Drug Class Description
protein kinase inhibitor

Generic Name
Dasatinib (as monohydrate)

Drug Description
SPRYCEL® 20mg film-coated tabletsSPRYCEL® 50mg film-coated tabletsSPRYCEL® 70mg film-coated tabletsSPRYCEL® 100mg film-coated tablets

Presentation
Film-coated tablet (tablet)20 mg: the film-coated tablet is white to off-white, biconvex, round with “BMS” debossed on one side and “527” on the other side.50 mg: the film-coated tablet is white to off-white, biconvex, oval with “BMS” debossed on one side and “528” on the other side.70 mg: the film-coated tablet is white to off-white, biconvex, round with “BMS” debossed on one side and “524” on the other side.100 mg: the film-coated tablet is white to off-white, biconvex, oval tablet with “BMS 100” debossed on one side and “852” on the other side.

Indications
SPRYCEL is indicated for the treatment of adults with chronic, accelerated or blast phase chronic myeloid leukaemia (CML) with resistance or intolerance to prior therapy including imatinib mesilate.SPRYCEL is also indicated for the treatment of adults with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy.

Adult Dosage
Therapy should be initiated by a physician experienced in the diagnosis and treatment of patients with leukaemia.The recommended starting dose for chronic phase CML is 100 mg dasatinib once daily, administered orally.The recommended starting dose for accelerated, myeloid or lymphoid blast phase (advanced phase) CML or Ph+ALL is 140 mg once daily, administered orally.Tablets must not be crushed or cut, they must be swallowed whole. SPRYCEL can be taken with or without a meal and should be taken consistently either in the morning or in the evening.Treatment duration: in clinical trials, treatment with SPRYCEL was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment after the achievement of a complete cytogenetic response (CCyR) has not been investigated.To achieve the recommended dose, SPRYCEL is available as 20 mg, 50 mg, 70 mg and 100 mg film-coated tablets. Dose increase or reduction is recommended based on patient response and tolerability.Dose escalation:In clinical trials of adult CML and Ph+ ALL patients, dose escalation to 140 mg once daily (chronic phase CML) or 180 mg once daily (advanced phase CML or Ph+ ALL) was allowed in patients who did not achieve a haematologic or cytogenetic response at the recommended starting dose.Dose adjustment for undesirable effects:Myelosuppression:In clinical trials, 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 summarized in Table 1.Table 1: Dose adjustments for neutropenia and thrombocytopeniaChronic Phase CML (starting dose 100 mg once daily)ANC < 0.5 x 109 /land/orPlatelets < 50 x 109 /l1 Stop treatment until ANC 1.0 x 109 /l and platelets 50 x 109 /l.2 Resume treatment at the original starting dose.3 If platelets < 25 x 109 /l and/or recurrence of ANC < 0.5 x 109 /l for > 7 days, repeat step 1 and resume treatment at a reduced dose of 80 mg once daily (second episode) or discontinue (third episode).Accelerated and Blast Phase CML and Ph+ ALL (starting dose 140 mg once daily)ANC < 0.5 x 109 /land/orPlatelets < 10 x 109 /l1 Check if cytopenia is related to leukaemia (marrow aspirate or biopsy).2 If cytopenia is unrelated to leukaemia, stop treatment until ANC 1.0 x 109 /l and platelets 20 x 109 /l and resume at the original starting dose.3 If recurrence of cytopenia, repeat step 1 and resume treatment at a reduced dose of 100 mg once daily (second episode) or 80 mg once daily (third episode).4 If cytopenia is related to leukaemia, consider dose escalation to 180 mg once daily.ANC: absolute neutrophil countNon-haematological adverse reactions:If a severe non-haematological adverse reaction develops with dasatinib, treatment must be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the initial severity of the event.Paediatric patients: SPRYCEL is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy.Elderly patients: no clinically relevant age-related pharmacokinetic differences have been observed in these patients. No specific dose recommendation is necessary in the elderly.Hepatic impairment: no clinical trials were conducted with SPRYCEL in patients with moderate to severe hepatic impairment (trials excluded patients with ALT and/or AST > 2.5 times the upper limit of the normal range and/or total bilirubin > 2 times the upper limit of the normal range). Since dasatinib is mainly metabolised through the liver, exposure to dasatinib is expected to increase if liver function is impaired. SPRYCEL should be used with caution in patients with moderate to severe hepatic impairment.Renal impairment: no clinical trials were conducted with SPRYCEL in patients with decreased renal function (trials excluded patients with serum creatinine concentration > 1.5 times the upper limit of the normal range). Since the renal clearance of dasatinib and its metabolites is < 4%, a decrease in total body clearance is not expected in patients with renal insufficiency.

