DASATRUE Tablets (Dasatinib 50/70 mg)

Table of Content

Chronic myeloid leukemia (CML) accounts for 20% of all adult leukemias and is the most common adult leukemia in India.

Tyrosine kinase inhibitors (TKIs) are the cornerstone drugs for management of CML, with imatinib (first generation TKI) being commonly used as first-line treatment. Despite the impressive results observed with imatinib, primary and secondary resistances to imatinib occur. Resistance to imatinib led to the development of novel TKIs such as dasatinib.

Dasatinib, a second generation TKI is a smaller molecule than imatinib and it establishes less interactions with its targets: nuclear magnetic resonance studies have evidenced that dasatinib binds the target receptor in CML (BCR-ABL) very versatilely, in both active and inactive conformations. Compared to imatinib, dasatinib enables patients with CML to achieve faster and deeper treatment responses.

DASATRUE Tablets are available in strengths of 50mg and 70mg.

DASATRUE is indicated for the treatment of

  • Adults with chronic, accelerated or myeloid or lymphoid blast phase CML.
  • Newly diagnosed adults with CML in chronic phase.
  • Pediatric patients with Philadelphia chromosome positive CML (Ph+ CML) in chronic phase.

Not be sold by retail without the prescription of a Registered Medical Practitioner only

1. Generic Name

Dasatinib Tablets 50/70 mg

2. Qualitative and Quantitative Composition

50 mg

70 mg

Each film-coated tablet contains:

Dasatinib 

(As monohydrate) 50 mg

Excipients ……. q.s.

Colours: Titanium Dioxide IP.

Each film-coated tablet contains:

Dasatinib 

(As monohydrate) 70 mg

Excipients …. q.s.

Colours: Titanium Dioxide IP.

The excipients used are Microcrystalline Cellulose, Hydroxypropyl cellulose, Isopropyl alcohol, Croscarmellose Sodium, Magnesium stearate, Opadry white.

3. Dosage Form and Strength

Oral (Film-coated tablets) and 50/70 mg

4. Clinical Particulars

4.1 Therapeutic Indication

DASATRUE is indicated for the treatment of

  • Adults with chronic, accelerated or myeloid or lymphoid blast phase chronic myeloid leukaemia (CML).
  • Newly diagnosed adults with CML in chronic phase.
  • Paediatric patients with Philadelphia chromosome positive CML (Ph+ CML) in chronic phase.

4.2 Posology and Method of Administration

DASATRUE is for oral use only. DASATRUE tablets should not be crushed, cut, or chewed; they should be swallowed whole. DASATRUE can be taken with or without a meal, either in the morning or in the evening.

Adult Patients

The recommended starting dose of DASATRUE for chronic phase CML is 100 mg administered orally once daily. The recommended starting dose of DASATRUE for accelerated, myeloid or lymphoid blast phase (advanced phase) CML is 140 mg administered orally once daily.

Paediatric Population (Ph+ CML-CP)

The recommended starting dose for children and adolescents is based on body weight (see Table 1). The dose should be recalculated every 3 months based on changes in body weight, or more often if necessary. Dose increase or reduction is recommended based on individual patient response and tolerability. There is no experience with DASATRUE treatment in children under 1 year of age.

Table 1. Dosage of DASATRUE for paediatric patients with Ph+ CML-CP

Body weight (kg)

Daily dose(mg)

10 to less than 20 kg

40mg

20 to less than 30 kg

60mg

30 to less than 45 kg

70mg

at least 45 kg

100mg

a: Tablet dosing is not recommended for patients weighing less than 10 kg.

Treatment Duration

In clinical studies, treatment with dasatinib in adults with Ph+ CML-CP, accelerated, myeloid or lymphoid blast phase (advanced phase) CML,  and paediatric patients with Ph+ CML-CP 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 has not been investigated.

Dose Escalation

In clinical studies in adult CML patients, dose escalation to 140 mg once daily (chronic phase CML) or 180 mg once daily (advanced phase CML) was allowed in patients who did not achieve a haematologic or cytogenetic response at the recommended starting dose. The following dose escalations shown in Table 2 are recommended in paediatric patients with Ph+ CML-CP who do not achieve a haematologic, cytogenetic and molecular response at the recommended time points, per current treatment guidelines, and who tolerate the treatment.

