Paclitaxel Injection Instruction

Date of approval: November 14, 2008
Date of revision: (1) March 23, 2009
(2) November 5, 2011
(3) January 8, 2015
(4) March 10, 2017
(5) September 25, 2017
(6) XXXX, XXXX, XXXX, XXXX
 Paclitaxel Injection Instructions
Please read the instructions carefully and use under the guidance of a physician
 Warning.
This product should be administered in a healthcare facility specializing in the use of cytotoxic chemotherapeutic agents and under the supervision of an experienced oncologist.
Contraindicated in patients with hypersensitivity to polyoxyethylene castor oil, patients with solid tumors with baseline neutrophil counts less than 1500 cells/mm3 or patients with AIDS-associated Kaposi’s sarcoma with baseline neutrophil counts less than 1000 cells/mm3, pregnant and lactating women.
 Drug Name
Generic name: Paclitaxel Injection
Previously known as: None
Trade name: Tysol®
English name：Paclitaxel Injection
Hanyu Pinyin: Zishanchun Zhusheye
 Ingredients
The main ingredient of this product is paclitaxel
Chemical name: 5β,20-epoxy-1,2α,4,7β,10β,13α-hexahydroxypaclitaxel-11-ricin-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-benzoyl-3-phenylisoserine.
Chemical structure formula.
 
 
 
 
 
 
 
 Molecular formula: C47H51NO14
Molecular weight: 853.9
Commercially available Tysol® is a 30mg (5ml)/vial multiple use formulation size. Each ml of sterile injectable solution contains 6 mg of paclitaxel, 527 mg of purified polyoxyethylene castor oil (CremophorEL) and 49.7% (vol/vol) anhydrous ethanol.
Paclitaxel is a natural product with antitumor activity. Paclitaxel is a white or off-white crystalline powder, highly lipophilic and insoluble in water.
 Properties】It is a colorless to slightly yellowish viscous clear liquid.
 Indications】
First-line and follow-up treatment of progressive ovarian cancer.
Adjuvant therapy for patients with lymph node positive breast cancer after combination chemotherapy with standard regimen containing adriamycin.
Breast cancer patients with metastatic breast cancer who have failed combination chemotherapy or recurred within 6 months of adjuvant chemotherapy.
First-line treatment for patients with non-small cell lung cancer.
Second-line treatment for AIDS-associated Kaposi’s sarcoma (Kaposi’s sarcoma).
 Specification】5ml: 30mg
 Dosage]
Note: Exposure of undiluted concentrated solutions to plasticized polyvinyl chloride (PVC) utensils used to prepare drip solutions is not advocated. To reduce patient exposure to DEHP plastic substances [di-(2-ethylhexyl)phthalate)] that may be released from PVC drip bags or other devices, The diluted solution should be stored in glass bottles, polypropylene bottles or (polypropylene, polyolefin-based) plastic bags, with polyethylene lined delivery devices for drip injection.
Prophylactic Dosing.
To prevent serious allergic reactions, all patients treated with this product should be given prior prophylactic dosing, usually dexamethasone 20 mg orally about 12 and 6 hours prior to treatment with this product, or dexamethasone 20 mg intravenously about 30 to 60 minutes prior to treatment with this product; diphenhydramine (or its equivalent) 50 mg, 30 to 60 minutes prior to paclitaxel by sedation or deep intramuscular injection, and intravenous cimetidine (300 mg) or ranitidine (50 mg) given 30 to 60 minutes prior to this injection.
Dosage.
For patients with ovarian cancer, the following therapies are recommended.
For patients with untreated ovarian cancer, the following therapies are recommended as an option, once every 3 weeks. Before selecting the appropriate therapy, its different toxicities should be considered.
(1) intravenous drip of 175 mg/m2 for >3 hours and cisplatin 75 mg/m2; or
(2) an intravenous drip of 135 mg/m2 over 24 hours with cisplatin 75 mg/m2.
For patients with ovarian cancer who have already received chemotherapy, several doses and regimens are currently available, but the optimal dosing regimen is not known. The recommended regimen is either 135 mg/m2 or 175 mg/m2 given intravenously over 3 hours every 3 weeks.
For patients with breast cancer, the following regimens are recommended.
The adjuvant regimen for lymph node-positive breast cancer is 175 mg/m2 dosed intravenously over greater than 3 hours every 3 weeks for 4 courses of therapy, sequentially following adriamycin-containing combination chemotherapy, which was used in clinical studies for 4 courses of adriamycin combined with cyclophosphamide chemotherapy.
The effective regimen for patients with metastatic disease who have failed initial chemotherapy or who develop recurrence within 6 months of adjuvant chemotherapy is 175 mg/m2 administered intravenously over a 3-hour drip every 3 weeks.