Child Dosage
SPRYCEL is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy.

Contra Indications
Hypersensitivity to the active substance or to any of the excipients.

Special Precautions
Clinically relevant interactionsDasatinib is a substrate and an inhibitor of cytochrome P450 (CYP) 3A4. Therefore, there is a potential for interaction with other concomitantly administered medicinal products that are metabolized primarily by or modulate the activity of CYP3A4 .Concomitant use of dasatinib and medicinal products that potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin) may increase exposure to dasatinib. Therefore, in patients receiving dasatinib, coadministration of a potent CYP3A4 inhibitor is not recommended.Concomitant use of dasatinib and medicinal products 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, coadministration of alternative medicinal products with less potential for CYP3A4 induction should be selected.Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4 substrate. Therefore, caution is warranted when dasatinib is coadministered with CYP3A4 substrates of narrow therapeutic index, such as astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids (ergotamine, dihydroergotamine).The concomitant use of dasatinib 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.Special populationsThere are currently no data available from clinical trials with SPRYCEL in patients with moderate to severe liver impairment. Caution is recommended when administering SPRYCEL to patients with moderate to severe hepatic impairment.Important adverse reactionsMyelosuppression: treatment with dasatinib is associated with anaemia, neutropenia and thrombocytopenia. Their occurrence is more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML. Complete blood counts should be performed weekly for the first 2 months, and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding dasatinib temporarily or by dose reduction.In a Phase III dose-optimisation study in patients with chronic phase CML, grade 3 or 4 myelosuppression was reported more frequently in patients treated with 70 mg twice daily than in patients treated with 100 mg once daily.Bleeding: in all clinical studies, severe central nervous system (CNS) haemorrhage occurred in < 1% of patients. Nine cases were fatal and 6 of them were associated with Common Toxicity Criteria (CTC) grade 4 thrombocytopenia. Grade 3 or 4 gastrointestinal haemorrhage occurred in 4% of patients and generally required treatment interruptions and transfusions. Other grade 3 or 4 haemorrhage occurred in 2% of patients. Most bleeding related events were typically associated with grade 3 or 4 thrombocytopenia.Patients were excluded from participation in initial SPRYCEL clinical trials if they took medicinal products that inhibit platelet function or anticoagulants. In subsequent trials, the use of anticoagulants, acetylsalicylic acid, and non-steroidal anti-inflammatory drugs (NSAIDs) was allowed concurrently with SPRYCEL if the platelet count was > 50,000-75,000/mm3. Caution should be exercised if patients are required to take medicinal products that inhibit platelet function or anticoagulants.Fluid retention: dasatinib is associated with fluid retention. In all clinical studies, grade 3 or 4 fluid retention was reported in 10% of patients, including grade 3 or 4 pleural and pericardial effusion reported in 7% and 1% of patients, respectively. Grade 3 or 4 ascites and generalised oedema were each reported in < 1% of patients. Grade 3 or 4 pulmonary oedema was reported in 1% of patients. Patients who develop symptoms suggestive of pleural effusion such as dyspnoea or dry cough should be eva luated by chest X-ray. Severe pleural effusion may require thoracocentesis and oxygen therapy. Fluid retention events were typically managed by supportive care measures that include diuretics and short courses of steroids. While the safety profile of SPRYCEL 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 should be monitored closely. Fluid retention was reported less frequently in patients treated with once daily schedule compared to twice daily in two