TAXOL (paclitaxel) Injection is a clear, colorless to slightly yellow viscous solution. It is supplied as a nonaqueous solution intended for dilution with a suitable parenteral fluid prior to intravenous infusion. TAXOL is available in 30 mg (5 mL), 100 mg (16.7 mL), and 300 mg (50 mL) multidose vials. Each mL of sterile nonpyrogenic solution contains 6 mg paclitaxel, 527 mg of purified Cremophor® EL* (polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, USP.

Paclitaxel is a natural product with antitumor activity. TAXOL (paclitaxel) is obtained via a semi-synthetic process from Taxus baccata. 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 (2R,3S)-N-benzoyl-3-phenylisoserine.

Paclitaxel has the following structural formula:

Paclitaxel is a white to off-white crystalline powder with the empirical formula C47H51NO14 and a molecular weight of 853.9. It is highly lipophilic, insoluble in water, and melts at around 216-217° C.

TAXOL is indicated as first-line and subsequent therapy for the treatment of advanced carcinoma of the ovary. As first-line therapy, TAXOL is indicated in combination with cisplatin.

TAXOL 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.)

TAXOL 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.

TAXOL, 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.

TAXOL is indicated for the second-line treatment of AIDS-related Kaposi's sarcoma.

Note: Contact of the undiluted concentrate with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC infusion bags or sets, diluted TAXOL solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

All patients should be premedicated prior to TAXOL administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours before TAXOL, diphenhydramine (or its equivalent) 50 mg IV 30 to 60 minutes prior to TAXOL, and cimetidine (300 mg) or ranitidine (50 mg) IV 30 to 60 minutes before TAXOL.

For patients with carcinoma of the ovary, the following regimens are recommended (see Clinical Studies: Ovarian Carcinoma):

1. For previously untreated patients with carcinoma of the ovary, one of the following recommended regimens may be given every 3 weeks. In selecting the appropriate regimen, differences in toxicities should be considered (see TABLE 11 in ADVERSE REACTIONS: Disease-Specific Adverse Event Experiences).
   1. TAXOL administered intravenously over 3 hours at a dose of 175 mg/m² followed by cisplatin at a dose of 75 mg/m²; or
   2. TAXOL administered intravenously over 24 hours at a dose of 135 mg/m² followed by cisplatin at a dose of 75 mg/m².
2. In patients previously treated with chemotherapy for carcinoma of the ovary, TAXOL has been used at several doses and schedules; however, the optimal regimen is not yet clear. The recommended regimen is TAXOL 135 mg/m² or 175 mg/m² administered intravenously over 3 hours every 3 weeks.

For patients with carcinoma of the breast, the following regimens are recommended (see Clinical Studies: Breast Carcinoma):

1. For the adjuvant treatment of node-positive breast cancer, the recommended regimen is TAXOL, at a dose of 175 mg/m² intravenously over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used 4 courses of doxorubicin and cyclophosphamide (see Clinical Studies: Breast Carcinoma).
2. After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, TAXOL at a dose of 175 mg/m² administered intravenously over 3 hours every 3 weeks has been shown to be effective.

For patients with non-small cell lung carcinoma, the recommended regimen, given every 3 weeks, is TAXOL administered intravenously over 24 hours at a dose of 135 mg/m² followed by cisplatin, 75 mg/m².

For patients with AIDS-related Kaposi's sarcoma, TAXOL administered at a dose of 135 mg/m² given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m² given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45- 50 mg/m²/week). In the 2 clinical trials evaluating these schedules (see Clinical Studies: AIDS-Related Kaposi's Sarcoma), the former schedule (135 mg/m² every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m² every 2 weeks).

Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients:

1. Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO);
2. Initiate or repeat treatment with TAXOL only if the neutrophil count is at least 1000 cells/mm³;
3. Reduce the dose of subsequent courses of TAXOL by 20% for patients who experience severe neutropenia (neutrophil < 500 cells/mm³ for a week or longer); and
4. Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.

For the therapy of patients with solid tumors (ovary, breast, and NSCLC), courses of TAXOL should not be repeated until the neutrophil count is at least 1500 cells/mm³ and the platelet count is at least 100,000 cells/mm³. TAXOL should not be given to patients with AIDS-related Kaposi's sarcoma if the baseline or subsequent neutrophil count is less than 1000 cells/mm³. Patients who experience severe neutropenia (neutrophil < 500 cells/mm³ for a week or longer) or severe peripheral neuropathy during TAXOL therapy should have dosage reduced by 20% for subsequent courses of TAXOL. The incidence of neurotoxicity and the severity of neutropenia increase with dose.

