Chemical formula: C₂₂H₂₆ClN₇O₂S Molecular mass: 488.006 g/mol PubChem compound: 3062316
Dasatinib interacts in the following cases:
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 medicinal products that induce CYP3A4 activity (e.g. dexamethasone, 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, alternative medicinal products with less enzyme induction potential should be used. Concomitant use of dexamethasone, a weak CYP3A4 inducer, with dasatinib is allowed; dasatinib AUC is predicted to decrease approximately 25% with concomitant use of dexamethasone, which is not likely to be clinically meaningful.
Concomitant 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.
The concomitant use of strong CYP3A4 inhibitors and grapefruit juice with dasatinib should be avoided. If possible, an alternative concomitant medication with no or minimal enzyme inhibition potential should be selected. If dasatinib must be administered with a strong CYP3A4 inhibitor, consider a dose decrease to:
For patients taking dasatinib 60 mg or 40 mg daily, consider interrupting the dose of dasatinib until the CYP3A4 inhibitor is discontinued, or switching to a lower dose. Allow a washout period of approximately 1 week after the inhibitor is stopped before reinitiating dasatinib.
These reduced doses of dasatinib are predicted to adjust the area under the curve (AUC) to the range observed without CYP3A4 inhibitors; however, clinical data are not available with these dose adjustments in patients receiving strong CYP3A4 inhibitors. If dasatinib is not tolerated after dose reduction, either discontinue the strong CYP3A4 inhibitor or interrupt dasatinib until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before the dasatinib dose is increased.
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 dasatinib reduced the AUC of a single dose of dasatinib by 55% and the Cmax by 58%. However, when antacids were administered 2 hours prior to a single dose of dasatinib, 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 dasatinib.
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 dasatinib reduced dasatinib exposure by 61%. In a study of 14 healthy subjects, administration of a single 100-mg dose of dasatinib 22 hours following a 4-day, 40-mg omeprazole dose at steady state reduced the AUC of dasatinib by 43% and the Cmax of dasatinib by 42%. The use of antacids should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving dasatinib therapy.
BCR-ABL tyrosine kinase inhibitors have been associated with thrombotic microangiopathy (TMA), including individual case reports for dasatinib. If laboratory or clinical findings associated with TMA occur in a patient receiving dasatinib, treatment with dasatinib 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 dasatinib should not be resumed.
In patients with chronic phase CML (n=548), 5 patients (1%) receiving dasatinib had grade 3 or 4 haemorrhage. In clinical studies in patients with advanced phase CML receiving the recommended dose of dasatinib (n=304), severe central nervous system (CNS) haemorrhage occurred in 1% of patients. One case was fatal and was associated with Common Toxicity Criteria (CTC) grade 4 thrombocytopaenia. Grade 3 or 4 gastrointestinal haemorrhage occurred in 6% of patients with advanced phase CML and generally required treatment interruptions and transfusions. Other grade 3 or 4 haemorrhage occurred in 2% of patients with advanced phase CML. Most bleeding related adverse reactions in these patients were typically associated with grade 3 or 4 thrombocytopaenia. Additionally, in vitro and in vivo platelet assays suggest that dasatinib treatment reversibly affects platelet activation.
Caution should be exercised if patients are required to take medicinal products that inhibit platelet function or anticoagulants.
PAH (pre-capillary pulmonary arterial hypertension confirmed by right heart catheterization) has been reported in association with dasatinib treatment. In these cases, PAH was reported after initiation of dasatinib therapy, including after more than one year of treatment.
Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating dasatinib therapy. An echocardiography should be performed at treatment initiation in every patient presenting symptoms of cardiac disease and considered in patients with risk factors for cardiac or pulmonary disease. Patients who develop dyspnoea and fatigue after initiation of therapy should be evaluated for common etiologies including pleural effusion, pulmonary oedema, anaemia, or lung infiltration. In accordance with recommendations for management of non-haematologic adverse reactions the dose of dasatinib should be reduced or therapy interrupted during this evaluation. If no explanation is found, or if there is no improvement with dose reduction or interruption, the diagnosis of PAH should be considered. The diagnostic approach should follow standard practice guidelines. If PAH is confirmed, dasatinib 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 dasatinib therapy.