The recommended regimen for patients with non-small cell lung cancer is.
175 mg/m2, intravenous drip over 3 hours. 1 dose every 3 weeks.
For AIDS-associated Kaposi’s sarcoma, the recommended regimen is
135 mg/m2, IV over 3 hours, once every 3 weeks; or 100 mg/m2, IV over 3 hours (dose intensity of 45-50 mg/m2/week), once every 2 weeks. In clinical studies, 135 mg/m2 given intravenously once every 3 weeks for a titration duration greater than 3 hours was more toxic than the latter. In addition, the latter regimen (100 mg/m2 given intravenously every 2 weeks for a titration time greater than 3 hours) was used in all patients with poorer physical status.
Given that progressive HIV patients are immunosuppressed, a modified regimen is recommended for these patients.
Reducing the dose of dexamethasone in the three prophylactic medications to 10 mg orally (instead of 20 mg).
first or repeat treatment with this product only if the neutrophil count is at least 1000 cells/mm3.
For patients with severe neutropenia (neutrophils less than 500/mm3 for one week or longer), reduce the dose of paclitaxel by 20% in subsequent courses
Use of G-CSF when clinically indicated.
For treatment of patients with solid tumors (ovarian, breast, and non-small cell lung cancer), reintroduce this product only if neutrophils are at least 1,500/mm3 and platelets are at least 100,000/mm3. This product should not be used in patients with AIDS-associated Kaposi’s sarcoma with a neutrophil count below 1,000/mm3 at baseline or follow-up. Patients who develop severe neutropenia (neutrophils less than 500/mm3 for one week or longer) or severe peripheral neurologic disease during the course of this product should have the dose of paclitaxel reduced by 20% in subsequent therapy. The incidence of neurotoxicity and severe neutropenia increases with increasing dose use.
The risk of toxicity may be elevated in patients with impaired hepatic function, particularly the risk of grade III-IV myelosuppression. For 3-hour infusions and 24-hour infusions, see Table 1 for the recommended dose adjustments for the first course. Further dose reductions in subsequent courses should be judged on the basis of individual tolerability. Patients should be monitored closely for the development of profound myelosuppression. Table 1: Dosing recommendations for patients with impaired hepatic function based on clinical trial dataa
Degree of impaired liver function Transaminase level Bilirubin levelb Recommended paclitaxel dosec 24-hour infusion<2×ULN and ≤1.5mg/dL135mg/m22-<10×ULN and ≤1.5mg/dL100mg/m2<10×ULN and 1.6-7.5mg/dL50mg/m2≥10×ULN or>7.5mg/dL not suitable for 3-hour infusion<10×ULN and ≤1.25×ULN175mg/m2<10×ULN and 1.26-2.0×ULN135mg/m2<10×ULN and 2.01-5.0×ULN90mg/m2≥10×ULN or>5.0× ULN should not be used a The above recommended doses are based on doses for patients without hepatic impairment (135 mg/m2, titrated over 24 hours or 175 mg/m2, titrated over 3 hours); no clinical data are available for other dose adjusted regimens (e.g., AIDS-associated Kaposi’s sarcoma)
b Differences in bilirubin level criteria between the 3-hour infusion and the 24-hour infusion are due to differences in clinical trial design.
c This is a dose recommendation for the 1st course; further dose reduction in subsequent courses should be judged on the basis of individual tolerability.
 Duration of therapy.
To be determined by physician based on medical condition.
Formulation Guideline.
This product must be diluted prior to titration. It should be diluted in 0.9% sodium chloride injection, or in 5% dextrose injection, or in 5% dextrose plus 0.9% sodium chloride injection or in 5% dextrose Ringer’s solution to a final concentration of 0.3 to 1.2 mg/mL. The physicochemical properties of this solution remain stable for up to 27 hours at ambient temperature (approximately 25°C) and under room lighting conditions. Before injecting such drug, both the solution and the container should be checked for particulate matter or color change by the naked eye under possible conditions.
During dilution preparation, the solution may appear as a mist, due to the dilution solvent used for preparation. When this solution is passed through an intravenous drip line with a filter (0.22 μm orifice) attached, no significant decrease in potency has been demonstrated.
Exposure of undiluted concentrated solutions to plasticized polyvinyl chloride (PVC) vessels used to prepare drip solutions is not advocated. PVC infusion bags or infusion sets can release (DEHP) [di-(2-ethylhexyl) phthalate], and to minimize patient exposure to the plasticizer DEHP, diluted solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin). polyolefin bags) and should be administered in a PVC-free infusion set, such as one lined with polyethylene.