Hepatic Impairment: Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III-IV myelosuppression (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Hepatic). Recommendations for dosage adjustment for the first course of therapy are shown in TABLE 17 for both 3- and 24-hour infusions. Further dose reduction in subsequent courses should be based on individual tolerance. Patients should be monitored closely for the development of profound myelosuppression.

TABLE 17: RECOMMENDATIONS FOR DOSING IN PATIENTS WITH HEPATIC IMPAIRMENT BASED ON CLINICAL TRIAL DATA^a

Degree of Hepatic Impairment
Transaminase Levels	Bilirubin Levelsb	Recommended TAXOL Dosec
24-hour infusion
< 2 × ULN and	≤ 1.5 mg/dL	135 mg/m2
2 to < 10 × ULN and	≤ 1.5 mg/dL	100 mg/m2
< 10 × ULN and	1.6-7.5 mg/dL	50 mg/m2
≥ 10 × ULN or	> 7.5 mg/dL	Not recommended
3-hour infusion
< 10 × ULN and	≤ 1.25 x ULN	175 mg/m2
< 10 × ULN and	1.26-2.0 × ULN	135 mg/m2
< 10 × ULN and	2.01-5.0 × ULN	90 mg/m2
≥ 10 × ULN or	> 5.0 x ULN	Not recommended
a These recommendations are based on dosages for patients without hepatic impairment of 135 mg/m2 over 24 hours or 175 mg/m2 over 3 hours; data are not available to make dose adjustment recommendations for other regimens (eg, for AIDS-related Kaposi's sarcoma). b Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to differences in clinical trial design. c Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance.

Preparation and Administration Precautions

TAXOL is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised in handling TAXOL. The use of gloves is recommended. If TAXOL solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. If TAXOL contacts mucous membranes, the membranes should be flushed thoroughly with water. Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration (see PRECAUTIONS: Injection Site Reaction).

Preparation for Intravenous Administration

TAXOL (paclitaxel) Injection must be diluted prior to infusion. TAXOL should be diluted in 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; or 5% Dextrose in Ringer's Injection to a final concentration of 0.3 to 1.2 mg/mL. The solutions are physically and chemically stable for up to 27 hours at ambient temperature (approximately 25° C) and room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. No significant losses in potency have been noted following simulated delivery of the solution through IV tubing containing an in-line (0.22 micron) filter.

Data collected for the presence of the extractable plasticizer DEHP [di-(2- ethylhexyl)phthalate] show that levels increase with time and concentration when dilutions are prepared in PVC containers. Consequently, the use of plasticized PVC containers and administration sets is not recommended. TAXOL solutions should be prepared and stored in glass, polypropylene, or polyolefin containers. Non-PVC containing administration sets, such as those which are polyethylene-lined, should be used.

TAXOL 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.

The Chemo Dispensing Pin™ device or similar devices with spikes should not be used with vials of TAXOL since they can cause the stopper to collapse resulting in loss of sterile integrity of the TAXOL solution.

Stability

Unopened vials of TAXOL (paclitaxel) Injection are stable until the date indicated on the package when stored between 20°-25° C (68°-77° F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration, components in the TAXOL vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation. There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25° C) and lighting conditions for up to 27 hours.

NDC 0015-3475-30..........30 mg/5 mL multidose vial individually packaged in a carton.
NDC 0015-3476-30..........100 mg/16.7 mL multidose vial individually packaged in a carton.
NDC 0015-3479-11.......... 300 mg/50 mL multidose vial individually packaged in a carton.

Storage

Store the vials in original cartons between 20°-25° C (68°-77° F). Retain in the original package to protect from light.

Handling and Disposal

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.^1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing TAXOL Injection. This includes all handling activities in clinical settings, pharmacies, storerooms, and home healthcare settings, including during unpacking and inspection, transport within a facility, and dose preparation and administration.

REFERENCES

1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society; 1999:32- 41.

2. Recommendations for the safe handling of cytotoxic drugs. Washington, DC: Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, National Institutes of Health; 1992. US Dept of Health and Human Services, Public Health Service Publication NIH 92-2621.

3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1592.

4. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.

5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Aust. 1983;1:426-428.

6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from The Mount Sinai Medical Center. CA Cancer J Clin. 1983;33:258-263.

7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049.

8. Controlling occupational exposure to hazardous drugs. (OSHA Work-Practice Guidelines.) Am J Health-Syst Pharm. 1996;53:1669-1685.

