Paclitaxel: Package Insert and Label Information (Page 3 of 5)

ADVERSE REACTIONS

Pooled Analysis of Adverse Event Experiences from Single-Agent Studies Data in the following table are based on the experience of 812 patients (493 with ovarian carcinoma and 319 with breast carcinoma) enrolled in 10 studies who received single-agent paclitaxel injection. Two hundred and seventy-five patients were treated in 8, Phase 2 studies with paclitaxel doses ranging from 135 to 300 mg/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 paclitaxel. Two hundred and thirty-six patients with breast carcinoma received paclitaxel (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 PACLITAXEL

Percent of Patients (n=812)
· B one Marrow —Neutropenia <2,000/mm3 90
<500/mm3 52
—Leukopenia <4,000/mm3 90
<1,000/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 · Hy persensitivity Reactionb 2
—All 41
—Severe 2
· Card i ovascular —Vital Sign Changesc
—Bradycardia (n=537) 3
—Hypotension (n=532) 12
—Significant Cardiovascular Events 1
· A bnormal ECG
—All Pts 23
—Pts with normal baseline (n=559) 14
· Peripheral Neuropathy
—Any symptoms 60
—Severe symptoms 3
· My algia/Arthralgia
—Any symptoms 60
—Severe symptoms 8
· G astrointestinal
—Nausea and vomiting 52
—Diarrhea 38
—Mucositis 31
· Alopecia 87
· Hep atic (Pts with normal baseline and on study data)
—Bilirubin elevations (n=765) 7
—Alkaline phosphatase elevations (n=575) 22
—AST (SGOT) elevations (n=591) 19
· Injecti on Site Reaction 13

a Based on worst course analysis.
b All patients received premedication.
c During the first 3 hours of infusion.
Severe events are defined as at least Grade III toxicity.
None of the observed toxicities were clearly influenced by age.
Disease-Specific Adverse Event Experiences
First-Line Ovary in Combination For the 1084 patients who were evaluable for safety in the Phase 3 first-line ovary combination therapy studies, TABLE 11 shows the incidence of important adverse events. For both studies, the analysis of safety was based on all courses of therapy (6 courses for the GOG-111 study and up to 9 courses for the Intergroup study).

TABLE 11. 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)
· B one Marrow —Neutropenia <2,000/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 Paclitaxel (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 paclitaxel 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
175/3b (n=95) 175/24b (n=105) 135/3b (n=98) 135/24b (n=105)
  • B one Marrow
—Neutropenia <2,000/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 Hy persensitivity Reactionc 26 29 20 18
—All 41 45 38 45
—Severe 2 0 2 1
  • Peripheral Neuropathy
—Any symptoms 63 60 55 42
—Severe symptoms 1 2 0 0
  • Muc ositis
—Any symptoms 17 35 21 25
—Severe symptoms 0 3 0 2

a Based on worst course analysis.

b Paclitaxel dose in mg/m2 /infusion duration in hours.

c All patients received premedication.

Severe events are defined as at least Grade III toxicity.

TABLE 13. FREQUENCYa OF IMPORTANT SEVEREb ADVERSE EVENTS IN THE PHASE 3 ADJUVANT BREAST CARCINOMA STUDY

Perce nt of Patients
Earl y Population T otal Population
ACc (n=166) ACc followed by Td (n = 15 9) ACc (n=1551) ACc followed by Td (n=1570)
· B one 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
· Hy persensitivity Reactionf 1 4 1 2
· Card i ovascular Events 1 2 1 2
· Neuromotor Toxicity 1 1 <1 1
· Neurosensory Toxicity 3 <1 3
· My algia/Arthralgia 2 <1 2
· Nause a/Vomiting 13 18 8 9
· Muc ositis 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 4 courses.

