Dasatinib

Common name: Dasatinib

Trade name: Sprycel

All names: Dasatinib, Spryce, Dasanix

Indications:

This product is used to treat adult patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase, accelerated phase and blast phase (blast myeloblastosis and blast phase) who are resistant or intolerant to imatinib mesylate.

Usage and dosage:

Specifications: Dasatinib tablets: (1) 20mg; (2) 50mg; (3) 70mg.

The usage and dosage of this product may be different in different dosage forms and specifications. Please read the specific drug instructions for use, or follow your doctor's advice.

Dasatinib tablets:

1. Treatment should be carried out by physicians with experience in the diagnosis and treatment of leukemia.

2. The recommended starting dose for patients with Ph+ chronic phase CML is dasatinib 100 mg, taken orally once a day. The time of administration should be consistent, either in the morning or in the evening.

3. The recommended starting dose for patients with CML in the Ph+ accelerated phase and blast phase (acute myeloblastosis and acute lymphadenopathy) is 70 mg, twice a day, taken orally in the morning and evening (see [Precautions]).

4. The tablets must not be crushed or cut and must be swallowed whole. This product can be taken with food or on an empty stomach.

5. Duration of treatment: In clinical trials, treatment with this product continued until the disease progressed or the patient no longer tolerated the treatment. The impact of discontinuing treatment after achieving complete cytogenetic response (CCyR) has not been studied.

6. In order to achieve the recommended dosage, this product is available in three specifications: 20mg, 50mg, and 70mg film-coated tablets. Dose increases or decreases are recommended based on patient response and tolerability.

7. Dose escalation: In clinical trials of adult Ph+ CML patients, if the patient fails to achieve hematological or cytogenetic remission at the recommended starting dose, the dose can be increased to 140 mg once a day for patients with chronic phase CML, and to 90 mg twice a day for patients with advanced phase (accelerated phase and blast crisis) CML.

8. Dose adjustment when adverse reactions occur (see instructions for details).

Adverse reactions:

The most common non-hematological adverse reactions reported by Chinese patients at the same stage of the disease include pleural effusion, diarrhea, headache, upper respiratory tract infection, pulmonary infection, nasopharyngitis, fatigue and fever. (See instructions for details)

Contraindications:

This product is prohibited for patients who are allergic to dasatinib or any excipient.

Notes:

1. Clinically relevant interactions:

(1) Dasatinib is a substrate and inhibitor of cytochrome P450 (CYP) 3A4. Therefore, interactions may occur when used concurrently with other drugs that are primarily metabolized by CYP3A4 or can modulate CYP3A4 activity (see Drug Interactions).

(2) Concomitant use of dasatinib with drugs that potently inhibit CYP3A4 (such as ketoconazole, traconazole, erythromycin, clarithromycin, ritonavir, telithromycin) may increase the exposure of dasatinib. Therefore, concomitant use of strong CYP3A4 inhibitors is not recommended in patients receiving dasatinib (see Drug Interactions).

(3) Concomitant use of dasatinib with drugs that can induce CYP3A4 (such as dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, or Chinese herbal preparations containing hypericin, also known as St. John's wort) can greatly reduce the exposure of dasatinib, which may increase the risk of treatment failure. Therefore, patients receiving dasatinib should be combined with drugs that induce less CYP3A4 enzyme (see Drug Interactions).

(4) Concomitant use of dasatinib and CYP3A4 substrates may increase the exposure of CYP3A4 substrates. Therefore, caution should be exercised when dasatinib is coadministered with CYP3A4 substrates with a narrow therapeutic index, including astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, or the ergot alkaloids (ergotamine, dihydroergotamine) (see Drug Interactions).

(5) Concomitant use of dasatinib with histamine-2 (H2) antagonists (e.g., famotidine), proton pump inhibitors (e.g., omeprazole), or aluminum/magnesium hydroxide may decrease dasatinib exposure. Therefore, concurrent use of H2 antagonists and proton pump inhibitors is not recommended, and aluminum hydroxide/magnesium hydroxide formulations should be administered at least 2 hours before or 2 hours after dasatinib (see Drug Interactions).