Bristol-Myers Squibb Company, Princeton, NJ 08543, USA. Rev July 2007. FDA rev date: 3/5/2003

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 TAXOL. Two hundred and seventy-five patients were treated in 8, Phase 2 studies with TAXOL doses ranging from 135 to 300 mg/m² 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/m²) and 2 schedules (3 or 24 hours) of TAXOL. Two hundred and thirty-six patients with breast carcinoma received TAXOL (135 or 175 mg/m²) administered over 3 hours in a controlled study.

TABLE 10: SUMMARY^a OF ADVERSE EVENTS IN PATIENTS WITH SOLID TUMORS RECEIVING SINGLE-AGENT TAXOL

	Percent of Patients (n=812)
•Bone Marrow
-Neutropenia < 2000/mm3	90
< 500/mm3	52
-Leukopenia < 4000/mm3	90
< 1000/mm3	17
-Thrombocytopenia < 100,000/mm3	20
< 50,000/mm3	7
-Anemia < 11 g/dL	78
< 8 g/dL	16
-Infections	30
-Bleeding	14
-Red Cell Transfusions	25
-Platelet Transfusions	2
•Hypersensitivity Reactionb
-All	41
-Severe†	2
•Cardiovascular
-Vital Sign Changesc
-Bradycardia (n=537)	3
-Hypotension (n=532)	12
-Significant Cardiovascular Events	1
•Abnormal ECG
-All Pts	23
-Pts with normal baseline (n=559)	14
•Peripheral Neuropathy
-Any symptoms	60
-Severe symptoms†	3
•Myalgia/Arthralgia
-Any symptoms	60
-Severe symptoms†	8
•Gastrointestinal
-Nausea and vomiting	52
-Diarrhea	38
-Mucositis	31
•Alopecia	87
•Hepatic (Pts with normal baseline and on study data)
-Bilirubin elevations (n=765)	7
-Alkaline phosphatase elevations (n=575)	22
-AST (SGOT) elevations (n=591)	19
•Injection Site Reaction	13
a Based on worst course analysis. b All patients received premedication. c During the first 3 hours of infusion. †Severe events are defined as at least Grade III toxicity.None of the observed toxicities were clearly influenced by age.

Disease-Specific Adverse Event Experiences

First-Line Ovary in Combination: For the 1084 patients who were evaluable for safety in the Phase 3 first-line ovary combination therapy studies, TABLE 11 shows the incidence of important adverse events. For both studies, the analysis of safety was based on all courses of therapy (6 courses for the GOG-111 study and up to 9 courses for the Intergroup study).

TABLE 11: FREQUENCY^a OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 FIRST- LINE OVARIAN CARCINOMA STUDIES

	Percent of Patients
	Intergroup		GOG-111
	T175/3b	C750c	T135/24b	C750c
	c75c	c75c	c75c	c75c
	(n=339)	(n=336)	(n=196)	(n=213)
• Bone Marrow
-Neutropenia < 2000/mm3	91d	95d	96	92
< 500/mm3	33d	43d	81d	58d
-Thrombocytopenia < 100,000/mm3e	21d	33d	26	30
< 50,000/mm3	3d	7d	10	9
-Anemia < 11 g/dLf	96	97	88	86
< 8 g/dL	3d	8d	13	9
-Infections	25	27	21	15
-Febrile Neutropenia	4	7	15d	4d
•Hypersensitivity Reaction
-All	11d	6d	8d,g	1d,g
-Severe†	1	1	3d,g	-d,g
• Neurotoxicityh
-Any symptoms	87d	52d	25	20
-Severe symptoms†	21d	2d	3d	-d
•Nausea and Vomiting
-Any symptoms	88	93	65	69
-Severe symptoms†	18	24	10	11
• Myalgia/Arthralgia
-Any symptoms	60d	27d	9d	2d
-Severe symptoms†	6d	1d	1	-
•Diarrhea
-Any symptoms	37d	29d	16d	8d
-Severe symptoms†	2	3	4	1
•Asthenia
-Any symptoms	NC	NC	17d	10d
-Severe symptoms†	NC	NC	1	1
• Alopecia
-Any symptoms	96d	89d	55d	37d
-Severe symptoms†	51d	21d	6	8
a Based on worst course analysis. b TAXOL (T) dose in mg/m2/infusion duration in hours. c Cyclophosphamide (C) or cisplatin (c) dose in mg/m2. d p < 0.05 by Fisher exact test. e < 130,000/mm3 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 TAXOL 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
	175/3b	175/24b	135/3b	135/24b
	(n=95)	(n=105)	(n=98)	(n=105)
•Bone Marrow
-Neutropenia < 2000/mm3	78	98	78	98
< 500/mm3	27	75	14	67
-Thrombocytopenia < 100,000/mm3	4	18	8	6
< 50,000/mm3	1	7	2	1
-Anemia < 11 g/dL	84	90	68	88
< 8 g/dL	11	12	6	10
-Infections	26	29	20	18
•Hypersensitivity Reactionc
-All	41	45	38	45
-Severe†	2	0	2	1
•Peripheral Neuropathy
-Any symptoms	63	60	55	42
-Severe symptoms†	1	2	0	0
•Mucositis
-Any symptoms	17	35	21	25
-Severe symptoms†	0	3	0	2
a Based on worst course analysis. b TAXOL dose in mg/m2/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 SEVEREb ADVERSE EVENTS IN THE PHASE 3 ADJUVANT BREAST CARCINOMA STUDY