d Paclitaxel (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 paclitaxel following AC therapy may be compared with AC therapy alone. Compared to patients who received AC alone, patients who received AC followed by paclitaxel experienced more Grade III/IV neurosensory toxicity, more Grade III/IV myalgia/arthralgia, more Grade III/IV neurologic pain (5% vs 1%), more Grade III/IV flu-like symptoms (5% vs 3%), and more Grade III/IV hyperglycemia (3% vs 1%). During the additional 4 courses of treatment with paclitaxel, 2 deaths (0.1%) were attributed to treatment. During paclitaxel treatment, Grade IV neutropenia was reported for 15% of patients, Grade II/III neurosensory toxicity for 15%, Grade II/III myalgias for 23%, and alopecia for 46%.
The incidences of severe hematologic toxicities, infections, mucositis, and cardiovascular events increased with higher doses of doxorubicin.
Breast Cancer After Failure of Initial Chemotherapy For the 458 patients who received single-agent paclitaxel in the Phase 3 breast carcinoma study, the following table shows the incidence of important adverse events by treatment arm (each arm was administered by a 3-hour infusion).

TABLE 14. 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 135/3b
(n=229) (n=229)
  • B one Marrow
—Neutropenia <2,000/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
  • Hy persensitivity Reactionc
—All 36 31
—Severe 0 <1
  • Peripheral Neuropathy
—Any symptoms 70 46
—Severe symptoms 7 3
  • Muc ositis
—Any symptoms 23 17
—Severe symptoms 3 <1

a Based on worst course analysis.

b Paclitaxel dose in mg/m2 /infusion duration in hours.

c All patients received premedication.

Severe events are defined as at least Grade III toxicity.

TABLE 15. FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 STUDY FOR FIRST-LINE NSCLC

Percent of Patients
T135/24b c75 (n=195) T250/24c c75 (n=197) VP100d c75 (n=196)
  • Bone Marrow
—Neutropenia <2,000/mm3 <500/mm3 8974e 8665 8455
—Thrombocytopenia < normal<50,000/mm3 486 6812 6216
—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—Severe symptoms 21e 3 42e 11 91
  • Nausea /Vomiting
—Any symptoms—Severe symptoms 8527 8729 8122
  • Mucositis
—Any symptoms—Severe symptoms 181 284 162
  • Neuromotor Toxicity
—Any symptoms—Severe symptoms 376 4712 447
  • Neurosensory Toxicity
—Any symptoms—Severe symptoms 4813 6128e 258
  • Cardiovascular Events
—Any symptoms—Severe symptoms 3313 3912 248

a Based on worst course analysis.

b Paclitaxel (T) dose in mg/m2 /infusion duration in hours; cisplatin (c) dose in mg/m2.

c Paclitaxel 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 paclitaxel treatment arm (T250/c75) than in the low-dose paclitaxel arm (T135/c75). Compared to the cisplatin/etoposide arm, patients in the low-dose paclitaxel arm experienced more arthralgia/myalgia of any grade and more severe neutropenia. The incidence of febrile neutropenia was not reported in this study.

Kaposi’s Sarcoma

The following table shows the frequency of important adverse events in the 85 patients with KS treated with 2 different single-agent paclitaxel regimens.

TABLE 16. FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE AIDS-RELATED KAPOSI’S SARCOMA STUDIES

Percent of Patients
Study CA139-174 paclitaxel 10 0/3b q 3 wk (n=29) Study CA139-281 paclitaxel 10 0/3b q 2 wk (n=56)
· B one Marrow
—Neutropenia <2,000/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
· Opp ortunistic 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
· Hy persensitivity Reactionc
—All 14 9
· Card i ovascular
—Hypotension 17 9
—Bradycardia 3
· Peripheral Neuropathy
—Any 79 46
—Severe 10 2
· My algia/Arthralgia
—Any 93 48
—Severe 14 16
· G astrointestinal
—Nausea and Vomiting 69 70
—Diarrhea 90 73
—Mucositis 45 20
· Ren al (creatinine elevation)
—Any 34 18
—Severe 7 5
· Disc ontinuation for drug toxicity 7 16

a Based on worst course analysis.