Table 2: Dose escalation for paediatric patients with Ph+ CML-CP
 

Dose (maximum dose per day)

 

Starting dose

Escalation

Tablets

40 mg

60 mg

70 mg

100 mg

50 mg

70 mg

90 mg

120 mg

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.

Guidelines for dose modifications in adults are summarised in Table 3 and in paediatric patients with Ph+ CML-CP in Table 4.

Table 3: Dose Adjustments for Neutropaenia and Thrombocytopaenia in Adults

Adults with chronic phase CML

(starting dose 100 mg once daily)

ANC <0.5 x 109/L

and/or

platelets <50 x 109/L

  1. Stop DASATRUE until ANC ≥1.0 x 109/L and platelets ≥50 x 109/L.
  2. Resume treatment at the original starting dose if recovery occurs in ≤7 days.
  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 DASATRUE 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 DASATRUE (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 x 109/L

and/or

platelets <10 x 109/L

  1. Check if cytopaenia is related to leukaemia (marrow aspirate or biopsy).
  2. If cytopaenia is unrelated to leukaemia, stop DASATRUE until ANC ≥1.0 x 109/L and platelets ≥ 20 x 109/L and resume at the original starting dose.
  3. If recurrence of cytopaenia, repeat step 1 and resume DASATRUE 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.

ANC: absolute neutrophil count

Table 4: 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).
  2. If cytopaenia is unrelated to leukaemia, stop DASATRUE until ANC ≥1.0 × 109/L and platelets ≥75 × 109/L and resume at the original starting dose or at a reduced dose.
  3. If cytopaenia recurs, repeat marrow aspirate/biopsy and resume DASATRUE at a reduced dose.
 

Dose (maximum dose per day)

 

Original starting dose

One-level dose reduction

Two-level dose reduction

Tablets

40 mg

20 mg

*

 

60 mg

40 mg

20 mg

 

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), DASATRUE should be interrupted, and may be subsequently resumed at a reduced dose. Temporary dose reductions for intermediate degrees of cytopenia and disease response should be implemented as needed.

Non-Hematologic Adverse Reactions

If a moderate, grade 2, non-haematologic adverse reaction develops with DASATRUE, 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-haematologic adverse reaction develops with DASATRUE, 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 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. In CML-CP paediatric patients with non-haematologic adverse reactions, the dose reduction recommendations for haematologic adverse reactions that are described above should be followed.

4.3 Contraindications

None

4.4 Special Warnings and Precautions for Use

Myelosuppression

Treatment with DASATRUE is associated with severe (NCI CTC Grade 3 or 4) thrombocytopaenia, neutropaenia, and anaemia. Their occurrence is more frequent in patients with advanced phase CML than in chronic phase CML.

In a dose-optimization study in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML, Grade 3 or 4 myelosuppression was reported less frequently in patients treated with 100 mg once daily than in patients treated with other dosing regimens. In patients with chronic phase CML, perform complete blood counts (CBC) weekly for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding DASATRUE temporarily or dose reduction.

Bleeding Related Events

DASATRUE can cause serious and fatal bleeding. In all CML studies, Grade ≥3 central nervous system (CNS) haemorrhages, including fatalities, occurred in <1% of patients receiving Dasatinib. The incidence of Grade 3/4 haemorrhage, occurred in 5.8% of adult patients and generally required treatment interruptions and transfusions. The incidence of Grade 5 haemorrhage occurred in 0.4% of adult patients. The most frequent site of haemorrhage was gastrointestinal. Most bleeding events in clinical studies were associated with severe thrombocytopenia. In addition to causing thrombocytopaenia in human subjects, dasatinib caused platelet dysfunction in vitro.

Concomitant medications that inhibit platelet function or anticoagulants may increase the risk of haemorrhage.

Fluid Retention

DASATRUE may cause fluid retention. After 5 years of follow-up in the adult randomized newly diagnosed chronic phase CML study (n=258), Grade 3 or 4 fluid retention was reported in 5% of patients, including 3% of patients with Grade 3 or 4 pleural effusion. In adult patients with newly diagnosed or imatinib-resistant or -intolerant chronic phase CML, Grade 3 or 4 fluid retention occurred in 6% of patients treated with dasatinib tablets at the recommended dose (n=548). In adult patients with advanced phase CML treated with dasatinib tablets at the recommended dose (n=304), Grade 3 or 4 fluid retention was reported in 8% of patients, including Grade 3 or 4 pleural effusion reported in 7% of patients. In pediatric patients with chronic phase CML, cases of Grade 1 or 2 fluid retention were reported in 10.3% of patients.

