DASATINIB

DASATINIB (das-a'ti-nib) Sprycel Classifications: antineoplastic agent; tyrosine kinase inhibitor; biologic response modifier ; Therapeutic:antineoplastic; tyrosine kinase inhibitor Prototype: Gefitinib Pregnancy Category: D

Availability

20 mg, 50 mg, and 70 mg tablets

Action

Dasatinib is a BCR-ABL tyrosine kinase inhibitor. BCR-ABL tyrosine kinase is an enzyme produced by a chromosome translocation (Philadelphia chromosome, Ph) associated with chronic myeloid leukemia (CML) and certain types of acute lymphocytic leukemias (Ph⁺ ALL).

Therapeutic Effect

Dasatinib inhibits the growth of CML and ALL cell lines overexpressing BCR-ABL kinase.

Uses

Treatment of chronic, accelerated, or myeloid or lymphoid blast phase chronic myelogenous leukemia (CML) in adults resistant or intolerant to prior therapy. Treatment of Philadelphia chromosome–positive (Ph⁺) acute lymphocytic leukemia (ALL) in adults resistant or intolerant to prior therapy.

Contraindications

Hypersensitivity to dasatinib; pregnancy (category D); lactation; active bleeding. Concurrent use of anticoagulants or antiplatelet drugs; hypokalemia; hypomagnesemia. Safety and efficacy in children <18 y have not been established.

Cautious Use

Hepatic impairment; bacterial or viral infection; history of GI bleeding; interstitial pneumonia; pleural effusion; QT prolongation; concurrent use of antiarrhythmic drugs.

Route & Dosage

CML and Philadelphia Chromosome-Positive ALL Adult: PO Starting dose 70 mg b.i.d. May increase/decrease dose by 20 mg based on response Dosage Adjustments for Neutropenia and Thrombocytopenia Chronic phase CML where absolute neutrophil count (ANC) <0.5 x 109/L and/or platelets <50 x 109/L Step 1: DC dasatinib until the ANC ≥1 x 109/L and platelets ≥50 x 109/L Step 2: Resume at 70 mg b.i.d. Step 3: If platelets <25 x109/L and/or recurrence of ANC <0.5 x 109/L for >7 d, repeat step 1 and resume at 50 mg b.i.d. (second episode) or 40 mg b.i.d. (third episode) Accelerated phase CML, blast phase CML, and Ph+ ALL where ANC <0.5 x 109/L and/or platelets <10 x 109/L Step 1: Assure that cytopenia is unrelated to the underlying leukemia. If so, DC until ANC ≥1 x 109/L and platelets ≥20 x 109/L Step 2: Resume at 70 mg b.i.d. Step 3: If cytopenia recurs, repeat step 1 and resume at 50 mg b.i.d. (second episode) or 40 mg b.i.d. (third episode) Step 4: If cytopenia is related to the underlying leukemia, may increase to 100 mg b.i.d.

Administration

Oral

• Do not crush or break tablets. They should be swallowed whole.
• Ensure that hypokalemia and hypomagnesemia are corrected prior to administering dasatinib.
• Store at 15°–30° C (59°–86° F).

Adverse Effects (≥1%)

Body as a Whole: Chills, contusion, febrile neutropenia, hemorrhage, infection, malaise, pain, pyrexia, tumor lysis syndrome, weight gain or weight loss. CNS: Asthenia, anxiety, confusional state, CNS bleeding, depression, dizziness, dysgeusia, fatigue, headache, insomnia, neuropathy, somnolence, syncope, tremor, vertigo. CV: Arrhythmia, chest pain, angina, congestive heart failure, pericardial effusion, cardiomegaly, hypertension, hypotension, myocardial infarction, palpitations. GI: Abdominal distention and pain, anal fissure, anorexia, ascites, colitis, constipation, diarrhea, dysphagia, gastritis, GI bleeding, nausea, oral soft tissue disorder, vomiting, mucosal inflammation. Hematologic: Anemia, neutropenia, pancytopenia, thrombocytopenia, anemia, elevated ALT and AST, hypocalcemia, hypophosphatemia. Metabolic: Appetite disturbances, fluid retention, edema, hyperuricemia. Musculoskeletal: Arthralgia, musculoskeletal pain, muscle inflammation, myalgia, musculoskeletal stiffness. Respiratory: Asthma, cough, dyspnea, lung infiltration, plural effusion, pneumonia, pulmonary edema, pulmonary hypertension, upper respiratory tract infection. Skin: Acne, alopecia, dermatitis, dry skin, hyperhidrosis, nail disorder, photosensitivity reaction, pigmentation disorder, pruritus, skin rash. Special Senses: Conjunctivitis, dry eye, tinnitus. Urogenital: Gynecomastia, renal failure, urinary frequency.

Interactions

Drug: Aluminum- and magnesium-based antacids decrease dasatinib absorption. azole antifungal agents (e.g., ketoconazole, itraconazole), macrolide antibiotics (e.g., clarithromycin, erythromycin, telithromycin), hiv protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, saquinavir), nefazodone, and other inhibitors of CYP3A4 may increase dasatinib levels. Compounds that induce CYP3A4 (e.g., carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin) may decrease dasatinib levels. proton pump inhibitors and h ₂ antagonists may reduce the absorption of dasatinib due to long-term suppression of gastric acid secretion. Dasatinib may alter the plasma concentrations of other drugs that require CYP3A4 and have a narrow therapeutic window (e.g., cyclosporine, ergot alkaloids). Dasatinib increases the levels of simvastatin. Food: Food enhances the bioavailability of dasatinib. Herbal: St. John's wort may decrease the level of dasatinib.

Pharmacokinetics

Peak: 0.5–6 h. Distribution: 93–96% protein bound. Metabolism: Extensive hepatic metabolism. Elimination: Fecal. Half-Life: 3–5 h.

Nursing Implications

Assessment & Drug Effects

• Monitor for and report S&S of fluid retention (e.g., pleural or pericardial effusion, peripheral or pulmonary edema, ascites).
• Monitor for S&S of cardiac dysfunction (e.g., heart failure, arrhythmias). ECG monitoring may be needed to evaluate potential QT interval prolongation.
• Monitor for numerous adverse side effects of dasatinib. Immediately report suspected bleeding or infection.
• Lab tests: Baseline and periodic serum potassium and magnesium; baseline CBC with differential (including ANC and platelet count), weekly for first 2 mo, then monthly; periodic LFTs.

Patient & Family Education

• Take antacids (if needed for GI distress) 2 h before or after dasatinib.
• Do not use OTC medications for heartburn (other than antacids) without consulting physician.
• Inform your physician if you are pregnant or planning to become pregnant, as dasatinib may harm the fetus.
• Report immediately to your health care provider any of the following: bleeding (including wine- or coke-colored urine, or black tarry stools) or easy bruising, fever or other signs of an infection, severe lethargy or weakness.

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Common adverse effects in italic, life-threatening effects underlined; generic names in bold; classifications in SMALL CAPS; Canadian drug name; Prototype drug