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Taxol

Taxol

SIDE EFFECTS

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: 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 < 11g/dL 78
   < 8g/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 (SCOT) 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: 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 < llg/dLf 96 97 88 86
< 8g/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 ld 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
aBased on worst course analysis.
bTAXOL (T) dose in mg/m2/infusion duration in hours.
cCyclophosphamide (C) or cisplatin (c) dose in mg/m2.
dp < 0.05 by Fisher exact test.
e < 130,000/mm3 in the Intergroup study.
f < 12 g/dL in the Intergroup study.
gAll patients received premedication.
hIn 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 in 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: FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 SECOND-LINE OVARIAN CARCINOMA STUDY

  Percent of Patients
    175/24b
(n=105)
135/3b
(n=98)
135/24b
(n=105)
175/3b
(n=95)
•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
< 8g/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
aBased on worst course analysis.
bAXOL dose in mg/m2/infusion duration in hours.
cAll 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: FREQUENCYa OF IMPORTANT SEVEREb ADVERSE EVENTS IN THE PHASE 3 ADIUVANT RREAST CARCINOMA STUDY

  Percent of Patients
  Early Population Total Population
  ACc
(n=166)
ACc followed by Td
(n=159)
ACc
(n=1551)
ACcfollowed by Td
(n=1551)
•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
aBased on worst course analysis.
bSevere events are defined as at least Grade III toxicity.
cPatients 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.
dTAXOL (T) following 4 courses of AC at a dose of 175 mg/m2/3 hours every 3 weeks for 4 courses.
eThe incidence of febrile neutropenia was not reported in this study.
fAll 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: 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 < llg/dL 55 47
   < 8g/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
aBased on worst course analysis.
bTAXOL dose in mg/m2/infusion duration in hours.
cAll 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: FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 STUDY FOR FIRST-LINE NSCLC

  Percent of Patients
  T135/24b
c75
(n=195)
T250/240c
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
   < 8g/dL 22 19 28
   - Infections 38 31 35
•Hypersensitivity Reactionf
   - All 16 27 13
   - Severe 1 4e 1
•Arthralgial 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
•Newomotor Toxicity
   - Any symptoms 37 47 44
   - Severe symptoms 6 12 7
•Newosensory Toxicity
   - Any symptoms 48 61 25
   - Severe symptoms 13 28e 8
•Cardiovascular Events
   - Any symptoms 33 39 24
   - Severe symptoms 13 12 8
aBased on worst course analysis.
bTAXOL (T) dose in mg/m /infusion duration in hours; cisplatin (c) dose in mg/m .
c TAXOL dose in mg/m2/infusion duration in hours with G-CSF support; cisplatin dose in mg/m2.
dEtoposide (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.

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: FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE AIDS-RELATED KAPOSFS 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
< 8g/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
aBased on worst course analysis.
bTAXOL dose in mg/m /infusion duration in hours.
cAll 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 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 reported. 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): In clinical trials, all patients received premedication prior to TAXOL administration (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.

Chills, shock, and back pain in association with hypersensitivity reactions have been reported.

Cardiovascular: Hypotension, during the first 3 hours of infusion, occurred in 12% of all patients and 3% of all courses administered. Bradycardia, during the first 3 hours of infusion, occurred in 3% of all patients and 1% of all courses. In the Phase 3 second-line ovarian study, neither dose nor schedule had an effect on the frequency of hypotension and bradycardia. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. The frequency of hypotension and bradycardia were not influenced by prior anthracycline therapy.

Significant cardiovascular events possibly related to single-agent 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. 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.)

Atrial fibrillation and supraventricular tachycardia have been reported.

Respiratory: Interstitial pneumonia, lung fibrosis, and pulmonary embolism have been reported. Radiation pneumonitis has been reported in patients receiving concurrent radiotherapy.

Pleural effusion and respiratory failure have been reported.

Neurologic: The assessment of neurologic toxicity was conducted differently among the studies as evident from the data reported in each individual study (see TABLES 10-16). 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.

Autonomic neuropathy resulting in paralytic ileus has been reported. Optic nerve and/or visual disturbances (scintillating scotomata) have also been reported, particularly in patients who have received higher doses than those recommended. These effects generally have been reversible. However, reports in the literature of abnormal visual evoked potentials in patients have suggested persistent optic nerve damage. Postmarketing reports of ototoxicity (hearing loss and tinnitus) have also been received.

Convulsions, dizziness, and headache have been reported.

Arthralgia/Myalgia: There was no consistent relationship between dose or schedule of 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.

Hepatic necrosis and hepatic encephalopathy leading to death have been reported.

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 with gynecological cancers treated with TAXOL and cisplatin may have an increased risk of renal failure with the combination therapy of paclitaxel and cisplatin in gynecological cancers as compared to cisplatin alone.

Gastrointestinal (GI): Nausea/vomiting, diarrhea, and mucositis were reported by 52%, 38%, and 31% of all patients, respectively. These manifestations were usually mild to moderate. Mucositis was schedule dependent and occurred more frequently with the 24-hour than with the 3-hour infusion.

In patients with poor-risk AIDS-related Kaposi's sarcoma, nausea/vomiting, diarrhea, and mucositis were reported by 69%, 79%, and 28% of patients, respectively. One-third of

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.

Intestinal obstruction, intestinal perforation, pancreatitis, ischemic colitis, dehydration, esophagitis, constipation, and ascites have been reported. Neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, was 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.

More severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been reported. In some cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to 10 days.

A specific treatment for extravasation reactions is unknown at this time. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

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.

Skin abnormalities related to radiation recall as well as maculopapular rash, pruritus, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported. In postmarketing experience, diffuse edema, thickening, and sclerosing of the skin have been reported following TAXOL administration. TAXOL has been reported to exacerbate signs and symptoms of scleroderma.

Reports of asthenia and malaise have been received as part of the continuing surveillance of 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.

Conjunctivitis, increased lacrimation, anorexia, confusional state, photopsia, visual floaters, vertigo, and increase in blood creatinine have been reported.

Accidental Exposure: Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness.

Read the Taxol (paclitaxel) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

In a Phase 1 trial using escalating doses of TAXOL (110-200mg/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 CYP3 A4. Caution should be exercised when TAXOL is concomitantly administered with known substrates (eg, midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (eg, rifampin and carbamazepine) of CYP3A4. (See CLINICAL PHARMACOLOGY.)

Caution should also be exercised when TAXOL is concomitantly administered with known substrates (eg, repaglinide and rosiglitazone), inhibitors (eg, gemfibrozil), and inducers (eg, rifampin) of CYP2C8. (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 HI 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.

More severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been reported. In some cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to 10 days.

A specific treatment for extravasation reactions is unknown at this time. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

Read the Taxol Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 6/13/2011
This monograph has been modified to include the generic and brand name in many instances.

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