Centocor Ortho Biotech Receives FDA Complete Response Letter Regarding Doxil( R) for the Treatment of Advanced Breast Cancer
Horsham, Pa., September 10, 2009 - Centocor Ortho Biotech Products, L.P. today announced that it received a Complete Response letter from the U.S. Food and Drug Administration (FDA) regarding its Supplemental New Drug Application (sNDA) for DOXIL (doxorubicin HCI liposome injection) in combination with docetaxel for the treatment of women with locally advanced and metastatic breast cancer.
Centocor Ortho Biotech is evaluating the FDA's letter and will respond to the agency as quickly as possible.
The sNDA for DOXIL was submitted to the FDA in September 2008. DOXIL currently is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after prior platinum-based therapy. DOXIL in combination with bortezomib is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy. DOXIL is also indicated for the treatment of AIDS-related Kaposi's sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy.
DOXIL is marketed in the United States by Centocor Ortho Biotech Products, L.P., and in Israel by Janssen-Cilag. Schering-Plough Corporation, under a licensing agreement, has exclusive rights to market the medication as CAELYX throughout the rest of the world, excluding Japan and Israel. For more information about DOXIL, please visit www.DOXIL.com.
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 for Injection arm and 42 patients (13%) in the VELCADE plus DOXIL 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 or AIDS-related Kaposi's sarcoma, 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, or 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 ARs >20% (VELCADE plus DOXIL 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%) o In addition, 19% vs <1% reported HFS
- In patients with AIDS related Kaposi's sarcoma, ARs reported in ≥5% of DOXIL-treated patients were: neutropenia (ANC <1000/mm3, 46%; <500/mm3, 11%), anemia (Hb <10 g/dL, 58%; <8 g/dL, 16%), thrombocytopenia (<150,000 platelets/mm3, 61%), nausea (18%), asthenia (7%), fever (8%), alopecia (9%), vomiting (8%), diarrhea (5%), and stomatitis (5%)
Please visit www.doxil.com for the full Prescribing Information, including Boxed WARNINGS.
About Centocor Ortho Biotech Products, L.P.
Centocor Ortho Biotech redefines the standard of care in immunology, nephrology, and oncology. The company was formed when Centocor, Inc. and Ortho Biotech Products, L.P. were consolidated in late 2008, and was renamed Centocor Ortho Biotech. Built upon a pioneering history, Centocor Ortho Biotech harnesses innovations in large-molecule and small-molecule research to create important new therapeutic options. Beyond its innovative medicines, Centocor Ortho Biotech is at the forefront of developing education and public policy initiatives to ensure patients and their families, caregivers, advocates, and healthcare professionals have access to the latest treatment information, support services, and quality care.
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