Taxol (Paclitaxel) - Side Effects and Adverse Reactions

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 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

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.
SUMMARYa 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 Reaction b
—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

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

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
FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA STUDIES
		Percent of Patients
		Intergroup		GOG-111
		T175/3b c75c (n=339)	C750c c75c (n=336)	T135/24b c75c (n=196)	C750c c75c (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
•  Neurotoxicity h
—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

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

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.
FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 SECOND-LINE OVARIAN CARCINOMA STUDY
		Percent of Patients
		175/3b (n=95)	175/24b (n=105)	135/3b (n=98)	135/24b (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 Reaction c
—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

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

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 4 courses.
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.
FREQUENCYa OF IMPORTANT SEVEREb ADVERSE EVENTS IN THE PHASE 3 ADJUVANT BREAST CARCINOMA STUDY
		Percent of Patients
		Early Population		Total Population
		ACc (n=166)	ACc followed by Td (n=159)	ACc (n=1551)	ACc followed by Td (n=1570)
•  Bone Marrow e
—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

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

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.
FREQUENCYa 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 (n=229)	135/3b (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

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

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.
fAll patients received premedication.
† Severe events are defined as at least Grade III toxicity.
FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 STUDY FOR FIRST-LINE NSCLC
		Percent of Patients
		T135/24b c75 (n=195)	T250/24c c75 (n=197)	VP100d c75 (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

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

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.
FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE AIDS-RELATED KAPOSI’S SARCOMA STUDIES
		Percent of Patients
		Study CA139-174 TAXOL 135/3b q 3 wk (n=29)	Study CA139-281 TAXOL 100/3b q 2 wk (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

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.