Patients who develop symptoms suggestive of pleural effusion such as dyspnoea or dry cough should be evaluated by chest X-ray or additional diagnostic imaging as appropriate. Severe pleural effusion may require thoracentesis and oxygen therapy. Fluid retention events were typically managed by supportive care measures that include diuretics or short courses of steroids. In dose-optimization studies, fluid retention events were reported less frequently with once daily dosing than with other dosing regimens.

Cardiovascular Events

DASATRUE can cause cardiac dysfunction. After 5 years of follow-up in the randomized newly diagnosed chronic phase CML trial in adults (n=258), the following cardiac adverse reactions occurred: cardiac ischemic events (3.9% dasatinib vs 1.6% imatinib), cardiac-related fluid retention (8.5% dasatinib vs 3.9% imatinib), and conduction system abnormalities, most commonly arrhythmia and palpitations (7.0% dasatinib vs 5.0% imatinib). Two cases (0.8%) of peripheral arterial occlusive disease occurred with imatinib and 2 (0.8%) transient ischemic attacks occurred with dasatinib. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.

Pulmonary Arterial Hypertension

DASATRUE may increase the risk of developing pulmonary arterial hypertension (PAH) in adult and paediatric patients which may occur any time after initiation, including after more than 1 year of treatment. Manifestations include dyspnoea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of DASATRUE. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating DASATRUE and during treatment. If PAH is confirmed, DASATRUE should be permanently discontinued.

QT Prolongation

DASATRUE may increase the risk of prolongation of QTc in patients including those with hypokalaemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Correct hypokalaemia or hypomagnesemia prior to and during DASATRUE administration.

Severe Dermatologic Reactions

Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported in patients treated with dasatinib. Discontinue permanently in patients who experience a severe mucocutaneous reaction during treatment if no other aetiology can be identified.

Tumour Lysis Syndrome

Tumour lysis syndrome has been reported in patients with resistance to prior imatinib therapy, primarily in advanced phase disease. Due to potential for tumour lysis syndrome, maintain adequate hydration, correct uric acid levels prior to initiating therapy with DASATRUE, and monitor electrolyte levels. Patients with advanced stage disease and/or high tumour burden may be at increased risk and should be monitored more frequently.

Embryo-Foetal Toxicity

Based on limited human data, DASATRUE can cause foetal harm when administered to a pregnant woman. Adverse pharmacologic effects of dasatinib including hydrops foetalis, foetal leukopenia, and foetal thrombocytopaenia have been reported with maternal exposure to dasatinib. Advise females of reproductive potential to avoid pregnancy, which may include the use of effective contraception, during treatment with DASATRUE and for 30 days after the final dose.

Effects on Growth and Development in Paediatric Patients

In paediatric trials of dasatinib in chronic phase CML after at least 2 years of treatment, adverse reactions associated with bone growth and development were reported in 5 (5.2%) patients, one of which was severe in intensity (Growth Retardation Grade 3). These 5 cases included cases of epiphyses delayed fusion, osteopenia, growth retardation, and gynaecomastia. Of these 5 cases, 1 case of osteopenia and 1 case of gynaecomastia resolved during treatment.

Monitor bone growth and development in paediatric patients.

4.5 Drugs Interactions

Active Substances that may Increase Dasatinib Plasma Concentrations

In vitro studies indicate that dasatinib is a cytochrome P450 enzyme 3A4 (CYP3A4) substrate. Concomitant use of DASATRUE and 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 DASATRUE, systemic administration of a potent CYP3A4 inhibitor is not recommended. If concomitant administration of a strong CYP3A4 inhibitor cannot be avoided, consider a DASATRUE dose reduction.

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 evaluate 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 Concentrations

When dasatinib was administered following 8 daily evening administrations of 600 mg rifampicin, a potent CYP3A4 inducer, the area under the curve (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 DASATRUE 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 DASATRUE is allowed; dasatinib AUC is predicted to decrease approximately 25% with concomitant use of dexamethasone, which is not likely to be clinically meaningful. If concomitant administration of a strong CYP3A4 inducer cannot be avoided, consider a DASATRUE dose increase.

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 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, 40mg omeprazole dose at steady state reduced the AUC of dasatinib by 43% and the maximum plasma concentration (Cmax) of dasatinib by 42%. The use of antacids should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving DASATRUE 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 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 DASATRUE. Avoid simultaneous administration of DASATRUE with antacids.

