Paclitaxel

For patients with non-small cell lung carcinoma , the recommended regimen, given every 3 weeks, is paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m 2 followed by cisplatin, 75 mg/m 2 . For patients with AIDS-related Kaposi’s sarcoma , paclitaxel administered at a dose of 135 mg/m 2 given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m 2 given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45 to 50 mg/m 2 /week).

In the 2 clinical trials evaluating these schedules (see CLINICAL STUDIES, AIDS-Related Kaposi’s Sarcoma ), the former schedule (135 mg/m 2 every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m 2 every 2 weeks).

Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients: Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO); Initiate or repeat treatment with paclitaxel only if the neutrophil count is at least 1,000 cells/mm 3 ; Reduce the dose of subsequent courses of paclitaxel by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm 3 for a week or longer); and Initiate concomitant hematopoietic growth factor (G-CSF) as clinicallyindicated.

For the therapy of patients with solid tumors (ovary, breast and NSCLC), courses of paclitaxel should not be repeated until the neutrophil count is at least 1,500 cells/mm 3 and the platelet count is at least 100,000 cells/mm 3 . Paclitaxel should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline or subsequent neutrophil count is less than 1,000 cells/mm 3 .

Patients who experience severe neutropenia (neutrophil <500 cells/mm 3 for a week or longer) or severe peripheral neuropathy during paclitaxel therapy should have dosage reduced by 20% for subsequent courses of paclitaxel. The incidence of neurotoxicity and the severity of neutropenia increase with dose.

Preparation and Administration Precautions Paclitaxel is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised in handling paclitaxel. The use of gloves is recommended. If paclitaxel solution contacts the skin, wash the skin immediately and thoroughly with soap and water.

Following topical exposure, events have included tingling, burning and redness. If paclitaxel contacts mucous membranes, the membranes should be flushed thoroughly with water. Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported.

Hepatic Impairment Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III–IV myelosuppression (see CLINICAL PHARMACOLOGY and PRECAUTIONS, Hepatic ). Recommendations for dosage adjustment for the first course of therapy are shown in TABLE 17 for both 3- and 24-hour infusions.

Further dose reduction in subsequent courses should be based on individual tolerance. Patients should be monitored closely for the development of profound myelosuppression. TABLE 17. 0 x ULN Not recommended a These recommendations are based on dosages for patients without hepatic impairment of 135 mg/m 2 over 24 hours or 175 mg/m 2 over 3 hours; data are not available to make dose adjustment recommendations for other regimens (eg, for AIDS-related Kaposi’s sarcoma).

b Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to differences in clinical trial design. c Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance.

Preparation and Administration Precautions Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing paclitaxel Injection.

If paclitaxel solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. If paclitaxel contacts mucous membranes, the membranes should be flushed thoroughly with water.

Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

(See PRECAUTIONS, Injection Site Reaction ). Preparation for Intravenous Administration Paclitaxel must be diluted prior to infusion. 2 mg/mL. The solutions are physically and chemically stable for up to 27 hours at ambient temperature (approximately 25°C) and room lighting conditions.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle.

V. 22 micron) filter. Data collected for the presence of the extractable plasticizer DEHP [di-(2-ethylhexyl) phthalate] show that levels increase with time and concentration when dilutions are prepared in PVC containers. Consequently, the use of plasticized PVC containers and administration sets is not recommended.

Paclitaxel solutions should be prepared and stored in glass, polypropylene, or polyolefin containers. Non-PVC containing administration sets, such as those which are polyethylene-lined, should be used. 22 microns. Use of filter devices such as IVEX-2® filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

The Chemo Dispensing Pin™ device or similar devices with spikes should not be used with vials of paclitaxel since they can cause the stopper to collapse resulting in loss of sterile integrity of the paclitaxel solution. Stability Unopened vials of paclitaxel are stable until the date indicated on the package when stored between 20° to 25°C (68° to 77°F), in the original package.

Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration components in the paclitaxel vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation.

There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25°C) and lighting conditions for up to 27 hours.

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 1,084 patients who were evaluable for safety in the Phase 3 first-line ovary combination therapy studies, TABLE 11 shows the incidence of important adverse events.