b Paclitaxel 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 paclitaxel at a dose of 135 mg/m2 every 3 weeks than in the study utilizing paclitaxel 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
The following discussion refers to the overall safety database of 812 patients with solid tumors treated with single-agent paclitaxel in clinical studies. Toxicities that occurred with greater severity or frequency in previously untreated patients with ovarian carcinoma or NSCLC who received paclitaxel in combination with cisplatin or in patients with breast cancer who received paclitaxel after doxorubicin/cyclophosphamide in the adjuvant setting and that occurred with a difference that was clinically significant in these populations are also described.
The frequency and severity of important adverse events for the Phase 3 ovarian carcinoma, breast carcinoma, NSCLC, and the Phase 2 Kaposi’s sarcoma 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 paclitaxel for the treatment of ovarian, breast, or lung carcinoma or Kaposi’s sarcoma, but patients with AIDS-related Kaposi’s sarcoma may have more frequent and severe hematologic toxicity, infections (including opportunistic infections, see TABLE 16), and febrile neutropenia. These patients require a lower dose intensity and supportive care (see CLINICAL STUDIES, AIDS-Related Kaposi’s Sarcoma). Toxicities that were observed only in or were noted to have occurred with greater severity in the population with Kaposi’s sarcoma and that occurred with a difference that was clinically significant in this population are described. Elevated liver function tests and renal toxicity have a higher incidence in KS patients as compared to patients with solid tumors.
Hematologic
Bone marrow suppression was the major dose-limiting toxicity of paclitaxel. Neutropenia, the most important hematologic toxicity, was dose and schedule dependent and was generally rapidly reversible. Among patients treated in the Phase 3 second-line ovarian study with a 3-hour infusion, neutrophil counts declined below 500 cells/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 paclitaxel 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 paclitaxel plus cisplatin arm than in the control arm. Grade IV neutropenia occurred in 81% on the paclitaxel plus cisplatin arm versus 58% on the cyclophosphamide plus cisplatin arm, and febrile neutropenia occurred in 15% and 4% respectively. On the paclitaxel/cisplatin arm, there were 35/1074 (3%) courses with fever in which Grade IV neutropenia was reported at some time during the course. When paclitaxel followed by cisplatin was administered to patients with advanced NSCLC in the ECOG study, the incidences of Grade IV neutropenia were 74% (paclitaxel 135 mg/m2 /24 hours followed by cisplatin) and 65% paclitaxel 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 paclitaxel dose and schedule. In the Phase 3 second-line ovarian study, bleeding episodes were reported in 10% of the patients; no patients treated with the 3-hour infusion received platelet transfusions. In the adjuvant breast carcinoma trial, the incidence of severe thrombocytopenia and platelet transfusions increased with higher doses of doxorubicin.
Anemia (Hb <11 g/dL) was observed in 78% of all patients and was severe (Hb <8 g/dL) in 16% of the cases. No consistent relationship between dose or schedule and the frequency of anemia was observed. Among all patients with normal baseline hemoglobin, 69% became anemic on study but only 7% had severe anemia. Red cell transfusions were required in 25% of all patients and in 12% of those with normal baseline hemoglobin levels.
Hypersensitivity Reactions (HSRs)
All patients received premedication prior to paclitaxel administration (see WARNINGS and PRECAUTIONS, Hypersensitivity Reactions). The frequency and severity of HSRs were not affected by the dose or schedule of paclitaxel administration. In the Phase 3 second-line ovarian study, the 3-hour infusion was not associated with a greater increase in HSRs when compared to the 24-hour infusion. Hypersensitivity reactions were observed in 20% of all courses and in 41% of all patients. These reactions were severe in less than 2% of the patients and 1% of the courses. No severe reactions were observed after course 3 and severe symptoms occurred generally within the first hour of paclitaxel infusion. The most frequent symptoms observed during these severe reactions were dyspnea, flushing, chest pain, and tachycardia. Abdominal pain, pain in the extremities, diaphoresis, and hypertension were also noted.
