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, USP 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 & 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 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 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, diphenhydramine (or its equivalent) 50 mg I.V. 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) or ranitidine (50 mg) I.V. 30 to 60 minutes before paclitaxel. For patients with carcinoma of the ovary the following regimen is recommended (see CLINICAL STUDIES, Ovarian Carcinoma ): 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 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 administered intravenously over 24 hours at a dose of 135 mg/m 2 followed by cisplatin at a dose of 75 mg/m 2 . In patients previously treated with chemotherapy for carcinoma of the ovary, paclitaxel 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 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 ): For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel, 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 ). After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel 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 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 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: Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO); Initiate or repeat treatment with paclitaxel only if the neutrophil count is at least 1,000 cells/mm 3 ; Reduce the dose of subsequent courses of paclitaxel by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm 3 for a week or longer); and Initiate concomitant hematopoietic growth factor (G-CSF) as clinicallyindicated. For the therapy of patients with solid tumors (ovary, breast and NSCLC), courses of paclitaxel should not be repeated until the neutrophil count is at least 1,500 cells/mm 3 and the platelet count is at least 100,000 cells/mm 3 . Paclitaxel should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline or subsequent neutrophil count is less than 1,000 cells/mm 3 . Patients who experience severe neutropenia (neutrophil <500 cells/mm 3 for a week or longer) or severe peripheral neuropathy during paclitaxel therapy should have dosage reduced by 20% for subsequent courses of paclitaxel. The incidence of neurotoxicity and the severity of neutropenia increase with dose. Preparation and Administration Precautions Paclitaxel is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised in handling paclitaxel. The use of gloves is recommended. If paclitaxel solution contacts the skin, wash the skin immediate

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 Injection. 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 <2,000/mm 3 <500/mm 3 - Leukopenia <4,000/mm 3 <1,000/mm 3 - Thrombocytopenia <100,000/mm 3 <50,000/mm 3 - Anemia <11 g/dL <8 g/dL - Infections - Bleeding - Red Cell Transfusions - Platelet Transfusions 90 52 90 17 20 7 78 16 30 14 25 2 Hypersensitivity Reaction b - All - Severe † 41 2 Cardiovascular - Vital Sign Changes c - Bradycardia (n=537) - Hypotension (n=532) - Significant Cardiovascular Events 3 12 1 Abnormal ECG - All Pts - Pts with normal baseline (n=559) 23 14 Peripheral Neuropathy - Any symptoms - Severe symptoms † 60 3 Myalgia/Arthralgia - Any symptoms - Severe symptoms † 60 8 Gastrointestinal - Nausea and vomiting - Diarrhea - Mucositis 52 38 31 Alopecia 87 Hepatic (Pts with normal baseline and on study data) - Bilirubin elevations (n=765) - Alkaline phosphatase elevations (n=575) - AST (SGOT) elevations (n=591) 7 22 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 1,084 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 <2,000/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 Athenia - 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, neurotoxicity was collected as either neuromotor or neurosensory symptoms. † Severe events are defined as at least Grade III toxicity. NC Not Collected. Second-Line Ovary: For the 403 patients who received single-agent paclitaxel injection in the Phase 3 second-line ovarian carcinoma study, the following table shows the incidence of important adverse events. TABLE 12. FREQUENCY a OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 SECOND-LINE OVARIAN CARCINOMA STUDY Percent of Patients 175/3 b (n=95) 175/24 b (n=105) 135/3 b (n=98) 135/24 b (n=105) Bone Marrow - Neutropenia <2,000/mm 3 <500/mm 3 - Thrombocytopenia <100,000/mm 3 <50,000/mm 3 - Anemia <11 g/dL <8 g/dL - Infections 78 27 4 1 84 11 26 98 75 18 7 90 12 29 78 14 8 2 68 6 20 98 67 6 1 88 10 18 Hypersensitivity Reaction c - All - Severe † 41 2 45 0 38 2 45 1 Peripheral Neuropathy - Any symptoms - Severe symptoms † 63 1 60 2 55 0 42 0 Mucositis - Any symptoms - Severe symptoms † 17 0 35 3 21 0 25 2 a Based on worst course analysis. b Paclitaxel dose in mg/m 2 /i

Drug Interactions In a Phase 1 trial using escalating doses of paclitaxel (110 to 200 mg/m 2 ) and cisplatin (50 or 75 mg/m 2 ) given as sequential infusions, myelosuppression was more profound when paclitaxel was given after cisplatin than with the alternate sequence (i.e., paclitaxel before cisplatin). Pharmacokinetic data from these patients demonstrated a decrease in paclitaxel clearance of approximately 33% when paclitaxel was administered following cisplatin. The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Caution should be exercised when administering paclitaxel concomitantly with known substrates or inhibitors of the cytochrome P450 isoenzymes CTP2C8 and CYP3A4. Caution should be exercised when paclitaxel is concomitantly administered with known substrates (e.g., midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (e.g., rifampin and carbamazepine) of CYP3A4. (see CLINICAL PHARMACOLOGY ). Caution should also be exercised when paclitaxel is concomitantly administered with known substrates (e.g., repaglinide and rosiglitazone), inhibitors (e.g., gemfibrozil), and inducers (e.g., rifampin) of CYP2C8. (see CLINICAL PHARMACOLOGY ). Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors (ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of CYP3A4, have not been evaluated in clinical trials. Reports in the literature suggest that plasma levels of doxorubicin (and its active metabolite doxorubicinol) may be increased when paclitaxel and doxorubicin are used in combination.