da-SAti-nib

• Chronic phase Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) that is either newly diagnosed or resistant/intolerant to prior therapy including imatinib.
• Accelerated, or myeloid or lymphoid blast phase Ph+ CML resistant/intolerant to prior therapy including imatinib.
• Ph+ acute lymphoblastic leukemia (ALL) that is either newly diagnosed (children) or resistant/intolerant to prior therapy (adults).

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

• Decreased progression of leukemias.

Absorption: Well absorbed following oral administration. Absorption is pH dependent.

Distribution: Extensively distributed into extravascular space.

Protein Binding: 96%.

Metabolism/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.

Contraindicated in:

• OB: Pregnancy (may cause fetal harm)
• Lactation: 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
• Rep: Women of reproductive potential.

CV: HF, MI, edema, hypertension, hypotension, palpitations, QTc interval prolongation.

Derm: ERYTHEMA MULTIFORME, STEVENS-JOHNSON SYNDROME, rash, acne, alopecia, dry skin, flushing, nail disorder, photosensitivity, pigment disorder, sweating, urticaria.

EENT: conjunctivitis, dry eye, tinnitus.

Endo: gynecomastia.

F and E: hypocalcemia.

GI: diarrhea, nausea, abdominal pain, altered appetite, ascites, dysgeusia, dyspepsia, ileus, mucositis, vomiting.

GU: RENAL FAILURE, urinary frequency.

Hemat: BLEEDING EVENTS, anemia, neutropenia, thrombocytopenia.

Metab: ↓growth (children), hyperuricemia.

MS: musculoskeletal pain, muscle inflammation/weakness.

Neuro: tremor , SEIZURES, fatigue, headache, altered affect, anxiety, confusion, depression, drowsiness, insomnia, malaise, syncope, vertigo.

Resp: PULMONARY EDEMA, PULMONARY HYPERTENSION, dyspnea, asthma, pleural effusion, pneumonitis.

Misc: INFECTION(INCLUDING HEPATITIS B VIRUS REACTIVATION), PALMAR-PLANTAR ERYTHRODYSESTHESIA , TUMOR LYSIS SYNDROME, bleeding, fever.

Drug-Drug:

• The following drugs may ↑ dasatinib levels and risk of toxicity by inhibiting CYP 3A4: ketoconazole, itraconazole, clarithromycin, ritonavir, atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, 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 antagonists 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.

Drug-Natural Products:

• St. John's wort may ↓ levels and effectiveness; avoid concurrent use.

Drug-Food:

• Grapefruit juice may ↑ levels and risk of toxicity; avoid concurrent use.

Accelerated, or Myeloid or Lymphoid Blast Phase Ph+ CML

• PO (Adults): 140 mg once daily; may ↑ to 180 mg once daily if hematologic or cytogenetic response is not achieved; continue until disease progression or unacceptable toxicity; Concurrent strong CYP3A4 inhibitor — 40 mg once daily; continue until disease progression or unacceptable toxicity.

Chronic Phase Ph+ CML

• PO (Adults): 100 mg once daily; may ↑ to 140 mg once daily if hematologic or cytogenetic response is not achieved; continue until disease progression or unacceptable toxicity; Concurrent strong CYP3A4 inhibitor — 20 mg once daily; continue until disease progression or unacceptable toxicity.
• PO (Children 45 kg): 100 mg once daily; may ↑ to 120 mg once daily if hematologic or cytogenetic response is not achieved; continue until disease progression or unacceptable toxicity; Concurrent strong CYP3A4 inhibitor — 20 mg once daily; continue until disease progression or unacceptable toxicity.
• PO (Children 30–<45 kg): 70 mg once daily; may ↑ to 90 mg once daily if hematologic or cytogenetic response is not achieved; continue until disease progression or unacceptably toxicity; Concurrent strong CYP3A4 inhibitor — 20 mg once daily; continue until disease progression or unacceptable toxicity.
• PO (Children 20–<30 kg): 60 mg once daily; may ↑ to 70 mg once daily if hematologic or cytogenetic response is not achieved; continue until disease progression or unacceptable toxicity; Concurrent strong CYP3A4 inhibitor — Discontinue dasatinib and then reinitiate 1 wk after discontinuing CYP3A4 inhibitor.
• PO (Children 10–<20 kg): 40 mg once daily; may ↑ to 50 mg once daily if hematologic or cytogenetic response is not achieved; continue until disease progression or unacceptable toxicity; Concurrent strong CYP3A4 inhibitor — Discontinue dasatinib and then reinitiate 1 wk after discontinuing CYP3A4 inhibitor.

