Paclitaxel 6 mg/mL Injection, Solution

WARNINGS 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 ). 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/mm3 (>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.

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) · B one Marrow —Neutropenia <2,000/mm 3 90 <500/mm 3 52 —Leukopenia <4,000/mm 3 90 <1,000/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 · Hy persensitivity Reaction b 2 —All 41 —Severe † 2 · Card i ovascular —Vital Sign Changes c —Bradycardia (n=537) 3 —Hypotension (n=532) 12 —Significant Cardiovascular Events 1 · A bnormal ECG —All Pts 23 —Pts with normal baseline (n=559) 14 · Peripheral Neuropathy —Any symptoms 60 —Severe symptoms † 3 · My algia/Arthralgia —Any symptoms 60 —Severe symptoms † 8 · G astrointestinal —Nausea and vomiting 52 —Diarrhea 38 —Mucositis 31 · Alopecia 87 · Hep atic (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 · Injecti on 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) · B one 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 · 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, neurotoxicity was…

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. Hematology Paclitaxel therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm 3 .

In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving paclitaxel. Patients should not be re-treated with subsequent cycles of paclitaxel until neutrophils recover to a level >1,500 cells/mm 3 and platelets recover to a level >100,000 cells/mm 3 . In the case of severe neutropenia (<500 cells/mm 3 for 7 days or more)during a course of paclitaxel therapy, a 20% reduction in dose for subsequent courses of therapy is recommended.

For patients with advanced HIV disease and poor-risk AIDS-related Kaposi's sarcoma, paclitaxel, at the recommended dose for this disease, can be initiated and repeated if the neutrophil count is at least 1,000 cells/mm 3 . Hypersensitivity Reactions : Patients with a history of severe hypersensitivity reactions to products containing polyoxyl 35 castor oil (e.g., cyclosporin for injection concentrate and teniposide for injection concentrate) should not be treated with paclitaxel. In order to avoid the occurrence of severe hypersensitivity reactions, all patients treated with paclitaxel should be premedicated with corticosteroids (such as dexamethasone), diphenhydramine and H 2 antagonists (such as cimetidine or ranitidine).

Minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia do not require interruption of therapy. However, severe reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria require immediate discontinuation of paclitaxel and aggressive symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with paclitaxel.

Cardiovascular Hypotension, bradycardia, and hypertension have been observed during administration of paclitaxel, but generally do not require treatment. Occasionally paclitaxel infusions must be interrupted or discontinued because of initial or recurrent hypertension. Frequent vital sign monitoring, particularly during…