Tazatred 20/50/70/100 20 mg, 50 mg, 70 mg, 100 mg Tablet

TAZATRED is indicated for the treatment of adults with newly diagnosed Philadelphia chromosome- positive (Ph+) chronic myeloid leukaemia (CML) in chronic phase. TAZATRED 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. TAZATRED 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 TAZATRED for chronic phase CML is 100 mg once daily, administered orally. TAZATRED can be taken with or without a meal and should be taken consistently either in the morning or in the evening.

The recommended starting dosage of TAZATRED for accelerated, myeloid or lymphoid blast phase (advanced phase) CML or Ph+ ALL is 70 mg twice daily, administered orally. TAZATRED 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.

Table 1: Dose Adjustments for Neutropenia and Thrombocytopenia
Chronic Phase CML (starting dose 100 mg once daily)
ANC* < 0,5 x 10 9 /L or Platelets < 50 x 10 9 /L
1. Stop TAZATRED until ANC u2265 1,0 x 10 9 /L and platelets u2265 50 x 10 9 /L.
2. Resume treatment with TAZATRED at the original starting dose.
3. If platelets < 25 x 10 9 /L or recurrence of ANC 7 days, repeat Step 1 and or resume TAZATRED at a reduced dose of 80 mg once daily for second episode. For third episode, further reduce dose to 50 mg once daily (for newly diagnosed patients) or discontinue TAZATRED (for patients resistant or intolerant to prior therapy including imatinib).

Accelerated Phase CML, Blast Phase CML and Ph+ ALL (Starting dose 70 mg twice daily)
ANC* < 0,5 x 10 9 /L or Platelets < 10 x 10 9 /L
1. Check if cytopenia is related to leukaemia (marrow aspirate or biopsy).
2. If cytopenia is unrelated to leukaemia, stop TAZATRED until ANC u2265 1,0 x 10 9 /L and platelets u2265 20 x 10 9 /L and resume at the original starting dose.
3. If recurrence of cytopenia, repeat Step 1 and resume TAZATRED at a reduced dose of 50 mg twice daily (second episode).
4. If cytopenia is related to leukaemia, consider dose escalation to 100 mg twice daily.
*ANC: absolute neutrophil count

Non-haematological adverse reactions: If a severe non-haematological adverse reaction develops with TAZATRED use, treatment must be withheld until the event has resolved or improved. Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the severity and recurrence of the event (see Section 4.4).
Special populations
Renal Impairment: (See Section 5.1 and 5.2).
Hepatic Impairment: (See Section 5.1 and 5.2).
Elderly population: No clinically relevant age-related pharmacokinetic differences have been observed. No specific dose recommendation is necessary in the elderly.
Paediatric Patients: The safety and efficacy of TAZATRED in patients < 18 years of age have not been established.
Method of administration
TAZATRED can be taken with or without a meal and should be taken consistently in the morning and in the evening. Tablets should not be crushed or cut; they should be swallowed whole.

• Hypersensitivity to the active substance (dasatinib) or to any of the excipients (see Section 6.1).
• The concomitant use of H2 antagonists or proton pump inhibitors with TAZATRED is not recommended.

Myelosuppression
Treatment with TAZATRED is very commonly associated with thrombocytopenia, neutropenia and anaemia, which occur earlier and more frequently in patients with advanced phase CML or Ph+ ALL than in patients with chronic phase CML.

In patients with chronic phase CML, complete blood counts (CBCs) should be performed every two weeks for 12 weeks, then every 3 months thereafter, or as clinically indicated. In patients with advanced phase CML or Ph+ ALL, CBCs should be performed weekly for the first 2 months and then monthly thereafter, or as clinically indicated.

Myelosuppression is generally reversible and usually managed by withholding TAZATRED temporarily or by dose reduction (see Sections 4.2 and 4.8).
Bleeding related events
In patients with chronic phase CML, severe haemorrhage occurred in 5 patients receiving dasatinib at the recommended dose (n=548). In patients with advanced phase CML or Ph+ ALL, severe central nervous system (CNS) haemorrhage, including fatalities, occurred in 1 % of patients receiving dasatinib at the recommended dose (n=304). Severe gastrointestinal haemorrhage, including fatalities, occurred in 6 % of patients and generally required treatment interruptions and transfusions. Other cases of severe haemorrhage occurred in 2 % of patients. Most bleeding events in clinical studies were associated with severe thrombocytopenia.

