Abraxane (Paclitaxel) for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

Abraxane (Paclitaxel) is a cytotoxic drug and, as with other potentially toxic paclitaxel compounds, caution should be exercised in handling Abraxane (Paclitaxel) . The use of gloves is recommended. If Abraxane (Paclitaxel) (lyophilized cake or reconstituted suspension) contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure to paclitaxel, events may include tingling, burning and redness. If Abraxane (Paclitaxel) contacts mucous membranes, the membranes should be flushed thoroughly with water.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Limiting the infusion of Abraxane (Paclitaxel) to 30 minutes, as directed, reduces the likelihood of infusion-related reactions

No premedication to prevent hypersensitivity reactions is required prior to administration of Abraxane (Paclitaxel) .

Abraxane (Paclitaxel) is supplied as a sterile lyophilized powder for reconstitution before use. .

Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel.

Calculate the exact total dosing volume of 5 mg/mL suspension required for the patient: Dosing volume (mL) = Total dose (mg)/5 (mg/mL)

The reconstituted suspension should be milky and homogenous without visible particulates. If particulates or settling are visible, the vial should be inverted again to ensure complete resuspension prior to use. Discard the reconstituted suspension if precipitates are observed. Discard any unused portion.

Inject the appropriate amount of reconstituted Abraxane (Paclitaxel) into an empty, sterile IV bag [plasticized polyvinyl chloride (PVC) containers, PVC or non-PVC type IV bag]. The use of specialized DEHP-free solution containers or administration sets is not necessary to prepare or administer Abraxane (Paclitaxel) infusions. The use of an in line filter is not recommended.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Unopened vials of Abraxane (Paclitaxel) are stable until the date indicated on the package when stored between 20°C to 25°C (68°F to 77°F) in the original package. Neither freezing nor refrigeration adversely affects the stability of the product.

Stability of Reconstituted Suspension in the Vial
Stability of Reconstituted Suspension in the Infusion Bag

Single use vials containing 100 mg of paclitaxel.

Abraxane (Paclitaxel) should not be used in patients who have baseline neutrophil counts of

Abraxane (Paclitaxel) can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryo-fetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations.

There are no adequate and well-controlled studies in pregnant women receiving Abraxane (Paclitaxel) . If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving Abraxane (Paclitaxel) .

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reactions (≥ 20%) are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, diarrhea.

No drug interaction studies have been conducted with Abraxane (Paclitaxel) .

The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering Abraxane (Paclitaxel) concomitantly with medicines known to inhibit (e.g. ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4.

Pregnancy Category D

There are no adequate and well-controlled studies in pregnant women using Abraxane (Paclitaxel) . Based on its mechanism of action and findings in animals, Abraxane (Paclitaxel) can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving Abraxane (Paclitaxel) .

Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m (approximately 2% of the daily maximum recommended human dose on a mg/m basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m (approximately 1% of the daily maximum recommended human dose on a mg/m basis).

There is no known antidote for Abraxane (Paclitaxel) overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.

Abraxane (Paclitaxel) , a microtubule inhibitor, is an albumin-bound form of paclitaxel with a mean particle size of approximately 130 nanometers. Paclitaxel exists in the particles in a non-crystalline, amorphous state. Abraxane (Paclitaxel) is supplied as a white to yellow, sterile, lyophilized powder for reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion. Each single-use vial contains 100 mg of paclitaxel (bound to human albumin) and approximately 900 mg of human albumin (containing sodium caprylate and sodium acetyltryptophanate). Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel. Abraxane (Paclitaxel) is free of solvents.

The active agent in Abraxane (Paclitaxel) is paclitaxel. The chemical name for paclitaxel is 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2,3)--benzoyl-3-phenylisoserine.

Paclitaxel has the following structural formula:

Paclitaxel is a white to off-white crystalline powder with the empirical formula CHNO and a molecular weight of 853.91. It is highly lipophilic, insoluble in water, and melts at approximately 216°C to 217°C.

Absorption
The drug exposure (AUCs) was dose proportional over 80 to 375 mg/m and the pharmacokinetics of paclitaxel for Abraxane (Paclitaxel) were independent of the duration of administration. At the recommended Abraxane (Paclitaxel) clinical dose, 260 mg/m, the mean maximum concentration of paclitaxel, which occurred at the end of the infusion, was 18,741 ng/mL. The mean total clearance was 15 L/hr/m. The mean volume of distribution was 632 L/m; the large volume of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel.

The pharmacokinetic data of 260 mg/m Abraxane (Paclitaxel) administered over 30 minutes was compared to the pharmacokinetics of 175 mg/m paclitaxel injection over 3 hours. The clearance of Abraxane (Paclitaxel) was larger (43%) than for the clearance of paclitaxel injection and the volume of distribution of Abraxane (Paclitaxel) was also higher (53%). Differences in C and C corrected for dose reflected differences in total dose and rate of infusion. There were no differences in terminal half-lives.

Distribution         In vitro
Excretion
2
Effect of Hepatic Impairment
The 260 mg/m dose for mild impairment and the 200 mg/m dose for moderate hepatic impairment adjusted the paclitaxel exposure to the range seen in patients with normal hepatic function (mean AUC0-∞ = 14789 ± 6703). The 130 mg/m dose in patients with severe hepatic impairment resulted in lower paclitaxel exposures than those seen in normal subjects. In addition, patients with severe hepatic impairment had higher mean cycle 1 absolute neutrophil count (ANC) nadir values than those with mild and moderate hepatic impairment.

A starting dose of 130 mg/m is recommended in patients with severe hepatic impairment. Escalation of the dose up to 200 mg/m should be considered for subsequent cycles in patients with severe hepatic impairment based on individual tolerance. The 200 mg/m dose has not been evaluated in patients with severe hepatic impairment, but it is predicted to adjust the paclitaxel AUC to the range observed in patients with normal hepatic function. There are no data for patients with AST > 10 x ULN and bilirubin > 5.0 x ULN

Drug Interactions

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.

2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999.

3. American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs. . 2006;63:1172-1193.

4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

Manufactured for:        Celgene Corporation

                                       Summit, NJ 07901

Abraxane (Paclitaxel) is a registered trademark of Abraxis BioScience, LLC.

©2005-2011 Abraxis BioScience, LLC.

All Rights Reserved.

Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation

U.S. Patent Numbers: 5,439,686; 5,498,421; 6,096,331; 6,506,405; 6,537,579; 6,749,868; 6,753,006; 7,820,788; 7,923,536; and RE41,884

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