In clinical studies, 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 in adults are summarised in Table 1 and in paediatric patients with Ph+ CML-CP in Table 2. Guidelines for paediatric patients with Ph+ ALL treated in combination with chemotherapy are in a separate paragraph following the tables.
Table 1. Dose adjustments for neutropaenia and thrombocytopaenia in adults:
|/3<>Adults with chronic phase CML (starting dose 100 mg once daily) |/3<>ANC <0.5 × 109/L
and/or platelets <50 × 109/L| 1. Stop treatment until ANC ≥1.0 × 109/L andplatelets ≥50 × 109/L.|
| 2. Resume treatment at the original starting dose. | ||
| 3. If platelets <25 × 109/L and/or recurrence of ANC <0.5 × 109/L for >7 days, repeat step 1 and resume treatment 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 (for patients resistant or intolerant to prior therapy including imatinib). | ||
| Adults with accelerated and blast phase CML and Ph+ ALL (starting dose 140 mg once daily) | ANC <0.5 × 109/L and/or platelets <10 × 109/L | 1.Check if cytopaenia is related to leukaemia (marrow aspirate or biopsy). |
| 2. If cytopaenia is unrelated to leukaemia, stop treatment until ANC ≥1.0 × 109/L and platelets ≥20 × 109/L and resume at the original starting dose. | ||
| 3. If recurrence of cytopaenia, 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 cytopaenia is related to leukaemia, consider dose escalation to 180 mg once daily. |
Table 2. Dose adjustments for neutropaenia and thrombocytopaenia in paediatric patients with Ph+ CML-CP:
| 1. If cytopaenia persists for more than 3 weeks, check if cytopaenia is related to leukaemia (marrow aspirate or biopsy). | Dose (maximum dose per day) | |||
|---|---|---|---|---|
| Original starting dose | One-level dose reduction | Two-level dose reduction | ||
| 2. If cytopaenia is unrelated to leukaemia, stop treatment until ANC ≥1.0 × 109/L and platelets ≥75 × 109/L and resume at the original starting dose or at a reduced dose. | Tablets | 40 mg | 20 mg | * |
| 60 mg | 40 mg | 20 mg | ||
| 3. If cytopaenia recurs, repeat marrow aspirate/biopsy and resume treatment at a reduced dose. | 70 mg | 60 mg | 50 mg | |
| 100 mg | 80 mg | 70 mg | ||
ANC: absolute neutrophil count
* lower tablet dose not available
For paediatric patients with Ph+ CML-CP, if Grade ≥3 neutropaenia or thrombocytopaenia recurs during complete haematologic response (CHR), dasatinib should be interrupted, and may be subsequently resumed at a reduced dose. Temporary dose reductions for intermediate degrees of cytopaenia and disease response should be implemented as needed.
For paediatric patients with Ph+ ALL, no dose modification is recommended in cases of haematologic Grade 1 to 4 toxicities. If neutropaenia and/or thrombocytopaenia result in delay of the next block of treatment by more than 14 days, dasatinib should be interrupted and resumed at the same dose level once the next block of treatment is started. If neutropaenia and/or thrombocytopaenia persist and the next block of treatment is delayed another 7 days, a bone marrow assessment should be performed to assess cellularity and percentage of blasts. If marrow cellularity is <10%, treatment with dasatinib should be interrupted until ANC >500/μL (0.5 × 109/L), at which time treatment may be resumed at full dose. If marrow cellularity is >10%, resumption of treatment with dasatinib may be considered.
Dasatinib is associated with fluid retention. In the Phase III clinical study in patients with newly diagnosed chronic phase CML, grade 3 or 4 fluid retention was reported in 13 patients (5%) in the dasatinib-treatment group and in 2 patients (1%) in the imatinib-treatment group after a minimum of 60 months follow-up. In all dasatinib treated patients with chronic phase CML, severe fluid retention occurred in 32 patients (6%) receiving dasatinib at the recommended dose (n=548). In clinical studies in patients with advanced phase CML or Ph+ ALL receiving dasatinib at the recommended dose (n=304), grade 3 or 4 fluid retention was reported in 8% of patients, including grade 3 or 4 pleural and pericardial effusion reported in 7% and 1% of patients, respectively. In these patients grade 3 or 4 pulmonary oedema and pulmonary hypertension were each reported in 1% of patients.