The minor hypersensitivity reactions consisted mostly of flushing (28%), rash (12%), hypotension (4%), dyspnea (2%), tachycardia (2%), and hypertension (1%). The frequency of hypersensitivity reactions remained relatively stable during the entire treatment period.
Chills, shock, and back pain in association with hypersensitivity reactions have been reported.
Cardiovascular
Hypotension, during the first 3 hours of infusion, occurred in 12% of all patients and 3% of all courses administered. Bradycardia, during the first 3 hours of infusion, occurred in 3% of all patients and 1% of all courses. In the Phase 3 second-line ovarian study, neither dose nor schedule had an effect on the frequency of hypotension and bradycardia. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. The frequency of hypotension and bradycardia were not influenced by prior anthracycline therapy.
Significant cardiovascular events possibly related to single-agent paclitaxel occurred in approximately 1% of all patients. These events included syncope, rhythm abnormalities, hypertension, and venous thrombosis. One of the patients with syncope treated with paclitaxel at 175 mg/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 paclitaxel in combination with cisplatin in the Phase 3 study, significant cardiovascular events occurred in 12 to 13%. This apparent increase in cardiovascular events is possibly due to an increase in cardiovascular risk factors in patients with lung cancer.
Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 23% of all patients. Among patients with a normal ECG prior to study entry, 14% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, sinus tachycardia, and premature beats. Among patients with normal ECGs at baseline, prior therapy with anthracyclines did not influence the frequency of ECG abnormalities.
Cases of myocardial infarction have been reported. Congestive heart failure, including cardiac dysfunction and reduction of left ventricular ejection fraction or ventricular failure, has been reported typically in patients who have received other chemotherapy, notably anthracyclines (see PRECAUTIONS, Drug Interactions).
Atrial fibrillation and supraventricular tachycardia have been reported.
Respiratory
Interstitial pneumonia, lung fibrosis, and pulmonary embolism have been reported. Radiation pneumonitis has been reported in patients receiving concurrent radiotherapy.
Pleural effusion and respiratory failure have been reported.
Neurologic
The assessment of neurologic toxicity was conducted differently among the studies as evident from the data reported in each individual study (see TABLES 10 to 16). Moreover, the frequency and severity of neurologic manifestations were influenced by prior and/or concomitant therapy with neurotoxic agents.
In general, the frequency and severity of neurologic manifestations were dose-dependent in patients receiving single-agent paclitaxel. Peripheral neuropathy was observed in 60% of all patients (3% severe) and in 52% (2% severe) of the patients without pre-existing neuropathy. The frequency of peripheral neuropathy increased with cumulative dose. Paresthesia commonly occurs in the form of hyperesthesia. Neurologic symptoms were observed in 27% of the patients after the first course of treatment and in 34 to 51% from course 2 to 10. Peripheral neuropathy was the cause of paclitaxel discontinuation in 1% of all patients. Sensory symptoms have usually improved or resolved within several months of paclitaxel discontinuation. Pre-existing neuropathies resulting from prior therapies are not a contraindication for paclitaxel therapy.
In the Intergroup first-line ovarian carcinoma study (see TABLE 11), neurotoxicity included reports of neuromotor and neurosensory events. The regimen with paclitaxel 175 mg/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 paclitaxel 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 paclitaxel is given in combination with cisplatin 75 mg/m2 , the incidence of severe neurotoxicity is more common at a paclitaxel 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 paclitaxel followed by cisplatin resulted in a greater incidence of severe neurotoxicity compared to the incidence in patients with ovarian or breast cancer treated with single-agent paclitaxel. Severe neurosensory symptoms were noted in 13% of NSCLC patients receiving paclitaxel 135 mg/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 paclitaxel 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, rare reports in the literature of abnormal visual evoked potentials in patients have suggested persistent optic nerve damage. Postmarketing reports of ototoxicity (hearing loss and tinnitus) have also been received.
