PACLITAXEL: 77,334 Adverse Event Reports & Safety Profile

Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is paclitaxel formulated as albumin‑bound nanoparticles with a mean particle size of approximately 130 nanometers. Paclitaxel exists in the particles in a non-crystalline, amorphous state. Paclitaxel is a microtubule inhibitor. 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 R ,3 S )- N -benzoyl-3-phenylisoserine. The empirical formula is C 47 H 51 NO 14 and the molecular weight is 853.91. Paclitaxel has the following structural formula: Paclitaxel is a white to off-white crystalline powder. It is highly lipophilic, insoluble in water, and melts at approximately 216°C to 217°C.

Paclitaxel

Protein-Bound Particles for Injectable Suspension (Albumin-Bound) 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‑dose vial contains 100 mg of paclitaxel (bound to human albumin) and approximately 900 mg of human albumin (containing sodium caprylate and sodium acetyltryptophanate), and sodium hydroxide and hydrochloric acid for pH adjustment. Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel formulated as albumin‑bound particles.

Paclitaxel

Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is free of solvents.

Structural

Formula

AND USAGE Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is a microtubule inhibitor indicated for the treatment of:

• Metastatic 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. ( 1.1 )
• Locally advanced or metastatic non-small cell lung cancer (NSCLC), as first-line treatment in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. ( 1.2 )
• Metastatic adenocarcinoma of the pancreas as first-line treatment, in combination with gemcitabine. ( 1.3 )

1.1 Metastatic Breast Cancer Paclitaxel protein-bound particles for injectable suspension (albumin-bound) 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.

1.2 Non-Small Cell Lung Cancer Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

1.3 Adenocarcinoma of the Pancreas Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

AND ADMINISTRATION Do not substitute Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) for other non-protein-bound paclitaxel products. ( 2.1 ) Extravasation : Closely monitor the infusion site for extravasation and infiltration. ( 2.1 )

Metastatic Breast

Cancer (MBC) : Recommended dosage of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is 260 mg/m 2 intravenously over 30 minutes every 3 weeks. ( 2.2 ) Non-Small Cell Lung Cancer (NSCLC) : Recommended dosage of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is 100 mg/m 2 intravenously over 30 minutes on Days 1, 8, and 15 of each 21-day cycle; administer carboplatin on Day 1 of each 21-day cycle immediately after Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound). ( 2.2 ) Adenocarcinoma of the Pancreas : Recommended dosage of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is 125 mg/m 2 intravenously over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle; administer gemcitabine on Days 1, 8 and 15 of each 28-day cycle immediately after Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound). ( 2.4 ) Use in Patients with Hepatic Impairment: Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is not recommended for use in patients with AST greater than 10 x the upper limit of normal (ULN); or bilirubin greater than 5 x ULN or patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment. For MBC or NSCLC, reduce starting dose in patients with moderate to severe hepatic impairment. ( 2.5 )

Dose

Reductions for Adverse Reactions : Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicities. ( 2.6 )

See Full Prescribing

Information for instructions on reconstitution of lyophilized powder, and preparation and administration of the injection.

2.1 Important Administration Instructions DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS.

Paclitaxel

Protein-Bound Particles for Injectable Suspension (Albumin-Bound) has different dosage and administration instructions from other paclitaxel products. Closely monitor the infusion site for extravasation or drug infiltration during administration. Limiting the infusion of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) to 30 minutes may reduce the risk of infusion-related reactions [see Adverse Reactions ( 6.2 )]. Consider premedication in patients who have had prior hypersensitivity reactions to Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound). Do not re-challenge patients who experience a severe hypersensitivity reaction to Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) [see Contraindications ( 4 ) and Warnings and Precautions ( 5.5 )].

2.2 Recommended Dosage for Metastatic Breast Cancer After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is 260 mg/m 2 administered intravenously over 30 minutes every 3 weeks.

2.3 Recommended Dosage for Non-Small Cell Lung Cancer The recommended dose of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is 100 mg/m 2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21-day cycle immediately after Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) <span class="opacity-50 text-xs">[see Clinical Studies ( 14.2 )]</span> .

2.4 Recommended Dosage for Adenocarcinoma of the Pancreas The recommended dose of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is 125 mg/m 2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) on Days 1, 8 and 15 of each 28-day cycle <span class="opacity-50 text-xs">[see Clinical Studies ( 14.3 )]</span>.

2.5 Dosage Modifications for Hepatic Impairment For patients with moderate or severe hepatic impairment, reduce the starting dose of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) as shown in Table 1.

Table

1: Recommendations for Starting Dose in Patients with Moderate and Severe Hepatic Impairment AST = Aspartate Aminotransferase; MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer; ULN = Upper limit of normal. a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 260 mg/m 2 for patients with metastatic breast cancer or 100 mg/m 2 for patients with non-small cell lung cancer in subsequent courses should be considered if the patient tolerates the reduced dose for two cycles. c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic or lung cancer.

Ast

Levels Bilirubin Levels Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) Dose a MBC NSCLC c Adenocarcinoma of Pancreas c Moderate < 10 x ULN AND > 1.5 to ≤ 3 x ULN 200 mg/m 2 b 80 mg/m 2 b not recommended Severe < 10 x ULN AND > 3 to ≤ 5 x ULN 200 mg/m 2 b 80 mg/m 2 b not recommended > 10 x ULN OR > 5 x ULN not recommended not recommended not recommended

2.6 Dosage Modifications for Adverse Reactions Metastatic Breast Cancer Patients who experience severe neutropenia (neutrophils less than 500 cells/mm 3 for a week or longer) or severe sensory neuropathy during Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) therapy should have dosage reduced to 220 mg/m 2 for subsequent courses of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound). For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m 2 .

For Grade

3 sensory neuropathy hold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 , 5.2 ) and Adverse Reactions ( 6.1 )] . Non-Small Cell Lung Cancer Do not administer Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm 3 and platelet count is at least 100,000 cells/mm 3 [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 )]. In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil count of at least 1500 cells/mm 3 and platelet count of at least 100,000 cells/mm 3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm 3 and platelet count of at least 50,000 cells/mm 3 on Days 8 or 15 of the cycle. Upon resumption of dosing, permanently reduce Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and carboplatin doses as outlined in Table 2.

Withhold Paclitaxel

Protein-Bound Particles for Injectable Suspension (Albumin-Bound) for Grade 3-4 peripheral neuropathy.

Resume Paclitaxel

Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and carboplatin at reduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completely resolves [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )] .