Patients who develop symptoms suggestive of pleural effusion such as dyspnoea or dry cough should be evaluated by chest X-ray. Grade 3 or 4 pleural effusion may require thoracocentesis and oxygen therapy. Fluid retention adverse reactions were typically managed by supportive care measures that include diuretics and short courses of steroids. Patients aged 65 years and older are more likely than younger patients to experience pleural effusion, dyspnoea, cough, pericardial effusion and congestive heart failure, and should be monitored closely.
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 dasatinib. 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 dasatinib should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.
If a pleural effusion is diagnosed, dasatinib should be interrupted until patient is examined, asymptomatic or has returned to baseline. If the episode does not improve within approximately one week, a course of diuretics or corticosteroids or both concurrently should be considered (see dose level should be considered. Following resolution of a subsequent episode, dasatinib at one dose level reduction should be reintroduced. Following resolution of a severe (grade 3 or 4) episode, treatment can be resumed as appropriate at a reduced dose depending on the initial severity of the adverse reaction.
In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarisation (QT Interval). In 258 dasatinib-treated patients and 258 imatinib-treated patients with a minimum of 60 months follow-up in the Phase III study in newly diagnosed chronic phase CML, 1 patient (<1%) in each group had QTc prolongation reported as an adverse reaction. The median changes in QTcF from baseline were 3.0 msec in dasatinib-treated patients compared to 8.2 msec in imatinib-treated patients. One patient (<1%) in each group experienced a QTcF >500 msec. In 865 patients with leukaemia treated with dasatinib in Phase II clinical studies, 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 with resistance or intolerance to prior imatinib therapy who received dasatinib in clinical studies, 15 (1%) had QTc prolongation reported as an adverse reaction. Twenty-one of these 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 hypokalaemia or hypomagnesaemia, 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. Hypokalaemia or hypomagnesaemia should be corrected prior to dasatinib administration.
Based on human experience, dasatinib is suspected to cause congenital malformations including neural tube defects, and harmful pharmacological effects on the foetus when administered during pregnancy. Studies in animals have shown reproductive toxicity. Dasatinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with dasatinib. If dasatinib is used during pregnancy, the patient must be informed of the potential risk to the foetus.
There is insufficient/limited information on the excretion of dasatinib in human or animal breast milk. Physico-chemical and available pharmacodynamic/toxicological data on dasatinib point to excretion in breast milk and a risk to the suckling child cannot be excluded. Breast-feeding should be stopped during treatment with dasatinib.
Both sexually active men and women of childbearing potential should use effective methods of contraception during treatment.
In animal studies, the fertility of male and female rats was not affected by treatment with dasatinib. Physicians and other healthcare providers should counsel male patients of appropriate age about possible effects of dasatinib on fertility, and this counseling may include consideration of semen deposition.
Dasatinib 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. Therefore, caution should be recommended when driving a car or operating machines.
The data described below reflect the exposure to dasatinib as single-agent therapy at all doses tested in clinical studies (N=2,900), including 324 adult patients with newly diagnosed chronic phase CML, 2,388 adult patients with imatinib-resistant or -intolerant chronic or advanced phase CML or Ph+ ALL, and 188 paediatric patients.
In the 2,712 adult patients with either chronic phase CML, advanced phase CML or Ph+ ALL, the median duration of therapy was 19.2 months (range 0 to 93.2 months). In a randomized trial in patients with newly diagnosed chronic phase CML, the median duration of therapy was approximately 60 months. The median duration of therapy in 1,618 adult patients with chronic phase CML was 29 months (range 0 to 92.9 months). The median duration of therapy in 1,094 adult patients with advanced phase CML or Ph+ ALL was 6.2 months (range 0 to 93.2 months). Among 188 patients in paediatric studies, the median duration of therapy was 26.3 months (range 0 to 99.6 months). In the subset of 130 chronic phase CML dasatinib-treated paediatric patients, the median duration of therapy was 42.3 months (range 0.1 to 99.6 months).
