Paclitaxel

INDICATIONS AND USAGE Paclitaxel Injection USP is indicated as subsequent therapy for the treatment of advanced carcinoma of the ovary. As first-line therapy, paclitaxel injection is indicated in combination with cisplatin. Paclitaxel Injection USP is indicated for the adjuvant treatment of node-positive breast cancer administered sequentially to standard doxorubicin-containing combination chemotherapy. In the clinical trial, there was an overall favorable effect on disease-free and overall survival in the total population of patients with receptor-positive and receptor-negative tumors, but the benefit has been specifically demonstrated by available data (median follow-up 30 months) only in the patients with estrogen and progesterone receptor-negative tumors (see CLINICAL STUDIES, Breast Carcinoma ). Paclitaxel Injection USP 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. Paclitaxel Injection USP, in combination with cisplatin, is indicated for the first-line treatment of non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy. Paclitaxel Injection USP is indicated for the second-line treatment of AIDS-related Kaposi’s sarcoma.

DOSAGE AND ADMINISTRATION Note: Contact of the undiluted concentrate with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC infusion bags or sets, diluted paclitaxel injection solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. All patients should be premedicated prior to paclitaxel injection administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours before paclitaxel injection, diphenhydramine (or its equivalent) 50 mg IV 30 to 60 minutes prior to paclitaxel injection, and cimetidine (300 mg) or ranitidine (50 mg) IV 30 to 60 minutes before paclitaxel injection. For patients with carcinoma of the ovary , the following regimens are recommended (see CLINICAL STUDIES, Ovarian Carcinoma ): 1) For previously untreated patients with carcinoma of the ovary, one of the following recommended regimens may be given every 3 weeks. In selecting the appropriate regimen, differences in toxicities should be considered (see TABLE 11 in ADVERSE REACTIONS, Disease-Specific Adverse Event Experiences ). Paclitaxel injection administered intravenously over 3 hours at a dose of 175 mg/m 2 followed by cisplatin at a dose of 75 mg/m 2 ; or Paclitaxel injection administered intravenously over 24 hours at a dose of 135 mg/m 2 followed by cisplatin at a dose of 75 mg/m 2 . 2) In patients previously treated with chemotherapy for carcinoma of the ovary, paclitaxel injection has been used at several doses and schedules; however, the optimal regimen is not yet clear (see CLINICAL STUDIES, Ovarian Carcinoma ). The recommended regimen is paclitaxel injection 135 mg/m 2 or 175 mg/m 2 administered intravenously over 3 hours every 3 weeks. For patients with carcinoma of the breast , the following is recommended (see CLINICAL STUDIES, Breast Carcinoma ): 1) For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel injection, at a dose of 175 mg/m 2 intravenously over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used 4 courses of doxorubicin and cyclophosphamide (see CLINICAL STUDIES, Breast Carcinoma ). 2) After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel injection at a dose of 175 mg/m 2 administered intravenously over 3 hours every 3 weeks has been shown to be effective. For patients with non-small cell lung carcinoma , the recommended regimen, given every 3 weeks, is paclitaxel injection administered intravenously over 24 hours at a dose of 135 mg/m 2 followed by cisplatin, 75 mg/m 2 . For patients with AIDS-related Kaposi’s sarcoma , paclitaxel injection administered at a dose of 135 mg/m 2 given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m 2 given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45 to 50 mg/m 2 /week). In the 2 clinical trials evaluating these schedules (see CLINICAL STUDIES, AIDS-Related Kaposi’s Sarcoma ), the former schedule (135 mg/m 2 every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m 2 every 2 weeks). Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients: 1) Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO); 2) Initiate or repeat treatment with paclitaxel injection only if the neutrophil count is at least 1000 cells/mm 3 ; 3) Reduce the dose of subsequent courses of paclitaxel inje …

CONTRAINDICATIONS Paclitaxel injection is contraindicated in patients who have a history of hypersensitivity reactions to paclitaxel injection or other drugs formulated in polyoxyl 35 castor oil, NF. Paclitaxel injection should not be used in patients with solid tumors who have baseline neutrophil counts of < 1500 cells/mm 3 or in patients with AIDS-related Kaposi’s sarcoma with baseline neutrophil counts of < 1000 cells/mm 3 .

