Dasatinib

Dasatinib is an oral multi-targeted kinase inhibitor. It inhibits the BCR-ABL kinase with sub-nanomolar potency (0.6–0.8 nM), together with SRC family kinases and other oncogenic kinases, including c-KIT, the ephrin (EPH) receptor kinases and the PDGFβ receptor. It binds both the inactive and the active conformation of the BCR-ABL enzyme.

Mechanism of Action

• BCR-ABL: in chronic myeloid leukaemia the BCR-ABL tyrosine kinase is deregulated and drives the growth, proliferation and survival of leukaemic blood cells. Dasatinib blocks it, and in leukaemia cell lines that overexpress BCR-ABL it inhibits cell growth. DrugBank notes a higher binding affinity than imatinib.
• Imatinib resistance: in laboratory studies dasatinib was active in leukaemia cell lines that were sensitive or resistant to imatinib. It overcame resistance caused by BCR-ABL overexpression, BCR-ABL kinase domain mutations, activation of alternative pathways involving the SRC family kinases (LYN, HCK) and overexpression of the multidrug resistance gene.
• SRC family and other kinases: dasatinib inhibits SRC family kinases at sub-nanomolar concentrations, which adds to its activity beyond BCR-ABL.
• Animal models: in mouse models of CML, dasatinib prevented progression from the chronic to the blast phase and prolonged the survival of mice carrying patient-derived CML cells at various sites, including the central nervous system.
• Metabolites: five metabolites are pharmacologically active (M4, M5, M6, M20, M24). M4 is as potent as dasatinib but makes up only about 5% of the AUC, and M5 and M6 are more than 10 times less active. The metabolites are unlikely to play a major role in the observed pharmacology.
• QT interval: laboratory data suggest dasatinib could prolong ventricular repolarisation; clinical QTc prolongation was uncommon (see Special Instructions).

Pharmacokinetics

• Absorption: rapid, with peak concentrations 0.5–3 hours after a dose. Exposure rises about in proportion to dose between 25 and 120 mg twice daily. At 100 mg once daily, DrugBank gives a peak concentration of 82.2 ng/mL and an AUC of 397 ng·h/mL. A high-fat meal 30 minutes before a 100 mg dose raised AUC by 14% and a low-fat meal by 21%; these changes are not clinically relevant. Variability in exposure is higher when fasting (47% CV) than after a light-fat meal (39%) or a high-fat meal (32%).
• Distribution: apparent volume of distribution 2,505 L, indicating wide distribution outside the blood vessels; about 96% bound to plasma proteins in vitro.
• Metabolism: extensive, mainly by CYP3A4 (FMO3 and UGT enzymes also contribute, per DrugBank). Unchanged dasatinib made up 29% of circulating radioactivity after a 100 mg dose.
• Elimination: mean terminal half-life about 3–5 hours (the SmPC also quotes about 5–6 hours in patients), with a mean apparent oral clearance of 363.8 L/h. Elimination is mainly faecal: within 10 days about 85% of a dose was recovered in faeces and 4% in urine (DrugBank). Renal clearance of dasatinib and its metabolites is under 4%.
• Special populations: no clinically relevant age-related differences. A single-dose study showed that patients with mild, moderate or severe hepatic impairment can receive the usual starting dose, with caution. A fall in clearance is not expected in renal impairment.

Sprycel film-coated tablets are indicated for:

• Adults, newly diagnosed CML: newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myelogenous leukaemia (CML) in the chronic phase.
• Adults, resistant or intolerant CML: chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including imatinib.
• Adults, Ph+ ALL: Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy.
• Children, CML: newly diagnosed Ph+ CML in chronic phase (Ph+ CML-CP), or Ph+ CML-CP resistant or intolerant to prior therapy including imatinib.
• Children, ALL: newly diagnosed Ph+ ALL in combination with chemotherapy.

