IMPORTANT SAFETY INFORMATION

BOXED WARNINGS

Cardiotoxicity, infusion reaction, myelosuppression, liver impairment, substitution

• The use of DOXIL^® may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m²
  • Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dose
  • Cardiac toxicity may also occur at lower cumulative doses (400 mg/m²) in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy
• Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL^®. In most patients, these reactions have resolved within several hours to a day once the infusion is terminated. In some patients, reactions resolved with slowing of the infusion rate
  • Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have occurred. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use
  • The initial rate of infusion should be 1 mg/min to minimize the risk of infusion reactions
• Severe myelosuppression may occur
• DOXIL^® dosage should be reduced in patients with impaired hepatic function
• Accidental substitution has resulted in severe side effects. Do not substitute for doxorubicin HCl on a mg per mg basis

Contraindications

• Patients with a history of hypersensitivity reactions to a conventional doxorubicin formulation or the components of DOXIL^®
• Nursing mothers

Additional Safety Information

• Cardiac function should be carefully monitored
  • Congestive heart failure or cardiomyopathy may occur after discontinuation of anthracycline therapy
  • For patients with a history of cardiovascular disease, or if the results of cardiac monitoring indicate possible cardiac injury, the benefit of therapy must be weighed against the risk of myocardial injury
  • In the randomized multiple myeloma study, 25 patients (8%) in the VELCADE^® arm and 42 patients (13%) in the DOXIL^® plus VELCADE^® arm experienced left ventricular ejection fraction decrease (defined as absolute decrease ≥15% over baseline or a ≥5% decrease below institutional lower limit of normal)
• Myelosuppression may occur; frequently monitor complete blood count (including platelet count), at least prior to each dose of DOXIL^®
  • In patients with recurrent ovarian cancer, hematologic toxicity (based on platelet count or absolute neutrophil count) may require dose reduction or delay in administration of DOXIL^®
  • In patients with multiple myeloma, hematologic toxicity (based on platelet count, absolute neutrophil count, hemoglobin level, or neutropenia with fever) may require dose reduction, delay in administration, or suspension of DOXIL^® and/or VELCADE^®
  • Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage
  • Sepsis occurring during neutropenia has resulted in discontinuation of treatment and in rare cases of death
• DOXIL^® may potentiate the toxicity of other anticancer therapies, especially hematologic toxicities, when used in combination with other therapies that suppress bone marrow
• Hand-foot syndrome (HFS) may occur during therapy with DOXIL^®
  • Based on HFS toxicity grade, dose reduction, delay in administration, or discontinuation of DOXIL^® may be required
  • HFS was generally observed after 2 to 3 cycles of treatment, but may occur earlier
    • The reaction was mild in most patients, resolving in 1 to 2 weeks
    • The reaction can be severe and debilitating in some patients, resulting in discontinuation of therapy
• DOXIL^® is an irritant, not a vesicant; use precautions to avoid extravasation
• DOXIL^® can cause fetal harm when used during pregnancy
• Recall reaction has occurred with DOXIL^® administration after radiotherapy
• DOXIL^® may interact with drugs known to interact with the conventional formulation of doxorubicin HCl
• In patients with recurrent ovarian cancer, the most common all-grade adverse reactions (ARs) ≥20% (DOXIL^® vs topotecan, respectively) included: asthenia (40% vs 51%), fever (21% vs 31%), nausea (46% vs 63%), stomatitis (41% vs 15%), vomiting (33% vs 44%), diarrhea (21% vs 35%), anorexia (20% vs 22%), dyspnea (15% vs 23%), HFS (51% vs 1%), and rash (29% vs 12%)
  • In addition, 19% vs 52.3% reported alopecia (all grades)
  • Grade 3/4 hematologic ARs reported in ≥5% (DOXIL^® vs topotecan, respectively) were neutropenia (12% vs 76%) and anemia (6% vs 29%)
• In patients with multiple myeloma, the most common all-grade adverse reactions ≥20% (DOXIL^® plus VELCADE^® vs VELCADE^®, respectively) included: neutropenia (36% vs 22%), thrombocytopenia (33% vs 28%), anemia (25% vs 21%), fatigue (36% vs 28%) , pyrexia (31% vs 22%), asthenia (22% vs 18%), nausea (48% vs 40%), diarrhea (46% vs 39%), vomiting (32% vs 22%), constipation (31% vs 31%), mucositis/stomatitis (20% vs 5%), peripheral neuropathy (42% vs 45%), neuralgia (17% vs 20%), and rash (22% vs 18%)
  • In addition, 19% vs <1% reported HFS

Please click here to see full Prescribing Information, including Boxed WARNINGS, for DOXIL^®.

VELCADE^® is a registered trademark of Millennium Pharmaceuticals, Inc.

INDICATION

• DOXIL^® in combination with VELCADE^® is indicated for the treatment of patients with multiple myeloma who have not previously received VELCADE^® and have received at least one prior therapy

Reference: 1. Data on file. Janssen Products, LP, Horsham, PA.

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