Table

2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Reactions in NSCLC Adverse Reaction Occurrence Weekly Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) Dose (mg/m 2 )

Every

3-Week Carboplatin Dose (AUC mg•min/mL)

Neutropenic

Fever (ANC less than 500/mm 3 with fever >38°C) OR Delay of next cycle by more than 7 days for ANC less than 1500/mm 3 OR ANC less than 500/mm 3 for more than 7 days First 75

4.5 Second 50 3 Third Discontinue Treatment Platelet count less than 50,000/mm 3 First 75

4.5 Second Discontinue Treatment Severe sensory Neuropathy – Grade 3 or 4 First 75

4.5 Second 50 3 Third Discontinue Treatment Adenocarcinoma of the Pancreas Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3.

Table

3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas Dose Level Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) (mg/m 2 ) Gemcitabine (mg/m 2 ) Full dose 125 1,000 1 st dose reduction 100 800 2 nd dose reduction 75 600 If additional dose reduction required Discontinue Discontinue Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4.

Table

4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas ANC = Absolute Neutrophil Count Cycle Day ANC (cells/mm 3 ) Platelet count (cells/mm 3 )

Paclitaxel

Protein-Bound Particles for Injectable Suspension (Albumin-Bound) / Gemcitabine Day 1 < 1,500 OR < 100,000 Delay doses until recovery Day 8 500 to < 1,000 OR 50,000 to < 75,000 Reduce 1 dose level < 500 OR < 50,000 Withhold doses Day 15: If Day 8 doses were reduced or given without modification: 500 to < 1,000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8 < 500 OR < 50,000 Withhold doses Day 15: If Day 8 doses were withheld: ≥ 1,000 OR ≥ 75,000 Reduce 1 dose level from Day 1 500 to < 1,000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1 < 500 OR < 50,000 Withhold doses Recommended dose modifications for other adverse reactions in patients with adenocarcinoma of the pancreas are provided in Table 5.

Table

5: Dose Modifications for Other Adverse Reactions in Patients with Adenocarcinoma of the Pancreas Adverse Reaction Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound)

Gemcitabine Febrile

Neutropenia: Grade 3 or 4 Withhold until fever resolves and ANC ≥ 1,500; resume at next lower dose level Peripheral Neuropathy: Grade 3 or 4 Withhold until improves to ≤ Grade 1; resume at next lower dose level No dose reduction Cutaneous Toxicity: Grade 2 or 3 Reduce to next lower dose level; discontinue treatment if toxicity persists Gastrointestinal Toxicity: Grade 3 mucositis or diarrhea Withhold until improves to ≤ Grade 1; resume at next lower dose level

2.7 Preparation for Intravenous Administration Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is a hazardous drug. Follow applicable special handling and disposal procedures. 1 The use of gloves is recommended.

If Paclitaxel

Protein-Bound Particles for Injectable Suspension (Albumin-Bound) (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 Paclitaxel

Protein-Bound Particles for Injectable Suspension (Albumin-Bound) contacts mucous membranes, the membranes should be flushed thoroughly with water.

Paclitaxel

Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is supplied as a sterile lyophilized powder for reconstitution before use. Read the entire preparation instructions prior to reconstitution. Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride Injection, USP. Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum of 1 minute, using the sterile syringe to direct the solution flow onto the INSIDE WALL OF THE VIAL. DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly onto the lyophilized cake as this will result in foaming. Once the injection is complete, allow the vial to sit for a minimum of 5 minutes to ensure proper wetting of the lyophilized cake/powder. Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of any cake/powder occurs. Avoid generation of foam. If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides. Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel. The reconstituted suspension should be milky and homogenous without visible particulates. If particulates or settling are visible, the vial should be gently inverted again to ensure complete resuspension prior to use. Discard the reconstituted suspension if precipitates are observed. Discard any unused portion. Calculate the exact total dosing volume of 5 mg/mL suspension required for the patient and slowly withdraw the dosing volume of the reconstituted suspension from the vial(s) into a syringe: Dosing volume (mL)=Total dose (mg)/5 (mg/mL). Inject the appropriate amount of reconstituted Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) into an empty, sterile intravenous bag [plasticized polyvinyl chloride (PVC) containers, PVC or non-PVC type intravenous bag]. The use of specialized DEHP-free solution containers or administration sets is not necessary to prepare or administer Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) infusions. The use of medical devices containing silicone oil as a lubricant (i.e., syringes and intravenous bags) to reconstitute and administer Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) may result in the formation of proteinaceous strands. Visually inspect the reconstituted Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) suspension in the intravenous bag prior to administration. Discard the reconstituted suspension if proteinaceous strands, particulate matter or discoloration are observed. Figure

2.8 Stability Unopened vials of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) are stable until the date indicated on the package when stored between 20ºC to 25ºC (68ºF to 77ºF) (see USP Controlled Room Temperature) in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Stability of Reconstituted Suspension in the Vial Reconstituted Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) in the vial should be used immediately, but may be refrigerated at 2ºC to 8ºC (36ºF to 46ºF) for a maximum of 24 hours if necessary. If not used immediately, each vial of reconstituted suspension should be replaced in the original carton to protect it from bright light. Discard any unused portion. Stability of Reconstituted Suspension in the Infusion Bag The suspension for infusion when prepared as recommended in an infusion bag should be used immediately, but may be refrigerated at 2°C to 8°C (36°F to 46°F) and protected from bright light for a maximum of 24 hours. The total combined refrigerated storage time of reconstituted Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) in the vial and in the infusion bag is 24 hours. This may be followed by storage in the infusion bag at ambient temperature (approximately 25°C) and lighting conditions for a maximum of 4 hours. Discard any unused portion.

Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is contraindicated in patients with:

• Baseline neutrophil counts of < 1,500 cells/mm 3 [see Warnings and Precautions (5.1) ]
• A history of severe hypersensitivity reactions to paclitaxel protein-bound particles for injectable suspension (albumin-bound) [see Warnings and Precautions (5.5) ]
• Neutrophil counts of < 1,500 cells/mm 3 . ( 4 )
• Severe hypersensitivity reactions to paclitaxel protein-bound particles for injectable suspension (albumin-bound). ( 4 )

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, USP. Two hundred and seventy-five patients were treated in eight Phase 2 studies with paclitaxel doses ranging from 135 to 300 mg/m 2 administered over 24 hours (in four 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 two doses (135 or 175 mg/m 2 ) and two 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 <500/mm 3 - Thrombocytopenia <100,000/mm 3e <50,000/mm 3 - Anemia <11 g/dL f <8 g/dL - Infections - Febrile Neutropenia 91 d 33 d 21 d 3 d 96 3 d 25 4 95 d 43 d 33 d 7 d 97 8 d 27 7 96 81 d 26 10 88 13 21 15 d 92 58 d 30 9 86 9 15 4 d
• Hypersensitivity Reaction - All - Severe † 11 d 1 6 d 1 8 d,g 3 d,g 1 d,g – d,g
• Neurotoxicity h - Any symptoms - Severe symptoms † 87 d 21 d 52 d 2 d 25 3 d 20 – d
• Nausea and Vomiting - Any symptoms - Severe symptoms † 88 18 93 24 65 10 69 11
• Myalgia/Arthralgia - Any symptoms - Severe symptoms † 60 d 6 d 27 d 1 d 9 d 1 2 d –
• Diarrhea - Any symptoms - Severe symptoms † 37 d 2 29 d 3 16 d 4 8 d 1
• Asthenia - Any symptoms - Severe symptoms † NC NC NC NC 17 d 1 10 d 1
• Alopecia - Any symptoms - Severe symptoms † 96 d 51 d 89 d 21 d 55 d 6 37 d 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, neuro toxicity 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, USP 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 3,121 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=1,551) AC c followed by T d (n=1,570 )

• Bone Marrow e - Neutropenia <500/mm 3 - Thrombocytopenia <50,000/mm 3 - Anemia <8 g/dL - Infections - Fever Without Infection 79 27 17 6 – 76 25 21 14 3 48 11 8 5 <1 50 11 8 6 1
• Hypersensitivity Reaction f 1 4 1 2
• Cardio vascular Events 1 2 1 2
• Neuromotor Toxicity 1 1 <1 1
• Neurosensory Toxicity – 3 <1 3
• Myalga/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%. The incidences of severe hematologic toxicities, infections, mucositis, and cardio vascular events increased with higher doses of doxorubicin.

Breast Cancer After

Failure of Initial Chemotherapy: For the 458 patients who received single-agent paclitaxel in the Phase 3 breast carcinoma study, the following table shows the incidence of important adverse events by treatment arm (each arm was administered by a 3-hour infusion).

Table

14. Frequency a of Important Adverse Events in the Phase 3 Study of Breast Cancer after Failure of Initial Chemotherapy or within 6 Months of Adjuvant Chemotherapy Percent of Patients 175/3 b (n=229) 135/3 b (n=229)

• 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 - Febrile Neutropenia 90 28 11 3 55 4 23 2 81 19 7 2 47 2 15 2
• Hypersensitivity Reaction c - All - Severe † 36 0 31 <1
• Peripheral Neuropathy - Any symptoms - Severe symptoms † 70 7 46 3
• Mucositis - Any symptoms - Severe symptoms † 23 3 17 <1 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 and peripheral neuropathy were dose related. There was one severe hypersensitivity reaction (HSR) observed at the dose of 135 mg/m 2 . First-Line NSCLC in Combination: In the study conducted by the Eastern Cooperative Oncology Group (ECOG), patients were randomized to either paclitaxel (T) 135 mg/m 2 as a 24 -hour infusion in combination with cisplatin (c) 75 mg/m 2 , paclitaxel (T) 250 mg/m 2 as a 24 -hour infusion in combination with cisplatin (c) 75 mg/m 2 with G-CSF support, or cisplatin (c) 75 mg/m 2 on day 1, followed by etoposide (VP) 100 mg/m 2 on days 1, 2, and 3 (control). The following table shows the incidence of important adverse events.

Table

15. Frequency a of Important Adverse Events in the Phase 3 Study for First-Line NSCLC Percent of Patients T135/24 b c75 (n=195) T250/24 c c75 (n=197) VP100 d c75 (n=196)

• Bone Marrow - Neutropenia <2,000/mm 3 <500/mm 3 - Thrombocytopenia <normal <50,000/mm 3 - Anemia <normal <8 g/dL - Infections 89 74 e 48 6 94 22 38 86 65 68 12 96 19 31 84 55 62 16 95 28 35
• Hypersensitivity Reaction f - All - Severe † 16 1 27 4 e 13 1
• Arthralgia/Myalgia - Any symptoms - Severe symptoms † 21 e 3 42 e 11 9 1
• Nausea/Vomiting - Any symptoms - Severe symptoms † 85 27 87 29 81 22
• Mucositis - Any symptoms - Severe symptoms † 18 1 28 4 16 2
• Neuromotor Toxicity - Any symptoms - Severe symptoms † 37 6 47 12 44 7
• Neurosensory Toxicity - Any symptoms - Severe symptoms † 48 13 61 28 e 25 8
• Cardiovascular Events - Any symptoms - Severe symptoms † 33 13 39 12 24 8 a Based on worst course analysis. b Paclitaxel (T) dose in mg/m 2 /infusion duration in hours; cisplatin (c) dose in mg/m 2 . c Paclitaxel dose in mg/m 2 /infusion duration in hours with G-CSF support; cisplatin dose in mg /m 2 . d Etoposide (VP) dose in mg/m 2 was administered IV on days 1, 2, and 3; cisplatin dose in mg /m 2 . e p<0.05. f All patients received premedication. † Severe events are defined as at least Grade III Toxicity. Toxicity was generally more severe in the high-dose paclitaxel treatment arm (T250/c75) than in the low-dose paclitaxel arm (T135/c75). Compared to the cisplatin/etoposide arm, patients in the low-dose paclitaxel arm experienced more arthralgia/myalgia of any grade and more severe neutropenia. The incidence of febrile neutropenia was not reported in this study. Kaposi’s Sarcoma: The following table shows the frequency of important adverse events in the 85 patients with KS treated with 2 different single-agent paclitaxel regimens.

