SPRYCEL® (dasatinib) INDICATION & IMPORTANT SAFETY INFORMATION

Indication

SPRYCEL® (dasatinib) is indicated for the treatment of adults with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of SPRYCEL is based on cytogenetic and major molecular response rates. The trial is ongoing and further data will be required to determine long-term outcome.

Important Safety Information

Myelosuppression:

Treatment with SPRYCEL® (dasatinib) can cause severe (NCI CTC Grade 3/4) thrombocytopenia, neutropenia, and anemia. Their occurrence is more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.

  • Perform complete blood counts (CBCs) weekly for the first 2 months and then monthly thereafter, or as clinically indicated
  • Myelosuppression was generally reversible and usually managed by dose interruption, dose reduction, or discontinuation
  • Hematopoietic growth factor has been used in patients with resistant myelosuppression

Bleeding Related Events:

SPRYCEL caused platelet dysfunction in vitro and thrombocytopenia in humans. In all clinical trials, severe central nervous system (CNS) hemorrhage, including fatalities, occurred in 1% of patients receiving SPRYCEL. Severe gastrointestinal hemorrhage, including fatalities, occurred in 4% of patients and generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 2% of patients.

  • Most bleeding events were associated with severe thrombocytopenia. Exercise caution in patients required to take medications that inhibit platelet function or anticoagulants

Fluid Retention:

SPRYCEL is associated with fluid retention. In clinical trials, fluid retention was severe in up to 10% of patients. Severe ascites, pulmonary edema, and generalized edema were each reported in ≤1% of patients.

  • Patients who develop symptoms suggestive of pleural effusion, such as dyspnea or dry cough, should be evaluated by chest X-ray
  • Severe pleural effusion may require thoracentesis and oxygen therapy
  • Fluid retention was typically managed by supportive care measures that included diuretics or short courses of steroids

QT Prolongation:

In vitro data suggest that SPRYCEL has the potential to prolong cardiac ventricular repolarization (QT interval).

  • In 865 patients with leukemia treated with SPRYCEL in five phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms
  • In clinical trials of patients treated with SPRYCEL (N=2440), 16 patients (1%) had QTc prolongation as an adverse reaction.
    Twenty-two patients (1%) experienced a QTcF >500 ms
  • Administer SPRYCEL with caution to patients who have or may develop prolongation of QTc, including patients with hypokalemia, hypomagnesemia, or congenital long QT syndrome and patients taking anti-arrhythmic drugs, other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy
    • — Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration

Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction:

Cardiac adverse reactions were reported in 7% of 258 patients taking SPRYCEL, including 1.6% of patients with cardiomyopathy, heart failure congestive, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction.

  • Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately

Pulmonary Arterial Hypertension (PAH):

SPRYCEL may increase the risk of developing PAH, which may occur any time after initiation, including after more than one year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of SPRYCEL.

  • Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and during treatment. If PAH is confirmed, SPRYCEL should be permanently discontinued

Use in Pregnancy:

SPRYCEL may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of SPRYCEL in pregnant women.

  • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant when taking SPRYCEL

Nursing Mothers:

It is unknown whether SPRYCEL is excreted in human milk.

  • Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue SPRYCEL

Drug Interactions:

SPRYCEL is a CYP3A4 substrate and a weak time-dependent inhibitor of CYP3A4.

  • Drugs that may increase SPRYCEL plasma concentrations are:
    • CYP3A4 inhibitors: Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 should be avoided. If administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and a SPRYCEL dose reduction should be considered
    • Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease or temporary discontinuation should be considered
      • Grapefruit juice may also increase plasma concentrations of SPRYCEL and should be avoided
  • Drugs that may decrease SPRYCEL plasma concentrations are:
    • CYP3A4 inducers: If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered
    • Strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) should be avoided. Alternative agents with less enzyme induction potential should be considered. If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicity
      • St John’s Wort may decrease SPRYCEL plasma concentrations unpredictably and should be avoided
    • Antacids may decrease SPRYCEL drug levels. Simultaneous administration of SPRYCEL and antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL
    • H2 antagonists/proton pump inhibitors (eg, famotidine and omeprazole): Long-term suppression of gastric acid secretion by use of H2 antagonists or proton pump inhibitors is likely to reduce SPRYCEL exposure. Therefore, concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended
  • Drugs that may have their plasma concentration altered by SPRYCEL are:
    • CYP3A4 substrates (eg, simvastatin) with a narrow therapeutic index should be administered with caution in patients receiving SPRYCEL

Adverse Reactions:

The safety data reflect exposure to SPRYCEL in 258 patients with newly diagnosed chronic phase CML in a clinical trial (minimum of
36 months follow up; median duration of therapy was 37 months).

The majority of SPRYCEL-treated patients experienced adverse reactions at some time. Patients aged 65 years and older are more likely to experience toxicity. In the newly diagnosed chronic phase CML trial, the cumulative discontinuation rate was 9% with a minimum of
36 months follow up.

  • In newly diagnosed chronic phase CML patients:
    • The most frequently reported serious adverse reactions included pleural effusion (4%), hemorrhage (2%), congestive heart failure (1%),
      pulmonary hypertension (1%), and pyrexia (1%)
    • The most frequently reported adverse reactions (reported in ≥10% of patients) included myelosuppression,
      fluid retention events (pleural effusion and superficial localized edema), diarrhea, headache, musculoskeletal pain, rash, and nausea
    • Grade 3/4 laboratory abnormalities included neutropenia (24%), thrombocytopenia (19%), anemia (12%), hypophosphatemia (7%), hypocalcemia (3%),
      elevated bilirubin (1%), and elevated creatinine (1%)
  • Grade 3/4 elevations of transaminase or bilirubin and Grade 3/4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML
    • Elevations in transaminase or bilirubin were usually managed with dose reduction or interruption
    • Patients developing Grade 3/4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation

Please see the US full Prescribing Information.