The majority of dasatinib-treated patients experienced adverse reactions at some time. In the overall population of 2,712 dasatinib-treated adult subjects, 520 (19%) experienced adverse reactions leading to treatment discontinuation.
The overall safety profile of dasatinib in the paediatric Ph+ CML-CP population was similar to that of the adult population, regardless of formulation, with the exception of no reported pericardial effusion, pleural effusion, pulmonary oedema, or pulmonary hypertension in the paediatric population. Of the 130 dasatinib-treated paediatric subjects with CML-CP, 2 (1.5%) experienced adverse reactions leading to treatment discontinuation.
The following adverse reactions, excluding laboratory abnormalities, were reported in patients treated with dasatinib used as single-agent therapy in clinical studies and post-marketing experience. 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); not known (cannot be estimated from available post-marketing data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Summary of adverse reactions:
Very common: infection (including bacterial, viral, fungal, non-specified)
Common: 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)
Not known: hepatitis B reactivation
Very Common: myelosuppression (including anaemia, neutropaenia, thrombocytopaenia)
Common: febrile neutropaenia
Uncommon: lymphadenopathy, lymphopaenia
Rare: aplasia pure red cell
Uncommon: hypersensitivity (including erythema nodosum)
Rare: anaphylactic shock
Uncommon: hypothyroidism
Rare: hyperthyroidism, thyroiditis
Common: appetite disturbancesa, hyperuricaemia
Uncommon: tumour lysis syndrome, dehydration, hypoalbuminemia, hypercholesterolemia
Rare: diabetes mellitus
Common: depression, insomnia
Uncommon: anxiety, confusional state, affect lability, libido decreased
Very common: headache
Common: neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence
Uncommon: CNS bleedingb*, syncope, tremor, amnesia, balance disorder
__Rare cerebrovascular accident, transient ischaemic attack, convulsion, optic neuritis, VIIth nerve paralysis, dementia, ataxia
Common: visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye
Uncommon: visual impairment, conjunctivitis, photophobia, lacrimation increased
Common: tinnitus
Uncommon: hearing loss, vertigo
Common: congestive heart failure/cardiac dysfunctionc,, pericardial effusion, arrhythmia (including tachycardia), palpitations
Uncommon: myocardial infarction (including fatal outcome), electrocardiogram QT prolonged, pericarditis, ventricular arrhythmia (including ventricular tachycardia), angina pectoris, cardiomegaly, electrocardiogram T wave abnormal, troponin increased
Rare: cor pulmonale, myocarditis, acute coronary syndrome, cardiac arrest, electrocardiogram PR prolongation, coronary artery disease, pleuropericarditis
Not known: atrial fibrillation/atrial flutter
Very common: haemorrhaged*
Common: hypertension, flushing
Uncommon: hypotension, thrombophlebitis, thrombosis
Rare: deep vein thrombosis, embolism, livedo reticularis
Not known: thrombotic microangiopathy
__Very common pleural effusion*, dyspnoea
Common: pulmonary oedema*, pulmonary hypertension*, lung infiltration, pneumonitis, cough
Uncommon: pulmonary arterial hypertension, bronchospasm, asthma
Rare: pulmonary embolism, acute respiratory distress syndrome
Not known: interstitial lung disease
Very common: diarrhoea, vomiting, nausea, abdominal pain
Common: gastrointestinal bleeding*, colitis (including neutropaenic colitis), gastritis, mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, oral soft tissue disorder
Uncommon: pancreatitis (including acute pancreatitis), upper gastrointestinal ulcer, oesophagitis, ascites*, anal fissure, dysphagia, gastroesophageal reflux disease
Rare: protein-losing gastroenteropathy, ileus, anal fistula
Not known: fatal gastrointestinal haemorrhage*
Uncommon: hepatitis, cholecystitis, cholestasis
Very common: skin rashe
Common: alopecia, dermatitis (including eczema), pruritus, acne, dry skin, urticaria, hyperhidrosis
Uncommon: neutrophilic dermatosis, photosensitivity, pigmentation disorder, panniculitis, skin ulcer, bullous conditions, nail disorder, palmar-plantar erythrodysesthesia syndrome, hair disorder
Rare: leukocytoclastic vasculitis, skin fibrosis
Not known: Stevens-Johnson syndromef
Very common: musculoskeletal paing
Common: arthralgia, myalgia, muscular weakness, musculoskeletal stiffness, muscle spasm
Uncommon: rhabdomyolysis, osteonecrosis, muscle inflammation, tendonitis, arthritis
Rare: epiphyses delayed fusionh, growth retardationh
Uncommon: renal impairment (including renal failure), urinary frequency, proteinuria
Not known: nephrotic syndrome
Rare: abortion
Uncommon: gynecomastia, menstrual disorder
Very common: peripheral oedemai, fatigue, pyrexia, face oedemaj
Common: asthenia, pain, chest pain, generalised oedema*k, chills
Uncommon: malaise, other superficial oedemal
Rare: gait disturbance
Common: weight decreased, weight increased
Uncommon: blood creatine phosphokinase increased, gamma-glutamyltransferase increased
Common: contusion
a Includes decreased appetite, early satiety, increased appetite.
