Dasatinib Teva 20 mg, 50 mg, 70 mg or 100 mg FC tablets

DASATINIB TEVA is indicated for the treatment of adults with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML) in chronic phase. DASATINIB TEVA is indicated for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukaemia (CML) with resistance or intolerance to prior therapy including imatinib. DASATINIB TEVA is also indicated for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) with resistance or intolerance to prior therapy.

Posology: The recommended starting dosage of DASATINIB TEVA for chronic phase CML is 100 mg once daily, administered orally. The recommended starting dosage of DASATINIB TEVA for accelerated, myeloid or lymphoid blast phase (advanced phase) CML or Ph+ ALL is 70 mg twice daily, administered orally.

DASATINIB TEVA can be taken with or without a meal and should be taken consistently in the morning and in the evening. Dose increase or reduction is recommended based on individual patient response and tolerability. Dose escalation: In clinical trials of CML and Ph+ ALL, dose escalation to a total maximum of 70 mg twice daily (chronic phase CML) or 90 mg twice daily (advanced phase CML or Ph+ ALL) was allowed in patients who did not achieve a haematologic or cytogenetic response at the recommended starting dosage. Dose adjustment for undesirable effects: Myelosuppression: Myelosuppression was managed by dose interruption, dose reduction, or discontinuation of study therapy. Platelet transfusion and red cell transfusion were used as appropriate. Haematopoietic growth factor has been used in patients with resistant myelosuppression. Guidelines for dose modifications are summarised in TABLE 1.

DASATINIB TEVA is contraindicated in patients with hypersensitivity to dasatinib or to any other component of DASATINIB TEVA listed in section 6.1. The concomitant use of H2 antagonists or proton pump inhibitors with DASATINIB TEVA is not recommended.

Clinically relevant interactions: Dasatinib is a substrate and an inhibitor of cytochrome P450 (CYP) 3A4. Therefore, there is a potential for interaction with other concomitantly administered medicines that are metabolised primarily by or modulate the activity of CYP3A4 (see section 4.5). Concomitant use of DASATINIB TEVA and medicinal products that potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may increase exposure to dasatinib. Therefore, in patients receiving DASATINIB TEVA, co-administration of a potent CYP3A4 inhibitor is not recommended (see section 4.5).

Concomitant use of DASATINIB TEVA and medicines that induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or herbal preparations containing Hypericum perforatum, also known as St. John's Wort) may substantially reduce exposure to dasatinib, potentially increasing the risk of therapeutic failure. Therefore, in patients receiving DASATINIB TEVA, co-administration of alternative medicines with less potential for CYP3A4 induction should be selected (see section 4.5).

Concomitant use of DASATINIB TEVA and a CYP3A4 substrate may increase exposure to the CYP3A4 substrate. Therefore, caution is warranted when DASATINIB TEVA is co-administered with CYP3A4 substrates of narrow therapeutic index, such as astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids (ergotamine, dihydroergotamine) (see section 4.5).

The concomitant use of DASATINIB TEVA and a histamine-2 (H2) antagonist (e.g. famotidine), proton pump inhibitor (e.g. omeprazole), or aluminium hydroxide/magnesium hydroxide may reduce the exposure to dasatinib. Thus, H2 antagonists and proton pump inhibitors are not recommended, and aluminium hydroxide/magnesium hydroxide products should be administered up to 2 hours prior to, or 2 hours following the administration of DASATINIB TEVA (see sections 4.3 and 4.5).

Active substances that may increase dasatinib plasma concentrations: In vitro studies indicate that dasatinib is a CYP3A4 substrate. Concomitant use of DASATINIB TEVA and medicines or substances which potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, atazanavir, indinavir, nelfinavir, saquinavir, telithromycin, grapefruit juice) may increase exposure to dasatinib and should be avoided. Therefore, in patients receiving DASATINIB TEVA, systemic administration of a potent CYP3A4 inhibitor is not recommended (see section 4.2).

Active substances that may decrease dasatinib plasma concentrations: When dasatinib was administered following 8 daily evening administrations of 600 mg rifampicin, a potent CYP3A4 inducer, the AUC of dasatinib was decreased by 82%. Other medicines that induce CYP3A4 activity (e.g. dexamethasone, phenytoin, carbamazepine, phenobarbital or herbal preparations containing Hypericum perforatum, also known as St. Johnu00b4s Wort) may also increase metabolism and decrease dasatinib plasma concentrations. Therefore, concomitant use of potent CYP3A4 inducers with dasatinib is not recommended. In patients in whom rifampicin or other CYP3A4 inducers are indicated, alternative medicines with less enzyme induction potential should be used.

Women of childbearing potential/Contraception in males and females: Sexually active male or female patients taking DASATINIB TEVA should use adequate contraception during treatment. Women of childbearing potential should use effective contraceptive measures while on treatment and for 6 months following completion of treatment with DASATINIB TEVA. Similarly, men should be recommended to use effective contraceptive measures and to not father a child while receiving treatment with DASATINIB TEVA and for 3 months following completion of treatment.

Pregnancy: DASATINIB TEVA may cause foetal harm when administered to a pregnant woman. There have been post-marketing reports of spontaneous abortion and foetal and infant anomalies from women who have taken DASATINIB TEVA during pregnancy. DASATINIB TEVA is not recommended for use in women who are pregnant or contemplating pregnancy. If DASATINIB TEVA is used during pregnancy, or if the patient becomes pregnant while taking DASATINIB TEVA, the patient should be apprised of the potential hazard to the foetus.