	Percent of Patients
	Early Population		Total Population
	ACc	ACc followed by Td	ACc	ACc followed by Td
	(n=166)	(n=159)	(n=1551)	(n=1570)
•Bone Marrowe
-Neutropenia < 500/mm3	79	76	48	50
-Thrombocytopenia < 50,000/mm3	27	25	11	11
-Anemia < 8 g/dL	17	21	8	8
-Infections	6	14	5	6
-Fever Without Infection	-	3	< 1	1
• Hypersensitivity Reactionf	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/m2 cyclophosphamide and doxorubicin (AC) at doses of either 60 mg/m2,75 mg/m2, or 90 mg/m2 (with prophylactic G-CSF support and ciprofloxacin), every 3 weeks for 4courses. d TAXOL (T) following 4 courses of AC at a dose of 175 mg/m2/3 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 TAXOL (paclitaxel) following AC therapy may be compared with AC therapy alone. Compared to patients who received AC alone, patients who received AC followed by TAXOL 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 TAXOL, 2 deaths (0.1%) were attributed to treatment. During TAXOL 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 cardiovascular events increased with higher doses of doxorubicin.

Breast Cancer After Failure of Initial Chemotherapy: For the 458 patients who received single-agent TAXOL 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
	175/3b	135/3b
	(n=229)	(n=229)
• Bone Marrow
-Neutropenia < 2000/mm3	90	81
< 500/mm3	28	19
-Thrombocytopenia < 100,000/mm3	11	7
< 50,000/mm3	3	2
-Anemia < 11 g/dL	55	47
< 8 g/dL	4	2
-Infections	23	15
-Febrile Neutropenia	2	2
• Hypersensitivity Reactionc
-All	36	31
-Severe†	0	< 1
• Peripheral Neuropathy
-Any symptoms	70	46
-Severe symptoms†	7	3
•Mucositis
-Any symptoms	23	17
-Severe symptoms†	3	< 1
a Based on worst course analysis. b TAXOL dose in mg/m2/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/m².

First-Line NSCLC in Combination: In the study conducted by the Eastern Cooperative Oncology Group (ECOG), patients were randomized to either TAXOL (T) 135 mg/m² as a 24-hour infusion in combination with cisplatin (c) 75 mg/m², TAXOL (T) 250 mg/m² as a 24-hour infusion in combination with cisplatin (c) 75 mg/m² with G-CSF support, or cisplatin (c) 75 mg/m² on day 1, followed by etoposide (VP) 100 mg/m² 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
	T135/24b	T250/24c	VP100d
	c75	c75	c75
	(n=195)	(n=197)	(n=196)
• Bone Marrow
-Neutropenia < 2000/mm3	89	86	84
< 500/mm3	74e	65	55
-Thrombocytopenia < normal	48	68	62
< 50,000/mm3	6	12	16
-Anemia < normal	94	96	95
< 8 g/dL	22	19	28
-Infections	38	31	35
•Hypersensitivity Reactionf
-All	16	27	13
-Severe†	1	4e	1
•Arthralgia/Myalgia
-Any symptoms	21e	42e	9
-Severe symptoms†	3	11	1
•Nausea/Vomiting
-Any symptoms	85	87	81
-Severe symptoms†	27	29	22
•Mucositis
-Any symptoms	18	28	16
-Severe symptoms†	1	4	2
•Neuromotor Toxicity
-Any symptoms	37	47	44
-Severe symptoms†	6	12	7
•Neurosensory Toxicity
-Any symptoms	48	61	25
-Severe symptoms†	13	28e	8
•Cardiovascular Events
-Any symptoms	33	39	24
-Severe symptoms†	13	12	8
a Based on worst course analysis. b TAXOL (T) dose in mg/m2/infusion duration in hours; cisplatin (c) dose in mg/m2. c TAXOL dose in mg/m2/infusion duration in hours with G-CSF support; cisplatin dose in mg/m2. d Etoposide (VP) dose in mg/m2 was administered IV on days 1, 2, and 3; cisplatin dose in mg/m2. 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 TAXOL treatment arm (T250/c75) than in the low-dose TAXOL arm (T135/c75). Compared to the cisplatin/etoposide arm, patients in the low-dose TAXOL 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 TAXOL (paclitaxel) regimens.