b Includes central nervous system haemorrhage, cerebral haematoma, cerebral haemorrhage, extradural haematoma, haemorrhage intracranial, haemorrhagic stroke, subarachnoid haemorrhage, subdural haematoma, and subdural haemorrhage.
c Includes brain natriuretic peptide increased, ventricular dysfunction, left ventricular dysfunction, right ventricular dysfunction, cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased and ventricular failure, left ventricular failure, right ventricular failure, and ventricular hypokinesia.
d Excludes gastrointestinal bleeding and CNS bleeding; these adverse reactions are reported under the gastrointestinal disorders system organ class and the nervous system disorders system organ class, respectively.
e Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalised erythema, genital rash, heat rash, milia, miliaria, pustular psoriaisis, rash, rash erythematous, rash follicular, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, skin exfoliation, skin irritation, toxic skin eruption, urticaria vesiculosa, and vasculitic rash.
f In the post-marketing setting, individual cases of Stevens-Johnson syndrome have been reported. It could not be determined whether these mucocutaneous adverse reactions were directly related to dasatinib or to concomitant medicinal product.
g Musculoskeletal pain reported during or after discontinuing treatment.
h Frequency reported as common in paediatric studies.
i Gravitational oedema, localised oedema, oedema peripheral.
j Conjunctival oedema, eye oedema, eye swelling, eyelid oedema, face oedema, lip oedema, macular oedema, oedema mouth, orbital oedema, periorbital oedema, swelling face.
k Fluid overload, fluid retention, gastrointestinal oedema, generalised oedema, peripheral swelling, oedema, oedema due to cardiac disease, perinephric effusion, post procedural oedema, visceral oedema.
l Genital swelling, incision site oedema, oedema genital, penile oedema, penile swelling, scrotal oedema, skin swelling, testicular swelling, vulvovaginal swelling.
* For additional details, see section "Description of selected adverse reactions"
Treatment with dasatinib is associated with anaemia, neutropaenia and thrombocytopaenia. Their occurrence is earlier and more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML.
Bleeding drug-related adverse reactions, ranging from petechiae and epistaxis to grade 3 or 4 gastrointestinal haemorrhage and CNS bleeding, were reported in patients taking dasatinib.
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”. In the newly diagnosed chronic phase CML study after a minimum of 60 months follow-up, dasatinib-related fluid retention adverse reactions included pleural effusion (28%), superficial oedema (14%), pulmonary hypertension (5%), generalised oedema (4%), and pericardial effusion (4%). Congestive heart failure/cardiac dysfunction and pulmonary oedema were reported in <2% of patients.
The cumulative rate of dasatinib-related pleural effusion (all grades) over time was 10% at 12 months, 14% at 24 months, 19% at 36 months, 24% at 48 months and 28% at 60 months. A total of 46 dasatinib-treated patients had recurrent pleural effusions. Seventeen patients had 2 separate adverse reactions, 6 had 3 adverse reactions, 18 had 4 to 8 adverse reactions and 5 had >8 episodes of pleural effusions.
The median time to first dasatinib-related grade 1 or 2 pleural effusion was 114 weeks (range: 4 to 299 weeks). Less than 10% of patients with pleural effusion had severe (grade 3 or 4) dasatinib-related pleural effusions. The median time to first occurrence of grade ≥3 dasatinib-related pleural effusion was 175 weeks (range: 114 to 274 weeks). The median duration of dasatinib-related pleural effusion (all grades) was 283 days (~40 weeks).