Phase III dose-optimisation studies.QT Prolongation: in vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT Interval). In 865 patients with leukaemia treated with dasatinib in Phase II clinical trials, the mean changes from baseline in QTc interval using Fridericia's method (QTcF) were 4 - 6 msec; the upper 95% confidence intervals for all mean changes from baseline were < 7 msec. Of the 2,182 patients who received dasatinib in clinical trials, 14 (< 1%) had QTc prolongation reported as an adverse reaction. Twenty-one patients (< 1%) experienced a QTcF > 500 msec. Dasatinib should be administered with caution to patients who have or may develop prolongation of QTc. These include patients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking anti-arrhythmic medicinal products or other medicinal products which lead to QT prolongation, and cumulative high dose anthracycline therapy. Hypokalemia or hypomagnesemia should be corrected prior to dasatinib administration.Patients with uncontrolled or significant cardiovascular disease were not included in the clinical studies.LactoseThis medicinal product contains 135 mg of lactose monohydrate in a 100 mg daily dose and 189 mg of lactose monohydrate in a 140 mg daily dose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Interactions
Active substances that may increase dasatinib plasma concentrationsIn vitro studies indicate that dasatinib is a CYP3A4 substrate. Concomitant use of dasatinib and medicinal products which potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin) may increase exposure to dasatinib. Therefore, in patients receiving dasatinib, systemic administration of a potent CYP3A4 inhibitor is not recommended.At clinically relevant concentrations, binding of dasatinib to plasma proteins is approximately 96% on the basis of in vitro experiments. No studies have been performed to eva luate dasatinib interaction with other protein-bound medicinal products. The potential for displacement and its clinical relevance are unknown.Active substances that may decrease dasatinib plasma concentrationsWhen 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 medicinal products that induce CYP3A4 activity (e.g. dexamethazone, phenytoin, carbamazepine, phenobarbital or herbal preparations containing Hypericum perforatum, also known as St. John´s 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, alternaive medicinal products with less enzyme induction potential should be used.Histamine-2 antagonists and proton pump inhibitors:Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (e.g. famotidine and omeprazole) is likely to reduce dasatinib exposure. In a single-dose study in healthy subjects, the administration of famotidine 10 hours prior to a single dose of SPRYCEL reduced dasatinib exposure by 61%. The use of antacids should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving SPRYCEL therapy.Antacids:Non-clinical data demonstrate that the solubility of dasatinib is pH-dependent. In healthy subjects, the concomitant use of aluminium hydroxide/magnesium hydroxide antacids with SPRYCEL reduced the AUC of a single dose of SPRYCEL by 55% and the Cmax by 58%. However, when antacids were administered 2 hours prior to a single dose of SPRYCEL, no relevant changes in dasatinib concentration or exposure were observed. Thus, antacids may be administered up to 2 hours prior to or 2 hours following SPRYCEL.Active substances that may have their plasma concentrations altered by dasatinibConcomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4 substrate. In a study in healthy subjects, a single 100 mg dose of dasatinib increased AUC and Cmax exposure to simvastatin, a known CYP3A4 substrate, by 20 and 37% respectively. It cannot be excluded that the effect is larger after multiple doses of dasatinib. Therefore, CYP3A4 substrates known to have a narrow therapeutic index (e.g. astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids (ergotamine, dihydroergotamine)) should be administered with caution in patients receiving dasatinib.In vitro data indicate a potential risk for interaction with CYP2C8 substrates, such as glitazones.