TABLE 16: FREQUENCY^a OF IMPORTANT ADVERSE EVENTS IN THE AIDS-RELATED KAPOSI'S SARCOMA STUDIES

	Percent of Patients
	Study CA139-174	Study CA139-281
	TAXOL 135/3b q 3 wk	TAXOL 100/3b q 2 wk
	(n=29)	(n=56)
•Bone Marrow
-Neutropenia < 2000/mm3	100	95
< 500/mm3	76	35
-Thrombocytopenia < 100,000/mm3	52	27
< 50,000/mm3	17	5
-Anemia < 11 g/dL	86	73
< 8 g/dL	34	25
-Febrile Neutropenia	55	9
•Opportunistic Infection
-Any	76	54
-Cytomegalovirus	45	27
-Herpes Simplex	38	11
-Pneumocystis carinii	14	21
-M. avium intracellulare	24	4
-Candidiasis, esophageal	7	9
-Cryptosporidiosis	7	7
-Cryptococcal meningitis	3	2
-Leukoencephalopathy	-	2
•Hypersensitivity Reactionc
-All	14	9
•Cardiovascular
-Hypotension	17	9
-Bradycardia	3	-
•Peripheral Neuropathy
-Any	79	46
-Severe†	10	2
•Myalgia/Arthralgia
-Any	93	48
-Severe†	14	16
•Gastrointestinal
-Nausea and Vomiting	69	70
-Diarrhea	90	73
-Mucositis	45	20
• Renal (creatinine elevation)
-Any	34	18
-Severe†	7	5
• Discontinuation for drug toxicity	7	16
a Based on worst course analysis. b TAXOL dose in mg/m2/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 TAXOL (paclitaxel) at a dose of 135 mg/m² every 3 weeks than in the study utilizing TAXOL at a dose of 100 mg/m² 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 protease inhibitors, whose effect on paclitaxel metabolism has not yet been studied.

Adverse Event Experiences by Body System

Unless otherwise noted, the following discussion refers to the overall safety database of 812 patients with solid tumors treated with single-agent TAXOL in clinical studies. Toxicities that occurred with greater severity or frequency in previously untreated patients with ovarian carcinoma or NSCLC who received TAXOL in combination with cisplatin or in patients with breast cancer who received TAXOL 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 studies are presented above 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 TAXOL 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 trend of incidence in KS patients as compared to patients with solid tumors.

Hematologic: Bone marrow suppression was the major dose-limiting toxicity of TAXOL. 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/mm³ in 14% of the patients treated with a dose of 135 mg/m² compared to 27% at a dose of 175 mg/m² (p=0.05). In the same study, severe neutropenia ( < 500 cells/mm³) 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 TAXOL was administered to patients with ovarian carcinoma at a dose of 135 mg/m²/24 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 TAXOL plus cisplatin arm than in the control arm. Grade IV neutropenia occurred in 81% on the TAXOL plus cisplatin arm versus 58% on the cyclophosphamide plus cisplatin arm, and febrile neutropenia occurred in 15% and 4% respectively. On the TAXOL/cisplatin arm, there were 35/1074 (3%) courses with fever in which Grade IV neutropenia was reported at some time during the course. When TAXOL followed by cisplatin was administered to patients with advanced NSCLC in the ECOG study, the incidences of Grade IV neutropenia were 74% (TAXOL 135 mg/m²/24 hours followed by cisplatin) and 65% (TAXOL 250 mg/m²/24 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/m² or 175 mg/m² given as 3-hour infusions, respectively. Urinary tract infections and upper respiratory tract infections were the most frequently reported infectious complications. In the immunosuppressed 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 uncommon, and almost never severe ( < 50,000 cells/mm³). Twenty percent of the patients experienced a drop in their platelet count below 100,000 cells/mm³ at least once while on treatment; 7% had a platelet count < 50,000 cells/mm³ 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 TAXOL 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 TAXOL (see WARNINGS and PRECAUTIONS: Hypersensitivity Reactions). The frequency and severity of HSRs were not affected by the dose or schedule of TAXOL 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 occurred generally within the first hour of TAXOL 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.

