dasatinib


Also found in: Wikipedia.

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.

dasatinib

(da-sati-nib) ,

Sprycel

(trade name)

Classification

Therapeutic: antineoplastics
Pharmacologic: enzyme inhibitors
Pregnancy Category: D

Indications

genetic implication Chronic, accelerated, or myeloid or lymphoid blast phase Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy (including imatinib).genetic implication Newly diagnosed chronic phase Ph+ CML.genetic implication Ph+ acute lymphoblastic leukemia (ALL) resistant/intolerant to prior therapy.

Action

Inhibits tyrosine kinases resulting in inhibition of leukemic cell lines, including those resistant to imatinib.

Therapeutic effects

Decreased progression of leukemias.

Pharmacokinetics

Absorption: Well absorbed following oral administration. Absorption is pH dependent.
Distribution: Extensively distributed into extravascular space.
Protein Binding: 96%.
Metabolism and Excretion: Extensively metabolized, mostly by the CYP3A4 enzyme system. 85% eliminated in feces, mostly as metabolites; 4% eliminated in urine, mostly as metabolites.
Half-life: 3–5 hr.

Time/action profile

ROUTEONSET PEAKDURATION
POunknown0.5–6 hr12 hr

Contraindications/Precautions

Contraindicated in: Obstetric / Lactation: Pregnancy or lactation.
Use Cautiously in: ↑ risk of QTc prolongation including hypokalemia, hypomagnesemia, congenital prolonged QT syndrome, concurrent antiarrhythmic drugs or other drugs that prolong QT interval including cumulative high-dose anthracycline therapy (correct electrolyte abnormalities prior to use); Concurrent use of anticoagulants or agents that inhibit platelet function; Pediatric: Safety not established.

Adverse Reactions/Side Effects

Central nervous system

  • seizures (life-threatening)
  • fatigue (most frequent)
  • headache (most frequent)
  • altered affect
  • anxiety
  • confusion
  • depression
  • drowsiness
  • insomnia
  • malaise
  • syncope
  • vertigo

Ear, Eye, Nose, Throat

  • conjunctivitis
  • dry eye
  • tinnitus

Respiratory

  • pulmonary edema (life-threatening)
  • pulmonary hypertension (life-threatening)
  • dyspnea (most frequent)
  • asthma
  • pleural effusion
  • pneumonitis

Cardiovascular

  • HF (life-threatening)
  • MI (life-threatening)
  • QTc prolongation (life-threatening)
  • peripheral edema (most frequent)
  • hypertension
  • hypotension
  • palpitations

Gastrointestinal

  • diarrhea (most frequent)
  • nausea (most frequent)
  • abdominal pain
  • altered appetite
  • ascites
  • dysgeusia
  • dyspepsia
  • ileus
  • mucositis
  • vomiting

Genitourinary

  • renal failure (life-threatening)
  • urinary frequency

Dermatologic

  • rash (most frequent)
  • acne
  • alopecia
  • dry skin
  • flushing
  • nail disorder
  • photosensitivity
  • pigment disorder
  • sweating
  • urticaria

Endocrinologic

  • gynecomastia

Fluid and Electrolyte

  • hypocalcemia

Hematologic

  • bleeding events (life-threatening)
  • anemia (most frequent)
  • neutropenia (most frequent)
  • thrombocytopenia (most frequent)

Metabolic

  • hyperuricemia

Musculoskeletal

  • musculoskeletal pain (most frequent)
  • muscle inflammation/weakness

Neurologic

  • tremor

Miscellaneous

  • infections (life-threatening)
  • palmar-plantar erythrodysesthesia (life-threatening)
  • tumor lysis syndrome (life-threatening)
  • bleeding
  • fever

Interactions

Drug-Drug interaction

The following drugs may ↑ dasatinib levels and risk of toxicity by inhibiting CYP 3A4: ketoconazole, itraconazole, clarithromycin, ritonavir, atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, telithromycin, and voriconazole ; concurrent use should be avoided. If concurrent use is required, ↓ dose of dasatinib may be required.The following drugs may ↓ dasatinib levels by inducing CYP 3A4: dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, and phenobarbital ; concurrent use should be avoided. If concurrent use is required, ↑ dose of dasatinib may be required.Antacids may alter absorption; simultaneous use should be avoided (dose at least 2 hours prior to or 2 hours after dasatinib).H2 blockers and proton pump inhibitors may also ↓ absorption and should be avoided; consider antacids as an alternative.Alfentanil, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine ) should be administered with caution because of their narrow therapeutic indices and the unpredictability of enzyme induction/inhibition.St. John's wort may ↓ levels and effectiveness; avoid concurrent use.Grapefruit juice may↑ levels and risk of toxicity; avoid concurrent use.