Adverse Reactions
The data described below reflect exposure to SPRYCEL in 2,182 patients in clinical trials with a minimum of 24 months follow-up (starting dose 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily). Of the 2,182 patients treated, 25% were 65 years of age, while 5% were 75 years of age. The median duration of therapy was 15 months (range 0.03-31 months).The majority of SPRYCEL-treated patients experienced adverse reactions at some time. Most reactions were of mild-to-moderate grade. Treatment was discontinued for adverse reactions in 14% of patients in chronic phase CML, 15% in accelerated phase CML, 15% in myeloid blast phase CML, 8% in lymphoid blast phase CML and 8% in Ph+ ALL. In the Phase III dose-optimisation study in patients with chronic phase CML, the rate of discontinuation for adverse drug reactions was lower for patients treated with 100 mg once daily than for those treated with 70 mg twice daily (8% and 15%, respectively); the rates of dose interruption and reduction were also lower for patients treated with 100 mg once daily than for those treated with 70 mg twice daily. Less frequent dose reductions and interruptions were also reported for patients with advanced phase CML and Ph+ ALL treated with 140 mg once daily than for those treated with 70 mg twice daily.The majority of imatinib-intolerant patients with chronic phase CML were able to tolerate treatment with dasatinib. In clinical studies of chronic phase CML, 10 of the 214 imatinib-intolerant patients had the same grade 3 or 4 non-hematologic toxicity with SPRYCEL as they did with prior imatinib; 8 of these 10 patients were managed with dose reduction and were able to continue SPRYCEL treatment.The most frequently reported adverse reactions were fluid retention (including pleural effusion), diarrhoea, headache, nausea, skin rash, dyspnoea, haemorrhage, fatigue, musculoskeletal pain, infection, vomiting, cough, abdominal pain and pyrexia. Drug-related febrile neutropenia was reported in 5% of patients.Miscellaneous adverse reactions such as pleural effusion, ascites, pulmonary oedema and pericardial effusion with or without superficial oedema may be collectively described as “fluid retention”. The use of dasatinib is associated with fluid retention with grade 3 or 4 cases in 10% of patients. Grade 3 or 4 pleural and pericardial effusion were reported in 7% and 1% of patients, respectively. Grade 3 or 4 ascites and generalised oedema were each reported in < 1%. One percent of patients experienced grade 3 or 4 pulmonary oedema. Fluid retention events were typically managed by supportive care measures that include diuretics or short courses of steroids. While the safety profile of SPRYCEL 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 should be monitored closely.Bleeding drug-related events, ranging from petechiae and epistaxis to grade 3 or 4 gastrointestinal haemorrhage and CNS bleeding, were reported in patients taking SPRYCEL. Severe CNS haemorrhage occurred in < 1% of patients. Nine cases were fatal and 6 of them were associated with CTC grade 4 thrombocytopenia. Grade 3 or 4 gastrointestinal haemorrhage occurred in 4% of patients and generally required treatment interruption and transfusions. Other grade 3 or 4 haemorrhage occurred in 2% of patients. Most bleeding related events were typically associated with grade 3 or 4 thrombocytopenia. Treatment with SPRYCEL is associated with anaemia, neutropenia and thrombocytopenia. Their occurrence is more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML.In the Phase III dose-optimisation study in patients with chronic phase CML (median duration of treatment of 22 months), the incidence of pleural effusion and congestive heart failure/cardiac dysfunction was lower in patients treated with SPRYCEL 100 mg once daily than in those treated with SPRYCEL 70 mg twice daily (Table 2a). Myelosuppression was also reported less frequently with the 100 mg once daily (see Laboratory test abnormalities below).Table 2a: Selected Adverse Drug Reactions Reported in Phase III Dose-Optimisation Study: Chronic Phase CML100 mg once dailyn = 165140 mg once dailyn = 16350 mg twice dailyn = 16770 mg twice dailyn = 167All GradesGrade 3/4All Grades Grade 3/4All Grades Grade 3/4All Grades Grade 3/4Preferred TermPercent (%) of PatientsDiarrhoea251294312274Fluid Retention3044073553810Superficial Oedema170171180191Pleural Effusion142255234235Generalised oedema305000< 10Congestive heart failure/cardiac dysfunction00411152Pericardial effusion21625221Pulmonary oedema00001131Pulmonary