Pleural effusion was usually reversible and managed by interrupting dasatinib treatment and using diuretics or other appropriate supportive care measures. Among dasatinib-treated patients with drug-related pleural effusion (n=73), 45 (62%) had dose interruptions and 30 (41%) had dose reductions. Additionally, 34 (47%) received diuretics, 23 (32%) received corticosteroids, and 20 (27%) received both corticosteroids and diuretics. Nine (12%) patients underwent therapeutic thoracentesis.
Six percent of dasatinib-treated patients discontinued treatment due to drug-related pleural effusion. Pleural effusion did not impair the ability of patients to obtain a response. Among the dasatinib-treated patients with pleural effusion, 96% achieved a cCCyR, 82% achieved a MMR, and 50% achieved a MR4.5 despite dose interruptions or dose adjustment.
PAH (pre-capillary pulmonary arterial hypertension confirmed by right heart catheterization) has been reported in association with dasatinib exposure. In these cases, PAH was reported after initiation of dasatinib therapy, including after more than one year of treatment. Patients with PAH reported during dasatinib treatment were often taking concomitant medicinal products or had co-morbidities in addition to the underlying malignancy. Improvements in haemodynamic and clinical parameters have been observed in patients with PAH following discontinuation of dasatinib.
In the Phase III study in patients with newly diagnosed chronic phase CML, one patient (<1%) of the dasatinib-treated patients had a QTcF >500 msec after a minimum of 12 months follow-up. No additional patients were reported to have QTcF >500 msec after a minimum of 60 months follow-up.
In 5 Phase II clinical studies in patients with resistance or intolerance to prior imatinib therapy, repeated baseline and on-treatment ECGs were obtained at pre-specified time points and read centrally for 865 patients receiving dasatinib 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 with resistance or intolerance to prior imatinib therapy who received dasatinib in clinical studies, 15 (1%) had QTc prolongation reported as an adverse reaction. Twenty-one patients (1%) experienced a QTcF >500 msec .
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.
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.
In the Phase III dose-optimisation study in patients with chronic phase CML with resistance or intolerance to prior imatinib therapy (median duration of treatment of 30 months), the incidence of pleural effusion and congestive heart failure/cardiac dysfunction was lower in patients treated with dasatinib 100 mg once daily than in those treated with dasatinib 70 mg twice daily. Myelosuppression was also reported less frequently in the 100 mg once daily treatment group (see Laboratory test abnormalities below). The median duration of therapy in the 100 mg once daily group was 37 months (range 1-91 months). Cumulative rates of selected adverse reactions that were reported in the 100 mg once daily recommended starting dose are shown in Table 1a.
Table 1a. Selected adverse reactions reported in a phase 3 dose optimisation study (imatinib intolerant or resistant chronic phase CML)a:
| Minimum of 2 years follow up | Minimum of 5 years follow up | Minimum of 7 years follow up | ||||
|---|---|---|---|---|---|---|
| All grades | Grade 3/4 | All grades | Grade 3/4 | All grades | Grade 3/4 | |
| Preferred term | Percent (%) of patients | |||||
| Diarrhoea | 27 | 2 | 28 | 2 | 28 | 2 |
| Fluid retention | 34 | 4 | 42 | 6 | 48 | 7 |
| Superficial oedema | 18 | 0 | 21 | 0 | 22 | 0 |
| Pleural effusion | 18 | 2 | 24 | 4 | 28 | 5 |
| Generalised oedema | 3 | 0 | 4 | 0 | 4 | 0 |
| Pericardial effusion | 2 | 1 | 2 | 1 | 3 | 1 |
| Pulmonary hypertension | 0 | 0 | 0 | 0 | 2 | 1 |
| Haemorrhage | 11 | 1 | 11 | 1 | 12 | 1 |
| Gastrointestinal bleeding | 2 | 1 | 2 | 1 | 2 | 1 |
a Phase 3 dose optimisation study results reported in recommended starting dose of 100 mg once daily (n=165) population
In the Phase III dose-optimisation study in patients with advanced phase CML and Ph+ ALL, the median duration of treatment was 14 months for accelerated phase CML, 3 months for myeloid blast CML, 4 months for lymphoid blast CML and 3 months for Ph+ ALL. Selected adverse reactions that were reported in the recommended starting dose of 140 mg once daily are shown in Table 1b. A 70 mg twice daily regimen was also studied. The 140 mg once daily regimen showed a comparable efficacy profile to the 70 mg twice daily regimen but a more favourable safety profile.