Table

16. Frequency a of Important Adverse Events in the Aids –Related Kaposi’s Sarcoma Studies Percent of Patients Study CA139-174 Paclitaxel 135/3 b q 3 wk (n=29) Study CA139-281 Paclitaxel 100/3 b q 2 wk (n=56)

• 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 - Febrile Neutropenia 100 76 52 17 86 34 55 95 35 27 5 73 25 9
• Opportunistic Infection - Any - Cytomegalovirus - Herpes Simplex - Pneumocystis carinii - M. avinum intracellulare - Candidiasis, esophageal - Cryptosporidiosis - Cryptococcal meningitis - Leukoencephalopathy 76 45 38 14 24 7 7 3 - 54 27 11 21 4 9 7 2 2
• Hypersensitivity Reaction c - All 14 9
• Cardio vascular - Hypotension - Bradycardia 17 3 9 –
• Peripheral Neuropathy - Any - Severe † 79 10 46 2
• Myalgia/Arthralgia - Any - Severe † 93 14 48 16
• Gastrointestinal - Nausea and Vomiting - Diarrhea - Mucositis 69 90 45 70 73 20
• Renal (creatinine elevation) - Any - Severe † 34 7 18 5
• Discontinuation for drug toxicity 7 16 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. As demonstrated in this table, toxicity was more pronounced in the study utilizing paclitaxel at a dose of 135 mg/m 2 every 3 weeks than in the study utilizing palcitaxel at a dose of 100 mg/m 2 every 2 weeks. Notably, severe neutropenia (76% vs 35%), febrile neutropenia (55% vs 9%), and opportunistic infections (76% vs 54%) were more common with the former dose and schedule. The differences between the 2 studies with respect to dose escalation and use of hematopoietic growth factors, as described above, should be taken into account. (See CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma. ) Note also that only 26% of the 85 patients in these studies received concomitant treatment with pro tease inhibitors, whose effect on paclitaxel metabolism has not yet been studied.

Adverse Event

Experiences by Body System: The following discussion refers to the overall safety database of 812 patients with solid tumors treated with single-agent paclitaxel in clinical studies. Toxicities that occurred with greater severity or frequency in previously untreated patients with ovarian carcinoma or NSCLC who received paclitaxel in combination with cisplatin or in patients with breast cancer who received paclitaxel after doxorubicin/cyclophosphamide in the adjuvant setting and that occurred with a difference that was clinically significant in these populations are also described. The frequency and severity of important adverse events for the Phase 3 ovarian carcinoma, breast carcinoma, NSCLC, and the Phase 2 Kaposi’s sarcoma carcinoma studies are presented bove in tabular form by treatment arm. In addition, rare events have been reported from postmarketing experience or from other clinical studies. The frequency and severity of adverse events have been generally similar for patients receiving paclitaxel for the treatment of ovarian, breast, or lung carcinoma or Kaposi’s sarcoma, but patients with AIDS-related Kaposi’s sarcoma may have more frequent and severe hematologic toxicity, infections (including opportunistic infections, see Table 16), and febrile neutropenia. These patients require a lower dose intensity and supportive care. (See CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma. ) Toxicities that were observed only in or were noted to have occurred with greater severity in the population with Kaposi’s sarcoma and that occurred with a difference that was clinically significant in this population are described. Elevated liver function tests and renal toxicity have a higher incidence in KS patients as compared to patients with solid tumors. Haematologic: Bone marrow suppression was the major dose-limiting toxicity of paclitaxel. Neutropenia, the most important hematologic toxicity, was dose and schedule dependent and was generally rapidly reversible. Among patients treated in the Phase 3 second line ovarian study with a 3-hour infusion, neutrophil counts declined below 500 cells/mm 3 in 14% of the patients treated with a dose of 135 mg/m 2 compared to 27% at a dose of 175 mg/m 2 (p=0.05). In the same study, severe neutropenia (<500 cells/mm 3 ) was more frequent with the 24 -hour than with the 3-hour infusion; infusion duration had a greater impact on myelosuppression than dose. Neutropenia did not appear to increase with cumulative exposure and did not appear to be more frequent nor more severe for patients previously treated with radiation therapy. In the study where paclitaxel was administered to patients with ovarian carcinoma at a dose of 135 mg/m 2 /24 hours in combination with cisplatin versus the control arm of cyclophosphamide plus cisplatin, the incidences of grade IV neutropenia and of febrile neutropenia were significantly greater in the paclitaxel plus cisplatin arm than in the control arm. Grade IV neutro penia occurred in 81% on the paclitaxel plus cisplatin arm versus 58% on the cyclophosphamide plus cisplatin arm, and febrile neutropenia occurred in 15% and 4% respectively. On the paclitaxel/cisplatin arm, there were 35/1074 (3%) courses with fever in which Grade IV neutro penia was reported at some time during the course. When paclitaxel followed by cisplatin was administered to patients with advanced NSCLC in the ECOG study, the incidences of Grade IV neutropenia were 74% (paclitaxel 135 mg/m 2 /24 hours followed by cisplatin) and 65% (paclitaxel 250 mg/m 2 /24 hours followed by cisplatin and G-CSF) compared with 55% in patients who received cisplatin/etoposide. Fever was frequent (12% of all treatment courses). Infectious episodes occurred in 30% of all patients and 9% of all courses; these episodes were fatal in 1% of all patients, and included sepsis, pneumonia and peritonitis. In the Phase 3 second-line ovarian study, infectious episodes were reported in 20% and 26% of the patients treated with a dose of 135 mg/m 2 or 175 mg/m 2 given as a 3-hour infusion respectively. Urinary tract infections and upper respiratory tract infections were the most frequently reported infectious complications. In the immuno suppressed patient population with advanced HIV disease and poor-risk AIDS-related Kaposi’s sarcoma, 61% of the patients reported at least one opportunistic infection. (See CLINICAL STUDIES: AIDS-Related Kaposi’s sarcoma. ) The use of supportive therapy, including G-CSF, is recommended for patients who have experienced severe neutropenia. (See DOSAGE AND ADMINISTRATION. ) Thrombocytopenia was reported. Twenty percent of the patients experienced a drop in their platelet count below 100,000 cells/mm 3 at least once while on treatment; 7% had a platelet count <50,000 cells/mm 3 at the time of their worst nadir. Bleeding episodes were reported in 4 of all courses and by 14% of all patients but most of the hemorrhagic episodes were localized and the frequency of these events was unrelated to the Paclitaxel Injection, USP dose and schedule. In the Phase 3 second-line ovarian study, bleeding episodes were reported in 10% of the patients; no patients treated with the 3-hour infusion received platelet transfusions. In the adjuvant breast carcinoma trial, the incidence of severe thrombocytopenia and platelet transfusions increased with higher doses of doxorubicin. Anemia (Hb <11 g/dL) was observed in 78% of all patients and was severe (Hb <8 g/dL) in 16% of the cases. No consistent relationship between dose or schedule and the frequency of anemia was observed. Among all patients with normal baseline hemoglobin, 69% became anemic on study but only 7% had severe anemia. Red cell transfusions were required in 25% of all patients and in 12% of those with normal baseline hemoglobin levels.