The product is to be administered through an infusion set with a filter fitted with a microporous membrane, the pore size of which should not exceed 0.22 μm. Both the inlet and outlet of the filter should be made of short, membrane-added PVC tubing, thus avoiding the release of large amounts of DEHP.
Devices with pointed tips should not be used to touch the vials, as they can damage the stopper and destroy the sterile environment of the solution.
Stability.
Before dilution :
Unopened product is stable when stored at room temperature 15°C-30°C and encapsulated as is, within the date indicated on its packaging. Refrigeration of unopened product does not produce adverse effects. The ingredients may precipitate under refrigerated conditions, but redissolve when brought to room temperature with or without shaking. Under these conditions, there is no effect on the quality of the product. If the solution becomes foggy or if insoluble precipitation is seen, the drug should be discarded. After opening, the product can be stored at room temperature (15-25°C) and under normal room light conditions for 28 days in the original box.
After dilution.
The drip solution prepared under the recommended conditions is stable under usual room temperature (approximately 25°C) and lighting conditions for up to 27 hours; the infusion is to be completed within this time. Precipitation has been reported to occur when the infusion time is longer than the recommended 3 hours, but such reports are rare. Do not stir, shake or shake vigorously as precipitation may occur. Before administration, rinse the infusion set thoroughly with a dilution that has no contraindications to dosing.
[Adverse reactions].
The information listed below is based on 812 patients (including 493 cases of ovarian cancer and 319 cases of breast cancer) treated with paclitaxel monotherapy in 10 clinical studies abroad. 275 cases were from 8 phase II clinical trials, and the doses used ranged from 135 to 300 mg/m2 titrated for 24 hours (4 of the studies used G- CSF to support hematopoiesis). 301 cases came from randomized studies of patients with stage III ovarian cancer, which compared two doses of paclitaxel (135 or 175 mg/m2) and two dosing methods (3 or 24 hours). There were also 236 patients with breast cancer from a comparative study using paclitaxel 135 or 175 mg/m2 administered for 3 hours.
 Table 2: Summary of adverse reactions in 812 patients with solid tumors treated with paclitaxel monotherapya
 -Bone marrow incidence (%) (n=812) -Neutropenia <2,000/mm3
90 <500/mm3
52 -Leukopenia <4000/mm3
90 <1000/mm3 17 - Thrombocytopenia <100,000/mm320 <50,000/mm3 7 - Anemia (hemoglobin) <11g/dL 78 <8g/dL 16 - Infection 30 - Bleeding 14 - Red blood cell transfusion 25 - Platelet transfusion 2 - Allergic reactionsb - All 41 - Severe +
2 -Cardiovascular-vital sign changesc
     -Bradycardia (N=537) 3 -Low blood pressure (N=532) 12 -Significant cardiovascular events 1 -Abnormal ECG -All patients 23 -Patients with normal base (N=559) 14 -Peripheral neuropathy -Any symptoms 60 -Severe symptoms + 3 -Muscle pain/arthralgia -Any symptoms 60 -Severe symptoms + 8 -Gastrointestinal -Nausea and vomiting 52 -Diarrhea 38    -Mucositis 31 -Hair loss
87 -Liver (patients with normal baseline values and study data) -Elevated bilirubin (N=765) 7 -Elevated alkaline phosphatase (N=575) 22 -Elevated AST (SGOT) (N=591) 19 -Injection site reactions 13a Analysis based on worst-case regimen.
b Prior prophylactic dosing in all patients.
c None of the toxic reactions seen at 3 hours of titration initiation were significantly influenced by age.
+ Serious events were defined as at least grade III toxicity.
    
Disease-specific adverse reactions
First-line ovarian cancer combination regimen: For the 1084 patients whose safety was evaluated in the phase III study of first-line ovarian cancer combination therapy, the occurrence of significant adverse events is presented in Table 3. Safety analyses for all studies were based on all courses of treatment (6 courses for the GOG-111 study and up to 9 courses for the Collaborative Group study).
 
 Table 3: Occurrence of important adverse events in phase III clinical studies of first-line treatment of ovarian cancera
 Percentage of patients Collaborative Group GOG-111T175/3b
c75c
(n=339)C750c
c75c
(n=336)T135/24b
c75c
(n=196)C750c
c75c
(n=213) Bone marrow Neutropenia <2000/mm3
<500/mm3
 91d
33d
 95d
43d
 96
81d
 92
58d thrombocytopenia
<100,000/mm3e
<50,000/mm3
 21d
3d
 33d
7
 26
10
 30
9 Anemia
<11g/dLf
<8g/dL
 96
3d
 97 d
8d
 88
13
 86
9- Infection 25272115- Neutropenic fever 4715d4d Allergic reaction – Any symptom 11d6d8d,g1d,g- Severe symptoms +113d,g-d,g Neurotoxic h – Any symptom 87d25d2520- Severe symptoms +21d2d3d-d Nausea and vomiting – Any symptom 88936569- Severe symptoms + 18241011 myalgia/arthralgia – any symptom 60d27d9d2d- severe symptom+6d1 d1- diarrhea – any symptom 37d29d16d8d- severe symptom+2341 weakness – any symptom NCNC17d10d- severe symptom+NCNC11 hair loss – any symptom 96d89d55d37d- severe symptom+ 51d21d68a Analysis based on the worst course of treatment.
