FDA Approves New Paclitaxel Formulation - Lyophilization Articles & Reports

FDA Approves New Paclitaxel Formulation
10 January 2005
Cheryl A. Thompson
American Society of Health-System Pharmacists
BETHESDA, MD, 10 January 2005 ? Abraxane, a formulation of paclitaxel that lacks a sometimes problematic solvent but takes at least seven minutes to dissolve, was approved Friday by the Food and Drug Administration for the second-line treatment of metastatic breast cancer.
American Pharmaceutical Partners Inc. will market the drug product on behalf of subsidiary American BioScience Inc. A spokesman said the product will be available to pharmacies within 45 days.
According to the official labeling (PDF), Abraxane is a freeze-dried formulation of paclitaxel particles with a mean size of about 130 nm and bound to albumin.
The paclitaxel protein-bound particles can be prepared for intravenous (i.v.) administration without the presence of polyoxyethylated castor oil and dehydrated alcohol, a solvent used in the formulation of conventional paclitaxel.
A warning box at the beginning of the label states that the albumin formulation of paclitaxel must not be substituted for or used with other formulations of the chemotherapy agent.
For one thing, the basic dose of paclitaxel protein-bound particles is 50 percent more than the typical dose of conventional paclitaxel.
American Pharmaceutical may market paclitaxel protein-bound particles for only one of the five indications for which conventional paclitaxel may be advertised: the treatment of metastatic breast cancer that did not respond to combination chemotherapy or that relapsed within six months of adjuvant chemotherapy. A patient's previous chemotherapy regimen should have included an anthracycline, such as doxorubicin, unless clinical conditions contraindicated the use of that type of drug
As with conventional paclitaxel, paclitaxel protein-bound particles must not be administered to patients whose neutrophil count at baseline is less than 1,500 cells per cubic millimeter.
Hypersensitivity reactions and severe neutropenia were less frequent problems among the women who received 260 mg of paclitaxel protein-bound particles per square meter of body surface area, compared with those treated with 175 mg of conventional paclitaxel per square meter, a corticosteroid, and an antihistamine, in the major clinical study. But, according to the new product's labeling, the women who received paclitaxel protein-bound particles more commonly had anemia, an abnormal electrocardiogram, sensory neuropathy, weakness, nausea, vomiting, diarrhea, and elevations in serum alkaline phosphatase and alanine aminotransferase.
The labeling for paclitaxel protein-bound particles recommends a dosage of 260 mg per square meter of body surface area administered by i.v. injection over 30 minutes every three weeks. This dose should be cut to 200 mg per square meter if severe neutropenia or severe sensory neuropathy develops. Patients who receive the new formulation of paclitaxel do not have to receive doses of a corticosteroid and an antihistamine beforehand.
Abraxane will be available in vials containing a freeze-dried powder cake of paclitaxel 100 mg and human albumin 900 mg.
Addition of 20 mL of 0.9 percent sodium chloride injection to a vial will, over the course of at least seven minutes, produce a 5-mg/mL milky suspension of paclitaxel. The sodium chloride solution must not be injected directly onto the drug cake. After addition of the fluid, the vial must sit for at least five minutes to ensure the drug is properly wetted. Then the vial must be swirled and inverted for at least two minutes until the powder or cake seems to completely dissolve and a homogenous suspension appears. If the contents of the vial foam or clump, then it must sit for at least 15 minutes until the foam subsides.
Doses of paclitaxel protein-bound particles may be prepared in polyvinyl chloride containers and delivered by regular i.v. administration sets. If not used immediately, the drug suspension may be stored at 2?8 degrees C for up to eight hours.