Side Effects > Paclitaxel

Paclitaxel Side Effects

Brand Names: Onxol, Taxol

Please note - some side effects for Paclitaxel may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Paclitaxel - for the Consumer

Paclitaxel

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Paclitaxel:

Cough; diarrhea; general feeling of discomfort; hair loss; mild discomfort, redness, or swelling at the injection site; mild joint or muscle pain; nausea; numbness, tingling, or burning of your arms, hands, legs, or feet; redness and/or sores on the mouth or lips; unusual weakness or tiredness; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Paclitaxel:

Severe allergic reactions (rash; hives; difficulty swallowing or breathing; tightness in the chest; flushing; swelling of the mouth, face, lips, tongue, or throat; hoarseness); blistering, swelling, redness, severe pain, or open sores on your skin or at the injection site; change in the amount of urine produced; chest pain; eye swelling or irritation; fainting; fast, slow, or irregular heartbeat; flu-like symptoms (fever, chills, sore throat); hearing trouble or loss of hearing; pale appearance; redness, swelling, or tenderness in the calf; ringing in the ears; seizures; severe joint or muscle pain; severe nausea, vomiting, or diarrhea; severe numbness, tingling, or burning in the arms, hands, legs, or feet; severe stomach pain; swelling of arms, hands, legs, or feet; sudden or severe dizziness, lightheadedness, or headache; unusual bruising or bleeding; vision changes or blurred vision.

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Paclitaxel Side Effects - for the Professional

Paclitaxel

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. Two hundred and seventy-five patients were treated in eight Phase 2 studies with Paclitaxel doses ranging from 135 to 300 mg/m2 administered over 24 hours (in four of these studies, G-CSF was administered as hematopoietic support). Three hundred and one patients were treated in the randomized Phase 3 ovarian carcinoma study which compared two doses (135 or 175 mg/m2) and two 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: Summary* of Adverse Events in Patients With Solid Tumors Receiving Single-Agent Paclitaxel Injection, USP

	Percent of Patients (n=812)
* Based on worst course analysis. † All patients received premedication. ‡ During the first 3 hours of infusion. § Severe events are defined as at least Grade III toxicity.
• Bone 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	2
• Hypersensitivity Reaction †
- All	41
- Severe§	2
• Cardiovascular
- Vital Sign Changes‡
- 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 (six courses for the GOG-111 study and up to nine courses for the Intergroup study).

Table 11: Frequency* of Important Adverse Events in the Phase 3 First-Line Ovarian Carcinoma Studies

	Percent of Patients
	Intergroup		GOG-111
	T175/3† c75‡ (n=339)	C750‡ c75‡ (n=336)	T135/24† c75‡ (n=196)	C750‡ c75‡ (n=213)
* Based on worst course analysis. † Paclitaxel (T) dose in mg/m2/infusion duration in hours. ‡ Cyclophosphamide (C) or cisplatin (c) dose in mg/m2 § p<0.05 by Fisher exact test. ¶ <130,000/mm3 in the Intergroup study. # <12 g/dL in the Intergroup study. Þ All patients received premedication. ß Severe events are defined as at least Grade III toxicity. à 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. NC Not Collected.
• Bone Marrow
- Neutropenia                              < 2000/mm3	91§	95§	96	92
<500/mm3	33§	43§	81§	58§
- Thrombocytopenia              <100,000/mm3¶	21§	33§	26	30
<50,000/mm3	3§	7§	10	9
- Anemia                                           <11 g/dL#	96	97	88	86
<8 g/dL	3§	8§	13	9
- Infections	25	27	21	15
- Febrile Neutropenia	4	7	15§	4§
• Hypersensitivity Reaction
- All	11§	6§	21§, Þ	21§, Þ
- Severeß	1	1	21§, Þ	21§, Þ
• Neurotoxicityà
- Any symptoms	87§	52§	25	20
- Severe symptomsß	21§	2§	3§	--§
• Nausea and Vomiting
- Any symptoms	88	93	65	69
- Severe symptomsß	18	24	10	11
• Myalgia/Arthralgia
- Any symptoms	60§	27§	9§	2§
- Severe symptomsß	6§	1§	1	---
• Diarrhea
- Any symptoms	37§	29§	16§	8§
- Severe symptomsß	2	3	4	1
• Asthenia
- Any symptoms	NC	NC	17§	10§
- Severe symptomsß	NC	NC	1	1
• Alopecia
- Any symptoms	96§	89§	55§	37§
- Severe symptomsß	51§	21§	6	8

Second-Line Ovary: For the 403 patients who received single-agent Paclitaxel injection, USP in the Phase 3 second-line ovarian carcinoma study, the following table shows the incidence of important adverse events.