2. Special groups: Based on the results of a single-dose pharmacokinetic study, patients with mild, moderate or severe hepatic impairment can receive the recommended starting dose (see [Usage and Dosage] and [Pharmacology and Toxicology] "Pharmacodynamic Characteristics"). However, this product should be used with caution in patients with liver function impairment (see [Usage and Dosage]).

3. Important adverse reactions:

(1) Myelosuppression: Dasatinib treatment will be accompanied by anemia, neutropenia and thrombocytopenia. These events are more common in patients with advanced CML or Ph+ ALL than in patients with chronic CML. Complete blood counts should be performed weekly for the first 2 months and monthly thereafter, or as clinically indicated. Myelosuppression is usually reversible by temporarily discontinuing dasatinib or reducing the dose (see [Dosage and Dosage] and [Adverse Reactions]). In a phase III dose optimization study in patients with chronic phase CML, grade 3 or 4 myelosuppression was more common in patients receiving 70 mg twice daily than in patients receiving 100 mg once daily.

(2) Bleeding-related events: In all clinical studies, the incidence of severe central nervous system (CNS) bleeding was <1%. Fatal consequences occurred in eight cases, six of which were associated with Common Toxicity Criteria (CTC) grade 4 thrombocytopenia. Grade 3 or 4 gastrointestinal bleeding occurs in 4% of patients and usually requires treatment interruption and blood transfusion. The incidence of other grade 3 or 4 bleeding was 2%. Most bleeding-related events were associated with grade 3 or 4 thrombocytopenia (see Adverse Reactions). In addition, in vitro and in vivo platelet assays suggest that treatment with this product has a reversible effect on platelet activation. Patients taking drugs that inhibit platelet function or anticoagulants were excluded from the initial clinical trials of this product. In subsequent trials, concomitant use with anticoagulants, acetylsalicylic acid, and nonsteroidal anti-inflammatory drugs (NSAIDs) was allowed if the patient's platelet count was >50,000-75,000/mm3. Caution should be exercised if patients require medications that inhibit platelet function or anticoagulants.

(3) Body fluid retention:

①Dasatinib treatment will be accompanied by body fluid retention.

② In all clinical studies, the incidence of grade 3 or 4 fluid retention was 10%, including the incidence of grade 3 or 4 pleural effusion and pericardial effusion at 7% and 1% respectively. The incidence of grade 3 or 4 ascites and generalized edema was <1%. The incidence of grade 3 or 4 pulmonary edema is 1%. Patients who develop symptoms suggestive of pleural effusion (such as dyspnea or dry cough) should undergo evaluation with a chest x-ray. Severe pleural effusion may require thoracentesis and oxygen administration. The conventional management of fluid retention events is supportive care, including diuretics and short-term hormonal therapy. Although the safety profile of this product in elderly patients is similar to that in younger patients, patients aged ≥65 years are more likely to experience events of fluid retention and dyspnea and should be closely observed. In two phase III dose optimization studies, the incidence of fluid retention was lower in patients on the once-daily regimen than in the twice-daily regimen (see Adverse Reactions).

(4) Pulmonary arterial hypertension (PAH):

① Pulmonary arterial hypertension (PAH) confirmed by right heart catheterization related to dasatinib treatment has been reported in post-marketing reports. In these cases, pulmonary hypertension was reported after initiation of dasatinib treatment, including more than one year after treatment. Patients who report pulmonary hypertension during dasatinib treatment are often taking concomitant medications or have comorbidities in addition to the underlying malignant disease.

② Before initiating dasatinib treatment, patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease. Patients who develop dyspnea and fatigue after initiating therapy should be evaluated for common causes, including pleural effusion, pulmonary edema, anemia, or pulmonary infiltrates. During this evaluation, guidelines for the management of non-hematological adverse reactions should be followed (see Dosage and Administration). If the adverse reaction is severe, treatment should be withheld until the event resolves or improves. If no other diagnosis is found, the diagnosis of pulmonary hypertension should be considered. If pulmonary hypertension is diagnosed, dasatinib should be permanently discontinued. Follow-up should be performed according to standard practice guidelines. Improvements in hemodynamic and clinical parameters were observed after discontinuation of dasatinib therapy in patients who developed pulmonary hypertension while receiving dasatinib.