hypertension00< 101011HaemorrhageGastrointestinal bleeding21205342In the Phase III dose-optimisation study in patients with advanced phase CML and Ph+ ALL (median duration of treatment of 14 months for accelerated phase CML, 3 months for myeloid blast CML, 4 months for lymphoid blast CML and 3 months for Ph+ ALL), fluid retention (pleural effusion and pericardial effusion) was reported less frequently in patients treated with SPRYCEL 140 mg once daily than in those treated with 70 mg twice daily (Table 2b).Table 2b: Selected Adverse Drug Reactions Reported in Phase III Dose-Optimisation Study: Advanced Phase CML and Ph+ ALL140 mg once dailyn = 30470 mg twice dailyn = 305All GradesGrade 3/4All GradesGrade 3/4Preferred TermPercent (%) of PatientsDiarrhoea283294Fluid Retention3264311Superficial oedema150191Pleural Effusion206327Generalised oedema2031Congestive heart failure/ cardiac dysfunction1021Pericardial effusion2162Pulmonary oedema1131Ascites0010Pulmonary hypertension0010HaemorrhageGastrointestinal bleeding86126In clinical trials, it was recommended that treatment with imatinib be discontinued at least 7 days before starting treatment with SPRYCEL.Adverse reactions:The following adverse reactions, excluding laboratory abnormalities, were reported in patients in SPRYCEL clinical trials. These reactions are presented by system organ class and by frequency. Frequencies are defined as: 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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.InvestigationsCommon: weight decreased, weight increasedUncommon: blood creatine phosphokinase increasedCardiac disordersCommon: congestive heart failure/cardiac dysfunctiona, pericardial effusion, arrhythmia (including tachycardia), palpitationsUncommon: myocardial infarction, electrocardiogram QT prolonged, pericarditis, ventricular arrhythmia (including ventricular tachycardia), angina pectoris, cardiomegalyRare: cor pulmonale, myocarditis, acute coronary syndromeBlood and lymphatic system disordersCommon: febrile neutropenia, pancytopeniaRare: aplasia pure red cellNervous system disordersVery common: headacheCommon: neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolenceUncommon: CNS bleeding, syncope, tremor, amnesiaRare: cerebrovascular accident, transient ischaemic attack, convulsionEye disordersCommon: visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eyeUncommon: conjunctivitisEar and labyrinth disordersCommon: tinnitusUncommon: vertigoRespiratory, thoracic and mediastinal disordersVery common: pleural effusion, dyspnoea, coughCommon: pulmonary oedema, pulmonary hypertension, lung infiltration, pneumonitisUncommon: bronchospasm, asthmaRare: acute respiratory distress syndromeGastrointestinal disordersVery common: diarrhoea, vomiting, nausea, abdominal painCommon: gastrointestinal bleeding, colitis (including neutropenic colitis), gastritis, mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, oral soft tissue disorderUncommon: pancreatitis, upper gastrointestinal ulcer, oesophagitis, ascites, anal fissure, dysphagiaRenal and urinary disordersUncommon: renal failure, urinary frequency, proteinuriaSkin and subcutaneous tissue disordersVery common: skin rashbCommon: alopecia, dermatitis (including eczema), pruritus, acne, dry skin, urticaria, hyperhidrosisUncommon: acute febrile neutrophilic dermatosis, photosensitivity, pigmentation disorder, panniculitis, skin ulcer, bullous conditions, nail disorder, palmar-plantar erythrodysesthesia syndromeMusculoskeletal and connective tissue disordersVery common: musculoskeletal painCommon: arthralgia, myalgia, muscle inflammation, muscular weakness, musculoskeletal stiffnessUncommon: rhabdomyolysisRare: tendonitisMetabolism and nutrition disordersCommon: anorexia, appetite disturbances, hyperuricaemiaInfections and infestationsVery common: infection (including bacterial, viral, fungal, non-specific)Common: sepsis (including fatal outcome), pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/inflammation, herpes viral infection, enterocolitis infectionInjury, poisoning, and procedural complicationsCommon: contusionNeoplasms benign, malignant and unspecified (including cysts and polyps)Uncommon: tumour lysis syndromeVascular disordersVery common: haemorrhagecCommon: hypertension, flushingUncommon: hypotension, thrombophlebitisRare: livedo reticularisGeneral disorders and administration site conditionsVery common: fatigue, superficial oedemad, pyrexiaCommon: asthenia, pain, chest pain, generalised oedema, chillsUncommon: malaise, temperature intoleranceImmune