Sprycel 10 mg/mL powder for oral suspension is indicated for the two paediatric indications above (Ph+ CML-CP, and newly diagnosed Ph+ ALL with chemotherapy). It is also used in adults with Ph+ CML-CP who cannot swallow tablets. The dose of the powder for oral suspension in adults with accelerated, myeloid or lymphoid blast phase CML or Ph+ ALL has not been determined.

• Hypersensitivity to dasatinib or to any of the excipients (tablets and powder for oral suspension).

The data reflect single-agent dasatinib at all doses tested in 2,900 patients: 324 adults with newly diagnosed chronic phase CML, 2,388 adults with imatinib-resistant or -intolerant chronic or advanced phase CML or Ph+ ALL, and 188 children. In the 2,712 adults the median treatment duration was 19.2 months. Most patients had a reaction at some point, and 19% (520 of 2,712) stopped treatment because of one. The profile in children with Ph+ CML-CP was similar to adults, except that pericardial effusion, pleural effusion, pulmonary oedema and pulmonary hypertension were not reported in them.

Very common (≥1/10): infection (bacterial, viral, fungal, non-specific); myelosuppression (anaemia, neutropenia, thrombocytopenia); headache; haemorrhage (not counting gastrointestinal and central nervous system bleeding, which are listed separately); pleural effusion; dyspnoea; diarrhoea, vomiting, nausea, abdominal pain; skin rash; musculoskeletal pain; peripheral oedema, fatigue, pyrexia, facial oedema.

Common (≥1/100 to <1/10): pneumonia, upper respiratory tract infection or inflammation, herpes virus infection (including cytomegalovirus), enterocolitis, sepsis (including uncommon fatal cases); febrile neutropenia; appetite disturbances, hyperuricaemia; depression, insomnia; neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence; visual disturbances (distorted or blurred vision, reduced visual acuity), dry eye; tinnitus; congestive heart failure or cardiac failure, pericardial effusion, arrhythmia (including tachycardia), palpitations; hypertension, flushing; pulmonary oedema, pulmonary hypertension, lung infiltration, pneumonitis, cough; gastrointestinal haemorrhage, colitis (including neutropenic colitis), gastritis, mucosal inflammation (mucositis, stomatitis), dyspepsia, abdominal distension, constipation, oral soft tissue disorder; alopecia, dermatitis (including eczema), pruritus, acne, dry skin, urticaria, hyperhidrosis; arthralgia, myalgia, muscle weakness, musculoskeletal stiffness, muscle spasm; asthenia, pain, chest pain, generalised oedema, chills; weight loss, weight gain; contusion.

Uncommon (≥1/1,000 to <1/100): lymphadenopathy, lymphopenia; hypersensitivity (including erythema nodosum); hypothyroidism; tumour lysis syndrome, dehydration, hypoalbuminaemia, hypercholesterolaemia; anxiety, confusional state, affect lability, decreased libido; central nervous system bleeding, syncope, tremor, amnesia, balance disorder; visual impairment, conjunctivitis, photophobia, increased lacrimation; hearing loss, vertigo; myocardial infarction (including fatal), QT prolongation on ECG, pericarditis, ventricular arrhythmia (including ventricular tachycardia), angina pectoris, cardiomegaly, abnormal T wave, raised troponin; hypotension, thrombophlebitis, thrombosis; pulmonary arterial hypertension, bronchospasm, asthma, chylothorax; pancreatitis (including acute), upper gastrointestinal ulcer, oesophagitis, ascites, anal fissure, dysphagia, gastro-oesophageal reflux disease; hepatitis, cholecystitis, cholestasis; neutrophilic dermatosis, photosensitivity, pigmentation disorder, panniculitis, skin ulcer, bullous conditions, nail disorder, palmar-plantar erythrodysaesthesia syndrome, hair disorder; rhabdomyolysis, osteonecrosis, muscle inflammation, tendinitis, arthritis; renal impairment (including renal failure), urinary frequency, proteinuria; gynaecomastia, menstrual disorder; malaise, other superficial oedema; raised creatine phosphokinase and gamma-glutamyltransferase.

