Dazatinib (Tablets) Instructions for Use

ATC Code

L01EA02 (Dasatinib)

Active Substance

Dasatinib (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agents; protein kinase inhibitors; BCR-ABL tyrosine kinase inhibitors

Pharmacological Action

Antitumor agent, protein tyrosine kinase inhibitor.

Dasatinib inhibits BCR-ABL tyrosine kinase and SRC family tyrosine kinases, as well as many other oncogenic kinases, including c-KIT, ephrin (EPH) receptor kinase, and PDGFβ receptor. Dasatinib binds to both active and inactive forms of the BCR-ABL enzyme and inhibits it at subnanomolar concentrations (0.6-0.8 nmol/ml).

In vitro, Dasatinib exhibits activity in cellular models of leukemia, both in imatinib-sensitive and imatinib-resistant cells. Dasatinib overcomes imatinib resistance associated with BCR-ABL overexpression, mutations in the BCR-ABL kinase domain, activation of alternative mechanisms inducing SRC family kinases (LYN, HCK), as well as with overexpression of the multidrug resistance gene.

Pharmacokinetics

After oral administration, absorption is rapid. The C_max of dasatinib is reached within 0.5-3 hours. AUC and elimination are dose-dependent in the dose range from 25 to 120 mg twice daily. When a single 100 mg dose of dasatinib is taken 30 minutes after a high-fat meal, the mean AUC increases by 14%; after a low-fat meal – by 21%. Food intake does not significantly affect absorption.

The apparent V_d of dasatinib is 2505 L, indicating significant distribution in the extravascular space. Dasatinib protein binding is 96%.

Dasatinib is metabolized mainly by the CYP3A4 isoenzyme. After oral administration of 100 mg of [¹⁴C]-dasatinib to healthy volunteers, 29% of the radioactivity in plasma was attributed to unchanged dasatinib. Based on plasma concentrations and in vitro activity, it can be assumed that metabolites do not play a major role in the pharmacological action of dasatinib.

It is excreted mainly via the intestines, predominantly as metabolites. After a single oral dose of [¹⁴C]-dasatinib, 4% and 85% of the radioactivity is excreted by the kidneys and intestines, respectively, over 10 days. Unchanged Dasatinib accounts for 0.1% and 19% of the dose excreted by the kidneys and intestines, respectively, the remainder of the dose consists of metabolites.

The mean overall terminal T_1/2 of dasatinib in patients is 5-6 hours.

The pharmacokinetics of dasatinib were studied in 8 patients with moderate hepatic impairment after a single 50 mg dose and in 5 patients with severe hepatic impairment after a single 20 mg dose compared to the pharmacokinetics in healthy volunteers after a 70 mg dose. The C_max and AUC values for dasatinib were 47% and 8% lower, respectively, with moderate liver damage, compared to values in healthy volunteers. In patients with severe hepatic impairment, the decrease in C_max and AUC values for dasatinib reached 43% and 28%, respectively.

Indications

Chronic myeloid leukemia in the chronic phase, accelerated phase, or lymphoid or myeloid blast crisis phase with resistance or intolerance to previous therapy, including imatinib.

Acute lymphoblastic leukemia with positive Philadelphia chromosome with resistance or intolerance to previous therapy.

ICD codes

Dosage Regimen

The recommended initial dose for adults with chronic myeloid leukemia in chronic phase or Philadelphia chromosome-positive acute lymphoblastic leukemia is 100 mg taken orally once daily.

For chronic myeloid leukemia in accelerated phase or blast crisis, the recommended initial dose is 140 mg taken orally once daily.

Administer tablets whole. Do not crush, cut, or chew them. Take dasatinib with or without food, consistently at approximately the same time each day. Avoid grapefruit juice during treatment.

Perform complete blood counts weekly for the first two months and then monthly thereafter, or as clinically indicated. Monitor for myelosuppression, which is common and may require dose interruption or reduction.