Caution should be exercised if patients are required to take medications that inhibit platelet function or anticoagulants.
Fluid Retention
Dasatinib is associated with fluid retention. After 5 years of follow-up in the Phase III newly diagnosed chronic phase CML study (n=258), severe fluid retention was reported in 13 patients (5 %) receiving dasatinib. In all patients with newly diagnosed or imatinib resistant or intolerant patients with chronic phase CML (n=548), severe fluid retention occurred in 32 (6 %) patients receiving TAZATRED at the recommended dose. In patients with advanced phase CML or Ph+ ALL receiving dasatinib, severe fluid retention was reported in 8 % of patients, including severe pleural and pericardial effusion reported in 7 % and 1 % of patients, respectively. In these patients, severe pulmonary oedema and severe pulmonary hypertension were reported in 1 % of patients.

Patients who develop symptoms suggestive of pleural effusion or other fluid retention, such as new or worsened dyspnoea on exertion or at rest, pleuritic chest pain, or dry cough should be evaluated promptly with chest X-ray or additional diagnostic imaging as appropriate. Fluid retention events were typically managed by supportive care measures that may include diuretics or short courses of steroids. Severe pleural effusion may require thoracentesis. Dose modification should be considered (see Section 4.2).

While the safety profile of dasatinib in the elderly population was similar to that in the younger population, patients aged 65 years and older are more likely to experience fluid retention events and dyspnoea and should be monitored closely.
Cardiac Adverse Reactions
Dasatinib was studied in a randomised trial of 519 patients with newly diagnosed CML in chronic phase which included patients with prior cardiac disease. The cardiac adverse reactions of congestive heart failure/cardiac dysfunction, pericardial effusion, arrhythmias, palpitations, QT prolongation, and myocardial infarction (including fatal) were reported in patients taking dasatinib. Adverse cardiac events were more frequent in patients with risk factors or a previous medical history of cardiac disease. Patients with risk factors or a history of cardiac disease should be monitored carefully for signs or symptoms consistent with cardiac dysfunction and should be evaluated and treated appropriately.
Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH), confirmed by right heart catheterisation, has been reported in association with dasatinib treatment, as in TAZATRED. In these cases, PAH was reported after initiation of dasatinib therapy, and also after more than one year of treatment.

Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating TAZATRED therapy. Patients who develop dyspnoea and fatigue after initiation of therapy should be evaluated for more common aetiologies including pleural effusion, pulmonary oedema, anaemia, or lung infiltration. During this evaluation, guidelines for non-haematologic adverse reactions should be followed (see Section 4.2). If the adverse reaction is severe, treatment must be withheld until the event has resolved or improved. If no alternative diagnosis is found, the diagnosis of PAH should be considered. If PAH is confirmed, TAZATRED should be permanently discontinued. Follow-up should be performed according to standard practice guidelines. Improvements in haemodynamic and clinical parameters have been observed in DASATINIB-treated patients with PAH following cessation of TAZATRED therapy.
QT Prolongation
In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarisation (QT interval). After 5 years of follow-up in the Phase III clinical study of newly diagnosed chronic phase CML, 1 patient (< 1 %) in each of the dasatinib and imatinib treatment groups had QTc prolongation reported as an adverse reaction. The median changes in QTcF from baseline were 3,0 msec in dasatinib-treated patients. One patient ( 500 msec. In 865 patients with leukaemia treated with dasatinib in Phase II clinical studies, the mean QTc interval changes from baseline using Fridericia's method (QTcF) were 4 - 6 msec; the upper 95 % confidence intervals for all mean changes from baseline were 500 msec.

TAZATRED should be administered with caution to patients who have or may develop prolongation of QT interval. These include patients with hypokalaemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking anti-dysrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Hypokalaemia or hypomagnesemia should be corrected prior to TAZATRED administration.
Thrombotic microangiopathy (TMA)
BCR-ABL tyrosine kinase inhibitors have been associated with thrombotic microangiopathy (TMA), including individual case reports for dasatinib (see section 4.8). If laboratory or clinical findings associated with TMA occur in a patient receiving TAZATRED, treatment with TAZATRED 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 TAZATRED should not be resumed.
Hepatitis B virus reactivation
BCR-ABL TKIs, including TAZATRED have been associated with hepatitis B virus (HBV) reactivation including acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome. Screening for HBV should be considered in accordance with guidelines before starting therapy with TAZATRED. Consultation with a medical practitioner with expertise in the treatment of HBV is recommended for patients who test positive for HBV serology. Patients who are carriers of HBV and require treatment with TAZATRED should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop reactivation of HBV while receiving TAZATRED, prompt consultation with a medical practitioner with expertise in the treatment of HBV is recommended.
Severe dermatologic reactions
Cases of severe mucocutaneous dermatologic reactions, including Stevens Johnson syndrome, toxic epidermal necrolysis and erythema multiforme, have been reported with the use of dasatinib. TAZATRED should be permanently discontinued in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can be identified.
Geriatric use
Patients aged 65 years and older are more likely to experience the commonly reported adverse reactions of fatigue, pleural effusion, dyspnoea, cough, lower gastrointestinal haemorrhage, and appetite disturbance, and are more likely to experience the less frequently reported events of abdominal distention, dizziness, pericardial effusion, congestive heart failure, and weight decrease, and should be monitored closely.