Ph+ ALL

• PO (Adults): 140 mg once daily; may ↑ to 180 mg once daily if hematologic or cytogenetic response is not achieved; continue until disease progression or unacceptable toxicity; Concurrent strong CYP3A4 inhibitor — 40 mg once daily; continue until disease progression or unacceptable toxicity.
• PO (Children 45 kg): 100 mg once daily started on or before Day 15 of induction chemotherapy; continue for 2 yr; Concurrent strong CYP3A4 inhibitor — 20 mg once daily started on or before Day 15 of induction chemotherapy; continue for 2 yr.
• PO (Children 30–<45 kg): 70 mg once daily started on or before Day 15 of induction chemotherapy; continue for 2 yr; Concurrent strong CYP3A4 inhibitor — 20 mg once daily started on or before Day 15 of induction chemotherapy; continue for 2 yr.
• PO (Children 20–<30 kg): 60 mg once daily started on or before Day 15 of induction chemotherapy; continue for 2 yr; Concurrent strong CYP3A4 inhibitor — Discontinue dasatinib and then reinitiate 1 wk after discontinuing CYP3A4 inhibitor.
• PO (Children 10–<20 kg): 40 mg once daily started on or before Day 15 of induction chemotherapy; continue for 2 yr; Concurrent strong CYP3A4 inhibitor — Discontinue dasatinib and then reinitiate 1 wk after discontinuing CYP3A4 inhibitor.

• 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.
• PO: Administer without regard to meals. Swallow tablets whole, do not crush, break or chew.
  • Recalculate pediatric dose every 3 months or more often based on changes in body weight.
  • Adult patients receiving chronic phase treatment who develop an ANC <0.5 × 10⁹/L and/or platelets <50 × 10⁹L: hold dasatinib until ANC 1.0 × 10⁹/L and platelets are 50 × 10⁹/L. Then resume 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.
  • Pediatric patients receiving chronic phase If cytopenia persists >3 weeks:check if cytopenia is related to leukemia (marrow aspirate or biopsy). If cytopenia is unrelated to leukemia, stop dasatinib until ANC 1.0 × 10⁹/L and platelets 75 × 10⁹/L and resume at original starting dose or at reduced dose. If cytopenia recurs, repeat marrow aspirate/biopsy and resume dasatinib at reduced dose. For pediatric patients with chronic phase CML, if Grade 3 neutropenia or thrombocytopenia recurs during complete hematologic response, interrupt SPRYCEL and resume at a reduced dose. Implement temporary dose reductions for intermediate degrees of cytopenia and disease response as needed
  • Patients receiving accelerated phase and blast crisis treatment who develop an ANC <0.5 × 10⁹/L and/or platelets <10 × 10⁹/L: determine if cytopenia is related to leukemia via marrow aspirate or biopsy. If cytopenia is unrelated to leukemia, hold 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.

Sprycel

Therapeutic Classification: antineoplastics

Pharmacologic Classification: enzyme inhibitors

• Tablets: 20 mg; 50 mg; 70 mg; 80 mg; 100 mg; 140 mg;

• 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. Fluid retention is usually dose related, more common in accelerated phase or blast crisis, and more common in the elderly. Treatment usually involves diuretics, supportive therapy, and interruption of dasatinib.
• Monitor for signs and symptoms of cardiac dysfunction.
• Monitor for signs and symptoms of pulmonary artery hypertension (dyspnea, fatigue, hypoxia, fluid retention) periodically during therapy. May occur after 1 yr of therapy.
• Monitor vital signs; may cause fever.
• Monitor growth and development in pediatric patients. May cause bone growth abnormalities, bone pain, or gynecomastia.
• Monitor for tumor lysis syndrome (malignant disease progression, high WBC counts, hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcamia, and/or dehydration). Prevent by maintaining adequate hydration and correcting uric acid levels prior to starting dasatinib.