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. 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 ) should be administered with caution in patients receiving dasatinib.

In vitro data indicate a potential risk for interaction with CYP2C8 substrates, such as glitazones. 

4.6 Use in Special Populations (such as pregnant women, lactating women, paediatric patients, geriatric patients etc.)

Women of Childbearing Potential/Contraception in Males and Females

Both sexually active men and women of childbearing potential should use effective methods of contraception during treatment.

Pregnancy

Based on human experience, DASATRUE 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. DASATRUE should not be used during pregnancy unless the clinical condition of the woman requires treatment with dasatinib. If DASATRUE is used during pregnancy, the patient must be informed of the potential risk to the foetus.

Breast-feeding

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 DASATRUE.

Fertility

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 DASATRUE on fertility, and this counselling may include consideration of semen deposition.

4.7 Effects on Ability to Drive and Use Machines

DASATRUE 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 DASATRUE. Therefore, caution should be recommended when driving a car or operating machines.

4.8 Undesirable Effects

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

  • Myelosuppression
  • Bleeding-related events
  • Fluid retention
  • Cardiovascular events
  • Pulmonary arterial hypertension
  • QT prolongation
  • Severe dermatologic reactions
  • Tumor lysis syndrome
  • Effects on growth and development in pediatric patients

Most common adverse reactions (≥15%) in patients receiving dasatinib as single-agent therapy included myelosuppression, fluid retention events, diarrhoea, headache, skin rash, haemorrhage, dyspnoea, fatigue, nausea, and musculoskeletal pain.

Most common adverse reactions (≥30%) in paediatric patients receiving dasatinib in combination with chemotherapy included mucositis, febrile neutropenia, pyrexia, diarrhoea, nausea, vomiting, musculoskeletal pain, abdominal pain, cough, headache, rash, fatigue, constipation, arrhythmia, hypertension, oedema, infections (bacterial, viral and fungal), hypotension, decreased appetite, hypersensitivity, dyspnoea, epistaxis, peripheral neuropathy, and altered state of consciousness.

Postmarketing Experience

The following additional adverse reactions have been identified during post approval use of dasatinib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infections: hepatitis B virus reactivation

Cardiac disorders: atrial fibrillation/atrial flutter

Respiratory, thoracic, and mediastinal disorders: interstitial lung disease

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome

Renal and urinary disorders: nephrotic syndrome

Blood and lymphatic system disorders: thrombotic microangiopathy

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Program of India by calling 1800 180 3024 or you can report to Cipla Ltd on 18002677779. By reporting side-effects, you can help provide more information on the safety of this product.

4.9 Overdose

Experience with overdose of dasatinib in clinical studies is limited to isolated cases. Overdosage of 280 mg per day for 1 week was reported in two patients and both developed severe myelosuppression and bleeding. Since DASATRUE is associated with severe myelosuppression, patients who ingested more than the recommended dosage should be closely monitored for myelosuppression and given appropriate supportive treatment.

Acute overdose in animals was associated with cardiotoxicity. Evidence of cardiotoxicity included ventricular necrosis and valvular/ventricular/atrial haemorrhage at single doses ≥100 mg/kg (600 mg/m2) in rodents. There was a tendency for increased systolic and diastolic blood pressure in monkeys at single doses ≥10 mg/kg (120 mg/m2).

5. Pharmacological Properties

5.1 Mechanism of Action

Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modelling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase.

In vitro, dasatinib was active in leukemic cell lines representing variants of imatinib mesylate sensitive and resistant disease. Dasatinib inhibited the growth of CML and ALL cell lines overexpressing BCR-ABL. Under the conditions of the assays, dasatinib was able to overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signalling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression.

5.2 Pharmacodynamic Properties

Dasatinib is a potent, sub-nanomolar inhibitor of the BCR-ABL kinase with potency at concentration of 0.6-0.8 nM. It binds to both the inactive and active conformations of the BCR-ABL enzyme.

Cardiac Electrophysiology

Of 2440 patients treated with dasatinib at all doses tested in clinical trials, 16 patients (<1%) had QTc prolongation reported as an adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms. In 865 patients with leukaemia treated with dasatinib 70 mg BID in five Phase 2 studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7 ms to 13.4 ms.