Rare (≥1/10,000 to <1/1,000): pure red cell aplasia; anaphylactic shock; hyperthyroidism, thyroiditis; diabetes mellitus; stroke, transient ischaemic attack, convulsions, optic neuritis, facial (VII) nerve palsy, dementia, ataxia; cor pulmonale, myocarditis, acute coronary syndrome, cardiac arrest, PR interval prolongation, coronary artery disease, pleuropericarditis; deep vein thrombosis, embolism, livedo reticularis; pulmonary embolism, acute respiratory distress syndrome; protein-losing gastroenteropathy, ileus, anal fistula; leukocytoclastic vasculitis, skin fibrosis; delayed epiphyseal fusion, growth retardation; miscarriage; gait disturbance.

Not known: hepatitis B reactivation; atrial fibrillation or flutter; thrombotic microangiopathy; interstitial lung disease; fatal gastrointestinal haemorrhage; Stevens-Johnson syndrome (single cases after marketing, for which a direct link with dasatinib rather than co-medication could not be established); nephrotic syndrome.

Fluid retention is a characteristic reaction. In a trial in newly diagnosed chronic phase CML with at least 60 months of follow-up, dasatinib-related fluid retention included pleural effusion (28%), superficial oedema (14%), pulmonary hypertension (5%), generalised oedema (4%) and pericardial effusion (4%); congestive heart failure and pulmonary oedema occurred in under 2%. The cumulative rate of pleural effusion was 10% at 12 months, 14% at 24 months, 19% at 36 months, 24% at 48 months and 28% at 60 months. Effusions were generally reversible and were managed by interrupting dasatinib and using diuretics or other supportive care, and 6% of patients stopped treatment because of pleural effusion.

Blood counts: the frequency of grade 3 or 4 neutropenia, thrombocytopenia and anaemia rises with the phase of disease. In imatinib-resistant or -intolerant patients it was 36%, 23% and 13% in chronic phase CML and 76%, 74% and 44% in lymphoid blast CML and Ph+ ALL. In newly diagnosed chronic phase CML the cumulative rates after at least 60 months were 29%, 22% and 13%. Recovery usually followed a short interruption and/or dose reduction. Grade 3 or 4 hypophosphataemia occurred in 4% after 12 months and 7% cumulatively after 60 months, and about 5% of patients had transient grade 3 or 4 hypocalcaemia.

Children with Ph+ ALL given dasatinib continuously with chemotherapy (126 patients; 2 stopped because of reactions) most often had febrile neutropenia (27.0%), nausea (20.6%), vomiting (20.6%), abdominal pain (14.3%), diarrhoea (12.7%), pyrexia (12.7%), headache (11.1%), decreased appetite (10.3%) and fatigue (10.3%); pleural effusion occurred in 5.6%.

Dasatinib is a substrate and an inhibitor of CYP3A4, so it interacts with medicines that are metabolised by or change the activity of this enzyme. It is about 96% bound to plasma proteins; no studies have tested displacement of other protein-bound medicines, and the clinical relevance is unknown.

• Potent CYP3A4 inhibitors (ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice): raise dasatinib exposure. Systemic potent CYP3A4 inhibitors are not recommended; the SmPC sets out the approach if one cannot be avoided.
• CYP3A4 inducers (rifampicin, dexamethasone, phenytoin, carbamazepine, phenobarbital, St John’s wort): lower exposure and may lead to treatment failure. Rifampicin 600 mg for 8 evenings cut dasatinib AUC by 82%. Alternatives with less enzyme induction should be chosen. Dexamethasone, a weak inducer, is allowed: its effect is predicted to lower AUC by about 25%, which is unlikely to be meaningful.
• Acid-reducing medicines: long-term gastric acid suppression with H2 antagonists (such as famotidine) or proton pump inhibitors (such as omeprazole) may reduce dasatinib exposure, so they are not recommended. Aluminium hydroxide/magnesium hydroxide antacids may also reduce exposure and are taken up to 2 hours before or 2 hours after dasatinib.
• CYP3A4 substrates with a narrow therapeutic index: dasatinib may raise their exposure, so caution is needed with astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil and ergot alkaloids (ergotamine, dihydroergotamine).
• QT-prolonging medicines: caution with anti-arrhythmic medicines and other medicines that prolong the QT interval, and with cumulative high-dose anthracycline therapy.
• Antiplatelet medicines and anticoagulants: caution, because of the bleeding risk.
• Food: avoid grapefruit and grapefruit juice, and St John’s wort. Dasatinib can be taken with or without a meal (a high-fat meal raised AUC by 14%, which is not clinically relevant), at a consistent time of day.

