Pharmacology
Doxorubicin Liposomal Injection Gets Full Approval For Refractory Ovarian Cancer
By Akanksha, Pharmacology Correspondent
Feb 8, 2005, 19:43

The U.S. Food and Drug Administration (FDA) has granted full approval to DOXIL(R)(doxorubicin HCl liposome injection) for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.Doxorubicin hydrochloride liposome injection originally received accelerated approval for refractory ovarian cancer in June 1999.As a result of the full approval,the product label for doxorubicin hydrochloride liposome injection has been updated to include survival,time to disease progression and tumor response rate data from a randomized Phase III clinical study.

Under accelerated approval,doxorubicin hydrochloride liposome injection was indicated for the treatment of metastatic ovarian cancer in patients with disease that was refractory to both paclitaxel- and platinum-based chemotherapy regimens. This approval was based on tumor response rates from three Phase II studies.According to the terms of the accelerated approval, Johnson & Johnson Pharmaceutical Research & Development,L.L.C.(J&JPRD) completed a randomized Phase III clinical study to formally demonstrate the drug's clinical benefit in patients with relapsed ovarian cancer.In March 2004,J&JPRD submitted a supplemental new drug application (sNDA) based on data from the Phase III study.

"The Phase III data provide evidence of the product's clinical benefit for patients with relapsed ovarian cancer," commented Alan N. Gordon, M.D., of the University of Arizona School of Medicine and Arizona Gynecologic Oncology, in Phoenix, Ariz., and lead author of the Phase III study.

In the randomized, multi-center, open-label, Phase III study, 474 patients with recurrent epithelial ovarian cancer were randomly assigned to receive either doxorubicin hydrochloride liposome injection 50 mg/m2 every 28 days or topotecan HCl 1.5 mg/m2/day for five consecutive days every 21 days. A total of 239 patients received doxorubicin hydrochloride liposome injection; 235 patients received topotecan HCl.

The primary endpoint,time to disease progression after starting therapy,was comparable for the two treatment groups.The median time to disease progression was 4.1 months for the doxorubicin hydrochloride liposome injection group and 4.2 months for the topotecan HCl group; the p value, a statistical measurement, was 0.617.

The overall median survival was 14.4 months for patients treated with doxorubicin hydrochloride liposome injection and 13.7 months for patients treated with topotecan HCl; the p value was 0.05. The p value was not adjusted for multiple comparisons. The overall tumor response rate for doxorubicin-treated patients was 19.7 percent and 17 percent for topotecan-treated patients. The Phase III data were published in the September 2001 issue of the Journal of Clinical Oncology and in the October 2004 issue of the journal Gynecologic Oncology.

Doxorubicin hydrochloride liposome injection is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.

Myocardial damage may lead to congestive heart failure and may be encountered as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2. The use of doxorubicin hydrochloride liposome injection may lead to cardiotoxicity.

Doxorubicin hydrochloride liposome injection should be administered to patients with a history of cardiovascular disease only when the benefit outweighs the risk. Acute infusion-associated reactions have occurred in up to 10 percent of patients treated with doxorubicin hydrochloride liposome injection.

Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. Severe myelosuppression may occur. Dosage should be reduced in patients with impaired hepatic function.

Accidental substitution of doxorubicin hydrochloride liposome injection for doxorubicin HCl has resulted in severe side effects. DO NOT SUBSTITUTE. The use of doxorubicin hydrochloride liposome injection should be limited to physicians experienced in the use of cancer chemotherapeutic agents.

In clinical studies in recurrent ovarian cancer, the most common side effects reported with doxorubicin hydrochloride liposome injection therapy included hand-foot syndrome, nausea, mouth sores (stomatitis), tiredness, abdominal pain, vomiting, constipation, rash, fever, reduced red blood cell count (anemia), reduced white blood cell count (neutropenia), weakness, hair loss, appetite loss and diarrhea. Some patients experienced infusion-related reactions and skin reactions.

Hand-foot syndrome, also known as palmar-plantar erythrodysesthesia (PPE), is characterized by symptoms of swelling, pain, redness and, for some patients, peeling of the skin on the hands and feet; in 23 percent of patients, these symptoms were severe.

In some patients enrolled in doxorubicin hydrochloride liposome injection clinical trials, heart-related side effects were reported, some of which were severe. Due to the serious, potentially permanent effects of some of these events, including the potential for bone marrow suppression, close monitoring is necessary.

Ovarian cancer is the most deadly form of gynecologic cancer. According to the American Cancer Society, an estimated 22,220 American women are expected to be diagnosed with ovarian cancer in 2005 and more than 16,000 of these women are expected to die from the disease. The Ovarian Cancer National Alliance reports that approximately 50 percent of women diagnosed with ovarian cancer die from it within five years. However, nearly 75 percent of ovarian cancer cases are diagnosed in later stages when the disease is more difficult to treat and the chance of five-year survival is only about 25 percent.
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DOXIL is marketed in the United States by Tibotec Therapeutics, a Division of Ortho Biotech Products, L.P., and in Israel by Janssen-Cilag. Schering- Plough Corporation, under a licensing agreement, has exclusive rights to market this medication as CAELYX(R) throughout the rest of the world, excluding Japan. J&JPRD and ALZA Corporation collaborated on the clinical development of DOXIL for ovarian cancer.

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