Rare reports of chills and shock, and reports of back pain in association with hypersensitivity reactions have been received as part of the continuing surveillance of TAXOL safety.

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 TAXOL (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 TAXOL at 175 mg/m² 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 TAXOL 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 rarely. 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)

Rare reports of atrial fibrillation and supraventricular tachycardia have been received as part of the continuing surveillance of TAXOL safety.

Respiratory: Rare reports of interstitial pneumonia, lung fibrosis, and pulmonary embolism have been received as part of the continuing surveillance of TAXOL safety. Rare reports of radiation pneumonitis have been received in patients receiving concurrent radiotherapy.

Rare reports of pleural effusion and respiratory failure have been received as part of the continuing surveillance of TAXOL safety.

Neurologic: The assessment of neurologic toxicity was conducted differently among the studies as evident from the data reported in each individual study (see TABLES 10-16). 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-agent TAXOL. 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 TAXOL discontinuation in 1% of all patients. Sensory symptoms have usually improved or resolved within several months of TAXOL discontinuation. Pre-existing neuropathies resulting from prior therapies are not a contraindication for TAXOL therapy.

In the Intergroup first-line ovarian carcinoma study (see TABLE 11), neurotoxicity included reports of neuromotor and neurosensory events. The regimen with TAXOL 175 mg/m² given by 3-hour infusion plus cisplatin 75 mg/m² 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 TAXOL 135 mg/m² given by 24-hour infusion plus cisplatin 75 mg/m² 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 TAXOL is given in combination with cisplatin 75 mg/m², the incidence of severe neurotoxicity is more common at a TAXOL dose of 175 mg/m² given by 3-hour infusion (21%) than at a dose of 135 mg/m² given by 24-hour infusion (3%).

In patients with NSCLC, administration of TAXOL 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 TAXOL. Severe neurosensory symptoms were noted in 13% of NSCLC patients receiving TAXOL 135 mg/m² by 24-hour infusion followed by cisplatin 75 mg/m² and 8% of NSCLC patients receiving cisplatin/etoposide (see TABLE 15).

Other than peripheral neuropathy, serious neurologic events following TAXOL administration have been rare ( < 1%) and have included grand mal seizures, syncope, ataxia, and neuroencephalopathy.

Rare reports of autonomic neuropathy resulting in paralytic ileus have been received as part of the continuing surveillance of TAXOL safety. 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.

Rare reports of convulsions, dizziness, and headache have been reported as part of continuing surveillance of TAXOL safety.

Arthralgia/Myalgia: There was no consistent relationship between dose or schedule of TAXOL 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 2 or 3 days after TAXOL 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 TAXOL 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 TAXOL was not associated with cumulative hepatic toxicity.

Rare reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of TAXOL safety.

Renal: Among the patients treated for Kaposi's sarcoma with TAXOL, 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 treated with TAXOL and cisplatin may have an increased risk of renal failure during 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 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 TAXOL was administered in combination with cisplatin appeared to be greater compared with the database for single-agent TAXOL 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.

Rare reports of intestinal obstruction, intestinal perforation, pancreatitis, ischemic colitis, dehydration, esophagitis, constipation, and ascites have been received as part of the continuing surveillance of TAXOL safety. Rare reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, were observed in patients treated with TAXOL 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 TAXOL at a different site, ie, "recall," has been reported rarely.

Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been received as part of the continuing surveillance of TAXOL safety. 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.

Other Clinical Events: Alopecia was observed in almost all (87%) of the patients. Transient skin changes due to TAXOL-related hypersensitivity reactions have been observed, but no other skin toxicities were significantly associated with TAXOL 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.

Rare reports of skin abnormalities related to radiation recall as well as reports of maculopapular rash, pruritus, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been received as part of the continuing surveillance of TAXOL safety.

Reports of asthenia and malaise have been received as part of the continuing surveillance of TAXOL safety. In the Phase 3 trial of TAXOL 135 mg/m² over 24 hours in combination with cisplatin as first-line 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.

Rare reports of conjunctivitis, increased lacrimation, anorexia, confusional state, photopsia, visual floaters, vertigo, and increase in blood creatinine have been received as part of the continuing surveillance of TAXOL safety.

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.