Hypersensitivity

Reactions (HSRs): All patients received premedication prior to paclitaxel (see WARNINGS and PRECAUTIONS: Hypersensitivity Reactions sections). The frequency and severity of HSRs were not affected by the dose or schedule of paclitaxel administration. In the Phase 3 second-line ovarian study, the 3-hour infusion was not associated with a greater increase in HSRs when compared to the 24-hour infusion. Hypersensitivity reactions were observed in 20% of all courses and in 41% of all patients. These reactions were severe in less than 2% of the patients and 1% of the courses. No severe reactions were observed after course 3 and severe symptoms o ccurred generally within the first hour o f paclitaxel infusion. The most frequent symptoms observed during these severe reactions were dyspnea, flushing, chest pain, and tachycardia. Abdominal pain, pain in the extremities, diaphoresis, and hypertension were also noted. The minor hypersensitivity reactions consisted mostly of flushing (28%), rash (12%), hypotension (4%), dyspnea (2%), tachycardia (2%), and hypertension (1%). The frequency of hypersensitivity reactions remained relatively stable during the entire treatment period. Chills, shock, and back pain in association with hypersensitivity reactions have been reported. Cardiovascular: Hypotension, during the first 3 hours of infusion, occurred in 12% of all patients and 3% of all courses administered. Bradycardia, during the first 3 hours of infusion, occurred in 3% of all patients and 1% of all courses. In the Phase 3 second-line ovarian study, neither dose nor schedule had an effect on the frequency of hypotension and bradycardia. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. The frequency of hypotension and bradycardia were not influenced by prior anthracycline therapy. Significant cardiovascular events possibly related to single-agent paclitaxel occurred in approximately 1% of all patients. These events included syncope, rhythm abnormalities, hypertension and venous thrombosis. One of the patients with syncope treated with paclitaxel at 175 mg/m 2 over 24 hours had progressive hypotension and died. The arrhythmias included asymptomatic ventricular tachycardia, bigeminy and complete AV block requiring pacemaker placement. Among patients with NSCLC treated with paclitaxel in combination with cisplatin in the Phase 3 study, significant cardiovascular events occurred in 12 to 13%. This apparent increase in cardiovascular events is possibly due to an increase in cardiovascular risk factors in patients with lung cancer. Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 23% of all patients. Among patients with a normal ECG prior to study entry, 14% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, sinus tachycardia, and premature beats. Among patients with normal ECGs at baseline, prior therapy with anthracyclines did not influence the frequency of ECG abnormalities. Cases of myocardial infarction have been reported. Congestive heart failure, including cardiac dysfunction and reduction of left ventricular ejection fraction or ventricular failure, has been reported typically in patients who have received other chemotherapy, notably anthracyclines. (See PRECAUTIONS: Drug Interactions section.) Atrial fibrillation and supraventricular tachycardia have been reported. Respiratory: Interstitial pneumonia, lung fibrosis, and pulmonary embolism have been reported. Radiation pneumonitis has been reported in patients receiving concurrent radiotherapy. Pleural effusion and respiratory failure have been reported. Neurologic: The assessment of neurologic toxicity was conducted differently among the studies as evident from the data reported in each individual study (see Tables 10 to 16). Moreover, the frequency and severity of neurologic manifestations were influenced by prior and/or concomitant therapy with neurotoxic agents. In general, the frequency and severity of neurologic manifestations were dose-dependent in patients receiving single-agency paclitaxel. Peripheral neuropathy was observed in 60% of all patients (3% severe) and in 52% (2% severe) of the patients without pre-existing neuropathy. The frequency of peripheral neuropathy increased with cumulative dose. Paresthesia commonly occurs in the form of hyperesthesia. Neurologic symptoms were observed in 27% of the patients after the first course of treatment and in 34% to 51% from course 2 to 10. Peripheral neuropathy was the cause of paclitaxel discontinuation in 1% of all patients. Sensory symptoms have usually improved or resolved within several months of paclitaxel discontinuation. Pre-existing neuropathies resulting from prior therapies are not a contraindication for paclitaxel therapy. In the Intergroup first-line ovarian carcinoma study (see Table 11), neurotoxicity included reports of neuromotor and neurosensory events. The regimen with paclitaxel 175 mg/m 2 given by 3-hour infusion plus cisplatin 75 mg/m 2 resulted in greater incidence and severity of neurotoxicity than the regimen containing cyclophosphamide and cisplatin, 87% (21% severe) versus 52% (2% severe), respectively. The duration of grade III or IV neurotoxicity cannot be determined with precision for the Intergroup study since the resolution dates of adverse events were not collected in the case report forms for this trial and complete follow-up documentation was available only in a minority of these patients. In the GOG first-line ovarian carcinoma study, neurotoxicity was reported as peripheral neuropathy. The regimen with paclitaxel 135 mg/m 2 given by 24-hour infusion plus cisplatin 75 mg/m 2 resulted in an incidence of neurotoxicity that was similar to the regimen containing cyclophosphamide plus cisplatin, 25% (3% severe) versus 20% (0% severe), respectively. Cross-study comparison of neurotoxicity in the Intergroup and GOG trials suggests that when paclitaxel is given in combination with cisplatin 75 mg/m 2 , the incidence of severe neurotoxicity is more common at a paclitaxel dose of 175 mg/m 2 given by 3-hour infusion (21%) than at a dose of 135 mg/m 2 given by 24-hour infusion (3%). In patients with NSCLC, administration of paclitaxel followed by cisplatin resulted in a greater incidence of severe neurotoxicity compared to the incidence in patients with ovarian or breast cancer treated with single-agent paclitaxel. Severe neurosensory symptoms were noted in 13% of NSCLC patients receiving paclitaxel 135 mg/m 2 by 24-hour infusion followed by cisplatin 75 mg/m 2 and 8% of NSCLC patients receiving cisplatin/etoposide (see Table 15). Other than peripheral neuropathy, serious neurologic events following paclitaxel administration have been rare (<1%) and have included grand mal seizures, syncope, ataxia, and neuroencephalopathy. Autonomic neuropathy resulting in paralytic ileus have been reported. Optic nerve and/or visual disturbances (scintillating scotomata) have also been reported, particularly in patients who have received higher doses than those recommended. These effects generally have been reversible. However, rare reports in the literature of abnormal visual evoked potentials in patients have suggested persistent optic nerve damage. Postmarketing reports of ototoxicity (hearing loss and tinnitus) have also been received. Convulsions, dizziness, and headache have been reported. Arthralgia/Myalgia: There was no consistent relationship between dose or schedule of paclitaxel and the frequency or severity of arthralgia/myalgia. Sixty percent of all patients treated experienced arthralgia/myalgia; 8% experienced severe symptoms. The symptoms were usually transient, occurred two or three days after paclitaxel administration, and resolved within a few days. The frequency and severity of musculoskeletal symptoms remained unchanged throughout the treatment period. Hepatic: No relationship was observed between liver function abnormalities and either dose or Schedule of paclitaxel administration. Among patients with normal baseline liver function 7%, 22%, and 19% had elevations in bilirubin, alkaline phosphatase, and AST (SGOT), respectively. Prolonged exposure to paclitaxel was not associated with cumulative hepatic toxicity. Hepatic necrosis and hepatic encephalopathy leading to death have reported. Renal: Among the patients treated for Kaposi’s sarcoma with paclitaxel, 5 patients had renal toxicity of grade III or IV severity. One patient with suspected HIV nephropathy of grade IV severity had to discontinue therapy. The other 4 patients had renal insufficiency with reversible elevations of serum creatinine. Patients with gynecological cancers treated with paclitaxel and cisplatin may have an increased risk of renal failure with the combination therapy of paclitaxel and cisplatin in gynecological cancers as compared to cisplatin alone. Gastrointestinal (GI): Nausea/vomiting, diarrhea, and mucositis were reported by 52%, 38%, and 31% of all patients, respectively. These manifestations were usually mild to moderate. Mucositis was schedule dependent and occurred more frequently with the 24-hour than with the 3-hour infusion. In patients with poor-risk AIDS-related Kaposi’s sarcoma, nausea/vomiting, diarrhea, and mucositis were reported by 69%, 79%, and 28% of patients, respectively. One-third of 43 patients with Kaposi’s sarcoma complained of diarrhea prior to study start. (See CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma. ) In the first-line Phase 3 ovarian carcinoma studies, the incidence of nausea and vomiting when paclitaxel was administered in combination with cisplatin appeared to be greater compared with the database for single-agent paclitaxel in ovarian and breast carcinoma. In addition, diarrhea of any grade was reported more frequently compared to the control arm, but there was no difference for severe diarrhea in these studies. Intestinal obstruction, intestinal perforation, pancreatitis, ischemic colitis, and dehydration have been reported. Neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, were observed in patients treated with paclitaxel alone and in combination with other chemotherapeutic agents.