Effect of other medicines on TAZATRED:
Medicines that may increase dasatinib plasma concentrations: CYP3A4 Inhibitors: Dasatinib is a CYP3A4 substrate. Concomitant use of TAZATRED and medicines that inhibit CYP3A4 (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, atazanavir, indinavir, nelfinavir, saquinavir, telithromycin, grapefruit juice) may increase exposure to TAZATRED and should be avoided. Selection of an alternate concomitant medication with no or minimal CYP3A4 inhibition potential is recommended. If systemic administration of a potent CYP3A4 inhibitor cannot be avoided, the patient should be closely monitored for toxicity.

Medicines that may decrease TAZATRED plasma concentrations:
CYP3A4 Inducers: Medicines that induce CYP3A4 activity (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or St. John's Wort (Hypericum perforatum)}, may reduce exposure to TAZATRED. Concomitant use of potent CYP3A4 inducers with TAZATRED is not recommended. In patients for whom CYP3A4 inducers are indicated, alternative agents with no or minimal CYP3A4 induction potential should be selected.

Rifampicin: Data from a study of 20 healthy subjects indicate that when a single morning dose of dasatinib was administered following 8 days of continuous evening administration of 600 mg of rifampicin, a potent CYP3A4 inducer, the mean Cmax and AUC of dasatinib were decreased by 81 % and 82 %, respectively.

Antacids (aluminium hydroxide/magnesium hydroxide products): Non-clinical data demonstrate that the solubility of dasatinib is pH dependent. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of TAZATRED. Simultaneous administration of TAZATRED with antacids should be avoided.

H2 Antagonists/Proton Pump Inhibitors: Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors reduces dasatinib exposure by > 60 %. The concomitant use of H2 antagonists or proton pump inhibitors with TAZATRED is not recommended. The use of antacids should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving TAZATRED therapy.
Effect of TAZATRED on other medicines:
CYP3A4 Substrates: Dasatinib is an inhibitor of CYP3A4. Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4 substrate. Therefore, CYP3A4 substrates known to have a narrow therapeutic index such as alfentanil, astemizole, cisapride, ciclosporin, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) should be administered with caution in patients receiving TAZATRED.

Simvastatin: Single dose data from a study of 54 healthy subjects indicate that the mean Cmax and AUC of simvastatin, a CYP3A4 substrate, were increased by 37 % and 20 %, respectively, when simvastatin was administered in combination with a single 100 mg dose of dasatinib.

Women of childbearing potential / Contraception in males and females:
Both sexually active men and women of childbearing potential should use effective methods of contraception during treatment.
Pregnancy:
TAZATRED 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 during pregnancy. TAZATRED is not recommended for use in women who are pregnant or contemplating pregnancy. If TAZATRED is used during pregnancy, or if the patient becomes pregnant while taking TAZATRED, the patient should be apprised of the potential hazard to the foetus.
Breastfeeding:
Women who are taking TAZATRED should not breastfeed.
Fertility:
In animal studies, the fertility of male and female rats was not affected by treatment with dasatinib. Healthcare providers should counsel male patients of appropriate age about possible effects of TAZATRED on fertility, and this counselling may include consideration of semen deposition.

Dasatinib has minor influence on the ability to drive and use machines. No studies on the effects on the ability to drive and use machines have been performed. Patients should be advised that they may experience adverse reactions such as dizziness or blurred vision during treatment with TAZATRED. Therefore, caution should be recommended when driving a car or operating machines.