In a Phase 1 trial using escalating doses of TAXOL (110- 200 mg/m²) and cisplatin (50 or 75 mg/m²) given as sequential infusions, myelosuppression was more profound when TAXOL was given after cisplatin than with the alternate sequence (ie, TAXOL before cisplatin). Pharmacokinetic data from these patients demonstrated a decrease in paclitaxel clearance of approximately 33% when TAXOL was administered following cisplatin.

The metabolism of TAXOL is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Caution should be exercised when administering TAXOL concomitantly with known substrates, inducers (eg, rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine), or inhibitors (eg, erythromycin, fluoxetine, gemfibrozil) of the cytochrome P450 isoenzymes CYP2C8 and CYP3A4. (See CLINICAL PHARMACOLOGY.)

Potential interactions between TAXOL, 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: TAXOL therapy should not be administered to patients with baseline neutrophil counts of less than 1500 cells/mm³. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving TAXOL. Patients should not be re-treated with subsequent cycles of TAXOL until neutrophils recover to a level > 1500 cells/mm³ and platelets recover to a level > 100,000 cells/mm³. In the case of severe neutropenia ( < 500 cells/mm³ for 7 days or more) during a course of TAXOL 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, TAXOL, at the recommended dose for this disease, can be initiated and repeated if the neutrophil count is at least 1000 cells/mm³.

Hypersensitivity Reactions: Patients with a history of severe hypersensitivity reactions to products containing Cremophor® EL (eg, cyclosporin for injection concentrate and teniposide for injection concentrate) should not be treated with TAXOL. In order to avoid the occurrence of severe hypersensitivity reactions, all patients treated with TAXOL should be premedicated with corticosteroids (such as dexamethasone), diphenhydramine and H₂ 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 TAXOL and aggressive symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with TAXOL.

Cardiovascular: Hypotension, bradycardia, and hypertension have been observed during administration of TAXOL, but generally do not require treatment. Occasionally TAXOL infusions must be interrupted or discontinued because of initial or recurrent hypertension. Frequent vital sign monitoring, particularly during the first hour of TAXOL infusion, is recommended. Continuous cardiac monitoring is not required except for patients with serious conduction abnormalities. (See WARNINGS.) When TAXOL 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 TAXOL.

TAXOL 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 TAXOL may be exacerbated in patients with serum total bilirubin > 2 times ULN (see CLINICAL PHARMACOLOGY). Extreme caution should be exercised when administering TAXOL 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 TAXOL at a different site, ie, "recall," has been reported rarely.

Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been received as part of the continuing surveillance of TAXOL safety. 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.

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 TAXOL in clinical trials. Fatal reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H2 antagonists. (See DOSAGE AND ADMINISTRATION.) Patients who experience severe hypersensitivity reactions to TAXOL 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. TAXOL should not be administered to patients with baseline neutrophil counts of less than 1500 cells/mm³ ( < 1000 cells/mm³ for patients with KS). Frequent monitoring of blood counts should be instituted during TAXOL treatment. Patients should not be re-treated with subsequent cycles of TAXOL until neutrophils recover to a level > 1500 cells/mm³ ( > 1000 cells/mm³ for patients with KS) and platelets recover to a level > 100,000 cells/mm³.

Severe conduction abnormalities have been documented in < 1% of patients during TAXOL therapy and in some cases requiring pacemaker placement. If patients develop significant conduction abnormalities during TAXOL infusion, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with TAXOL.

Pregnancy

TAXOL can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel during the period of organogenesis to rabbits at doses of 3.0 mg/kg/day (about 0.2 the daily maximum recommended human dose on a mg/m² 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 1.0 mg/kg/day (about 1/15 the daily maximum recommended human dose on a mg/m² 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 TAXOL 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 childbearing potential should be advised to avoid becoming pregnant.

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 TAXOL solutions should preferably be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

TAXOL 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of TAXOL (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/m² basis). At this dose, paclitaxel caused reduced fertility and reproductive indices, and increased embryo- and fetotoxicity. (See WARNINGS.)

Pregnancy: 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 TAXOL 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 TAXOL therapy.

Pediatric Use: The safety and effectiveness of TAXOL (paclitaxel) 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 TAXOL was infused intravenously over 3 hours at doses ranging from 350 mg/m² to 420 mg/m². The toxicity is most likely attributable to the high dose of the ethanol component of the TAXOL 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 safety of TAXOL for use in this population.