For both studies, the analysis of safety was based on all courses of therapy (6 courses for the GOG- 111 study and up to 9 courses for the Intergroup study). TABLE 11. FREQUENCY a OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA STUDIES Percent of Patients Intergroup GOG-111 T175/3 b c75 c (n=339) C750 c c75 c (n=336) T135/24 b c75 c (n=196) C750 c c75 c (n=213) Bone Marrow - Neutropenia <2,000/mm 3 91 d 95 d 96 92 <500/mm 3 33 d 43 d 81 d 58 d - Thrombocytopenia <100,000/mm 3e 21 d 33 d 26 30 <50,000/mm 3 3 d 7 d 10 9 - Anemia <11 g/dL f 96 97 88 86 <8 g/dL 3 d 8 d 13 9 - Infections 25 27 21 15 - Febrile Neutropenia 4 7 15 d 4 d Hypersensitivity Reaction - All 11 d 6 d 8 d,g 1 d,g - Severe † 1 1 3 d,g - d,g Neurotoxicity h - Any symptoms 87 d 52 d 25 20 - Severe symptoms † 21 d 2 d 3 d - d Nausea and Vomiting - Any symptoms 88 93 65 69 - Severe symptoms † 18 24 10 11 Myalgia/Arthralgia - Any symptoms 60 d 27 d 9 d 2 d - Severe symptoms † 6 d 1 d 1 - Diarrhea - Any symptoms 37 d 29 d 16 d 8 d - Severe symptoms † 2 3 4 1 Athenia - Any symptoms NC NC 17 d 10 d - Severe symptoms † NC NC 1 1 Alopecia - Any symptoms 96 d 89 d 55 d 37 d - Severe symptoms † 51 d 21 d 6 8 a Based on worst course analysis.

b Paclitaxel (T) dose in mg/m 2 /infusion duration in hours. c Cyclophosphamide (C) or cisplatin (c) dose in mg/m 2 . 05 by Fisher exact test. e <130,000/mm 3 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 injection in the Phase 3 second-line ovarian carcinoma study, the following table shows the incidence of important adverse events. TABLE 12. FREQUENCY a OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 SECOND-LINE OVARIAN CARCINOMA STUDY Percent of Patients 175/3 b (n=95) 175/24 b (n=105) 135/3 b (n=98) 135/24 b (n=105) Bone Marrow - Neutropenia <2,000/mm 3 <500/mm 3 - Thrombocytopenia <100,000/mm 3 <50,000/mm 3 - Anemia <11 g/dL <8 g/dL - Infections 78 27 4 1 84 11 26 98 75 18 7 90 12 29 78 14 8 2 68 6 20 98 67 6 1 88 10 18 Hypersensitivity Reaction c - All - Severe † 41 2 45 0 38 2 45 1 Peripheral Neuropathy - Any symptoms - Severe symptoms † 63 1 60 2 55 0 42 0 Mucositis - Any symptoms - Severe symptoms † 17 0 35 3 21 0 25 2 a Based on worst course analysis.

b Paclitaxel dose in mg/m 2 /infusion duration in hours. c All patients received premedication. † Severe events are defined as at least Grade III toxicity. Myelosuppression was dose and schedule related, with the schedule effect being more prominent.

2% of the courses overall. There was no apparent dose or schedule effect seen for the HSRs. Peripheral neuropathy was clearly dose-related, but schedule did not appear to affect the incidence. Adjuvant Breast For the Phase 3 adjuvant breast carcinoma study, the following table shows the incidence of important severe adverse events for the 3121 patients (total population) who were evaluable for safety as well as for a group of 325 patients (early population) who, per the study protocol, were monitored more intensively than other patients.

TABLE 13. FREQUENCY a OF IMPORTANT SEVERE b ADVERSE EVENTS IN THE PHASE 3 ADJUVANT BREAST CARCINOMA STUDY Percent of Patients Early Population Total Population AC c (n=166) AC c followed by T d (n=159) AC c (n=1551) AC c followed by T d (n=1570) Bone Marrow e - Neutropenia <500/mm 3 79 76 48 50 - Thrombocytopenia <50,000/mm 3 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 f 1 4 1 2 Cardiovascular Events 1 2 1 2 Neuromotor Toxicity 1 1 <1 1 Neurosensory Toxicity – 3 <1 3 Myalgia/Arthralgia – 2 <1 2 Nausea/Vomiting 13 18 8 9 Mucositis 13 4 6 5 a Based on worst course analysis.

b Severe events are defined as at least Grade III toxicity. c Patients received 600 mg/m 2 cyclophosphamide and doxorubicin (AC) at doses of either 60 mg/m 2 , 75 mg/m 2 , or 90 mg/m 2 (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/m 2 /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%).

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 a OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 STUDY OF BREAST CANCER AFTER FAILURE OF INITIAL CHEMOTHERAPY OR WITHIN 6 MONTHS OF ADJUVANT CHEMOTHERAPY Percent of Patients 175/3 b (n=229) 135/3 b (n=229) Bone Marrow - Neutropenia <2,000/mm 3 90 81 <500/mm 3 28 19 - Thrombocytopenia <100,000/mm 3 11 7 <50,000/mm 3 3 2 - Anemia <11 g/dL 55 47 <8 g/dL 4 2 - Infections 23 15 - Febrile Neutropenia 2 2 Hypersensitivity Reaction c - All 36 31 - Severe † 0 <1 Peripheral Neuropathy - Any symptoms 70 46 - Severe symptoms † 7 3 Mucositis - Any symptoms 23 17 - Severe symptoms † 3 <1 a Based on worst course analysis.

b Paclitaxel dose in mg/m 2 /infusion duration in hours. c All patients received premedication. † Severe events are defined as at least Grade III toxicity. Myelosuppression and peripheral neuropathy were dose related. There was one severe hypersensitivity reaction (HSR) observed at the dose of 135 mg/m 2 .