• 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. Pediatric patients with Ph+ ALL: If direct bilirubin >5 times upper limit of normal (ULN), interrupt treatment until baseline or grade <1. If AST/ALT over 15 times ULN, hold therapy until baseline or grade <1. For recurrent liver function test abnormalities,reduce dose if recurs after reinitiation of dasatinib.
  • Accelerated, or Myeloid or Lymphoid Blast Phase CML or Ph+ ALL: 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. Chronic Phase CML: Monitor CBC every 2 wk for 12 wk, then every 3 mo thereafter, or as clinically indicated. Advanced Phase CML or Ph+ ALL: perform CBC weekly for first 2 months and then monthly or as clinically indicated. Pediatric Patients with Ph+ ALL: perform CBCs prior to start of each block of chemotherapy and as clinically indicated. During consolidation blocks of chemotherapy, perform CBCs every 2 days until recovery.See Implementation.
  • Pediatric patients: If cytopenia persists >3 weeks:determine if cytopenia is related to leukemia (marrow aspirate or biopsy). If cytopenia is unrelated to leukemia, hold dasatinib until ANC 1.0 × 10⁹/L and platelets 75 × 10⁹/L and resume at original starting dose or at reduced dose. If cytopenia recurs, repeat marrow aspirate/biopsy and resume dasatinib at reduced dose. For pediatric patients with chronic phase CML, if Grade 3 neutropenia or thrombocytopenia recurs during complete hematologic response, hold dasatinib and resume at reduced dose. May use temporary dose reductions for intermediate degrees of cytopenia and disease response as needed. For pediatric patients with Ph+ ALL, if neutropenia and/or thrombocytopenia result in delay of next treatment by >14 days, hold dasatinib and resume at same dose level once next treatment is started. If neutropenia and/or thrombocytopenia persist and next treatment is delayed another 7 days, perform a bone marrow assessment to assess cellularity and percentage of blasts. If marrow cellularity is <10%, hold dasatinib until ANC >0.5 x 10⁹, then resume at full dose. If marrow cellularity is >10%, resumption of treatment may be considered.
  • May cause Grade 3 or 4 hypocalcemia requiring oral calcium supplements.
  • Correct hypokalemia or hypomagnesemia before administration.

• Risk for injury (Adverse Reactions).

• 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 avoid grapefruit and grapefruit juice during therapy; may increase risk of toxicity.
• Advise patient to notify health care professional immediately if signs and symptoms of infection (fever); bleeding (unusual bleeding, easy bruising); fluid retention (swelling, weight gain, dry cough, chest pain on respiration, shortness of breath); pulmonary arterial hypertension (shortness of breath, fatigue, hypoxia, swelling of ankles and legs; tumor lysis syndrome (nausea, vomiting, weakness, edema, shortness of breath, muscle cramps, seizures); rash; or bone growth abnormalities, bone pain, or gynecomastia in pediatric patients 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, especially St. John's Wort. 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.
• Rep: May have teratogenic effects. Advise patient to use effective contraception during and for 30 days after final dose and to avoid breast feeding during and for 2 wk after final dose. Advise patient notify health care professional if pregnancy is planned or suspected. 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. May cause damage to female and male reproductive tissues causing infertility.

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

NDC Code^*

• 0003- E.R. Squibb and Sons, L.L.C.
  • 0003-0524- SPRYCEL
    • 0003-0524-11- 1 BOTTLE in 1 CARTON (0003-0524-11) > 60 TABLET in 1 BOTTLE

• 0003- E.R. Squibb and Sons, L.L.C.
  • 0003-0527- SPRYCEL
    • 0003-0527-11- 1 BOTTLE in 1 CARTON (0003-0527-11) > 60 TABLET in 1 BOTTLE

• 0003- E.R. Squibb and Sons, L.L.C.
  • 0003-0528- SPRYCEL
    • 0003-0528-11- 1 BOTTLE in 1 CARTON (0003-0528-11) > 60 TABLET in 1 BOTTLE

• 0003- E.R. Squibb and Sons, L.L.C.
  • 0003-0852- SPRYCEL
    • 0003-0852-22- 1 BOTTLE in 1 CARTON (0003-0852-22) > 30 TABLET in 1 BOTTLE

• 0003- E.R. Squibb and Sons, L.L.C.
  • 0003-0855- SPRYCEL
    • 0003-0855-22- 1 BOTTLE in 1 CARTON (0003-0855-22) > 30 TABLET in 1 BOTTLE

• 0003- E.R. Squibb and Sons, L.L.C.
  • 0003-0857- SPRYCEL
    • 0003-0857-22- 1 BOTTLE in 1 CARTON (0003-0857-22) > 30 TABLET in 1 BOTTLE