System DisordersUncommon: hypersensitivity (including erythema nodosum)Hepatobiliary disordersUncommon: hepatitis, cholestasisRare: cholecystitisReproductive system and breast disordersUncommon: gynecomastia, irregular menstruationPsychiatric disordersCommon: depression, insomniaUncommon: anxiety, confusional state, affect lability, libido decreaseda Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased and ventricular failure.b Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, fungal rash, generalised erythema, genital rash, heat rash, milia, rash, rash erythematous, rash follicular, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, skin exfoliation, skin irritation and urticaria vesiculosa.c Excludes gastrointestinal bleeding and CNS bleeding; these ADRs are reported under the gastrointestinal disorders system organ class and the nervous system disorders system organ class, respectively.d Includes auricular swelling, conjunctival oedema, eye oedema, eye swelling, eyelid oedema, face oedema, gravitational oedema, lip oedema, localised oedema, macular oedema, oedema genital, oedema mouth, oedema peripheral, orbital oedema, penile oedema, periorbital oedema, pitting oedema, scrotal oedema, swelling face and tongue oedema.Laboratory test abnormalities:Haematology:In CML, cytopenias (thrombocytopenia, neutropenia, and anaemia) were a consistent finding. However, the occurrence of cytopenias was also clearly dependent on the stage of the disease. The frequency of grade 3 and 4 haematological abnormalities is presented in Table 3.Table 3: CTC Grades 3/4 Haematological Laboratory Abnormalities in Clinical Studies Chronic Phasea(n= 1,150)Accelerated Phase(n= 502)Myeloid Blast Phase(n= 280)Lymphoid Blast Phase and Ph+ ALL(n= 250)Percent (%) of PatientsHaematology ParametersNeutropenia47698078Thrombocytopenia41728178Anaemia19557546a The chronic phase data include patients treated with any dose of SPRYCELCTC grades: neutropenia (Grade 3 0.5–1.0 × 109/l, Grade 4 < 0.5 × 109/l); thrombocytopenia (Grade 3 10–50 × 109/l, Grade 4 < 10 × 109/l); anaemia (hemoglobin Grade 3 65–80 g/l, Grade 4 < 65 g/l).In the Phase III dose-optimisation study in patients with chronic phase CML, the frequency of neutropenia, thrombocytopenia and anaemia was lower in the SPRYCEL 100 mg once daily than in the SPRYCEL 70 mg twice daily group.In patients who experienced grade 3 or 4 myelosuppression, recovery generally occurred following brief dose interruptions and/or reductions and permanent discontinuation of treatment occurred in 5% of patients. Most patients continued treatment without further evidence of myelosuppression.Biochemistry:Grade 3 or 4 elevations of transaminases or bilirubin were reported in < 1% of patients with chronic phase CML but elevations were reported with an increased frequency of 1 to 7% of patients with advanced phase CML and Ph+ ALL. It was usually managed with dose reduction or interruption. In the phase III dose-optimisation studies, grade 3 or 4 elevations of transaminases or bilirubin were reported in 1% of patients with chronic phase CML with similar low incidence in the four treatment groups; elevations were reported in 2% to 4% of patients with advanced phase CML and Ph+ ALL.Approximately 5% of the dasatinib-treated patients who had normal baseline levels experienced grade 3 or 4 transient hypocalcemia at some time during the course of the study. In general, there was no association of decreased calcium with clinical symptoms. Patients developing grade 3 or 4 hypocalcemia often had recovery with oral supplementation. Grade 3 or 4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML and Ph+ ALL. Grade 3 or 4 elevations in creatinine were reported in < 1% of patients with chronic phase CML and were reported with an increased frequency of 1 to 4% of patients with advanced phase CML.Electrocardiogram:In 5 Phase II clinical trials in patients with leukaemia, repeated baseline and on-treatment ECGs were obtained at pre-specified time points and read centrally for 865 patients receiving SPRYCEL 70 mg twice daily. QT interval was corrected for heart rate by Fridericia's method. At all post-dose time points on day 8, the mean changes from baseline in QTcF interval were 4-6 msec, with associated upper 95% confidence intervals < 7 msec. Of the 2,182 patients who received SPRYCEL in clinical trials, 14 (< 1%) had QTc prolongation reported as an adverse reaction. Twenty-one patients (< 1%) experienced a QTcF > 500 msec.

Manufacturer
Bristol-Myers Squibb

Drug Availability
(POM)

Updated
12 August 2009