(5) QT interval prolongation:

In vitro data indicate that dasatinib may prolong ventricular repolarization (QT interval) (see [Pharmacology and Toxicology] "Preclinical Safety Data"). Among 865 leukemia patients treated with dasatinib in phase II clinical trials, the mean change in QTc interval (QTcF) corrected by Fridericia's method from baseline was 4-6 msec; the upper limit of the 95% confidence interval of all mean changes from baseline was <7 msec (see Adverse Reactions). Among 2182 patients receiving dasatinib in clinical trials, 14 (<1%) patients reported adverse reactions of QTc prolongation. 21 patients (≤1%) had QTcF>500msec. Dasatinib should be used with caution in patients who experience or are likely to experience QTc prolongation. These patients include patients with hypokalemia or hypomagnesemia, patients with congenital QT prolongation syndrome, patients taking antiarrhythmic drugs or other drugs that can cause QT prolongation, and patients receiving cumulative high doses of anthracyclines. Hypokalemia or hypomagnesemia should be corrected before administering dasatinib therapy.

(6) Cardiac adverse reactions: Patients with uncontrolled or significant cardiovascular disease are not enrolled in clinical studies. Those patients with signs or symptoms of cardiac dysfunction require monitoring and appropriate treatment.

(7) Lactose: The daily dose of 100 mg of this product contains 135 mg of lactose-hydrate, and the daily dose of 140 mg of this product contains 189 mg of lactose-hydrate. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this product.

4. Effects on the ability to drive and operate machines: Studies have not been conducted to evaluate the effect of dasatinib on the ability to drive and operate machines. Patients should be informed that some adverse reactions, such as dizziness or blurred vision, may occur during treatment with dasatinib. Therefore, it is recommended that caution be used when driving a car or operating machinery.

5. Disposal precautions: This product contains a tablet core, which is wrapped with a film coating to prevent health practitioners from coming into contact with active substances. However, if tablets are accidentally crushed or broken, health practitioners should wear disposable chemotherapy gloves and handle them appropriately to minimize the risk of skin exposure. Any unused pharmaceutical products or waste materials should be disposed of in compliance with local regulations.

6. Medication for pregnant and lactating women:

(1) Pregnancy: There are currently insufficient data on the use of dasatinib in pregnant women. Animal studies have confirmed the reproductive toxicity of this drug (see [Pharmacology and Toxicology]). The potential risks of dasatinib to humans are unknown. This product should not be used in pregnant women unless clearly needed. If this drug is taken during pregnancy, the patient must be informed of the potential risk to the fetus. In non-clinical studies, embryo-fetal toxicity was observed in rats and rabbits at plasma concentrations lower than those observed during treatment with dasatinib in humans. Fetal death was observed in rats. Dasatinib can cause embryo-fetal toxicity at the lowest doses tested in rats and rabbits (rats: 2.5 mg/kg/day [15 mg/m2/day] and rabbits: 0.5 mg/kg/day [6 mg/m2/day]). These doses produced maternal AUCs of 105 ng·hr/mL (0.3 times the AUC obtained in human females receiving 70 mg twice daily) and 44 ng·hr/mL (0.1 times the human AUC) in rats and rabbits, respectively. Embryo-fetal toxicity includes multiple skeletal deformities (scapula, humerus, femur, radius, ribs, clavicle), reduced ossification (sternum; thoracic, lumbar and sacral vertebrae; anterior phalanx; pelvis and hyoid body), edema and microhepatitis.

(2) Breastfeeding: There is currently insufficient and limited information on the excretion of dasatinib through human or animal milk. Physicochemical data and available pharmacodynamic/toxicological data on dasatinib indicate that the drug is excreted in breast milk and a risk to nursing infants and young children cannot be excluded. Breastfeeding should be stopped during treatment with this product.

(3) Fertility: The effect of dasatinib on sperm is unknown. Therefore, sexually active men and women should take effective contraceptive measures during treatment.

7. Medication for children: Due to the lack of safety and efficacy data, this product is not recommended for use in children and adolescents under 18 years old (see [Pharmacology and Toxicology] Pharmacodynamic Characteristics).