An analysis of the data from five Phase 2 studies in patients (70 mg BID) and a Phase 1 study in healthy subjects (100 mg single dose) suggests that there is a maximum increase of 3 to 6 milliseconds in Fridericia corrected QTc interval from baseline for subjects receiving therapeutic doses of dasatinib, with associated upper 95% confidence intervals <10 msec.

5.3 Pharmacokinetic Properties

Absorption

Cmax of dasatinib are observed between 0.5 and 6 hours (Tmax) following oral administration. Dasatinib exhibits dose proportional increases in AUC and linear elimination characteristics over the dose range of 15 mg to 240 mg/day. The overall mean terminal half-life of dasatinib is 3–5 hours. Data from a study of 54 healthy subjects administered a single, 100-mg dose of dasatinib 30 minutes following consumption of a high-fat meal resulted in a 14% increase in the mean AUC of dasatinib. The observed food effects were not clinically relevant.

Food Effect

A high-fat meal increased the mean AUC of dasatinib following a single dose of 100 mg by 14%. The total calorie content of the high-fat meal was 985 kcal. The calories derived from fat, carbohydrates, and protein were 52%, 34%, and 14% for the high-fat meal.

Distribution

In patients, dasatinib has an apparent volume of distribution of 2505 L, suggesting that the drug is extensively distributed in the extravascular space. Binding of dasatinib and its active metabolite to human plasma proteins in vitro was approximately 96% and 93%, respectively, with no concentration dependence over the range of 100–500 ng/mL.

Dasatinib is a P-gp substrate in vitro.

Metabolism

Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4 (CYP3A4). CYP3A4 was the primary enzyme responsible for the formation of the active metabolite. Flavin-containing monooxygenase 3 (FMO-3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also involved in the formation of dasatinib metabolites.

The exposure of the active metabolite, which is equipotent to dasatinib, represents approximately 5% of the dasatinib AUC. This indicates that the active metabolite of dasatinib is unlikely to play a major role in the observed pharmacology of the drug. Dasatinib also had several other inactive oxidative metabolites.

DASATRUE is a weak time-dependent inhibitor of CYP3A4. At clinically relevant concentrations, dasatinib does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1. DASATRUE is not an inducer of human CYP enzymes.

Elimination

Elimination is primarily via the feces. Following a single oral dose of -labeled dasatinib, approximately 4% and 85% of the administered radioactivity was recovered in the urine and feces, respectively, within 10 days. Unchanged dasatinib accounted for 0.1% and 19% of the administered dose in urine and feces, respectively, with the remainder of the dose being metabolites.

Special Populations

Age (15 to 86 years old), sex, and renal impairment (creatinine clearance 21.6 mL/min to 342.3 mL/min as estimated by Cockcroft Gault) have no clinically relevant effect on the pharmacokinetics of dasatinib.

Hepatic Impairment

Dasatinib doses of 50 mg and 20 mg were evaluated in eight patients with moderate (Child-Pugh class B) and seven patients with severe (Child-Pugh class C) hepatic impairment, respectively. Matched controls with normal hepatic function (n=15) were also evaluated and received a dasatinib dose of 70 mg. Compared to subjects with normal liver function, patients with moderate hepatic impairment had decreases in dose normalized Cmax and AUC by 47% and 8%, respectively. Patients with severe hepatic impairment had dose normalized Cmax decreased by 43% and AUC decreased by 28% compared to the normal controls. These differences in Cmax and AUC are not clinically relevant. Dose adjustment is not necessary in patients with hepatic impairment.

6. Nonclinical Properties

6.1 Animal Toxicology or Pharmacology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year carcinogenicity study, rats were administered oral doses of dasatinib at 0.3, 1, and 3 mg/kg/day. The highest dose resulted in a plasma drug exposure (AUC) level approximately 60% of the human exposure at 100 mg once daily. Dasatinib induced a statistically significant increase in the combined incidence of squamous cell carcinomas and papillomas in the uterus and cervix of high-dose females and prostate adenoma in low-dose males.

Dasatinib was clastogenic when tested in vitro in Chinese hamster ovary cells, with and without metabolic activation. Dasatinib was not mutagenic when tested in an in vitro bacterial cell assay (Ames test) and was not genotoxic in an in vivo rat micronucleus study.