Therapy must be started by a physician experienced in the diagnosis and treatment of leukaemia. Dasatinib is taken by mouth, with or without a meal, consistently either in the morning or in the evening, and not with grapefruit or grapefruit juice. The film-coated tablets are swallowed whole. They must not be crushed, cut or chewed, to keep dosing consistent and to minimise skin exposure, and they should not be dispersed, because exposure is lower than with a whole tablet. The powder for oral suspension is available for children, and for adults with chronic phase CML, who cannot swallow tablets.

Recommended Dose in Adults

• Chronic phase CML: 100 mg once daily.
• Accelerated, myeloid or lymphoid blast phase (advanced phase) CML, or Ph+ ALL: 140 mg once daily.
• Duration: in clinical studies, treatment continued until disease progression or until the patient no longer tolerated it. The effect of stopping treatment on long-term outcome after a cytogenetic or molecular response (complete cytogenetic response, major molecular response, MR4.5) has not been investigated.

Recommended Dose in Children and Adolescents (Ph+ CML-CP and Ph+ ALL)

Dasatinib is taken once daily, with the dose based on body weight. It is recalculated every 3 months for changes in weight, or more often if needed, and can be raised or lowered according to the patient’s response and tolerability. There is no experience in children under 1 year of age. The tablets and the powder for oral suspension are not bioequivalent; patients may switch between them, provided the dosing for the dosage form is followed.

• Film-coated tablets: 10 to under 20 kg, 40 mg; 20 to under 30 kg, 60 mg; 30 to under 45 kg, 70 mg; at least 45 kg, 100 mg. Tablets are not recommended under 10 kg.
• Powder for oral suspension (10 mg/mL after constitution): 5 to under 10 kg, 4 mL (40 mg); 10 to under 20 kg, 6 mL (60 mg); 20 to under 30 kg, 9 mL (90 mg); 30 to under 45 kg, 10.5 mL (105 mg); at least 45 kg, 12 mL (120 mg). The suspension is used in patients under 10 kg and in adults with chronic phase CML who cannot swallow tablets.
• The powder is constituted before use (see the SmPC, section 6.6, and the instructions for use). The constituted suspension may be mixed further with milk, yogurt, apple juice or applesauce.

Dose Adjustments

• Myelosuppression is generally reversible and is usually managed by withholding dasatinib for a time or by reducing the dose. Fluid retention is managed with supportive care, including diuretics and short courses of corticosteroids.
• If pulmonary arterial hypertension is suspected, the dose is reduced or treatment interrupted during the work-up, and dasatinib is stopped permanently if it is confirmed. After cardiac symptoms resolve, dasatinib can be resumed at the original dose for reactions of grade 2 or lower and at a reduced dose for grade 3 or higher.
• The SmPC (section 4.2) gives the dose levels and rules for neutropenia, thrombocytopenia, non-haematological reactions and strong CYP3A4 modulators.

Special Populations

• Elderly: no specific dose recommendation. Patients aged 65 and older are more likely to have fatigue, pleural effusion, dyspnoea, cough, lower gastrointestinal bleeding and appetite disturbances, and less often abdominal distension, dizziness, pericardial effusion, congestive heart failure and weight loss, so they are monitored carefully.
• Hepatic impairment: patients with mild, moderate or severe impairment may receive the recommended starting dose, but dasatinib is used with caution.
• Renal impairment: no clinical studies were done. Because renal clearance of dasatinib and its metabolites is under 4%, a fall in total clearance is not expected.
• Children: dosed by weight as above, with monitoring of bone growth and development.