Table 12: Frequency* of Important Adverse Events in the Phase 3 Second-Line Ovarian Carcinoma Study

	Percent of Patients
	175/3† (n=95)	175/24† (n=105)	135/3† (n=98)	135/24† (n=105)
* Based on worst course analysis. † Paclitaxel  dose in mg/m2/infusion duration in hours. ‡ All patients received premedication. § Severe events are defined as at least Grade III toxicity.
• Bone 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	26	29	20	18
• Hypersensitivity Reaction‡
- 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 3,121 patients (total population) who were evaluable for safety as well as for a group of 325 patients (early population) who, per the study protocol, were monitored more intensively than other patients.

Table 13: Frequency* of Important Severe† Adverse Events in the Phase 3 Adjuvant Breast Carcinoma Study

	Percent of Patients
	Early Population		Total Population
	AC‡  (n=166)	AC‡ followed by T§ (n=159)	AC‡ (n=1551)	AC‡ followed by T§  (n=1570)
* Based on worst course analysis. † Severe events are defined as at least Grade III toxicity. ‡ 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 four courses. § Paclitaxel (T) following four courses of AC at a dose of 175 mg/m2/3hours every 3 weeks for four courses. ¶ The incidence of febrile neutropenia was not reported in this study. # All patients were to receive premedication.
• Bone Marrow¶
- 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 Reaction#	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 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 four courses of treatment with Paclitaxel, two 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: Frequency* of Important Adverse Events in the Phase 3 Study of Breast Cancer After Failure of Initial Chemotherapy or Within 6 Months of Adjuvant Chemotherapy

	Percent of Patients
	175/3†  (n=229)	135/3†   (n=229)
* Based on worst course analysis † Paclitaxel  dose in mg/m2/infusion duration in hours. ‡ All patients received premedication. § Severe events are defined as at least Grade III toxicity.
• Bone 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
• Hypersensitivity Reaction‡
- 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 Paclitaxel injection, USP (T) 135 mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2, Paclitaxel (T) 250 mg/m2 as a 24 hour infusion in combination with cisplatin (c) 75 mg/m2 with G-CSF support, or cisplatin (c) 75 mg/m2 on day 1, followed by etoposide (VP) 100 mg/m2 on days 1, 2 and 3 (control).

The following table shows the incidence of important adverse events.

Table 15: Frequency* of Important Adverse Events in the Phase 3 Study for First-Line NSCLC

	Percent of Patients
	T135/24† c75 (n=195)	T250/24‡ c75 (n=197)	VP100§ c75 (n=196)
* Based on worst course analysis. † Paclitaxel (T) dose in mg/m2/infusion duration in hours; cisplatin (c) dose in mg/m2. ‡ Paclitaxel dose in mg/m2/infusion duration in hours with G-CSF support; cisplatin dose in mg/m2. § Etoposide (VP) dose in mg/m2 was administered I.V. on days 1, 2 and 3; cisplatin dose in mg/m2. ¶ p<0.05. # All patients received premedication. Þ Severe events are defined as at least Grade III toxicity.
• Bone Marrow
- Neutropenia                                                <2,000/mm3	89	86	84
<500/mm 3	74¶	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 Reaction #
- All	16	27	13
- SevereÞ	1	4¶	1
• Arthralgia/Myalgia
- Any symptoms	21¶	42¶	9
- Severe symptoms Þ	3	11	1
• Nausea/Vomiting
- Any symptoms	85	87	81
- Severe symptomsÞ	27	29	22
• Mucositis
- Any symptoms	18	28	16
- Severe symptomsÞ	1	4	2
• Neuromotor Toxicity
- Any symptoms	37	47	44
- Severe symptomsÞ	6	12	7
• Neurosensory Toxicity
- Any symptoms	48	61	25
- Severe symptomsÞ	13	28¶	8
• Cardiovascular Events
- Any symptoms	33	39	24
- Severe symptomsÞ	13	12	8

Toxicity was generally more severe in the high-dose Paclitaxel injection, USP 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 two different single-agent Paclitaxel regimens.

Table 16: Frequency* of Important Adverse Events in the AIDS-Related Kaposi’s Sarcoma Studies

	Percent of Patients
	Study CA139-174 Paclitaxel 135/3† q 3 wk (n=29)	Study CA139-281 Paclitaxel 100/3† q 2 wk (n=56)
* Based on worst course analysis. † Paclitaxel  dose in mg/m2/infusion duration in hours. ‡ All patients received premedication. § Severe events are defined as at least Grade III toxicity.
• Bone 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
• 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 Reaction‡
- 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 Paclitaxel injection, USP 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% versus 35%), febrile neutropenia (55% versus 9%), and opportunistic infections (76% versus 54%) were more common with the former dose and schedule. The differences between the two studies with respect to dose escalation and use of hematopoietic growth factors, as described above, should be taken into account. 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 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. 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 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 cyclosphosphamide 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. The use of supportive therapy, including G-CSF, is recommended for patients who have experienced severe neutropenia.