Breastfeeding: Women who are taking DASATINIB TEVA should not breastfeed.

DASATINIB TEVA has minor influence on the ability to drive and use machines. Patients should be advised that they may experience adverse reactions such as dizziness or blurred vision during treatment with DASATINIB TEVA. Therefore, caution should be recommended when driving a car or operating machines.

TABLE 2: TABULATED SUMMARY OF ADVERSE REACTIONS: Infections and infestations: Frequent infection (including bacterial, viral, fungal, non-specified), pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/inflammation, herpes virus infection (including cytomegalovirus - CMV), enterocolitis infection, sepsis (including uncommon cases with fatal outcomes) Frequency unknown hepatitis B reactivation Blood and lymphatic system disorders: Frequent myelosuppression (including anaemia, neutropenia, thrombocytopenia), febrile neutropenia Less frequent lymphadenopathy, lymphopenia, aplasia pure red cell Immune system disorders: Less frequent hypersensitivity (including erythema nodosum), anaphylactic shock Endocrine disorders: Less frequent hypothyroidism, hyperthyroidism, thyroiditis Metabolism and nutrition disorders: Frequent appetite disturbances, hyperuricaemia Less frequent tumour lysis syndrome, dehydration, hypoalbuminemia, hypercholesterolemia, diabetes mellitus Psychiatric disorders: Frequent depression, insomnia Less frequent anxiety, confusional state, affect lability, libido decreased Nervous system disorders: Frequent headache, dizziness, neuropathy (including peripheral neuropathy), dysgeusia, somnolence Less frequent CNS bleeding, amnesia, tremor, syncope, balance disorder, cerebrovascular accident, transient ischaemic attack, convulsion, optic neuritis, VII th nerve paralysis, dementia, ataxia Eye disorders: Frequent visual disorder (including visual disturbance, blurred vision and reduced visual acuity), dry eye Less frequent visual impairment, conjunctivitis, photophobia, increased lacrimation Ear and labyrinth disorders: Frequent tinnitus Less frequent hearing loss, vertigo Cardiac disorders: Frequent congestive heart failure/cardiac dysfunction, pericardial effusion, dysrhythmia (including tachycardia), palpitations Less frequent myocardial infarction (including fatal outcome), electrocardiogram QT prolonged, pericarditis, ventricular dysrhythmia (including ventricular tachycardia), angina pectoris, cardiomegaly, electrocardiogram T-wave abnormal, troponin increased, cor pulmonale, myocarditis, acute coronary syndrome, cardiac arrest, Frequency unknown atrial fibrillation/atrial flutter Vascular disorders: Frequent haemorrhage, hypertension, flushing Less frequent hypotension, thrombophlebitis, thrombosis, deep vein thrombosis, livedo reticularis Frequency unknown thrombotic microangiopathy, pulmonary embolism Respiratory, thoracic and mediastinal disorders: Frequent pleural effusion, dyspnoea, pulmonary oedema, pulmonary hypertension, lung infiltration, pneumonitis, cough Less frequent pulmonary arterial hypertension, bronchospasm, asthma, pulmonary embolism, acute respiratory distress syndrome, dysphonia Frequency unknown interstitial lung disease, acute respiratory distress syndrome Gastrointestinal disorders: Frequent diarrhoea, vomiting, nausea, abdominal pain, gastrointestinal bleeding, colitis (including neutropenic colitis), gastritis, mucosal inflammation, dyspepsia, abdominal distension, constipation, oral soft tissue disorder Less frequent pancreatitis (including acute pancreatitis), upper gastrointestinal ulcer, oesophagitis, ascites, anal fissure, dysphagia, gastroesophageal reflux disease, protein-losing gastroenteropathy, ileus, anal fistula Frequency unknown fatal gastrointestinal haemorrhage, acute pancreatitis Hepatobiliary disorders: Less frequent hepatitis, cholestasis, cholecystitis Frequency unknown hepatic failure including fatal events Skin and subcutaneous tissue disorders: Frequent skin rash, alopecia, dermatitis (including eczema), pruritus, acne, dry skin, urticaria, hyperhidrosis Less frequent neutrophilic dermatosis, photosensitivity, pigmentation disorder, panniculitis, skin ulcer, bullous conditions, nail disorder, palmar-plantar erythrodysesthesia syndrome, hair disorder, leukocytoclastic vasculitis, skin fibrosis Frequency unknown Stevens-Johnson syndrome Musculoskeletal and connective tissue disorders: Frequent musculoskeletal pain, arthralgia, myalgia, muscular weakness, musculoskeletal stiffness, muscle spasm Less frequent rhabdomyolysis, osteonecrosis, muscle inflammation, tendonitis, arthritis, epiphyses delayed fusion, growth retardation Renal and urinary disorders: Less frequent renal impairment (including renal failure), urinary frequency, proteinuria Frequency unknown nephrotic syndrome Pregnancy, puerperium and perinatal conditions: Less frequent abortion Reproductive system and breast disorders: Less frequent gynaecomastia, menstrual disorder General disorders and administration site conditions: Frequent peripheral oedema, fatigue, pyrexia, face oedema, asthenia, pain, chest pain, generalised oedema, chills Less frequent malaise, other superficial oedema Investigations: Frequent decreased weight, increased weight

Experience with overdose of DASATINIB TEVA in clinical studies is limited to isolated cases. Overdose of 280 mg per day for one week was reported in two patients and both developed a significant decrease in platelet counts. Since DASATINIB TEVA is associated with severe myelosuppression, patients who ingest more than the recommended dosage should be closely monitored for myelosuppression and appropriate supportive treatment given.