Route/Dosage

Accelerated, or myeloid or lymphoid blast phase CML or Ph+ ALL

Oral (Adults) 140 mg once daily; may ↑ to 180 mg once daily if hematologic or cytogenetic response is not achieved; Concurrent strong CYP3A4 inhibitor—Initiate at 40 mg once daily.

Chronic phase CML

Oral (Adults) 100 mg daily; may ↑ to 140 mg once daily if hematologic or cytogenetic response is not achieved; Concurrent strong CYP3A4 inhibitor—Initiate at 20 mg once daily.

Availability

Tablets: 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, 140 mg

Nursing implications

Nursing assessment

  • Monitor for fluid retention. Weigh regularly, and assess for signs of pleural effusion, pericardial effusion, pulmonary edema, ascites (dyspnea, periorbital edema, swelling in feet and ankles, weight gain). Evaluate unexpected weight gain. Monitor chest x-ray in patients with symptoms of pleural effusion (dyspnea, dry cough); may require thoracentesis and oxygen therapy. Edema is usually managed with diuretics and short courses of corticosteroids. General fluid retention is usually dose related, more common in accelerated phase or blast crisis, and is more common in the elderly. Treatment usually involves diuretics, supportive therapy, and interruption of dasatinib.
  • Monitor vital signs; may cause fever.
  • Lab Test Considerations: Monitor liver function before and monthly during treatment or when clinically indicated. May cause Grade 3 or 4 ↑ transamininases and bilirubin which may require dose reduction or interruption.
    • Monitor CBC weekly for the first 2 mo, then monthly during therapy or when clinically indicated. May cause severe (Grade 3 or 4) thrombocytopenia, neutropenia and anemia requiring dose modification. See Implementation.
    • May cause Grade 3 or 4 hypocalcemia requiring oral calcium supplements.
    • Hypokalemia or hypomagnesemia should be corrected before administration.

Potential Nursing Diagnoses

Risk for injury (Adverse Reactions)

Implementation

  • high alert: Fatalities have occurred with incorrect administration of chemotherapeutic agents. Before administering, clarify all ambiguous orders; double check single, daily, and course-of-therapy dose limits; have second practitioner independently double check original order and dose calculations. Therapy should be initiated by physician experienced in the treatment of patients with chronic myeloid leukemia.
  • Oral: Administer without regard to meals. Swallow tablets whole, do not crush, break or chew.
    • Patients receiving chronic phase treatment who develop an ANC <0.5 × 109/L and/or platelets <50 × 109L should stop dasatinib until ANC ≥1.0 × 109/L and platelets are ≥50 × 109/L. Then resume dasatinib treatment at original dose if recovery occurs ≤7 days. If platelets <25 x 109/L and/or recurrence of ANC <0.5 x 109/L for >7 days, repeat dose reduction and resume at 80 mg once daily if 2nd episode or 50 mg once daily if 3rd episode for newly diagnosed patients or discontinue for patients resistant or intolerant to prior therapy including imatinib.
    • Patients receiving accelerated phase and blast crisis treatment who develop an ANC <0.5 × 109/L and/or platelets <10 × 109/L should determine if cytopenia is related to leukemia via marrow aspirate or biopsy. If cytopenia is unrelated to leukemia, stop therapy until ANC ≥1.0 x 109/L and platelets ≥20 x 109/L and resume at original starting dose. If recurrence of cytopenia repeat temporary discontinuation and resume at 100 mg once daily for 2nd episode or 80 mg once daily for 3rd episode. If cytopenia is related to leukemia, consider dose escalation to 180 mg once daily.

Patient/Family Teaching

  • Explain purpose of dasatinib. Instruct patient to take dasatinib at the same time each day. Do not stop or change dose without consulting health care professional. If a dose is missed, omit and take next scheduled dose at regular time; do not double doses. Advise patient to read the Patient Information sheet prior to starting therapy and with each Rx refill in case of changes.
  • Advise patient to notify health care professional immediately if fever, bleeding or easy bruising, swelling, weight gain, or increasing shortness of breath or signs and symptoms of pulmonary arterial hypertension (shortness of breath, fatigue, and swelling (ankles and legs) occur.
  • May cause dizziness. Caution patients to avoid driving or other activities requiring alertness until response to medication is known.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken or if lactose intolerant and consult health care professional before taking any new medications. Advise patients to avoid taking medicines that reduce stomach acid to improve absorption. Medicines that neutralize stomach acid, such as antacids, may be used up to 2 hrs before or 2 hrs after dasatinib dose.
  • Inform patient that headache and musculoskeletal pain may occur; notify health care professional if severe.
  • May have teratogenic effects. Advise patient to use effective contraception and to notify health care professional if pregnancy is planned or suspected, or if breastfeeding. Women who are pregnant or may become pregnant should avoid handling crushed or broken tablets. Men receiving dasatinib should be advised to wear a condom to avoid pregnancy in their partner.