8. Elderly use: No clinically significant age-related differences in pharmacokinetics were observed in elderly patients. Specific dosage recommendations for elderly patients are not necessary. Although the safety profile of this product in older patients is similar to that in younger populations, patients aged ≥65 years are more likely to experience events of fluid retention and dyspnea and should be monitored closely.

9. Drug overdose: Overdose of this product in clinical studies is limited to individual cases. Overdose (280 mg/day for 1 week) was reported in 2 patients, both of whom had significant platelet count decreases. Because dasatinib is associated with grade 3 or 4 myelosuppression (see Precautions), patients who take more than the recommended dose should be closely monitored for myelosuppression and given appropriate supportive care. Acute overdose in animals is associated with cardiotoxicity. Evidence of cardiotoxicity includes ventricular myonecrosis and valvular/ventricular/atrial hemorrhage in rodents receiving a single dose of ≥100 mg/kg (600 mg/m2). A trend toward increased systolic and diastolic blood pressure in monkeys receiving a single dose of ≥10 mg/kg (120 mg/m2).

Storage:

Shade, seal, and store at room temperature (10-30℃).

Mechanism of action:

1. Dasatinib is a protein kinase inhibitor that can inhibit BCR-ABL kinase and SRC family kinases as well as many other selective oncogenic kinases, including c-KIT, ephrin (EPH) receptor kinase and PDGFβ receptor. Dasatinib is a potent, subnanomolar BCR-ABL kinase inhibitor with strong activity at concentrations of 0.6-0.8 nM. It binds to both inactive and active configurations of the BCR-ABL enzyme.

2. In in vitro studies, dasatinib is active in leukemia cell lines expressing various imatinib-sensitive and resistant diseases. The results of these nonclinical studies indicate that dasatinib can overcome imatinib resistance caused by: BCR-ABL overexpression, mutations in the BCR-ABL kinase region, activation of other signaling pathways including SRC family kinases (LYN, HCK), and overexpression of multidrug resistance genes. In addition, dasatinib inhibits SRC family kinases at subnanomolar concentrations.

3. In separate in vivo experiments using murine CML models, dasatinib was able to prevent the progression of chronic phase CML to blast phase and at the same time prolong the survival of tumor-bearing mice (derived from patient CML cell lines growing in different locations, including the central nervous system).

Safety and efficacy:

The clinical trial analyzed the efficacy of dasatinib in the treatment of patients with chronic myelogenous leukemia who were resistant or intolerant to imatinib. The trial included 119 CML patients who were resistant or intolerant to imatinib to receive dasatinib treatment, including 59 patients in the chronic phase, 25 patients in the accelerated phase, and 35 patients in the blast crisis phase. The dose for patients in the chronic phase is 100 mg once a day, and for patients in the accelerated phase and blast phase, the dose is 70 mg twice a day.

The trial results show that clinical trials confirm the durable efficacy of Dasatinib in the treatment of patients with chronic myelogenous leukemia who are resistant or intolerant to imatinib. Among them, the median treatment durations in the chronic phase, accelerated phase, and blast phase were 19.32, 20.99, and 3.22 months respectively.

The complete hematological remission (CHR) rate of 59 patients in the chronic phase was 91.5%, and 30 cases (50.8%) achieved major cytogenetic remission (MCyR), of which 25 cases (42.4%) were complete cytogenetic remission (CCyR). The median time to achieve major cytogenetic remission was 12.1 weeks.

The CHR rate and major hematological response (MaHR) rate of 25 patients in the accelerated phase were 52.0% and 84.0% respectively. 10 patients achieved major cytogenetic response, of which 9 were complete cytogenetic response; the median PFS period of patients in the accelerated phase was 25.7 months.

The CHR rate and MaHR rate of 35 patients in blast phase were 17.1% and 31.4% respectively, and the median time to achieve CHR and MaHR was 12.1 weeks; 8 patients in blast phase achieved major cytogenetic response, and the median duration of major cytogenetic response was 13.2 months; the median PFS and OS of patients in blast phase were 4.3 and 16.7 months respectively.