b Paclitaxel dose (mg/m2)/infusion time (hours).
c Cyclophosphamide (C) or cisplatin (c) dose of mg/m2.
d Fish exact test P<0.05.
e<130,000/mm3 in the collaborative group study.
f <12 g/dL in the Collaborative Group Study.
g Prior prophylactic dosing in all patients.
h Neurotoxicity classified in the GOG-111 study as peripheral neurological disease and in the Collaborative Group study as motor or sensory neurological symptoms.
+ Serious events defined as at least grade III toxicity.
NC was not included.
 Second-line ovarian cancer treatment: For the 403 patients in the phase III study of paclitaxel monotherapy in ovarian cancer in second line, the table below lists the occurrence of significant adverse events.
 Table 4: Occurrence of important adverse events in phase III clinical studies for second-line treatment of ovarian cancera
 Percentage of patients T175/3b
(n=95)C750b
(n=105)T135/24b
(n=98)C750b
(n=105) Bone marrow Neutropenia <2000/mm3
<500/mm3
 78
27
 98
75
 78
14
 98
67 Thrombocytopenia
<100,000/mm3
<50,000/mm3
 4
1
 18
7
 8
2
 6
1Anemia
<11g/dL
<8g/dL
 84
11
 90
12
 68
6
 88
10- Infection 26292018 Allergic reactionc – Any symptom 41453845- Severe symptom +2021 Peripheral nerve disease – Any symptom 63605542- Severe symptom +1200 Mucositis – Any symptom 17352125- Severe symptom +0302a Analysis according to the worst course of treatment.
b Paclitaxel dose (mg/m2)/infusion time (hours).
c Prior prophylactic dosing in all patients.
+ Serious events defined as at least grade III toxicity.
Bone marrow suppression was correlated with dose and dosing time, with the effect of dosing time being more prominent. Serious allergic reactions (HSRs) occurred rarely, in only 1% of patients and 0.2% of the total course of treatment. There was no significant correlation between severe allergic reactions and dose and dosing time. Peripheral nerve disease was strongly correlated with dose, but not with time of administration.
Adjuvant Breast Cancer: For the phase III clinical study of adjuvant breast cancer, the following table lists the occurrence of significant serious adverse events in 3121 patients (total population) whose safety with the drug was evaluated along with a group of 325 patients (early population). Patients in this group were monitored more closely than others in the study protocol.
Table 5: Occurrence of seriousb adverse events in the phase III clinical study of adjuvant breast cancer therapya
 Patient percentage Early population Total population ACc
(n=166)ACc sequential Td
(n=159)ACc
(n=1551)ACc sequential Td
(n=1570)Bone marrowe Neutropenia
<500/mm379764850 thrombocytopenia
<50,000/mm327251111 anemia
<8g/dL172188- infection61456- fever without infection-3<11 allergic reactionf1412 cardiovascular events1212 motor neurotoxicity11<11 sensory neurotoxicity-3<13 myalgia/arthralgia-2<12 nausea/vomiting131889 mucositis13465a Analysis based on worst course.
b Serious events defined as at least grade III toxicity.
c Patients received an AC regimen of cyclophosphamide at a dose of 600 mg/m2 and adriamycin at 60 mg/m2, 75 mg/m2, or 90 mg/m2 (prophylactic G-CSF support and ciprofloxacin) every 3 weeks for 4 courses of therapy.
d 4 courses of AC followed by sequential 4 courses of paclitaxel, 175 mg/m2, 3-hour intravenous infusion, repeated every 3 weeks.
e No neutropenic fever reported in this study.
f Prior prophylactic dosing in all patients.
