be distributed into human milk. The milk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total exposure would be expected to be low (~10% of a therapeutic dose). However, since the effects of low-dose exposure of the infant to imatinib are unknown, women should not breast-feed during treatment with imatinib.

Fertility
In non-clinical studies, the fertility of male and female rats was not affected. Studies on patients receiving Imatinib and its effect on fertility and gametogenesis have not been performed. Patients concerned about their fertility on Imatinib treatment should consult with their physician.

Patients should be advised that they may experience undesirable effects such as dizziness, blurred vision or somnolence during treatment with imatinib. Therefore, caution should be recommended when driving a car or operating machinery.

21 capsules in a blister. 3 or 6 blisters with a patient information leaflet in a carton.

Protect from moisture, at a temperature not above 25°C. List A. Keep away from children.

2 years. Do not use after the expiration date.

State enterprise ACADEMPHARM
220141, 5/3 Kuprevicha Street, Minsk, Belarus,
Phone / Fax +375 17 268 63 64
production@academpharm.by
To report adverse reactions use the electronic application form on the manufacturer’s website: https://academpharm.by/en