Adjust the dosage based on individual tolerance and disease response. Consider dose escalation to 140 mg once daily in chronic phase patients who do not achieve a hematologic or cytogenetic response at the 100 mg once daily dose.

For non-hematologic toxicity, manage severe events by temporarily interrupting treatment until the event resolves; subsequently resume at the original dose or consider a dose reduction if appropriate.

For hematologic toxicity, manage cytopenias with treatment interruption or dose reduction. In chronic phase CML, if ANC is less than 0.5 x 10⁹/L or platelets are less than 50 x 10⁹/L, interrupt therapy until ANC is at least 1.0 x 10⁹/L and platelets are at least 50 x 10⁹/L, then resume at the original starting dose. For recurrent cytopenias, interrupt again and resume at a reduced dose of 80 mg once daily.

In patients with hepatic impairment, use caution. A dose reduction should be considered for patients with moderate or severe hepatic impairment. The safety in severe hepatic impairment has not been fully established.

For patients taking strong CYP3A4 inhibitors, consider a dose reduction to 20 mg daily. If the inhibitor is discontinued, allow approximately one week before increasing the dasatinib dose to the prior level. Avoid concomitant use of strong CYP3A4 inducers. If co-administration is unavoidable, consider increasing the dasatinib dose, with careful monitoring.

Discontinue treatment in patients with pleural effusion and manage with diuretics or corticosteroids. Upon resolution, treatment may be resumed at a reduced dose.

Adverse Reactions

Most frequently (> 20%): fluid retention, diarrhea, headache, skin rash, nausea, hemorrhage, fatigue, dyspnea, myalgia, infectious complications, vomiting, cough, abdominal pain, fever, dasatinib-induced febrile neutropenia (5%).

Infections and infestations very common – infections (including bacterial, viral, fungal), pneumonia (including bacterial, viral, and fungal), upper respiratory tract infections, herpes infections, enterocolitis, sepsis (including fatal).

From the hematopoietic system: common – febrile neutropenia, pancytopenia; rare – erythroblastopenia.

From the blood coagulation system very common – bleeding.

From the immune system uncommon – hypersensitivity reactions (including erythema nodosum).

From the nervous system very common – headache; common – insomnia, depression, neuropathy (including peripheral neuropathy), dizziness, taste disturbance, drowsiness; uncommon – anxiety, emotional lability, psychosis, decreased libido, cerebral hemorrhage, tremor, syncope, amnesia; rare – seizures, cerebrovascular accident (stroke), transient ischemic attack.

From the organ of vision common – visual impairment, dry eyes; uncommon – conjunctivitis.

From the organ of hearing common – tinnitus; uncommon – vertigo.

From the cardiovascular system common – flushing, increased blood pressure, pericardial effusion, arrhythmia (including tachycardia), congestive heart failure/myocardial dysfunction, palpitations; uncommon – QT interval prolongation on ECG, angina pectoris, cardiomegaly, decreased blood pressure, thrombophlebitis, pericarditis, ventricular arrhythmia (including ventricular tachycardia), myocardial infarction; rare – cor pulmonale, myocarditis, acute coronary syndrome, livedo reticularis.

From the respiratory system very common – pleural effusion, dyspnea, cough; common – pulmonary infiltrates, pulmonary edema, pneumonitis, pulmonary hypertension; uncommon – bronchial asthma, bronchospasm; rare – acute respiratory distress syndrome.

From the digestive system very common – diarrhea, nausea, vomiting, abdominal pain; common – appetite disorder, mucosal inflammation (including mucositis/stomatitis), gastrointestinal bleeding, dyspepsia, abdominal distension, constipation, gastritis, oral mucosal lesion, colitis (including neutropenic colitis), anorexia; uncommon – dysphagia, ascites, anal fissures, upper GI ulcers, pancreatitis, esophagitis, cholestasis, cholecystitis, hepatitis.