 The safety information was obtained from different enrollment populations and therefore may underestimate the actual incidence of adverse events in the total population. However, because safety information was collected uniformly from different regimens, the safety of sequential paclitaxel treatment after AC regimen treatment can be compared with AC regimen treatment alone. More grade III/IV sensory neurotoxicity, grade III/IV myalgia/arthralgia, grade III/IV neuralgia (5% vs. 1%), grade III/IV flu-like symptoms (5% vs. 3%), and grade III/IV hyperglycemia (3% vs. 1%) occurred in patients treated with sequential paclitaxel after AC regimen compared with AC regimen alone. In the additional 4 courses of paclitaxel treatment, two patients died due to treatment (0.1%). In paclitaxel treatment, grade IV neutropenia occurred in 15% of patients, grade II/III sensory neurotoxicity in 15%, grade II/III myalgia in 23%, and alopecia in 46%.
The incidence of adverse events such as severe hematologic toxicity, infection, mucositis, and cardiovascular events is increased when combined with high doses of adriamycin.
Breast cancer that failed initial chemotherapy: For the 458 patients who received paclitaxel monotherapy in the phase III clinical study of breast cancer, the table below shows the incidence of significant adverse events in the treatment groups (each group was treated with a 3-hour continuous infusion).
Table 6: Incidence of important adverse events in phase III clinical studies of breast cancer that failed within 6 months of initial chemotherapy or adjuvant chemotherapya
 Percentage of patients 175/3b
(n=229)135/3b
(n=229) Bone marrow Neutropenia
<2000/mm3
<500/mm3
 90
28
 81
19 Thrombocytopenia
<100,000/mm3
<50,000/mm3
 11
3
 7
2 Anemia
<11g/dL
<8g/dL
 55
4
 47
2- Infection 2315- Neutropenic fever 22 Allergic reactionc – any symptom 3631- Severe symptoms +0<1 Peripheral neuropathy – any symptom 7046- Severe symptoms +73 Mucositis – any symptom 2317- Severe symptoms +3<1a Analysis based on worst course of treatment.
b Paclitaxel dose (mg/m2)/infusion time (hours).
c Prior prophylactic dosing in all patients.
+ Serious events were defined as at least grade III toxicity.
 Bone marrow suppression and peripheral neuropathy were both dose limiting. one severe allergic reaction (HSR) occurred at the 135 mg/m2 dose.
First-line dosing in combination therapy for non-small cell lung cancer: this study was conducted by the Eastern Collaborative Oncology Group (ECOG), and patients were randomized to paclitaxel 135 mg/m2 24-hour infusion combined with cisplatin 75 mg/m2, paclitaxel 250 mg/m2 24-hour infusion combined with cisplatin 75 mg/m2 and G-CSF support, or cisplatin 75 mg/m2 on day 1 followed by pedialyte glycosides 100 mg/m2 administered intravenously on days 1, 2, and 3 (control).
The incidence of significant adverse events is presented in Table 7.
 Table 7: Incidence of important adverse events in phase III clinical studies of first-line treatment of non-small cell lung cancera
 Percentage of patients T135/24b
c75
(n=195)T250/24c
c75
(n=197)VP100d
c75
(n=196) Bone marrow Neutropenia <2000/mm3
<500/mm3
 89
74e
 86
65
 84
55 Thrombocytopenia
<100,000/mm3
<50,000/mm3
 48
6
 68
12
 62
16 Anemia
<11g/dL
<8g/dL
 94
22
 96
19
 95
28- Infection 383135 allergic reactionf – any symptom 162713- Severe symptoms +14e1 myalgia/arthralgia – any symptom 21e42e9- Severe symptoms +3111 nausea/vomiting – any symptom 858781- Severe symptoms +272922 mucositis – any symptom 182816- Severe symptoms +142 motor neurotoxicity – any symptom 374744- severe symptoms +6127 sensory neurotoxicity – any symptom 486125- severe symptoms +1328e8 cardiovascular events – any symptom 333924- severe symptoms +13128a Analysis based on the worst course of treatment.
b paclitaxel dose (mg/m2)/infusion time (hours); cisplatin dose mg/m2.
c Paclitaxel dose (mg/m2)/infusion time (hours), G-CSF supportive therapy; cisplatin dose mg/m2.
d Pedialyte glycoside (VP) dose mg/m2, given intravenously on days 1, 2 and 3; cisplatin dose mg/m2.
e P<0.05.
f Prior prophylactic dosing in all patients.
+ Serious events were defined as at least grade III toxicity.
 Toxicity was usually more severe in the high-dose group (T250/c75) than in the low-dose group (T135/c75). Arthralgia/myalgia, as well as more severe neutropenia, occurred more frequently in patients treated with the low dose compared to the cisplatin/pedicillin group. No neutropenic fever was reported in this study.
 Kaposi’s sarcoma: The incidence of important adverse events in 85 patients receiving two different doses of paclitaxel monotherapy is listed in the table below.