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 Paclitaxel injection, USP dose and schedule. In the Phase 3 second-line ovarian study, bleeding episodes were reported in 10% of the patients; no patients treated with the 3-hour infusion received platelet transfusions. In the adjuvant breast carcinoma trial, the incidence of severe thrombocytopenia and platelet transfusions increased with higher doses of doxorubicin.

Anemia (Hb <11 g/dL) was observed in 78% of all patients and was severe (Hb <8 g/dL) in 16% of the cases. No consistent relationship between dose or schedule and the frequency of anemia was observed. Among all patients with normal baseline hemoglobin, 69% became anemic on study but only 7% had severe anemia. Red cell transfusions were required in 25% of all patients and in 12% of those with normal baseline hemoglobin levels.

Hypersensitivity Reactions (HSRs): All patients received premedication prior to Paclitaxel. 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.

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 Paclitaxel 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 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 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.

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

Respiratory: Rare reports of interstitial pneumonia, lung fibrosis, and pulmonary embolism have been received as part of the continuing surveillance of Paclitaxel 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 Paclitaxel injection, USP safety.

Neurologic: The assessment of neurologic toxicity was conducted differently among the studies as evident from the data reported in each individual study. 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, 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 a 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 injection, USP 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 injection, USP. 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.

Other than peripheral neuropathy, serious neurologic events following Paclitaxel 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 Paclitaxel 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 Paclitaxel safety.

Arthralgia/Myalgia: There was no consistent relationship between dose or schedule of Paclitaxel and the frequency or severity of arthralgia/myalgia. Sixty percent of all patients treated experienced arthralgia/myalgia; 8% experienced severe symptoms. The symptoms were usually transient, occurred two or three days after Paclitaxel administration, and resolved within a few days. The frequency and severity of musculoskeletal symptoms remained unchanged throughout the treatment period. Hepatic: No relationship was observed between liver function abnormalities and either dose or schedule of Paclitaxel administration. Among patients with normal baseline liver function 7%, 22%, and 19% had elevations in bilirubin, alkaline phosphatase, and AST (SGOT), respectively. Prolonged exposure to Paclitaxel was not associated with cumulative hepatic toxicity.

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

Renal: Among the patients treated for Kaposi’s sarcoma with Paclitaxel, five 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 four patients had renal insufficiency with reversible elevations of serum creatinine.

Patients treated with Paclitaxel 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.

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.

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 Paclitaxel safety. Rare reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, were observed in patients treated with Paclitaxel alone and in combination with other chemotherapeutic agents.

Injection Site Reaction: Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. These reactions have been observed more frequently with the 24-hour infusion than with the 3-hour infusion. Recurrence of skin reactions at a site of previous extravasation following administration of Paclitaxel at a different site, i.e., “recall”, has been reported 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 Paclitaxel safety. In some cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to ten days.

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

Other Clinical Events: Alopecia was observed in almost all (87%) of the patients. Transient skin changes due to Paclitaxel 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.

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 Paclitaxel safety.

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.

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

Side Effects by Body System

Hematologic

Hematologic side effects including bone marrow suppression have been the major dose-limiting toxicity. Neutropenia less than 2,000 cells/mm3 (90%) and less than 500 cells/mm3 (52%), is the most important hematological toxicity. Neutropenia has been both dose and schedule dependent, and generally rapidly reversible. The onset of neutropenia generally occurs after 8 to 10 days and recovery generally occurs after 15 to 21 days. Neutropenia does not appear to increase with cumulative exposure, nor to be more frequent or severe for patients previously treated with radiation therapy. Leukopenia less than 4,000 cells/mm3 (90%) and less than 1,000 cells/mm3 (17%), thrombocytopenia less than 100,000 cells/mm3 (20%) and less than 50,000 cells/mm3 (7%), and anemia less than 11 g/dl (78%) and less than 8 g/dl (16%) have been reported. Infections (30%), bleeding (14%), red cell transfusions (25%) and platelet transfusions (2%) have been reported. A case of paclitaxel-induced sickle cell crisis has also been reported.

Fever (12% of all treatment courses) has been reported. Fatal infectious episodes (1%) including sepsis, pneumonia and peritonitis have been reported.

Bleeding episodes (4% of all courses and 14% of all patients) have been reported. Most of the episodes were localized.

Hypersensitivity

Hypersensitivity side effects (41%), including severe reactions (2%) have been reported. The most frequent symptoms observed during the severe reactions were dyspnea, flushing, chest pain, and tachycardia. Minor hypersensitivity reactions consisted mostly of flushing (28%), rash (12%), hypotension (4%), dyspnea (2%), tachycardia (2%), and hypertension (1%). Three patients with transient pulmonary infiltrates caused by hypersensitivity reactions (after receiving treatment with paclitaxel and carboplatin) have been reported. A case of pneumonitis responsive to high-dose corticosteroids and a case of bullous fixed drug eruption have also been reported.