Geriatric Use: Of 2228 patients who received TAXOL 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 TAXOL 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 TAXOL 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 TAXOL IN CLINICAL STUDIES

	Patients (n/total [%])
	Neutropenia (Grade IV)		Peripheral Neuropathy (Grades III/IV)
INDICATION (Study/Regimen)	Age (y)		Age (y)
	≥ 65	< 65	≥ 65	< 65
• OVARIAN Cancer
(Intergroup First-Line/T175/3 c75a)	34/83 (41)	78/252 (31)	24/84 (29)*b	46/255 (18)b
(GOG-111 First-Line/T135/24 c75a)	48/61 (79)	106/129 (82)	3/62 (5)	2/134 (1)
(Phase 3 Second-Line/T175/3c)	5/19 (26)	21/76 (28)	1/19 (5)	0/76 (0)
(Phase 3 Second-Line/T175/24c)	21/25 (84)	57/79 (72)	0/25 (0)	2/80 (3)
(Phase 3 Second-Line/T135/3c)	4/16 (25)	10/81 (12)	0/17 (0)	0/81 (0)
(Phase 3 Second-Line/T135/24c)	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 Td)	56/102 (55)	734/1468 (50)	5/102 (5)e	46/1468 (3)e
• BREAST Cancer After Failure of Initial Therapy
(Phase 3/T175/3c)	7/24 (29)	56/200 (28)	3/25 (12)	12/204 (6)
(Phase 3/T135/3c)	7/20 (35)	37/207 (18)	0/20 (0)	6/209 (3)
•Non-Small Cell LUNG Cancer
(ECOG/T135/24 c75a)	58/71 (82)	86/124 (69)	9/71 (13)f	16/124 (13)f
(Phase 3/T175/3 c80a)	37/89 (42)*	56/267 (21)	11/91 (12)*	11/271 (4)
* p < 0.05 a TAXOL dose in mg/m2/infusion duration in hours; cisplatin doses in mg/m2. b Peripheral neuropathy was included within the neurotoxicity category in the Intergroup First-LineOvarian Cancer study (see TABLE 11). c TAXOL dose in mg/m2/infusion duration in hours. d TAXOL (T) following 4 courses of doxorubicin and cyclophosphamide (AC) at a dose of 175 mg/m2/3hours 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.)

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

TAXOL is contraindicated in patients who have a history of hypersensitivity reactions to TAXOL or other drugs formulated in Cremophor® EL (polyoxyethylated castor oil).

TAXOL should not be used in patients with solid tumors who have baseline neutrophil counts of < 1500 cells/mm³ or in patients with AIDS-related Kaposi's sarcoma with baseline neutrophil counts of < 1000 cells/mm³.

Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or "bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.

Following intravenous administration of TAXOL, paclitaxel plasma concentrations declined in a biphasic manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug. The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment.

Pharmacokinetic parameters of paclitaxel following 3- and 24-hour infusions of TAXOL at dose levels of 135 and 175 mg/m² were determined in a Phase 3 randomized study in ovarian cancer patients and are summarized in the following table.

TABLE 1: SUMMARY OF PHARMACOKINETIC PARAMETERS-MEAN VALUES

Dose (mg/m2)	Infusion Duration (h)	N (patients)	Cmax(ng/mL)	AUC(0-∞) (ng•h/mL)	T-HALF (h)	CLT (L/h/m2)
135	24	2	195	6300	52.7	21.7
175	24	4	365	7993	15.7	23.8
135	3	7	2170	7952	13.1	17.7
175	3	5	3650	15007	20.2	12.2
Cmax=Maximum plasma concentration AUC(0-∞)=Area under the plasma concentration-time curve from time 0 to infinity CLT=Total body clearance

It appeared that with the 24-hour infusion of TAXOL, a 30% increase in dose (135 mg/m² vs 175 mg/m²) increased the Cmax by 87%, whereas the AUC_(0-∞) remained proportional. However, with a 3-hour infusion, for a 30% increase in dose, the Cmax and AUC_(0-∞) were increased by 68% and 89%, respectively. The mean apparent volume of distribution at steady state, with the 24-hour infusion of TAXOL, ranged from 227 to 688 L/m², indicating extensive extravascular distribution and/or tissue binding of paclitaxel.

The pharmacokinetics of paclitaxel were also evaluated in adult cancer patients who received single doses of 15 to 135 mg/m² given by 1-hour infusions (n=15), 30 to 275 mg/m² given by 6-hour infusions (n=36), and 200 to 275 mg/m² given by 24-hour infusions (n=54) in Phase 1 and 2 studies. Values for CLT and volume of distribution were consistent with the findings in the Phase 3 study. The pharmacokinetics of TAXOL in patients with AIDS-related Kaposi's sarcoma have not been studied.

In vitro studies of binding to human serum