Table 1b. Selected adverse reactions reported in phase III dose-optimisation study: Advanced phase CML and Ph+ ALLa:
| 140 mg once daily n=304 | ||
|---|---|---|
| All grades | Grade 3/4 | |
| Preferred term | Percent (%) of patients | |
| Diarrhoea | 28 | 3 |
| Fluid retention | 33 | 7 |
| Superficial oedema | 15 | <1 |
| Pleural effusion | 20 | 6 |
| Generalised oedema | 2 | 0 |
| Congestive heart failure/cardiac dysfunctionb | 1 | 0 |
| Pericardial effusion | 2 | 1 |
| Pulmonary oedema | 1 | 1 |
| Haemorrhage | 23 | 8 |
| Gastrointestinal bleeding | 8 | 6 |
a Phase 3 dose optimisation study results reported at the recommended starting dose of 140 mg once daily (n=304) population at 2 year final study follow up.
b Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and ventricular failure.
In addition, there were two studies in a total of 161 paediatric patients with Ph+ ALL in which dasatinib was administered in combination with chemotherapy. In the pivotal study, 106 paediatric patients received dasatinib in combination with chemotherapy on a continuous dosing regimen. In a supportive study, of 55 paediatric patients, 35 received dasatinib in combination with chemotherapy on a discontinuous dosing regimen (two weeks on treatment followed by one to two weeks off) and 20 received dasatinib in combination with chemotherapy on a continuous dosing regimen. Among the 126 Ph+ ALL paediatric patients treated with dasatinib on a continuous dosing regimen, the median duration of therapy was 23.6 months (range 1.4 to 33 months).
Of the 126 Ph+ ALL paediatric patients on a continuous dosing regimen, 2 (1.6%) experienced adverse reactions leading to treatment discontinuation. Adverse reactions reported in these two paediatric studies at a frequency of ≥10% in patients on a continuous dosing regimen are shown in Table 2. Of note, pleural effusion was reported in 7 (5.6%) patients in this group, and is therefore not included in the table.
Table 2. Adverse reactions reported in ≥10% of paediatric patients with Ph+ ALL treated with dasatinib on a continuous dosing regimen in combination with chemotherapy (N=126)a:
| Percent (%) of patients | ||
|---|---|---|
| Adverse reaction | All grades | Grade 3/4 |
| Febrile neutropaenia | 27.0 | 26.2 |
| Nausea | 20.6 | 5.6 |
| Vomiting | 20.6 | 4.8 |
| Abdominal pain | 14.3 | 3.2 |
| Diarrhoea | 12.7 | 4.8 |
| Pyrexia | 12.7 | 5.6 |
| Headache | 11.1 | 4.8 |
| Decreased appetite | 10.3 | 4.8 |
| Fatigue | 10.3 | 0 |
a In the pivotal study, among 106 total patients, 24 patients received the powder for oral suspension at least once, 8 of whom received the powder for oral suspension formulation exclusively
In the Phase III newly diagnosed chronic phase CML study, the following grade 3 or 4 laboratory abnormalities were reported after a minimum of 12 months follow-up in patients taking dasatinib: neutropaenia (21%), thrombocytopaenia (19%), and anaemia (10%). After a minimum of 60 months follow-up, the cumulative rates of neutropaenia, thrombocytopaenia, and anaemia were 29%, 22% and 13%, respectively.
In dasatinib-treated patients with newly diagnosed chronic phase CML who experienced grade 3 or 4 myelosuppression, recovery generally occurred following brief dose interruptions and/or reductions and permanent discontinuation of treatment occurred in 1.6% of patients after a minimum of 12 months follow-up. After a minimum of 60 months follow-up the cumulative rate of permanent discontinuation due to grade 3 or 4 myelosuppression was 2.3%.