The frequency and severity of hypersensitivity reactions were not affected by the dose or schedule of administration. Severe symptoms have primarily been reported to occur within the first hour of the infusion.

Single dose intravenous dexamethasone can be used in combination with appropriated ancillary medications to prevent paclitaxel-related hypersensitivity reactions.

Cardiovascular

The manufacturer further states that abnormal ECG readings have been reported in 23% of all patients receiving paclitaxel and in 14% of the patients with normal baseline ECGs. The most frequently reported ECG modifications were nonspecific repolarization abnormalities, sinus bradycardia, sinus tachycardia and premature beats.

Cardiovascular side effects have included vital sign changes including bradycardia (3%) and hypotension (12%) during the first 3 hours of infusion as stated by the manufacturer. Significant cardiovascular events (1%) including syncope, rhythm abnormalities, hypertension and venous thrombosis have also been reported. A report from the Johns Hopkins oncology center stated that asymptomatic sinus bradycardia occurred in up to 29% of patients in phase 2 trails, and that other cardiac disturbances including atrioventricular conduction and bundle branch blocks, ventricular tachycardia, and possible ischemic manifestations had been reported (3%). A case of fatal myocardial infarction potentially induced by paclitaxel has also been reported.

Nervous system

Nervous system side effects including neurotoxicity, primarily including peripheral neurosensory manifestations (60%), have generally been mild to moderate in severity. However, severe symptoms (3%) have also been reported. Other serious neurologic events (less than 1%) have been reported including grand mal seizures, syncope, ataxia, neuroencephalopathy and autonomic neuropathy resulting in paralytic ileus. Disturbances of the optic nerve (19%) have also been reported.

The frequency and severity of neurologic manifestations have been dose dependent and cumulative. One study found that although the neurotoxicity was frequent, it remained mild or subclinical up to at least 1400 mg/m2 administered over 8 cycles.

Peripheral neuropathy may appear within 24 to 72 hours when high doses are administered. The frequency of peripheral neuropathy also has been reported to have increased with cumulative dose. It usually presents as a "stocking-and-glove" numbness and paresthesia.

At least 3 cases of phantom limb pain associated with paclitaxel use have been reported.

Gastrointestinal

Gastrointestinal side effects including nausea and vomiting (52%), diarrhea (38%) and mucositis (31%) have been reported. Intestinal obstruction, intestinal perforation and ischemic colitis have been reported rarely. Three cases of pancreatitis have also been reported.

Gastrointestinal effects can generally be treated with standard antiemetic antidiarrheal therapy and dietary changes.

Mucositis occurs most frequently in patients receiving high doses. It is schedule-dependent, occurring more frequently with 24 and 96 hour infusions.

The author of one of the case reports of pancreatitis suggested that it was the companion agent, cremophor that was the cause, rather than the paclitaxel itself.

Hepatic

Prolonged exposure to paclitaxel has not been associated with cumulative hepatic toxicity.

Hepatic side effects including elevations in bilirubin (7%), alkaline phosphatase (22%) and AST (SGOT) (19%) have been reported in patients with normal baseline levels. Hepatic necrosis and hepatic encephalopathy leading to death have been reported rarely. A case of fatal hepatic coma has also been reported.

Renal

Renal side effects including edema have been reported in 21% of all patients receiving paclitaxel and 17% of patients without baseline edema. Severe edema has been reported in 1% of patients.

Dermatologic

Dermatologic side effects including transient skin changes due to hypersensitivity reactions and skin abnormalities related to radiation recall have been reported. Alopecia (87%) and cumulative loss of body hair have also been reported. Some reports suggest that paclitaxel may cause vesicant reactions when extravasated. Nail changes including changes in pigmentation or discoloration of the nail bed have been reported (2%). Two cases of cutaneous lupus erythematosus and one case of systemic lupus erythematosus have been reported. Two cases of scleroderma-like reactions have been reported. A case of paclitaxel administration via a central vein producing a recall reaction at a site of prior paclitaxel extravasation has also been reported. A case of severe mucocutaneous toxicity has been reported.

Alopecia usually begins 1 to 2 weeks after treatment and is usually reversible.

Respiratory

Respiratory side effects including radiation recall pneumonitis have been reported.

Musculoskeletal

Musculoskeletal side effects including myalgia and/or arthralgia (60%), including severe symptoms (8%) have been reported.

Symptoms were usually transient, occurred two or three days after drug administration and resolved within five to seven days. Symptoms are more frequent and severe in patients receiving doses greater than 200 mg/m2.

Local

Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site.

Local side effects have included injection site reactions. Phlebitis has been reported rarely.

Other

Other side effects including cellulitis have been reported rarely.

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