ADVERSE REACTIONS Pooled Analysis of Adverse Event Experiences from Single-Agent Studies Data in the following table are based on the experience of 812 patients (493 with ovarian carcinoma and 319 with breast carcinoma) enrolled in 10 studies who received single-agent paclitaxel. Two hundred and seventy-five patients were treated in 8, Phase 2 studies with paclitaxel doses ranging from 135 to 300 mg/m 2 administered over 24 hours (in 4 of these studies, G-CSF was administered as hematopoietic support). Three hundred and one patients were treated in the randomized Phase 3 ovarian carcinoma study which compared 2 doses (135 or 175 mg/m 2 ) and 2 schedules (3 or 24 hours) of paclitaxel. Two hundred and thirty-six patients with breast carcinoma received paclitaxel (135 or 175 mg/m 2 ) administered over 3 hours in a controlled study. TABLE 10: SUMMARY a OF ADVERSE EVENTS IN PATIENTS WITH SOLID TUMORS RECEIVING SINGLE-AGENT PACLITAXEL Percent of Patients (n = 812) • Bone Marrow —Neutropenia < 2000/mm 3 90 < 500/mm 3 52 —Leukopenia < 4000/mm 3 90 < 1000/mm 3 17 —Thrombocytopenia < 100,000/mm 3 20 < 50,000/mm 3 7 —Anemia < 11 g/dL 78 < 8 g/dL 16 —Infections 30 —Bleeding 14 —Red Cell Transfusions 25 —Platelet Transfusions 2 • Hypersensitivity Reaction b —All 41 —Severe † 2 • Cardiovascular —Vital Sign Changes c —Bradycardia (n = 537) 3 —Hypotension (n = 532) 12 —Significant Cardiovascular Events 1 • Abnormal ECG —All Pts 23 —Pts with normal baseline (n = 559) 14 • Peripheral Neuropathy —Any symptoms 60 —Severe symptoms † 3 • Myalgia/Arthralgia —Any symptoms 60 —Severe symptoms † 8 • Gastrointestinal —Nausea and vomiting 52 —Diarrhea 38 —Mucositis 31 • Alopecia 87 • Hepatic (Pts with normal baseline and on study data) —Bilirubin elevations (n = 765) 7 —Alkaline phosphatase elevations (n = 575) 22 —AST (SGOT) elevations (n = 591) 19 • Injection Site Reaction 13 a Based on worst course analysis. b All patients received premedication. c During the first 3 hours of infusion. † Severe events are defined as at least Grade III toxicity. None of the observed toxicities were clearly influenced by age. Disease-Specific Adverse Event Experiences First-Line Ovary in Combination For the 1084 patients who were evaluable for safety in the Phase 3 first-line ovary combination therapy studies, TABLE 11 shows the incidence of important adverse events. For both studies, the analysis of safety was based on all courses of therapy (6 courses for the GOG-111 study and up to 9 courses for the Intergroup study). TABLE 11: FREQUENCY a OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA STUDIES Percent of Patients Intergroup GOG-111 T175/3 b c75 c (n = 339) C750 c c75 c (n = 336) T135/24 b c75 c (n = 196) C750 c c75 c (n = 213) • Bone Marrow —Neutropenia < 2000/mm 3 91 d 95 d 96 92 < 500/mm 3 33 d 43 d 81 d 58 d —Thrombocytopenia < 100,000/mm 3e 21 d 33 d 26 30 < 50,000/mm 3 3 d 7 d 10 9 —Anemia < 11 g/dL f 96 97 88 86 < 8 g/dL 3 d 8 d 13 9 —Infections 25 27 21 15 —Febrile Neutropenia 4 7 15 d 4 d • Hypersensitivity Reaction —All 11 d 6 d 8 d,g 1 d,g —Severe † 1 1 3 d,g — d,g • Neurotoxicity h —Any symptoms 87 d 52 d 25 20 —Severe symptoms † 21 d 2 d 3 d — d • Nausea and Vomiting —Any symptoms 88 93 65 69 —Severe symptoms † 18 24 10 11 • Myalgia/Arthralgia —Any symptoms 60 d 27 d 9 d 2 d —Severe symptoms † 6 d 1 d 1 — • Diarrhea —Any symptoms 37 d 29 d 16 d 8 d —Severe symptoms † 2 3 4 1 • Asthenia —Any symptoms NC NC 17 d 10 d —Severe symptoms † NC NC 1 1 • Alopecia —Any symptoms 96 d 89 d 55 d 37 d —Severe symptoms † 51 d 21 d 6 8 a Based on worst course analysis. b Paclitaxel (T) dose in mg/m 2 /infusion duration in hours. c Cyclophosphamide (C) or cisplatin (c) dose in mg/m 2 . d p < 0.05 by Fisher exact test. e < 130,000/mm 3 in the Intergroup study. f < 12 g/dL in the Intergroup study. g All patients received premedication. h In the GOG-111 study, neurotoxicity was collected as peripheral neuropathy and in the Intergroup study, neurotoxi …

DESCRIPTION Paclitaxel Injection USP is a clear, colorless to slightly yellow viscous solution. It is supplied as a nonaqueous solution intended for dilution with a suitable parenteral fluid prior to intravenous infusion. Paclitaxel Injection USP is available in 30 mg (5 mL), 100 mg (16.7 mL), 150 mg (25 mL), and 300 mg (50 mL) multidose vials. Each mL of sterile nonpyrogenic solution contains 6 mg paclitaxel, USP, 527 mg of polyoxyl 35 castor oil, 2 mg of anhydrous citric acid, and 49.7% (v/v) and 39.6% (w/v) dehydrated alcohol. Paclitaxel, USP is a semi-synthetic product with antitumor activity. Paclitaxel, USP is obtained from Taxus species. The chemical name for paclitaxel, USP is 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2 R ,3 S )- N -benzoyl-3-phenylisoserine. Paclitaxel, USP has the following structural formula: C 47 H 51 NO 14 M.W. 853.9 Paclitaxel, USP is a white to off-white crystalline powder. It is highly lipophilic, insoluble in water, and melts at around 216 to 217° C. structural formula

OVERDOSAGE There is no known antidote for paclitaxel injection overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, peripheral neurotoxicity, and mucositis. Overdoses in pediatric patients may be associated with acute ethanol toxicity (see PRECAUTIONS, Pediatric Use ).

HOW SUPPLIED Paclitaxel Injection USP is available as follows: NDC 0703- 3213 -01 30 mg/5 mL Carton containing 1 multiple-dose vial. NDC 0703- 3216 -01 100 mg/16.7 mL Carton containing 1 multiple-dose vial. NDC 0703- 3217 -01 150 mg/25 mL Carton containing 1 multiple-dose vial. NDC 0703- 3218 -01 300 mg/50 mL Carton containing 1 multiple-dose vial. Storage Store the vials in original cartons at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Retain in the original package to protect from light. Handling and Disposal See DOSAGE AND ADMINISTRATION, Preparation and Administration Precautions .