In patients with CML with resistance or intolerance to prior imatinib therapy, cytopaenias (thrombocytopaenia, neutropaenia, and anaemia) were a consistent finding. However, the occurrence of cytopaenias 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 ¾ haematological laboratory abnormalities in clinical studies in patients with resistance or intolerance to prior imatinib therapya:
| Chronic phase (n=165)b | Accelerated phase (n=157)c | Myeloid blast phase (n=74)c | Lymphoid blast phase and Ph+ ALL (n=168)c | |
|---|---|---|---|---|
| Percent (%) of patients | ||||
| Haematology parameters | ||||
| Neutropaenia | 36 | 58 | 77 | 76 |
| Thrombocytopaenia | 23 | 63 | 78 | 74 |
| Anaemia | 13 | 47 | 74 | 44 |
a Phase 3 dose optimisation study results reported at 2 year study follow up.
b CA180-034 study results in recommended starting dose of 100 mg once daily.
c CA180-035 study results in recommended starting dose of 140 mg once daily.
CTC grades: neutropaenia (Grade 3 ≥0.5 – <1.0 × 109/l, Grade 4 <0.5 × 109/l); thrombocytopaenia (Grade 3 ≥25 – <50 × 109/l, Grade 4 <25 × 109/l); anaemia (haemoglobin Grade 3 ≥65 – <80 g/l, Grade 4 <65 g/l).
Cumulative grade 3 or 4 cytopaenias among patients treated with 100 mg once daily were similar at 2 and 5 years including: neutropaenia (35% vs. 36%), thrombocytopaenia (23% vs. 24%) and anaemia (13% vs. 13%). 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.
In the newly diagnosed chronic phase CML study, grade 3 or 4 hypophosphataemia was reported in 4% of dasatinib-treated patients, and grade 3 or 4 elevations of transaminases, creatinine, and bilirubin were reported in ≤1% of patients after a minimum of 12 months follow-up. After a minimum of 60 months follow-up the cumulative rate of grade 3 or 4 hypophosphataemia was 7%, grade 3 or 4 elevations of creatinine and bilirubin was 1% and grade 3 or 4 elevations of transaminases remained 1%. There were no discontinuations of dasatinib therapy due to these biochemical laboratory parameters.
Grade 3 or 4 elevations of transaminases or bilirubin were reported in 1% of patients with chronic phase CML (resistant or intolerant to imatinib), 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 study in chronic phase CML, grade 3 or 4 elevations of transaminases or bilirubin were reported in ≤1% of patients with similar low incidence in the four treatment groups. In the Phase III dose-optimisation study in advanced phase CML and Ph+ALL, grade 3 or 4 elevations of transaminases or bilirubin were reported in 1% to 5% of patients across treatment groups.
Approximately 5% of the dasatinib-treated patients who had normal baseline levels experienced grade 3 or 4 transient hypocalcaemia 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 hypocalcaemia often had recovery with oral calcium supplementation. Grade 3 or 4 hypocalcaemia, hypokalaemia, and hypophosphataemia 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.
The safety profile of dasatinib administered as single-agent therapy in paediatric patients with Ph+ CML-CP was comparable to the safety profile in adults. The safety profile of dasatinib administered in combination with chemotherapy in paediatric patients with Ph+ ALL was consistent with the known safety profile of dasatinib in adults and the expected effects of chemotherapy, with the exception of a lower pleural effusion rate in paediatric patients as compared to adults.
In the paediatric CML studies, the rates of laboratory abnormalities were consistent with the known profile for laboratory parameters in adults.
In the paediatric ALL studies, the rates of laboratory abnormalities were consistent with the known profile for laboratory parameters in adults, within the context of an acute leukaemia patient receiving a background chemotherapy regimen.
While the safety profile of dasatinib in elderly was similar to that in the younger population, patients aged 65 years and older are more likely to experience the commonly reported adverse reactions such as fatigue, pleural effusion, dyspnoea, cough, lower gastrointestinal haemorrhage, and appetite disturbance and more likely to experience less frequently reported adverse reactions such as abdominal distention, dizziness, pericardial effusion, congestive heart failure, and weight decrease and should be monitored closely.
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