Dasatinib Taro

/ Taro International Ltd

The recommended starting dose for chronic phase CML is 100 mg once daily.
The recommended starting dose for accelerated, myeloid or lymphoid blast phase (advanced phase) CML or Ph+ ALL is 140 mg once daily.
Treatment duration:
In clinical studies, treatment with dasatinib was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment on long-term disease outcome after the achievement of a cytogenetic or molecular response [including complete cytogenetic response (CCyR), major molecular response (MMR) and MR4.5] has not been investigated.
Dose increase or reduction is recommended based on patient response and tolerability.
Dose escalation:
In clinical studies in 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 adverse reactions:
Myelosuppression: 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.
Non-haematologic adverse reactions: If a moderate, grade 2, non-haematologic adverse reaction develops with dasatinib, treatment should be interrupted until the adverse reaction has resolved or returned to baseline. The same dose should be resumed if this is the first occurrence and the dose should be reduced if this is a recurrent adverse reaction. If a severe grade 3 or 4, non-haematological adverse reaction develops with dasatinib, treatment must be withheld until the adverse reaction has resolved. Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the initial severity of the adverse reaction. For patients with chronic phase CML who received 100 mg once daily, dose reduction to 80 mg once daily with further reduction from 80 mg once daily to 50 mg once daily, if needed, is recommended. For patients with advanced phase CML or Ph+ ALL who received 140 mg once daily, dose reduction to 100 mg once daily with further reduction from 100 mg once daily to 50 mg once daily, if needed, is recommended.
Pleural effusion: 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. Following resolution of the first episode, reintroduction of dasatinib at the same 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.
Paediatric population:
The safety and efficacy of dasatinib in children and adolescents below 18 years of age have not yet been established. No data are available.
Elderly:
No clinically relevant age-related pharmacokinetic differences have been observed in these patients. No specific dose recommendation is necessary in elderly.
Hepatic impairment:
Patients with mild, moderate or severe hepatic impairment may receive the recommended starting dose. However, Dasatinib Taro should be used with caution in patients with hepatic impairment.
Renal impairment:
No clinical studies were conducted with dasatinib in patients with decreased renal function. 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.

Treatment of adult patients with:
• Newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukaemia (CML) in the chronic phase.
• Chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including imatinib mesilate.
• Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy.

Hypersensitivity to the active substance or to any of the inactive ingredients.

Myelosuppression: 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. In patients with advanced phase CML or Ph+ ALL, complete blood counts should be performed weekly for the first 2 months, and then monthly thereafter, or as clinically indicated. In patients with chronic phase CML, complete blood counts should be performed every 2 weeks for 12 weeks, then every 3 months thereafter or as clinically indicated. Myelosuppression is generally reversible and usually managed by withholding dasatinib temporarily or by dose reduction.
Bleeding: 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. 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.
Severe Dermatologic Reactions: Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported in patients treated with this drug. Discontinue permanently in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can be identified.
Lactose: This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Very common: Infection (including bacterial, viral, fungal, non-specified), myelosuppression (including anaemia, neutropaenia, thrombocytopaenia), headache, haemorrhage, pleural effusion, dyspnoea, diarrhoea, vomiting, nausea, abdominal pain, skin rash, musculoskeletal pain, peripheral oedemag, fatigue, pyrexia, face oedema.
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), febrile neutropaenia, appetite disturbances, hyperuricaemia, depression, insomnia, neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence, visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye, tinnitus, congestive heart failure/cardiac dysfunction, pericardial effusion, arrhythmia (including tachycardia), palpitations, hypertension, flushing, pulmonary oedema, pulmonary hypertension, lung infiltration, pneumonitis, cough, gastrointestinal bleeding, colitis (including neutropaenic colitis), gastritis, mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, oral soft tissue disorder, alopecia, dermatitis (including eczema), pruritus, acne, dry skin, urticaria, hyperhidrosis, arthralgia, myalgia, muscular weakness, musculoskeletal stiffness, muscle spasm, asthenia, pain, chest pain, generalised oedema, chills, weight decreased, weight increased, contusion.

Active substances that may increase dasatinib plasma concentrations:
In vitro studies indicate that dasatinib is a CYP3A4 substrate. Concomitant use with medicinal products or substances which potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may increase exposure to dasatinib. Therefore, in patients receiving dasatinib, systemic administration of a potent CYP3A4 inhibitor is not recommended.
Active substances that may decrease dasatinib plasma concentrations:
Medicinal products that induce CYP3A4 activity (e.g. rifampicin, dexamethasone, phenytoin, carbamazepine, phenobarbital or herbal preparations containing Hypericum perforatum, also known as St. John’s Wort) may increase metabolism and decrease dasatinib plasma concentrations. Therefore, concomitant use of potent CYP3A4 inducers 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.
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. The use of antacids should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving dasatinib therapy.
 Antacids:
Antacids may be administered up to 2 hours prior to or 2 hours following dasatinib.
Active substances that may have their plasma concentrations altered by dasatinib:
Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4 substrate. 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.

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.
Lactation:
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.

Experience with overdose of dasatinib in clinical studies is limited to isolated cases. The highest overdose of 280 mg per day for one week was reported in two patients and both developed a significant decrease in platelet counts. Since dasatinib is associated with grade 3 or 4 myelosuppression, patients who ingest more than the recommended dose should be closely monitored for myelosuppression and given appropriate supportive treatment.