dasatinib

Action

Inhibits growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL; this inhibition allows bone marrow to resume production of normal red cells, white cells, and platelets.

Availability

Tablets: 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, 140 mg (film-coated)

Indications and dosages

➣ Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase of CML

Adults: 100 mg P.O. daily in morning or evening; may increase dosage to 140 mg daily in patients who don't achieve a hematologic or cytogenetic response

➣ Chronic, accelerated or myeloid or lymphoid blast phase Ph+ CML in patients with resistance or intolerance to prior therapy, including imatinib; Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in patients with resistance or intolerance to prior therapy

Adults: 140 mg P.O. daily in two divided doses (70 mg b.i.d.) in morning and evening; may increase dosage to 180 mg daily in patients who don't achieve a hematologic or cytogenetic response

Dosage adjustment

• Myelosuppression

• Strong CYP3A4 inducers or inhibitors

Contraindications

None

Precautions

Use cautiously in:

• hepatic impairment

• myelosuppression

• comcomitant use of anticoagulants, aspirin, or NSAIDs

• patients with underlying cardiopulmonary disease

• concurrent use of strong CYP3A4 inducers or inhibitors (avoid use if possible)

• patients at risk for fluid retention or QT interval prolongation (including those with hypokalemia, hypomagnesemia, or congenital long-QT syndrome; those taking antiarrhythmics or other drugs that lead to QT prolongation; and cumulative highdose anthracycline therapy)

• concurrent use of histamine-2 (H₂) antagonists or proton pump inhibitors (not recommended)

• concurrent use of drugs that inhibit platelet function or anticoagulants

• pregnant or breastfeeding patients

• children younger than age 18 (safety and efficacy not established).

Administration

Evaluate patients for signs and symptoms of underlying cardiopulmonary disease before starting drug. If pulmonary arterial hypertension (PAH) is confirmed, permanently discontinue drug.

• Correct hypokalemia or hypomagnesemia before starting drug.

• Know that patients with CML or Ph+ ALL should have shown resistance to or intolerance of imatinib mesylate.

• Don't crush or cut tablets. Administer whole with or without food, but not with grapefruit juice.

• If tablets are inadvertently crushed or broken, wear disposable chemotherapy gloves. Pregnant personnel should avoid exposure to crushed or broken tablets.

• If patient needs antacid, give antacid at least 2 hours before or 2 hours after dasatinib.

• Know that hematopoietic growth factor may be used in patients with resistant myelosuppression.

Adverse reactions

CNS: headache, fatigue, asthenia, neuropathy, peripheral neuropathy, dizziness, somnolence, insomnia, depression, malaise, CNS bleeding

CV: palpitations, flushing, hypertension, prolonged QT interval, congestive heart failure, pericardial effusion, arrhythmia

EENT: visual disorder, dry eye

GI: diarrhea, nausea, vomiting, mucositis, stomatitis, dyspepsia, abdominal distention, constipation, gastritis, oral soft-tissue disorder, colitis, enterocolitis, anorexia, appetite disturbances, dysphagia, abdominal pain, anal fissure, upper GI ulcer, esophagitis

Hematologic: myelosuppression (anemia, neutropenia, thrombocytopenia, pancytopenia), febrile neutropenia, hemorrhage, GI bleeding

Metabolic: fluid retention

Musculoskeletal: arthralgia, myalgia, inflammation, weakness

Respiratory: dyspnea, upper respiratory tract infection, pneumonia, pneumonitis, cough, lung infiltration, pleural effusion, pulmonary edema, pulmonary hypertension

Skin: rash, pruritus, acne, alopecia, dry skin, hyperhydrosis, urticaria, dermatitis

Other: fever, chills, infection, herpesvirus infection, ascites, generalized edema, pain, chest pain, dysgeusia, weight changes, temperature intolerance, contusion, sepsis

Interactions

Drug-drug. Antacids: reduced dasatinib plasma concentration

Anticoagulants, platelet inhibitors (such as aspirin, NSAIDs): increased risk of bleeding

CYP3A4 substrates with narrow therapeutic index (such as alfentanil, astemizole, cisapride, cyclosporine, ergot alkaloids, fentanyl, pimozide, quinidine, simvastatin, sirolimus, tacrolimus, terfenadine): potentially increased concentration of these drugs

H₂ antagonists or proton-pump inhibitors (such as famotidine, omeprazole), strong CYP3A4 inducers (such as carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin: reduced dasatinib blood level Strong CYP3A4 inhibitors (such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole): increased dasatinib blood level

Drug-diagnostic tests. Calcium, neutrophils, phosphorus, platelets: decreased levels

ALT, AST, bilirubin, creatinine: increased levels

Drug-food. Grapefruit juice: increased dasatinib blood level

Drug-herbs. St. John's wort: unpredictable decrease in dasatinib blood level

Patient monitoring

Monitor patient for QT prolongation and hemorrhage.

• Be aware that severe thrombocytopenia, neutropenia, and anemia are more common in patients with advancedphase CML or Ph+ ALL than in those with chronic-phase CML. Monitor complete blood count weekly for first 2 months and then monthly thereafter, or as indicated.

• Monitor hepatic function tests.

• Be prepared to manage transaminase or bilirubin elevations with dosage reduction or therapy interruption.

• Stay alert for fluid retention. Be prepared to manage with supportive care measures, such as diuretics or short courses of steroids.

• Monitor calcium levels. Some patients who develop Grade 3 or 4 hypocalcemia during therapy may recover with oral calcium supplementation.

Monitor patient for signs and symptoms of PAH (dyspnea, fatigue, hypoxia, fluid retention), which may occur anytime after initiation, including after more than 1 year of treatment.

Patient teaching

• Instruct patient to take tablet whole with or without food. Caution patient not to break, crush, or cut tablet.

• Advise patient to avoid grapefruit juice.

• Tell patient to take antacids (if needed) at least 2 hours before or 2 hours after dasatinib.

Instruct patient to immediately report fever or chills (and other signs or symptoms of infection), unusual bleeding or bruising, shortness of breath, fatigue, fluid retention, swelling, or weight gain.

• Instruct patient to report troublesome nausea, vomiting, diarrhea, headache, musculoskeletal pain, fatigue, or rash.

• Teach patient that drug may increase risk of infection. Advise patient to wash hands frequently, wear a mask in public places, and avoid people with infections.

• Inform lactose-intolerant patient that drug contains lactose.

• Advise patient to avoid St. John's wort, NSAIDs (such as ibuprofen), and over-the counter drugs that contain aspirin during therapy.

• Advise female patient that drug may harm fetus. Caution her to avoid becoming pregnant. If drug is used during pregnancy or patient becomes pregnant while taking it, inform her of potential hazard to fetus.

• Advise breastfeeding patient to discuss with prescriber whether to discontinue breastfeeding or drug, taking into account importance of drug to mother.

• Advise male taking drug to use condom, to avoid getting partner pregnant.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, food, and herbs mentioned above.