From the skin very common – skin rash; common – pruritus, acne, alopecia, dry skin, hyperhidrosis, urticaria, dermatitis (including eczema); uncommon – skin ulcers, bullous dermatosis, pigmentation disorders, nail disorders, photosensitivity, acute febrile neutrophilic dermatosis, panniculitis, palmar-plantar erythrodysesthesia syndrome.

From the musculoskeletal system very common – musculoskeletal pain; common – arthralgia, myositis, muscle weakness, musculoskeletal stiffness; uncommon – increased blood CPK, rhabdomyolysis; rare – tendonitis.

From the urinary system uncommon – renal failure, frequent urination, proteinuria.

From the reproductive system uncommon – gynecomastia, menstrual cycle disorders.

Other very common – fluid retention, localized subcutaneous edema of various locations, tongue edema, lip edema, conjunctival edema, fatigue, fever; common – asthenia, pain, chest pain, generalized edema, chills, hyperuricemia; uncommon – malaise, intolerance to high and low temperatures, tumor lysis syndrome, hypoalbuminemia.

Contraindications

Pregnancy, lactation (breastfeeding); children and adolescents under 18 years of age; hypersensitivity to dasatinib.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Patients must use reliable methods of contraception during treatment and for at least 3 months after.

Special Precautions

Use with caution in hepatic insufficiency, concurrently with anticoagulants and drugs affecting platelet function; with QT interval prolongation or risk of its prolongation (also with concurrent use of drugs that prolong the QT interval); concurrently with substrates of the CYP3A4 isoenzyme, concurrent use with inhibitors or inducers of the CYP3A4 isoenzyme with a narrow therapeutic range.

During treatment, a complete blood count should be performed weekly for the first 2 months of treatment, and then monthly or more frequently, as clinically indicated. Bone marrow suppression is usually reversible and resolves with temporary discontinuation or dose reduction of dasatinib.

Most cases of bleeding during dasatinib use were associated with severe thrombocytopenia. Severe cerebral hemorrhage, including fatal, was reported in less than 1% of patients receiving Dasatinib; severe gastrointestinal bleeding was noted in 4% of patients. Other severe bleeding was reported in 2% of patients.

If shortness of breath or dry cough occurs, chest X-ray monitoring is necessary.

Effect on ability to drive vehicles and operate machinery

If the patient experiences treatment-related symptoms such as dizziness and visual disturbances affecting concentration and reaction speed, it is recommended to refrain from driving vehicles and engaging in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Drug Interactions

Dasatinib is a substrate of the CYP3A4 isoenzyme. Inhibitors of the CYP3A4 isoenzyme (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, atazanavir, indinavir, nelfinavir, saquinavir, telithromycin, grapefruit juice) may increase the plasma concentration of dasatinib, so their concomitant use with dasatinib should be avoided. Patients for whom systemic administration of a potent CYP3A4 isoenzyme inhibitor cannot be avoided should be closely monitored for timely detection of signs of toxicity.

Inducers of the CYP3A4 isoenzyme may decrease the plasma concentration of dasatinib. Concomitant use of potent inducers of the CYP3A4 isoenzyme with dasatinib should be avoided. Patients taking inducers of the CYP3A4 isoenzyme (e.g., dexamethasone, phenytoin, carbamazepine; rifampicin, phenobarbital, or St. John’s wort preparations) should be switched to drugs that do not have (or have minimal) ability to induce this isoenzyme.

Long-term suppression of gastric acid secretion by histamine H₂-receptor blockers and proton pump inhibitors (e.g., famotidine and omeprazole) may lead to a decrease in dasatinib concentration. Concomitant use of these drugs and dasatinib is not recommended. Antacids can be used as an alternative.

Dasatinib is an inhibitor of the CYP3A4 isoenzyme, so its concomitant use with substrates of the CYP3A4 isoenzyme may enhance the effect of that substrate. Substrates of the CYP3A4 isoenzyme with a narrow therapeutic range, such as alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, and ergot alkaloids (ergotamine, dihydroergotamine) should be used with caution in patients receiving Dasatinib.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.