Injection Site

Reaction: Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. These reactions have been observed more frequently with the 24-hour infusion than with the 3-hour infusion. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel at a different site, i.e., “recall”, has been reported. More severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been reported. In some cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to ten days. A specific treatment for extravasation reactions is unknown at this time. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

Other Clinical

Events: Alopecia was observed in almost all (87%) of the patients. Transient skin changes due to Paclitaxel Injection, USP-related hypersensitivity reactions have been observed, but no other skin toxicities were significantly associated with paclitaxel administration. Nail changes (changes in pigmentation or discoloration of nail bed) were uncommon (2%). Edema was reported in 21% of all patients (17% of those without baseline edema); only 1% had severe edema and none of these patients required treatment discontinuation. Edema was most commonly focal and disease-related. Edema was observed in 5% of all courses for patients with normal baseline and did not increase with time on study. Skin abnormalities related to radiation recall as well as reports of maculopapular rash, pruritus, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported. In postmarketing experience, diffuse edema, thickening, and sclerosing of the skin have been reported following paclitaxel administration. Paclitaxel has been reported to exacerbate signs and symptoms of scleroderma. Reports of asthenia and malaise have been received as part of the continuing surveillance of paclitaxel safety. In the Phase 3 trial of paclitaxel 135 mg/m over 24 hours in combination with cisplatin as firstline therapy of ovarian cancer, asthenia was reported in 17% of the patients, significantly greater than the 10% incidence observed in the control arm of cyclophosphamide/cisplatin. Conjunctivitis, increased lacrimation, anorexia, confusional state, photopsia, visual floaters, vertigo, and increase in blood creatinine have been reported.

Accidental

Exposure: Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

AND PRECAUTIONS Sensory neuropathy occurs frequently and may require dose reduction or treatment interruption. ( 5.2 ) Sepsis occurred in patients with or without neutropenia who received paclitaxel protein-bound particles for injectable suspension (albumin-bound) in combination with gemcitabine; interrupt paclitaxel protein-bound particles for injectable suspension (albumin-bound) and gemcitabine until sepsis resolves, and if neutropenia, until neutrophils are at least 1500 cells/mm 3 , then resume treatment at reduced dose levels. ( 5.3 ) Pneumonitis occurred with the use of paclitaxel protein-bound particles for injectable suspension (albumin-bound) in combination with gemcitabine; permanently discontinue treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound) and gemcitabine. ( 5.4 ) Severe hypersensitivity reactions with fatal outcome have been reported. Do not re-challenge with this drug. ( 4 , 5.5 ) Exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, consider dose reduction and closely monitor patients with hepatic impairment. ( 2.5 , 5.6 ) Paclitaxel protein-bound particles for injectable suspension (albumin-bound) contains albumin derived from human blood, which has a theoretical risk of viral transmission. ( 5.7 ) Paclitaxel protein-bound particles for injectable suspension (albumin-bound) can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ( 5.8 , 8.1 , 8.3 )

5.1 Severe Myelosuppression Severe myelosuppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of paclitaxel protein-bound particles for injectable suspension (albumin-bound). In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer. Monitor for severe neutropenia and thrombocytopenia by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do not administer paclitaxel protein-bound particles for injectable suspension (albumin-bound) to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm 3 <span class="opacity-50 text-xs">[see Contraindications ( 4 ) ]</span> . In the case of severe neutropenia (&lt;500 cells/mm 3 for seven days or more) during a course of paclitaxel protein-bound particles for injectable suspension (albumin-bound) therapy, reduce the dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound) in subsequent courses in patients with either MBC or NSCLC. In patients with MBC, resume treatment with every-3-week cycles of paclitaxel protein-bound particles for injectable suspension (albumin-bound) after ANC recovers to a level &gt;1,500 cells/mm 3 and platelets recover to a level &gt;100,000 cells/mm 3 . In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly paclitaxel protein-bound particles for injectable suspension (albumin-bound) and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm 3 and platelet count of at least 100,000 cells/mm 3 on Day 1 or to an ANC of at least 500 cells/mm 3 and platelet count of at least 50,000 cells/mm 3 on Days 8 or 15 of the cycle <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 ) ]</span>. In patients with adenocarcinoma of the pancreas, withhold paclitaxel protein-bound particles for injectable suspension (albumin-bound) and gemcitabine if the ANC is less than 500 cells/mm 3 or platelets are less than 50,000 cells/mm 3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm 3 or platelet count is less than 100,000 cells/mm 3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 ) ]</span>.