Dasatinib did not affect mating or fertility in male and female rats at plasma drug exposure (AUC) similar to the human exposure at 100 mg daily. In repeat dose studies, administration of dasatinib resulted in reduced size and secretion of seminal vesicles, and immature prostate, seminal vesicle, and testis. The administration of dasatinib resulted in uterine inflammation and mineralization in monkeys, and cystic ovaries and ovarian hypertrophy in rodents.

7. Description

DASATRUE (dasatinib) is a kinase inhibitor. The chemical name for dasatinib is N-(2­ chloro-6-methylphenyl)-2--2-methyl-4­ pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate. The molecular formula is C22H26ClN7O2S • H2O, which corresponds to a formula weight of 506.02 (monohydrate). The anhydrous free base has a molecular weight of 488.01. Dasatinib has the following chemical structure:

Dasatinib is a white to off-white powder. The drug substance is insoluble in water and slightly soluble in ethanol and methanol. Dasatinib tablets are white to off-white, biconvex, film-coated tablets containing dasatinib.

8. Pharmaceutical Particulars

8.1 Incompatibilities

Not Applicable

8.2 Shelf-life

As on pack

8.3 Packaging Information

Dasatinib Tablets 50/70 mg: HDPE bottle containing 60 tablets are packed in a mono carton along with pack insert.

8.4 Storage and Handing Instructions

 Do not stored above 30°C.

Keep all medicine out of reach & sight of children.

9. Patient Counselling Information

DASATRUE

Dasatinib Tablets for oral use

Advise the patient to read the patient labelling (Patient Information).

Bleeding

Inform patients of the possibility of serious bleeding and to report immediately any signs or symptoms suggestive of haemorrhage (unusual bleeding or easy bruising).

Myelosuppression

Inform patients of the possibility of developing low blood cell counts. Advise patients to immediately report fever particularly in association with any suggestion of infection.

Fluid Retention

Patients should be informed of the possibility of developing fluid retention (swelling, weight gain, dry cough, chest pain on respiration, or shortness of breath) and advised to seek medical attention promptly if those symptoms arise

Pulmonary Arterial Hypertension

Inform patients of the possibility of developing pulmonary arterial hypertension (dyspnoea, fatigue, hypoxia, and fluid retention) and advise them to seek medical attention promptly if those symptoms arise

Tumour Lysis Syndrome

Inform patients to immediately report and seek medical attention for any symptoms such as nausea, vomiting, weakness, oedema, shortness of breath, muscle cramps, and seizures, which may indicate tumour lysis syndrome.

Growth and Development in Paediatric Patients

Inform paediatric patients and their caregivers of the possibility of developing bone growth abnormalities, bone pain, or gynecomastia and advise them to seek medical attention promptly if those symptoms arise.

Embryo-Foetal Toxicity

• Advise pregnant women of the potential risk to a foetus

• Advise females of reproductive potential to avoid pregnancy, which may include use of effective contraception during treatment with DASATRUE and for 30 days after the final dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking DASATRUE.

Lactation

Advise women that breastfeeding is not recommended during treatment with DASATRUE and for 2 weeks after the final dose.

Gastrointestinal Complaints

Inform patients that they may experience nausea, vomiting, or diarrhoea with DASATRUE. Advise patients to seek medical attention if these symptoms are bothersome or persistent. Advise patients using antacids to avoid taking DASATRUE and antacids less than 2 hours apart.

Pain

Inform patients that they may experience headache or musculoskeletal pain with DASATRUE. Advise patients to seek medical attention if these symptoms are bothersome or persistent.

Fatigue

Inform patients that they may experience fatigue with DASATRUE. Advise patients to seek medical attention if this symptom is bothersome or persistent.

Rash

Inform patients that they may experience skin rash with DASATRUE. Advise patients to seek medical attention if this symptom is bothersome or persistent.

Lactose

Inform patients that DASATRUE contains 135 mg of lactose monohydrate in a 100-mg daily dose and 189 mg of lactose monohydrate in a 140-mg daily dose.

Missed Dose

Advise patients that if they miss a dose of DASATRUE, they should take the next scheduled dose at its regular time. The patient should not take two doses at the same time.

10. Details of Manufacturer

BDR Pharmaceuticals International Pvt. Ltd.

R. S. No. 578, Near Effluent Channel Road,

Vill. Luna, Tal. Padra,

Dist. Vadodara-391 440. Gujarat.

11. Details of Permission or Licence Number with Date

G/25/2071 issued on 17th March 2020

12. Date of Revision

 March, 2020