System Organ Class
Frequent
Infections and infestations
Infection (including bacterial, viral, fungal, non-specified), pneumonia (including bacterial, viral and fungal), upper respiratory tract infection/inflammation, herpes virus infection, enterocolitis infection, sepsis (including uncommon reports of fatal outcomes).
Hepatitis B reactivation
Blood and lymphatic system disorders
Myelosuppression (including anaemia, neutropenia, thrombocytopenia), febrile neutropenia.
Lymphadenopathy, lymphopenia, pure red cell aplasia.
Immune system disorders
Hypersensitivity (including erythema nodosum). Anaphylactic shock
Endocrine system disorders
Hypothyroidism, hyperthyroidism, thyroiditis.
Metabolism and nutrition disorders
Appetite disturbances, hyperuricaemia, Weight decreased; weight increased. tumour lysis syndrome, dehydration, hypoalbuminaemia, hypercholesterolaemia, diabetes mellitus.
Psychiatric disorders
Depression, insomnia. Anxiety, confusional state, affect lability, decrease of libido.
Nervous system disorders
Headache, dizziness, neuropathy (including peripheral neuropathy), dysgeusia, somnolence. CNS bleeding, amnesia, tremor, syncope, balance disorder, cerebrovascular accident, transient ischaemic attack, convulsion, optic neuritis, VIIth nerve paralysis, dementia, ataxia.
Eye disorders
visual disorder (including visual disturbance, blurred vision and reduced visual acuity), dry eye. visual impairment, conjunctivitis, photophobia, increased lacrimation.
Ear and labyrinth disorders
Tinnitus. Hearing loss, vertigo.
Cardiac disorders
Congestive heart failure/cardiac dysfunction, pericardial effusion, dysrhythmia (including tachycardia), palpitations. Cardiomegaly, angina pectoris, myocardial infarction (including fatal outcomes), electrocardiogram QT prolonged, pericarditis, ventricular dysrhythmia (Including ventricular tachycardia), electrocardiogram T wave abnormal, increased troponin, acute coronary syndrome, myocarditis, cor pulmonale, cardiac arrest, electrocardiogram PR prolongation, coronary artery disease, pleuropericarditis. Atrial fibrillation/atrial flutter.
Vascular disorders
Haemorrhage, hypertension, flushing. Hypotension, thrombophlebitis, deep vein thrombosis, pulmonary embolism, livedo reticularis.
Thrombotic microangiopathy.
Respiratory, thoracic and mediastinal disorders
Pleural effusion, dyspnoea, pulmonary oedema, pulmonary hypertension, lung infiltration, pneumonitis, cough. Pulmonary arterial hypertension, bronchospasm, asthma, dysphonia, acute respiratory distress syndrome. Interstitial lung disease.
Gastrointestinal disorders
Nausea, vomiting, diarrhoea, abdominal pain, gastrointestinal bleeding, abdominal distension, mucosal inflammation (Including mucositis/stomatitis), colitis (including neutropenic colitis), gastritis, oral soft tissue disorder, dyspepsia, constipation. Pancreatitis, upper gastrointestinal ulcer, oesophagitis, ascites, anal fissure, dysphagia, gastro-oesophageal reflux disease, protein-losing gastroenteropathy, ileus, acute pancreatitis, anal fistula Fatal gastrointestinal haemorrhage.
Hepatobiliary disorders
Hepatitis, cholestasis, cholecystitis.
Skin and subcutaneous tissue disorders
Skin rash, pruritus, alopecia, acne, dry skin, urticaria, hyperhidrosis, dermatitis (Including eczema). Neutrophilic dermatosis, photosensitivity, pigmentation disorder, panniculitis, skin ulcer, bullous conditions, nail disorder, palmar-plantar erythrodysaesthesia syndrome, hair disorder, leukocytoclastic vasculitis, skin fibrosis.
Musculoskeletal and connective tissue disorders
Musculoskeletal pain, arthralgia, myalgia, muscular weakness, musculoskeletal stiffness, muscle spasm. Rhabdomyolysis, osteonecrosis, tendonitis, muscle inflammation, Arthritis. Epiphyseal delayed fusion growth retardation.
Renal and urinary disorders
Renal failure, urinary frequency, proteinuria, renal impairment. Nephrotic syndrome.
Pregnancy, puerperium and perinatal conditions
Abortion.
Reproductive system and breast disorders
Gynaecomastia, menstrual disorder.
General disorders and administration site conditions
Peripheral oedema, fatigue, pyrexia, face oedema, asthenia, pain, chest pain, generalised oedema, chills Malaise, other superficial oedema, gait disturbance.
Investigations
Blood creatine phosphokinase increased, gamma-glutamyltransferase increased.
Injury, poisoning, and procedural complications
Contusion.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Experience with overdose of dasatinib 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 TAZATRED is associated with severe myelosuppression (see section 4.4), patients who ingest more than the recommended dose should be closely monitored for myelosuppression and given appropriate supportive treatment.