 Table 8: Incidence of important adverse events in AIDS-associated Kaposi’s sarcomaa
 Percentage of patients Study CA139-174
Paclitaxel 135/3b Every 3 weeks
(n=29) Study CA139-281
Paclitaxel 100/3b every 2 weeks
(n=56) Bone marrow Neutropenia <2000/mm3
<500/mm3
 100
76
 95
35 Thrombocytopenia
<100,000/mm3
<50,000/mm3
 52
17
 27
5Anemia
<11g/dL
<8g/dL
 86
34
 73
25- Neutropenic fever 559 Opportunistic infection – any infection 7654- Cytomegalovirus 4527- Herpes simplex virus 3811- Pneumocystis carinii 1421- Syncytial virus 244- Esophageal Candida albicans 79- Cryptosporidiosis 77- Cryptococcal meningitis 32- Cerebral leukoaraiosis-2 Allergic reactionc – any symptom 149 Cardiovascular – hypotension 179- Cardiac bradycardia3- peripheral neuropathy – any symptom7946- severe symptoms+102 myalgia/arthralgia – any symptom9348- severe symptoms+1416 gastrointestinal – nausea and vomiting6970- diarrhea9073- mucositis4520 renal (elevated creatinine) – any symptom3418- severe symptoms+75 interruption of treatment due to drug toxicity716a Analysis based on worst course of treatment.
b Paclitaxel dose (mg/m2)/infusion time (hours).
c Prior prophylactic dosing in all patients.
+ Serious events were defined as at least grade III toxicity.
 As seen in Table 8, paclitaxel at 135 mg/m2 once every 3 weeks was associated with more prominent toxicities compared to 100 mg/m2 once every 2 weeks. In particular, severe neutropenia (76% vs. 35%), neutropenic fever (55% vs. 9%), and opportunistic infections (76% vs. 35%) were more common at the former dose and dosing regimen. It should be taken into account that the differences between the two studies were due to the increased dose and the use of hematopoietic growth factors as described above. It should also be noted that of the 85 patients in these studies, 26% received protease inhibitor combination therapy, but the effect of protease inhibitors on paclitaxel metabolism has not been studied.
 Adverse effects in systemic systems
Unless otherwise mentioned, overall safety information is discussed below for the 812 patients with solid tumors treated with paclitaxel monotherapy. Toxicity occurred more severely and frequently in patients with previously untreated ovarian cancer or non-small cell lung cancer treated with paclitaxel in combination with cisplatin or in patients with breast cancer treated with paclitaxel after adjuvant therapy with adriamycin/cyclophosphamide, and there were clinically significant differences in the occurrence of toxicity in these populations. The incidence and severity of important adverse events in phase III clinical studies in ovarian cancer, breast cancer, and non-small cell lung cancer, as well as in phase II clinical studies in Kaposi’s sarcoma, are presented in tabular form above. In addition, rare adverse events have been reported in post-marketing use or in other clinical studies. In patients with ovarian cancer, breast cancer, non-small cell lung cancer, and Kaposi’s sarcoma treated with paclitaxel, the incidence and severity of adverse events are generally similar, except that hematopoietic toxicity, infections (including opportunistic infections), and neutropenic fever occur more frequently and severely in patients with AIDS-associated Kaposi’s sarcoma. These patients require a relatively low dose intensity and need supportive therapy. Adverse events that occurred only in patients with Kaposi’s sarcoma or were more severe in these patients, as well as adverse events that differed clinically significantly in this population, are described below. There was a trend toward an increased incidence of elevated liver function test markers and nephrotoxicity in patients with Kaposi’s sarcoma compared to patients with solid tumors.
Hematopoietic system.
Myelosuppression is the major dose-limiting toxicity of paclitaxel. Neutropenia, the most important hematopoietic system toxicity, is dose- and time-dependent and usually also results in rapid recovery. In a phase III second-line clinical study in ovarian cancer, patients received a 3-hour infusion of paclitaxel and 14% of patients in the 135 mg/m2 dose group had neutrophil counts below 500/mm3 compared to an incidence of 27% in the 175 mg/m2 group (p=0.05). Also in this study, severe neutropenia (<500 cells/mm3) occurred more frequently in the continuous 24-hour infusion than in the 3-hour infusion group; the duration of infusion had a greater effect on myelosuppression than the dose. Repeated administration did not increase the occurrence of neutropenia, nor did the frequency and severity of neutropenia occur in patients who had received prior radiation therapy.
