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.
Contraindications
Paclitaxel is contraindicated in patients who have a history of hypersensitivity reactions to paclitaxel or other drugs formulated in polyoxyl 35 castor oil. Paclitaxel should not be used in patients with solid tumors who have baseline neutrophil counts of <1,500 cells/mm 3 or in patients with AIDS-related Kaposi's sarcoma with baseline neutrophil counts of <1,000 cells/mm 3 .
Warnings and precautions
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2 to 4% of patients receiving paclitaxel in clinical trials. Fatal reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H 2 antagonists. (see DOSAGE AND ADMINISTRATION ).
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Patients who experience severe hypersensitivity reactions to paclitaxel should not be rechallenged with the drug. Bone marrow suppression (primarily neutropenia) is dose-dependent and is the dose-limiting toxicity. Neutrophil nadirs occurred at a median of 11 days. Paclitaxel should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm 3 (<1,000 cells/mm 3 for patients with KS). Frequent monitoring of blood counts should be instituted during paclitaxel treatment.
Patients should not be re-treated with subsequent cycles of paclitaxel until neutrophils recover to a level >1,500 cells/mm 3 (>1,000 cells/mm 3 for patients with KS) and platelets recover to a level >100,000 cells/mm 3 . Severe conduction abnormalities have been documented in <1% of patients during paclitaxel therapy and in some cases requiring pacemaker placement. If patients develop significant conduction abnormalities during paclitaxel infusion, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with paclitaxel.
Pregnancy Paclitaxel can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel during the period of organogenesis to rabbits at doses of 3 mg/kg/day (about 0.2 the daily maximum recommended human dose on a mg/m 2 basis) caused embryo- and fetotoxicity, as indicated by intrauterine mortality, increased resorptions, and increased fetal deaths. Maternal toxicity was also observed at this dose.
No teratogenic effects were observed at 1 mg/kg/day (about 1/15 the daily maximum recommended human dose on a mg/m 2 basis); teratogenic potential could not be assessed at higher doses due to extensive fetal mortality. There are no adequate and well-controlled studies in pregnant women. If paclitaxel 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 child-bearing potential should be advised to avoid becoming pregnant.
Interactions
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.
Pregnancy and breastfeeding
Pregnancy (See WARNINGS section).
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 /infusion duration in hours. c All patients received premedication. † Severe events are defined as at least Grade III toxicity.
Myelosuppression was dose and schedule related, with the schedule effect being more prominent. The development of severe hypersensitivity reactions (HSRs) was rare; 1% of the patients and 0.2% of the courses overall. There was no apparent dose or schedule effect seen for the HSRs. Peripheral neuropathy was clearly dose-related, but schedule did not appear to affect the incidence. Adjuvant Breast For the Phase 3 adjuvant breast carcinoma study, the following table shows the incidence of important severe adverse events for the 3121 patients (total population) who were evaluable for safety as well as for a group of 325 patients (early population) who, per the study protocol, were monitored more intensively than other patients.
TABLE 13. FREQUENCY a OF IMPORTANT SEVERE b ADVERSE EVENTS IN THE PHASE 3 ADJUVANT BREAST CARCINOMA STUDY Percent of Patients Early Population Total Population AC c (n=166) AC c followed by T d (n=159) AC c (n=1551) AC c followed by T d (n=1570) Bone Marrow e - Neutropenia <500/mm 3 79 76 48 50 - Thrombocytopenia <50,000/mm 3 27 25 11 11 - Anemia <8 g/dL 17 21 8 8 - Infections 6 14 5 6 - Fever Without Infection – 3 <1 1 Hypersensitivity Reaction f 1 4 1 2 Cardiovascular Events 1 2 1 2 Neuromotor Toxicity 1 1 <1 1 Neurosensory Toxicity – 3 <1 3 Myalgia/Arthralgia – 2 <1 2 Nausea/Vomiting 13 18 8 9 Mucositis 13 4 6 5 a Based on worst course analysis. b Severe events are defined as at least Grade III toxicity. c Patients received 600 mg/m 2 cyclophosphamide and doxorubicin (AC) at doses of either 60 mg/m 2 , 75 mg/m 2 , or 90 mg/m 2 (with prophylactic G-CSF support and ciprofloxacin), every 3 weeks for 4 courses. d Paclitaxel (T) following 4 courses of AC at a dose of 175 mg/m 2 /3 hours every 3 weeks for 4 courses. e The incidence of febrile neutropenia was not reported in this study. f All patients were to receive premedication.
The incidence of an adverse event for the total population likely represents an underestimation of the actual incidence given that safety data were collected differently based on enrollment cohort. However, since safety data were collected consistently across regimens, the safety of the sequential addition of paclitaxel following AC therapy may be compared with AC therapy alone. Compared to patients who received AC alone, patients who received AC followed by paclitaxel experienced more Grade III/IV neurosensory toxicity, more Grade III/IV myalgia/arthralgia, more Grade III/IV neurologic pain (5% vs 1%), more Grade III/IV flu-like symptoms (5% vs 3%), and more Grade III/IV hyperglycemia (3% vs 1%).
During the additional 4 courses of treatment with paclitaxel, 2 deaths (0.1%) were attributed to treatment. During paclitaxel treatment, Grade IV neutropenia was reported for 15% of patients, Grade II/III neurosensory toxicity for 15%, Grade II/III myalgias for 23%, and alopecia for 46%
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Composition
Active ingredients
PACLITAXEL 6MG/ML
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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