Myelosuppression

Dasatinib causes anaemia, neutropenia and thrombocytopenia, earlier and more often in advanced phase CML or Ph+ ALL than in chronic phase CML. In adults with advanced phase CML or Ph+ ALL on dasatinib alone, complete blood counts are done weekly for the first 2 months and monthly after that, or as indicated. In adults and children with chronic phase CML they are done every 2 weeks for 12 weeks, then every 3 months or as indicated. In children with Ph+ ALL on dasatinib with chemotherapy, counts are done before each chemotherapy block and as indicated, and every 2 days during consolidation blocks until recovery.

Bleeding

In chronic phase CML (548 patients), 5 patients (1%) had grade 3 or 4 haemorrhage. In advanced phase CML (304 patients at the recommended dose), severe central nervous system haemorrhage occurred in 1% (one fatal case, with grade 4 thrombocytopenia), grade 3 or 4 gastrointestinal haemorrhage in 6% (usually needing treatment interruption and transfusion), and other grade 3 or 4 haemorrhage in 2%. Most bleeding was linked to grade 3 or 4 thrombocytopenia. Platelet tests suggest dasatinib reversibly affects platelet activation. Caution is needed with medicines that inhibit platelet function and with anticoagulants.

Fluid Retention and Pleural Effusion

Grade 3 or 4 fluid retention was reported in 5% of newly diagnosed chronic phase patients on dasatinib after at least 60 months (13 patients) and 1% on imatinib (2 patients). Severe fluid retention occurred in 6% of chronic phase CML patients at the recommended dose (32 of 548). In advanced phase CML or Ph+ ALL (304 patients), grade 3 or 4 fluid retention occurred in 8%, with pleural effusion in 7%, pericardial effusion in 1%, and pulmonary oedema and pulmonary hypertension in 1% each. Patients with symptoms of pleural effusion, such as dyspnoea or dry cough, have a chest X-ray. Grade 3 or 4 effusion may need thoracocentesis and oxygen. Chylothorax has been reported in patients with pleural effusion. Patients aged 65 and older are more likely to have pleural effusion, dyspnoea, cough, pericardial effusion and congestive heart failure and are monitored closely.

Pulmonary Arterial Hypertension

Pre-capillary pulmonary arterial hypertension (PAH) confirmed by right heart catheterisation has been reported, including after more than a year of treatment. Patients are checked for cardiopulmonary disease before starting. An echocardiogram is done at the start in every patient with symptoms of heart disease and is considered in those with cardiac or pulmonary risk factors. Patients who develop dyspnoea and fatigue are assessed for common causes (pleural effusion, pulmonary oedema, anaemia, lung infiltration), and the dose is reduced or interrupted during this work-up. If no explanation is found, or there is no improvement, PAH is considered. If PAH is confirmed, dasatinib is stopped permanently. Haemodynamic and clinical improvement has been seen after stopping.

QT Prolongation and Cardiac Reactions

• QT interval: in newly diagnosed chronic phase CML (at least 60 months), 1 patient (under 1%) in each of the dasatinib and imatinib groups had QTc prolongation as a reaction, and the median change in QTcF was 3.0 msec on dasatinib against 8.2 msec on imatinib. Among 2,182 patients with imatinib resistance or intolerance, 15 (1%) had QTc prolongation as a reaction and 21 (1%) had a QTcF above 500 msec. Dasatinib is used with caution in patients who have or may develop QTc prolongation: low potassium or magnesium (corrected before starting), congenital long QT syndrome, anti-arrhythmic or other QT-prolonging medicines, and cumulative high-dose anthracycline therapy.
• Cardiac reactions: congestive heart failure or cardiac dysfunction, pericardial effusion, arrhythmias, palpitations, QT prolongation and myocardial infarction (including fatal) were reported, more often in patients with risk factors (hypertension, hyperlipidaemia, diabetes) or a history of heart disease (previous percutaneous coronary intervention, coronary artery disease). These patients are monitored for chest pain, shortness of breath and sweating. If such signs develop, dasatinib is interrupted and alternative CML treatment considered. Patients with uncontrolled or significant cardiovascular disease were not included in the studies.