In a study of paclitaxel 135 mg/m2/24 hours in combination with cisplatin for ovarian cancer, with cyclophosphamide in combination with cisplatin as the control group, the incidence of grade IV neutropenia and neutropenic fever was higher in the paclitaxel in combination with cisplatin group than in the control group. The incidence of grade IV neutropenia was 81% in the paclitaxel combined with cisplatin group compared with 58% in the cyclophosphamide combined with cisplatin group, while the incidence of neutropenic fever was 15% versus 4% in the two groups, respectively. In the paclitaxel/cisplatin group, fever occurred in 35 (3%) of 1074 courses, all with reported grade IV neutropenia. In the ECOG study of patients with progressive non-small cell lung cancer, the incidence of grade IV neutropenia with paclitaxel followed by cisplatin was 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 to 55% in the control cisplatin/pegylated glycosides group. 55%.
Fever was common (12% of all treatment courses). infections occurred in 30% of patients and in 9% of courses, and in 1% of patients infections were fatal, including sepsis, pneumonia, and peritonitis. In a phase III second-line clinical study in ovarian cancer, the incidence of infection was 20% and 26% in patients treated with paclitaxel doses of 135 mg/m2 and 175 mg/m2 infused over 3 hours, respectively. Urinary tract infections and upper respiratory tract infections were the most commonly reported infectious complications. In immunosuppressed patient populations such as those with progressive HIV infection and poor prognosis AIDS-associated Kaposi’s sarcoma, 61% of patients developed at least one opportunistic infection. For patients with severe neutropenia, supportive therapy including G-CSF is recommended. (See [Dosage]).
Thrombocytopenia has been reported. Platelets below 100,000/mm3 occurred at least once in 20% of patients on treatment; 7% had platelet counts less than 50,000/mm3 at the nadir. bleeding was reported in 4% of sessions and in 14% of patients, but the vast majority of bleeding was localized and its incidence did not correlate with either the dose or duration of paclitaxel. In a phase III clinical study of second-line treatment of ovarian cancer, the occurrence of bleeding was reported in 10% of patients; none of the patients who received a 3-hour transfusion required platelet transfusion. In clinical studies of adjuvant therapy for breast cancer, the frequency of severe thrombocytopenia and platelet transfusions increased with increasing doses of adriamycin.
Anemia (hemoglobin less than 11 g/dL) was seen in 78% of patients and severe anemia (hemoglobin less than 8 g/dL) in 16%. No significant correlation was observed between the incidence of anemia and drug dose and duration. Of all patients with normal baseline hemoglobin levels, 69% developed anemia during the study, but only 7% developed severe anemia. Twenty-five percent of all patients, compared with 12% of patients with normal baseline hemoglobin levels, required red blood cell transfusion therapy.
Acute myeloid leukemia and myelodysplastic syndromes have also been reported, but are rare.
Hypersensitivity reactions (HSRs).
All patients were pre-treated with medication prior to paclitaxel treatment. Neither the dose nor the duration of paclitaxel treatment affected the occurrence and extent of allergic reactions. In a phase III clinical study of second-line treatment of ovarian cancer, a 3-hour infusion did not increase the incidence of allergic reactions compared with a 24-hour infusion. Anaphylactic reactions occurred in 20% of sessions and 41% of patients. Severe allergic reactions occurred in less than 2% of patients and in 1% of sessions. no severe allergic reactions occurred after 3 sessions, and severe symptoms usually appeared in the first hour of paclitaxel treatment. Of those severe allergic reactions, the most common symptoms were: dyspnea, flushing, chest pain, tachycardia, abdominal pain, pain in the extremities, excessive sweating and hypertension were also found, and patient death was also reported, but rare.
Less severe allergic reactions included mainly flushing (28%), rash (12%), hypotension (4%), dyspnea (2%), tachycardia (2%), and hypertension (1%). The incidence of allergic reactions remained relatively stable throughout the treatment period.
Ongoing monitoring of the safety of paclitaxel also included occasional occurrences of chills, shock, and back pain associated with allergic reactions.
Cardiovascular system.    
The incidence of hypotension during the first 3 hours of infusion was 12% in all patients and 3% in all courses. The incidence of bradycardia during the first 3 hours of infusion was 3% in all patients and 1% in all sessions. In the phase III clinical study in ovarian cancer, neither hypotension nor bradycardia was affected by dose or duration of infusion. These changes in vital signs were usually asymptomatic and did not require specific treatment or interruption of therapy. The occurrence of hypotension and bradycardia was unaffected by prior anthracycline therapy.
Significant cardiovascular events in approximately 1% of patients may be associated with paclitaxel monotherapy. These cardiovascular events included syncope, arrhythmias, hypertension, and venous thrombosis. In patients on paclitaxel 175 mg/m2 24-hour infusion, there was one case of syncope that progressed to hypotension and death. Arrhythmias included asymptomatic ventricular tachycardia, duplex rhythm, and complete atrioventricular block requiring a pacemaker. In patients with non-small cell lung cancer receiving paclitaxel and cisplatin combination chemotherapy in a phase III clinical study, the rate of significant cardiovascular events was 12 to 13 percent. This significant increase in cardiovascular events may be due to an increase in cardiovascular risk factors in patients with lung cancer.
