Dasanat

Dasatinib (Dasatinib) instructions

Common name: Dasatinib

Trade name: Dasatinib

All names: Dasatinib, 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.

[Specifications]

50mg, 100mg

[Usage and Dosage]

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

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.

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

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.

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

Dose increases or decreases are recommended based on patient response and tolerance.

Dose escalation:

In clinical trials in 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 daily for patients with chronic phase CML, and to 90 mg twice daily for patients with advanced phase (accelerated phase and blast crisis) CML.

Dose adjustment when adverse reactions occur:

Myelosuppression:

In clinical trials, myelosuppression can be managed by interrupting dosing, reducing the dose, or discontinuing study treatment. Platelet and red blood cell transfusions are given when necessary. Hematopoietic growth factors can be used in patients with resistant myelosuppression (eg, neutropenic symptoms lasting more than 7 days).

Non-hematological adverse reactions:

If severe non-hematological adverse reactions occur during administration of dasatinib, treatment must be discontinued until the incident resolves. Subsequently, treatment may be restarted at an appropriately reduced dose based on the severity of the initial event.

Pediatric patients: 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").

Elderly Patients: No clinically significant age-related differences in pharmacokinetics have been observed in elderly patients. Specific dosage recommendations for elderly patients are not necessary.

Hepatic Impairment: Patients with mild, moderate, or severe hepatic impairment may receive the recommended starting dose. Nonetheless, this product should be used with caution in patients with hepatic impairment (see Precautions and Pharmacokinetics).

Renal impairment: Clinical trials of this product have not been conducted in patients with reduced renal function (patients with serum creatinine concentrations >1.5 times the upper limit of normal were excluded from the trials). Because the renal clearance of dasatinib and its metabolites is <4%, patients with renal insufficiency are not expected to experience reduced systemic clearance.

[Precautions]

Clinically relevant interactions

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).

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

Concomitant use of dasatinib with drugs that induce CYP3A4 (such as dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, or herbal preparations containing hypericin, also known as St. John's wort) can greatly reduce dasatinib exposure, 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).

Concomitant use of dasatinib and CYP3A4 substrates may increase exposure to 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).

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).

Important adverse reactions

Myelosuppression:

Dasatinib treatment is associated with 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 of 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.

Bleeding-related events:

The incidence of severe central nervous system (CNS) bleeding was <1% across all clinical studies. 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 had a platelet count of 50,000-75,000/mm3. Caution should be exercised if patients require medications that inhibit platelet function or anticoagulants.

Fluid retention:

Dasatinib treatment is associated with fluid retention. Across all clinical studies, the incidence of grade 3 or 4 fluid retention was 10%, including grade 3 or 4 pleural effusion and pericardial effusion in 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).

QT interval prolongation:

In vitro data indicate that dasatinib may prolong ventricular repolarization (QT interval) (see [Pharmacology and Toxicology] "Preclinical Safety Data"). Among 865 patients with leukemia treated with dasatinib in phase II clinical trials, the mean change from baseline in the Fridericia-corrected QTc interval (QTcF) was 4-6 msec; the upper limit of the 95% confidence interval for all mean changes from baseline was [7 msec (see Adverse Reactions). Among 2,182 patients who received 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.

Patients with uncontrolled or significant cardiovascular disease were not enrolled in clinical studies.

Congestive heart failure, left ventricular dysfunction, and myocardial infarction:

Cardiac adverse reactions were reported in 5.8% of 258 patients treated with dasatinib, including 1.6% of patients reporting cardiomyopathy, congestive heart failure, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction. Those patients with signs or symptoms of cardiac dysfunction require monitoring and appropriate treatment.

Lactose

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

[Contraindications]

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

[Drug use in pregnant and lactating women]

Pregnancy

There is 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.

Lactation

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.

No clinically relevant 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.

[Drug Interactions]

Active ingredients that may increase the plasma concentration of dasatinib[/u]

In vitro studies have shown that dasatinib is a substrate of CYP3A4. Concomitant use of dasatinib with drugs that potently inhibit CYP3A4 (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin) may increase dasatinib exposure. Therefore, systemic administration of strong CYP3A4 inhibitors is not recommended in patients receiving dasatinib.

According to the results of in vitro experiments, the binding rate of dasatinib to plasma proteins is approximately 96% at clinically relevant concentrations. Studies have not been conducted to evaluate the interaction of dasatinib with other protein-bound drugs. The likelihood of replacement and its clinical significance are unknown.

Active ingredients that may reduce dasatinib plasma concentrations

When dasatinib was administered with 600 mg of rifampin (a strong CYP3A4 inducer) nightly for 8 days, the AUC of dasatinib was reduced by 82%. Other drugs that induce CYP3A4 activity (such as dexamethasone, phenytoin, carbamazepine, phenobarbital, or hypericin-containing herbal preparations such as St. John's wort) may also increase dasatinib metabolism and decrease dasatinib plasma concentrations. Therefore, concomitant use of strong CYP3A4 inducers with dasatinib is not recommended. In patients who are eligible to receive rifampin or other CYP3A4 inducers, other drugs with less enzyme induction should be used.

