Imatinib Teva

/ Teva

Therapy should be initiated by a physician experienced in the treatment of patients with hematological 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 disturbances. 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 Treatment should be continued as long as the patient continues to benefit.
Monitoring of response to imatinib therapy in Ph+ CML patients should be performed routinely and when therapy is modified, to identify suboptimal response, loss of response to therapy, poor patient compliance, or possible drug-drug interaction. Results of monitoring should guide appropriate CML management.

For the treatment of adult patients and children 3 years of age and above with Ph+ chronic myeloid leukemia (Ph+ -CML) in chronic phase accelerated phase or blast crisis.-
Imatinib is also indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) integrated with chemotherapy.-
Adult patients with relapsed or refractory Ph + ALL as monotherapy.-
Adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and/or metastatic DFSP who are not eligible for surgery.-
Adult patients with myelodyspiastic/myeloproliferative diseases (MDS/MPD) associated with PDGFR (platelet – derived growth factor receptor) gene re- arrangements.-
Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1- PDGFR alfa fusion kinase (mutational analysis or FISH demonstration for CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFR alfa fusion kinase negative.-
Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-kit mutation.-
Imatinib is also indicated for the treatment of adult patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST)-
It is also indicated for adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.

Known hypersensitivity to the active ingredient or to any of the excipients of the preparation. Lactation.

When Imatinib is co-administered with other medicinal products, there is a potential for 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. 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 (TSH) levels should be closely monitored in such atients.
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 disease: 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 (TLS), correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of Imatinib.
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 being treated and they were more frequent in patients with accelerated phase CML or blast crisis as compared to patients with chronic phase CML. Treatment with Imatinib may be interrupted or the dose may be reduced. 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 (AGP), 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.
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. The long-term effects of prolonged treatment with imatinib on growth in children are unknown. Therefore, close monitoring of growth in children under imatinib treatment is recommended.

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 the co-administration of numerous medicinal products. In clinical trials in CML, drug 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 drug 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 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. The safety database for children with Ph+ALL is very limited though no new safety concerns have been identified. 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 reported as more than an isolated case are listed below, by system organ class and by frequency. Frequency categories are defined using the following convention: 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). Within each frequency grouping, undesirable effects are presented in order of frequency, the most frequent first.
Summary of adverse reactions and their frequencies:
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.
Neoplasm benign, malignant and unspecified (including cysts and polyps
Rare: Tumour lysis syndrome  Not known:   Tumour haemorrhage/tumour necrosis*
Immune system disorders:  Not known:  Anaphylactic shock*
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
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 pain^6. 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 generalised exanthematous pustulosis (AGEP).
Not known: Palmoplantar erythrodysesthesia syndrome*, lichenoid keratosis*, lichen planus*, toxic epidermal necrolysis*, drug rash with eosinophilia and systemic symptoms (DRESS*)
Musculoskeletal and connective tissue disorders
Very common:  Muscle spasm and cramps, musculoskeletal pain including myalgia, arthralgia, bone pain⁹
Common: Joint swelling.
Uncommon: Joint and muscle stiffness.
Rare:Muscular weakness, arthritis, rhabdomyolysis/myopathy.
Not known:  Avascular necrosis/hip necrosis*, growth retardation in children*
Renal and urinary disorders
Uncommon: Renal pain, haematuria, renal failure acute, urinary frequency increased.
Not known: Renal failure chronic.
Reproductive system and breast disorders
Uncommon: Gynaecomastia, erectile dysfunction, menorrhagia, menstruation irregular, sexual dysfunction, nipple pain, breast enlargement, scrotal oedema.
Rare: Haemorrhagic corpus luteum/haemorrhagic ovarian cyst.
General disorders and administration site conditions
Very common:  Fluid retention and oedema, fatigue.
Common:  Weakness, pyrexia, anasarca, chills, rigors
Uncommon: Chest pain, malaise.
Investigations
Very common: Weight increased.
Common: Weight decreased.
Uncommon: Blood creatinine increased, blood creatine phosphokinase increased, blood lactate dehydrogenase increased, blood alkaline phosphatase increased.
Rare: Blood amylase increased.
See prescribing information for full details.  

Active substances that may increase imatinib plasma concentrations: Substances 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.
Active substances that may decrease imatinib plasma concentrations: Substances 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 enzyme-inducing anti-epileptic drugs (EIAEDs) such as carbamazepine, oxcarbazepine and phenytoin. The plasma AUC for imatinib decreased by 73% compared to patients not on EIAEDs. 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. Therefore, 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, etc.). 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-drug interactions between imatinib and chemotherapy regimens are not well characterised. 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.

Women of childbearing potential: Women of childbearing potential must be advised to use effective contraception during treatment.
Pregnancy: There are limited data on the use of imatinib in pregnant women. Studies in animals have however shown reproductive toxicity and the potential risk for the fetus is unknown. Imatinib should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the fetus.
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 taking imatinib should not breast-feed.
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.

Experience with doses higher than the recommended therapeutic dose is limited. Isolated cases of Imatinib overdose have been reported spontaneously and in the literature. 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:
Adult population: 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: One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhoea. In the event of overdose, the patient should be observed and appropriate supportive treatment given.