First-Line NSCLC in Combination In the study conducted by the Eastern Cooperative Oncology Group (ECOG), patients were randomized to either paclitaxel (T) 135 mg/m 2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m 2 , paclitaxel (T) 250 mg/m 2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m 2 with G-CSF support, or cisplatin (c) 75 mg/m 2 on day 1, followed by etoposide (VP) 100 mg/m 2 on days 1, 2, and 3 (control).

The following table shows the incidence of important adverse events. TABLE 15. FREQUENCY a OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 STUDY FOR FIRST-LINE NSCLC Percent of Patients T135/24 b c75 (n=195) T250/24 c c75 (n=197) VP100 d c75 (n=196) Bone Marrow - Neutropenia <2,000/mm 3 <500/mm 3 - Thrombocytopenia <normal <50,000/mm 3 - Anemia <normal <8 g/dL - Infections 89 74 e 48 6 94 22 38 86 65 68 12 96 19 31 84 55 62 16 95 28 35 Hypersensitivity Reaction f - All - Severe † 16 1 27 4 e 13 1 Arthralgia/Myalgia - Any symptoms - Severe symptoms † 21 e 3 42 e 11 9 1 Nausea/Vomiting - Any symptoms - Severe symptoms † 85 27 87 29 81 22 Mucositis - Any symptoms - Severe symptoms † 18 1 28 4 16 2 Neuromotor Toxicity - Any symptoms - Severe symptoms † 37 6 47 12 44 7 Neurosensory Toxicity - Any symptoms - Severe symptoms † 48 13 61 28 e 25 8 Cardiovascular Events - Any symptoms - Severe symptoms † 33 13 39 12 24 8 a Based on worst course analysis.

b Paclitaxel (T) dose in mg/m 2 /infusion duration in hours; cisplatin (c) dose in mg/m 2 . c Paclitaxel dose in mg/m 2 /infusion duration in hours with G-CSF support; cisplatin dose in mg/m 2 . d Etoposide (VP) dose in mg/m 2 was administered IV on days 1, 2, and 3; cisplatin dose in mg/m 2 .

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. FREQUENCY a OF IMPORTANT ADVERSE EVENTS IN THE AIDS-RELATED KAPOSI’S SARCOMA STUDIES Percent of Patients Study CA139-174 Paclitaxel 135/3 b q 3 wk (n=29) Study CA139-281 Paclitaxel 100/3 b q 2 wk (n=56) Bone Marrow - Neutropenia <2,000/mm 3 100 95 <500/mm 3 76 35 - Thrombocytopenia <100,000/mm 3 52 27 <50,000/mm 3 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.

avinum intracellulare 24 4 - Candidiasis, esophageal 7 9 - Cryptosporidiosis 7 7 - Cryptococcal meningitis 3 2 - Leukoencephalopathy – 2 Hypersensitivity Reaction c - All 14 9 Cardiovascular - Hypotension 17 9 - Bradycardia 3 - Peripheral Neuropathy - Any 79 46 - Severe † 10 2 Myalgia/Arthralgia - Any 93 48 - Severe † 14 16 Gastrointestinal - Nausea and Vomiting 69 70 - Diarrhea 90 73 - Mucositis 45 20 Renal (creatinine elevation) - Any 34 18 - Severe † 7 5 Discontinuation for drug toxicity 7 16 a Based on worst course analysis.

b Paclitaxel dose in mg/m 2 /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/m 2 every 3 weeks than in the study utilizing paclitaxel at a dose of 100 mg/m 2 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 carcinoma 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.

05). In the same study, severe neutropenia (<500 cells/mm 3 ) 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/m 2 /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/m 2 /24 hours followed by cisplatin) and 65% (paclitaxel 250 mg/m 2 /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/m 2 or 175 mg/m 2 given as a 3-hour infusion 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/mm 3 at least once while on treatment; 7% had a platelet count <50,000 cells/mm 3 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/m 2 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-agency 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/m 2 given by 3-hour infusion plus cisplatin 75 mg/m 2 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/m 2 given by 24-hour infusion plus cisplatin 75 mg/m 2 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/m 2 , the incidence of severe neurotoxicity is more common at a paclitaxel dose of 175 mg/m 2 given by 3-hour infusion (21%) than at a dose of 135 mg/m 2 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/m 2 by 24-hour infusion followed by cisplatin 75 mg/m 2 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 have 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 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. Hepatic necrosis and hepatic encephalopathy leading to death have 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 wi th 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, 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. , “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 reports of 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/m 2 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 Alembic Pharmaceuticals, Inc. gov/medwatch.

There are no adequate and well-controlled studies in pregnant women. If paclitaxel is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.

Women of child-bearing potential should be advised to avoid becoming pregnant.