5.2 Severe Neuropathy Sensory neuropathy is dose- and schedule-dependent [ see Adverse Reactions (6.1) ]. If ≥ Grade 3 sensory neuropathy develops, withhold paclitaxel protein-bound particles for injectable suspension (albumin-bound) treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of paclitaxel protein-bound particles for injectable suspension (albumin-bound) <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) ]</span> .

5.3 Sepsis Sepsis occurred in 5% of patients with or without neutropenia who received paclitaxel protein-bound particles for injectable suspension (albumin-bound) in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt paclitaxel protein-bound particles for injectable suspension (albumin-bound) and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) ]</span> .

5.4 Pneumonitis Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving paclitaxel protein-bound particles for injectable suspension (albumin-bound) in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt paclitaxel protein-bound particles for injectable suspension (albumin-bound) and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound) and gemcitabine.

5.5 Severe Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Do not rechallenge patients who experience a severe hypersensitivity reaction to paclitaxel protein-bound particles for injectable suspension (albumin-bound) with this drug. <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . Cross-hypersensitivity between paclitaxel protein-bound particles for injectable suspension (albumin-bound) and other taxane products has been reported and may include severe reactions such as anaphylaxis. Closely monitor patients with a previous history of hypersensitivity to other taxanes during initiation of paclitaxel protein-bound particles for injectable suspension (albumin-bound) therapy.

5.6 Use in Patients with Hepatic Impairment The exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment. Closely monitor patients with hepatic impairment for severe myelosuppression. Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is not recommended in patients who have total bilirubin &gt;5 x ULN or AST &gt;10 x ULN. In addition, paclitaxel protein-bound particles for injectable suspension (albumin-bound) is not recommended in patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment (total bilirubin &gt;1.5 x ULN and AST ≤10 x ULN). Reduce the starting dose for patients with moderate or severe hepatic impairment <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 ) , Use in Specific Populations ( 8.7 ) , Clinical Pharmacology ( 12.3 ) ]</span> .

5.7 Albumin (Human) Paclitaxel protein-bound particles for injectable suspension (albumin-bound) contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

5.8 Embryo-Fetal Toxicity Based on mechanism of action and findings in animals, paclitaxel protein-bound particles for injectable suspension (albumin-bound) can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of paclitaxel formulated as albumin-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. Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception and avoid becoming pregnant during treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound) and for at least six months after the last dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound) <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) , Clinical Pharmacology (12.1) ]</span>. Based on findings from genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception and avoid fathering a child during treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound) and for at least three months after the last dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound) <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) , Nonclinical Toxicology (13.1) ]</span>.

PRECAUTIONS Contact of the undiluted concentrate with plasticized polyvinyl chloride (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 preferably be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. Paclitaxel injection should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns. Use of filter devices such as IVEX-2 ® filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

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 injection 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 CYP2C8 and CYP3A4. Caution should be exercised when paclitaxel injection 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 injection 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 injection, 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 injection therapy should not be administered to patients with baseline neutrophil counts of less than 1500 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 injection. Patients should not be re-treated with subsequent cycles of paclitaxel injection until neutrophils recover to a level > 1500 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 injection 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 injection, at the recommended dose for this disease, can be initiated and repeated if the neutrophil count is at least 1000 cells/mm 3 .

Hypersensitivity Reactions

Patients with a history of severe hypersensitivity reactions to products containing polyoxyl 35 castor oil, NF (e.g., cyclosporin for injection concentrate and teniposide for injection concentrate) should not be treated with paclitaxel injection. In order to avoid the occurrence of severe hypersensitivity reactions, all patients treated with paclitaxel injection 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 injection and aggressive symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with paclitaxel injection.

Cardiovascular

Hypotension, bradycardia, and hypertension have been observed during administration of paclitaxel injection, but generally do not require treatment. Occasionally paclitaxel injection infusions must be interrupted or discontinued because of initial or recurrent hypertension. Frequent vital sign monitoring, particularly during the first hour of paclitaxel injection infusion, is recommended. Continuous cardiac monitoring is not required except for patients with serious conduction abnormalities (see WARNINGS ). When paclitaxel injection is used in combination with doxorubicin for treatment of metastatic breast cancer, monitoring of cardiac function is recommended (see ADVERSE REACTIONS ).

Nervous System

Although the occurrence of peripheral neuropathy is frequent, the development of severe symptomatology is unusual and requires a dose reduction of 20% for all subsequent courses of paclitaxel injection. Paclitaxel injection contains dehydrated alcohol, USP, 396 mg/mL; consideration should be given to possible CNS and other effects of alcohol (see PRECAUTIONS, Pediatric Use ).

Hepatic

There is limited evidence that the myelotoxicity of paclitaxel may be exacerbated in patients with serum total bilirubin > 2 times ULN (see CLINICAL PHARMACOLOGY ). Extreme caution should be exercised when administering paclitaxel injection to such patients, with dose reduction as recommended in DOSAGE AND ADMINISTRATION , TABLE 17 .

Injection Site Reaction

Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. These reactions have been observed more frequently with the 24 hour infusion than with the 3 hour infusion. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall,” has been reported. More severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been reported. In some cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to 10 days. A specific treatment for extravasation reactions is unknown at this time. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of paclitaxel has not been studied. Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). Paclitaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay. Administration of paclitaxel prior to and during mating produced impairment of fertility in male and female rats at doses equal to or greater than 1 mg/kg/day (about 0.04 the daily maximum recommended human dose on a mg/m 2 basis). At this dose, to or greater than 1 mg/kg/day (about 0.04 the daily maximum recommended human on a mg/m 2 basis). At this dose, paclitaxel caused reduced fertility and reproductive indices, and increased embryo- and fetotoxicity (see WARNINGS ).