Convulsions, dizziness, and headache have been reported.
Arthralgia/Myalgia
There was no consistent relationship between dose or schedule of paclitaxel and the frequency or severity of arthralgia/myalgia. Sixty percent of all patients treated experienced arthralgia/myalgia; 8% experienced severe symptoms. The symptoms were usually transient, occurred 2 or 3 days after paclitaxel administration, and resolved within a few days. The frequency and severity of musculoskeletal symptoms remained unchanged throughout the treatment period.
Hepatic
No relationship was observed between liver function abnormalities and either dose or schedule of paclitaxel administration. Among patients with normal baseline liver function 7%, 22%, and 19% had elevations in bilirubin, alkaline phosphatase, and AST (SGOT), respectively. Prolonged exposure to paclitaxel was not associated with cumulative hepatic toxicity.
Hepatic necrosis and hepatic encephalopathy leading to death have been reported.
Renal
Among the patients treated for Kaposi’s sarcoma with paclitaxel, 5 patients had renal toxicity of grade III or IV severity. One patient with suspected HIV nephropathy of grade IV severity had to discontinue therapy. The other 4 patients had renal insufficiency with reversible elevations of serum creatinine.
Patients with gynecological cancers treated with paclitaxel and cisplatin may have an increased risk of renal failure with the combination therapy of paclitaxel and cisplatin in gynecological cancers as compared to cisplatin alone.
Gastrointestinal (GI)
Nausea/vomiting, diarrhea, and mucositis were reported by 52%, 38%, and 31% of all patients, respectively. These manifestations were usually mild to moderate. Mucositis was schedule dependent and occurred more frequently with the 24-hour than with the 3-hour infusion.
In patients with poor-risk AIDS-related Kaposi’s sarcoma, nausea/vomiting, diarrhea, and mucositis were reported by 69%, 79%, and 28% of patients, respectively. One-third of 43 patients with Kaposi’s sarcoma complained of diarrhea prior to study start (see CLINICAL STUDIES, AIDS-Related Kaposi’s Sarcoma).
In the first-line Phase 3 ovarian carcinoma studies, the incidence of nausea and vomiting when paclitaxel was administered in combination with cisplatin appeared to be greater compared with the database for single-agent paclitaxel in ovarian and breast carcinoma. In addition, diarrhea of any grade was reported more frequently compared to the control arm, but there was no difference for severe diarrhea in these studies.
Intestinal obstruction, intestinal perforation, pancreatitis, ischemic colitis and dehydration have been reported. Neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, was observed in patients treated with paclitaxel alone and in combination with other chemotherapeutic agents.
Injection Site Reaction
Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. These reactions have been observed more frequently with the 24-hour infusion than with the 3-hour infusion. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel at a different site, i.e., ”recall” has been reported.
More severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been reported. In some cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to 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 paclitaxel-related hypersensitivity reactions have been observed, but no other skin toxicities were significantly associated with paclitaxel administration. Nail changes (changes in pigmentation or discoloration of nail bed) were uncommon (2%). Edema was reported in 21% of all patients (17% of those without baseline edema); only 1% had severe edema and none of these patients required treatment discontinuation. Edema was most commonly focal and disease-related. Edema was observed in 5% of all courses for patients with normal baseline and did not increase with time on study.
Skin abnormalities related to radiation recall as well as maculopapular rash, pruritus, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported. In postmarketing experience, diffuse edema, thickening, and sclerosing of the skin have been reported following paclitaxel administration. Paclitaxel has been reported to exacerbate signs and symptoms of scleroderma.
Reports of asthenia and malaise have been received as part of the continuing surveillance of paclitaxel safety. In the Phase 3 trial of paclitaxel 135 mg/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.
To report SUSPECTED ADVERSE REACTIONS , contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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