Evaluation/Desired Outcomes

  • Decreased progression of leukemias. Most cytogenic responses occurred after 12 wks of therapy. Treatment should be continued as long as patient continues to benefit or until therapy is no longer tolerated by patient.

dasatinib

(dă-săt′ə-nĭb)
n.
A tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukemia and certain forms of acute lymphoblastic leukemia.

dasatinib

a miscellaneous antineoplastic.
indications This drug is used to treat chronic myelogenous leukemia, accelerated blast crisis, and chronic phase and acute lymphoblastic leukemia.
contraindications Pregnancy and known hypersensitivity to this drug prohibit its use.
adverse effects Adverse effects of this drug include headache, dizziness, insomnia, neuropathy, asthenia, arrhythmias, chest pain, congestive heart failure, pericardial effusion, constipation, diarrhea, GI bleeding, mucositis, stomatitis, fluid retention, edema, increased or decreased weight, pain, arthralgia, myalgia, cough, dyspnea, pulmonary edema and hypertension, pneumonia, and urinary tract infection. Life-threatening side effects include central nervous system hemorrhage, vomiting, neutropenia, thrombocytopenia, and bleeding. Common side effects include nausea, anorexia, abdominal pain, rash, and pruritus.
Mentioned in ?
References in periodicals archive ?
AMSTERDAM, June 17 /PRNewswire/ -- Bristol-Myers Squibb Company today presented interim data from a randomised Phase II study of the investigational compound dasatinib (140 mg/day) or imatinib (800 mg/day) in patients with chronic-phase chronic myelogenous leukaemia (CML) resistant to imatinib (less than or equal to 600 mg/day).
To address this need, pharmaceutical companies have developed several first-in-class molecules for the treatment of Ewing's Sarcoma, such as Yondelis, Zalypsis, sunitinib (Sutent), dasatinib (Sprycel), ganitumab and cixutumumab.
A Pivotal Phase II Trial of Ponatinib in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I BCR-ABL Mutation: 12-Month Follow-up of the PACE Trial [Abstract 163]
Bristol-Myers Squibb presented results from four single-arm, open-label Phase II studies of dasatinib - an oral, investigational compound.
The addition of nilotinib (Tasigna([R]), Novartis Oncology) and dasatinib (SPRYCEL([R]), Bristol-Myers Squibb) as primary treatment options for patients with CML are the most significant updates to the NCCN Guidelines for CML, noted Dr.
An analogous mutation (T315I) in the BCR-ABL fusion kinase in chronic myelogenous leukemia cells renders them resistant to ABL kinase inhibitors, gleevec and dasatinib.
BOSTON -- Patients with chronic myeloid leukemia (CML) who were treated with nilotinib are found to be associated with better treatment adherence, less hospitalizations, and lower total health care costs than patients treated with dasatinib, according to a new study released by Analysis Group Inc.
Investigators also showed that the leukemia cells were sensitive to several targeted therapeutic agents, imatinib and dasatinib, which are already being used against other leukemias, but not this subtype.
Major cytogenetic response (MCyR) rate of 33% in patients who had failed 2 TKIs - these patients failed imatinib and were also resistant to dasatinib or nilotinib
In January, 2013, Ministry of Health & Family Welfare forwarded to this Department, minutes of the meeting of the Committee set up under that Ministry for invoking provisions of Compulsory Licensing of Drugs in India in which it was recommended to put three drugs namely Herceptin, Dasatinib and Lxabepilone under Compulsory Licensing as per the provisions of Section 92 of the Patents Act, 1970.
Arnon Nagler, director of hematology at Sheba Medical Center, said "Iclusig is a very effective treatment option with utmost importance to CML or Ph+ALL patients who are resistant to dasatinib or nilotinib and for those patients with the T315I BCR-ABL mutation.
and Europe of dasatinib for the treatment of chronic myelogenous leukemia.