Pregnancy Teratogenic Effects Pregnancy

Category D (See WARNINGS . )

Nursing

Mothers It is not known whether the drug is excreted in human milk. Following intravenous administration of carbon 14 labeled paclitaxel to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving paclitaxel injection therapy.

Pediatric Use

The safety and effectiveness of paclitaxel injection in pediatric patients have not been established. There have been reports of central nervous system (CNS) toxicity (rarely associated with death) in a clinical trial in pediatric patients in which paclitaxel was infused intravenously over 3 hours at doses ranging from 350 mg/m 2 to 420 mg/m 2 . The toxicity is most likely attributable to the high dose of the ethanol component of the paclitaxel vehicle given over a short infusion time. The use of concomitant antihistamines may intensify this effect. Although a direct effect of the paclitaxel itself cannot be discounted, the high doses used in this study (over twice the recommended adult dosage) must be considered in assessing the discounted; the high doses used in this study safety of paclitaxel for use in this population.

Geriatric Use Of

2228 patients who received paclitaxel in 8 clinical studies evaluating its safety and effectiveness in the treatment of advanced ovarian cancer, breast carcinoma, or NSCLC, and 1570 patients who were randomized to receive paclitaxel in the adjuvant breast cancer study, 649 patients (17%) were 65 years or older and 49 patients (1%) were 75 years or older. In most studies, severe myelosuppression was more frequent in elderly patients; in some studies, severe neuropathy was more common in elderly patients.

In

2 clinical studies in NSCLC, the elderly patients treated with paclitaxel had a higher incidence of cardiovascular events. Estimates of efficacy appeared similar in elderly patients and in younger patients; however, comparative efficacy cannot be determined with confidence due to the small number of elderly patients studied. In a study of first-line treatment of ovarian cancer, elderly patients had a lower median survival than younger patients, but no other efficacy parameters favored the younger group. TABLE 9 presents the incidences of Grade IV neutropenia and severe neuropathy in clinical studies according to age. TABLE 9: SELECTED ADVERSE EVENTS IN GERIATRIC PATIENTS RECEIVING PACLITAXEL IN CLINICAL STUDIES Patients (n/total [%]) Neutropenia (Grade IV)

Peripheral

Neuropathy (Grades III/IV)

Indication

Age (y) Age (y) (Study/Regimen) ≥ 65 < 65 ≥ 65 < 65

• OVARIAN Cancer (Intergroup First-Line/T175/3 c75 a ) 34/83 (41) 78/252 (31) 24/84 (29)* b 46/255 (18) b (GOG-111 First-Line/T135/24 c75 a ) 48/61 (79) 106/129 (82) 3/62 (5) 2/134 (1) (Phase 3 Second-Line/T175/3 c ) 5/19 (26) 21/76 (28) 1/19 (5) 0/76 (0) (Phase 3 Second-Line/T175/24 c ) 21/25 (84) 57/79 (72) 0/25 (0) 2/80 (3) (Phase 3 Second-Line/T135/3 c ) 4/16 (25) 10/81 (12) 0/17 (0) 0/81 (0) (Phase 3 Second-Line/T135/24 c ) 17/22 (77) 53/83 (64) 0/22 (0) 0/83 (0) (Phase 3 Second-Line Pooled) 47/82 (57)* 141/319 (44) 1/83 (1) 2/320 (1)
• Adjuvant BREAST Cancer (Intergroup/AC followed by T d ) 56/102 (55) 734/1468 (50) 5/102 (5) e 46/1468 (3) e
• BREAST Cancer After Failure of Initial Therapy (Phase 3/T175/3 c ) 7/24 (29) 56/200 (28) 3/25 (12) 12/204 (6) (Phase 3/T135/3 c ) 7/20 (35) 37/207 (18) 0/20 (0) 6/209 (3)
• Non-Small Cell LUNG Cancer (ECOG/T135/24 c75 a ) 58/71 (82) 86/124 (69) 9/71 (13) f 16/124 (13) f (Phase 3/T175/3 c80 a ) 37/89 (42)* 56/267 (21) 11/91 (12)* 11/271 (4) * p < 0.05 a Paclitaxel dose in mg/m 2 /infusion duration in hours; cisplatin doses in mg/m 2 . b Peripheral neuropathy was included within the neurotoxicity category in the Intergroup First-Line Ovarian Cancer study (see TABLE 11 ). c Paclitaxel dose in mg/m 2 /infusion duration in hours. d Paclitaxel (T) following 4 courses of doxorubicin and cyclophosphamide (AC) at a dose of 175 mg/m 2 /3 hours every 3 weeks for 4 courses. e Peripheral neuropathy reported as neurosensory toxicity in the Intergroup Adjuvant Breast Cancer study (see TABLE 13 ). f Peripheral neuropathy reported as neurosensory toxicity in the ECOG NSCLC study (see TABLE 15 ). Information for Patients (See Patient Information Leaflet . )

Drug Interactions: In a Phase I 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. In the absence of formal clinical drug interaction studies, caution should be exercised when administering paclitaxel concomitantly with known substrates or inhibitors of the cytochrome P450 isoenzymes CYP2C8 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 section.) 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 retreated 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 seven 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, NF (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 Injection, USP, 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 the first hour of paclitaxel infusion, is recommended. Continuous cardiac monitoring is not required except for patients with serious conduction abnormalities. (See WARNINGS section.) When paclitaxel is used in combination with doxorubicin for treatment of metastatic breast cancer, monitoring of cardiac function is recommended. (See ADVERSE REACTIONS . )

Nervous

System: Although the occurrence of peripheral neuropathy is frequent, the development of severe symptomatology is unusual and requires a dose reduction of 20% for all subsequent courses of paclitaxel. Paclitaxel contains Dehydrated Alcohol USP, 396 mg/mL; consideration should be given to possible CNS and other effects of alcohol. (See PRECAUTIONS: Pediatric Use section.) Hepatic: There is limited evidence that the myelotoxicity of Paclitaxel may be exacerbated in patients with serum total bilirubin >2 times ULN (See CLINICAL PHARMACOLOGY ). Extreme caution should be exercised when administering Paclitaxel to such patients, with dose reduction as recommended in DOSAGE AND ADMINISTRATION , TABLE 17 .

Injection Site

Reaction: Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. These reactions have been observed more frequently with the 24-hour infusion than with the 3-hour infusion. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel at a different site, i.e., “recall”, has been reported. More severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been reported. In some cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to ten days. A specific treatment for extravasation reactions is unknown at this time. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.