Histamine 2 Antagonists and Proton Pump Inhibitors:

Chronic use of H2 antagonists or proton pump inhibitors (e.g., famotidine and omeprazole) that inhibit gastric acid secretion is likely to decrease dasatinib exposure. In a single-dose study in healthy subjects, administration of famotidine 10 hours before a single dose of dasatinib reduced dasatinib exposure by 61%. In patients receiving this product, consideration should be given to using antacids instead of H2 antagonists or proton pump inhibitors (see Precautions).

Antacids:

Nonclinical data confirm that the solubility of dasatinib is pH-dependent. In healthy subjects, the concurrent use of aluminum hydroxide/magnesium hydroxide antacids with this product reduced the AUC of a single dose of this product by 55% and the Cmax by 58%. However, no relevant changes in dasatinib concentration or exposure were observed when antacids were administered 2 hours before a single dose of dasatinib. Therefore, antacids can be taken 2 hours before or 2 hours after administration of this product (see [Precautions]).

Active ingredients whose plasma concentrations may be altered by dasatinib

Concomitant use of dasatinib and CYP3A4 substrates may increase the exposure of the CYP3A4 substrate. In a study in healthy subjects, a single 100 mg dose of dasatinib increased the AUC and Cmax of simvastatin, a known CYP3A4 substrate, by 20% and 37%, respectively. The possibility that this effect may be increased after multiple doses of dasatinib cannot be excluded. Therefore, caution should be exercised when dasatinib is used concomitantly with CYP3A4 substrates known to have a narrow therapeutic index, including astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, or the ergot alkaloids (ergotamine, dihydroergotamine) (see Precautions).

In vitro study data indicate that dasatinib has a potential risk of interacting with CYP2C8 substrates (such as glitazones).

[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 drug 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).

[Pharmacology and Toxicology]

Pharmacodynamic characteristics

Therapeutic grouping: protein kinase inhibitors, ATC code: L01XE06

Dasatinib inhibits 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.

In in vitro studies, dasatinib has activity in leukemia cell lines expressing a variety of 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.

In separate in vivo trials using murine CML models, dasatinib prevented the progression of chronic-phase CML to blast phase and prolonged the survival of tumor-bearing mice derived from patient CML cell lines grown in various locations, including the central nervous system.

[Pharmacokinetics]

The pharmacokinetics of dasatinib were evaluated based on 229 healthy adult subjects and 106 patients (including 22 Chinese patients).

Absorption:

Dasatinib is rapidly absorbed after oral administration, reaching peak concentration within 0.5-3 hours. After oral administration, the mean exposure (AUCτ) increased approximately proportionally to increasing doses over the dose range of 25 mg to 120 mg twice daily. The overall mean terminal half-life of dasatinib in patients is approximately 5-6 hours.

Data from healthy subjects indicate that a single 100 mg dose of dasatinib administered 30 minutes after a high-fat meal increased the mean AUC of dasatinib by 14%. Giving a low-fat diet 30 minutes before taking dasatinib increased the mean AUC of dasatinib by 21%. The observed food effects do not represent clinically relevant changes in exposure.

Distribution:

In patients, dasatinib has a large apparent volume of distribution (2,505L), indicating that the drug can be widely distributed extravascularly. In vitro tests show that dasatinib is approximately 96% bound to plasma proteins at clinically relevant concentrations.

Metabolism:

Dasatinib is widely metabolized in the human body, and multiple enzymes are involved in the formation of metabolites. In healthy subjects receiving 100 mg of [[sup]14[/sup]C]-labeled dasatinib, unchanged dasatinib accounted for 29% of circulating radioactivity in plasma. Plasma concentrations and activity measured in vitro indicate that metabolites of dasatinib are unlikely to play a major role in the observed pharmacological activity of the drug. CYP3A4 is the enzyme primarily responsible for the metabolism of dasatinib.

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

Clear:

The drug is primarily eliminated in the feces, mostly in the form of metabolites. After a single oral dose of [[sup]14[/sup]C]-labeled dasatinib, approximately 89% of the dose was eliminated within 10 days, with 4% and 85% of the radioactivity recovered in urine and feces, respectively. Uncirculated dasatinib accounts for 0.1% and 19% of the dose in urine and feces, respectively, with the remaining dose being metabolites.

Hepatic and renal impairment:

A single-dose pharmacokinetic study of dasatinib on hepatic impairment compared eight subjects with moderate hepatic impairment who received a dose of 50 mg and five subjects with severe hepatic impairment who received a dose of 20 mg, which is equivalent to healthy subjects receiving a dose of 70 mg. For subjects with moderate hepatic impairment equivalent to an adjusted dose of 70 mg, the mean Cmax and AUC of dasatinib were reduced by 47% and 8%, respectively, compared with subjects with normal liver function. For subjects with severe hepatic impairment equivalent to an adjusted dose of 70 mg, the mean Cmax and AUC of dasatinib were reduced by 43% and 28% respectively compared with subjects with normal liver function (see [Dosage and Dosage] and [Precautions]).

Dasatinib and its metabolites are rarely eliminated by the kidneys.

[Storage]

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