Thrombotic Microangiopathy

BCR-ABL tyrosine kinase inhibitors have been linked to thrombotic microangiopathy, including individual cases with Sprycel. If laboratory or clinical findings occur, dasatinib is stopped and a full evaluation, including ADAMTS13 activity and anti-ADAMTS13 antibody, is done. If the antibody is raised together with low ADAMTS13 activity, dasatinib is not restarted.

Hepatitis B Reactivation

Hepatitis B has reactivated in chronic carriers after BCR-ABL tyrosine kinase inhibitors, in some cases leading to acute liver failure, fulminant hepatitis, liver transplantation or death. Patients are tested for HBV infection before starting. Liver and hepatitis B specialists are consulted for patients with positive serology (including active disease) and for those who test positive during treatment. Carriers who need dasatinib are monitored closely for signs of active HBV infection throughout therapy and for several months afterwards.

Growth and Development in Children

In paediatric trials in Ph+ CML-CP (imatinib-resistant or intolerant, and newly diagnosed) after at least 2 years, treatment-related bone growth and development events were reported in 6 patients (4.6%), one severe (grade 3 growth retardation). They included delayed epiphyseal fusion, osteopenia, growth retardation and gynaecomastia. In children with newly diagnosed Ph+ ALL given dasatinib with chemotherapy for up to 2 years, one patient (0.6%) had grade 1 osteopenia. A downward trend in expected height has been seen, to the same degree as with chemotherapy alone and without an effect on expected weight or body mass index. Bone growth and development are monitored in children.

Pregnancy, Breastfeeding and Fertility

• Contraception: sexually active men and women of childbearing potential should use effective contraception during treatment.
• Pregnancy: from human experience, dasatinib is suspected to cause congenital malformations, including neural tube defects, and harmful pharmacological effects on the foetus. Animal studies showed reproductive toxicity. It should not be used in pregnancy unless the woman’s clinical condition requires it, and then she is told of the potential risk to the foetus.
• Breastfeeding: excretion into breast milk is likely and a risk to the suckling child cannot be excluded, so breastfeeding should be stopped during treatment.
• Fertility: fertility of male and female rats was not affected. Doctors should counsel male patients of appropriate age about possible effects on fertility, which may include consideration of semen deposition.

Excipients

• Tablets: they contain lactose monohydrate (27 to 189 mg, depending on strength). Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them.
• Powder for oral suspension: each mL contains about 291 mg sucrose, 2.1 mg sodium, 0.25 mg sodium benzoate, 0.25 mg benzoic acid, 0.017 mg benzyl alcohol and under 10 ppm sulphur dioxide (E220). Precautions linked to these excipients are in the powder’s own SmPC.

Effect on Driving

Dasatinib has a minor influence on the ability to drive and use machines. Patients may have dizziness or blurred vision, so caution is advised when driving or operating machines.

Sprycel tablets need no special storage conditions. They are supplied in aluminium blisters or in HDPE bottles with a child-resistant polypropylene closure and a silica gel desiccant (pack types vary by strength).

Sprycel powder for oral suspension is stored below 25 °C before constitution. Once constituted, the suspension is stable for 60 days in a refrigerator (2–8 °C) and must not be frozen. Constituted suspension mixed with milk, yogurt, apple juice or applesauce may be kept at or below 25 °C for up to 1 hour. No cold chain is needed for the unopened products.

Tablets: 3 years. Powder for oral suspension: 3 years for the unopened bottle; after constitution, 60 days in a refrigerator (2–8 °C). A mixture with milk, yogurt, apple juice or applesauce may be kept at or below 25 °C for up to 1 hour.

Prescription only (Rx), under restricted medical prescription (Annex II B). Therapy is started by a physician experienced in the diagnosis and treatment of leukaemia. Sprycel tablets and powder for oral suspension are taken at home, so they are supplied to the patient or to the treating clinic on prescription.