Patients often have ECG abnormalities at baseline. ECG abnormalities usually do not cause symptoms and are not dose-limiting and do not require intervention. ECG abnormalities were present in 23% of all patients. Of the patients with normal ECGs prior to study entry, 14% progressed to abnormal ECG recordings during treatment. The most common in ECG monitoring were nonspecific repolarization abnormalities, sinus bradycardia, sinus tachycardia, and preterm contractions. Prior anthracycline therapy did not affect the incidence of abnormal ECGs in patients with normal baseline ECGs.
The occurrence of myocardial infarction has been reported occasionally. Congestive heart failure including cardiac dysfunction and reduced left ventricular ejection fraction or ventricular failure has generally been reported in patients being treated with paclitaxel who had been treated with other chemotherapies (especially anthracyclines).
Ongoing monitoring of the safety of paclitaxel also includes the occasional occurrence of atrial fibrillation and supraventricular tachycardia.
Respiratory.
Ongoing monitoring of the safety of paclitaxel also includes the occasional occurrence of interstitial pneumonia, pulmonary fibrosis, and pulmonary embolism. Occasional radiation pneumonitis has also been reported in patients receiving concomitant radiation therapy.
Pleural effusions and respiratory failure have also been reported occasionally with ongoing monitoring of the safety of paclitaxel.
Neurological.
The information reported in each study suggests that neurotoxicity evaluations varied in these studies (see Table 2-8). Furthermore, the incidence and severity of neurologic clinical symptoms were influenced by prior and/or concurrent neurotoxic drug therapy.
The incidence and severity of neurological clinical symptoms were usually dose-dependent in patients receiving paclitaxel monotherapy. Peripheral neuropathy occurred in 60% (3% severe) of all patients, and in 52% (2% severe) of patients without prior neuropathy. Cumulative doses increased the incidence of peripheral neuropathy. Sensory abnormalities usually manifested as sensory hypersensitivity. Neurologic symptoms occur in 27% of patients after the first course and in 34% to 51% of patients during courses 2 through 10. 1% of patients discontinue paclitaxel treatment due to peripheral neuropathy. Sensory neurological symptoms usually improve or resolve within a few months after paclitaxel treatment is discontinued. Neuropathy due to prior therapy is not a contraindication to paclitaxel treatment.
In the Collaborative Group-initiated clinical study of first-line treatment of ovarian cancer (see Table 3), neurotoxicity included motor and sensory neuropathy. Neurotoxicity in the paclitaxel 175 mg/m2 continuous 3-hour infusion combined with cisplatin 75 mg/m2 treatment group, compared with the cyclophosphamide combined with cisplatin treatment group, occurred at 87% (21% severe) and 52% (2% severe), respectively. The duration of grade III or IV neurotoxicity in this study could not be precisely determined because the date of complete remission of adverse reactions was not collected in the case report form of the collaborative group study and only a few patients had complete follow-up material. Peripheral neuropathy was reported as neurotoxicity in the clinical study of first-line treatment of GOG ovarian cancer. The incidence of neurotoxicity was similar in the paclitaxel 135 mg/m2 24-hour infusion combined with cisplatin 75 mg/m2 treatment group compared with the cyclophosphamide combined with cisplatin treatment group, 25% (3% severe) and 20% (0% severe), respectively. A cross-sectional comparison of neurotoxicity in the Collaborative Group study and the GOG study suggested that when paclitaxel combined with cisplatin 75 mg/m2 was treated with paclitaxel 175 mg/m2 continuous 3-hour infusion compared with paclitaxel 135 mg/m224 hour infusion, severe neurotoxicity was more common in the former, and their incidence was 21% and 3%, respectively.
In patients with non-small cell lung cancer, treatment with paclitaxel in combination with cisplatin was associated with a higher incidence of severe neurotoxicity compared with paclitaxel monotherapy for ovarian or breast cancer. Severe sensory neurological symptoms occurred in 13% of patients with non-small cell lung cancer treated with paclitaxel 135 mg/m224 hour infusion combined with cisplatin 75 mg/m2 compared to 8% of patients with non-small cell lung cancer receiving cisplatin/pegylated glycosides (see Table 7).
In addition to peripheral neuropathy, other neurological adverse effects after paclitaxel treatment are relatively rare (<1%) and include grand mal seizures, syncope, ataxia, and cerebral neuronopathy.
Ongoing monitoring of paclitaxel safety has also reported occasional paralytic bowel obstruction due to autonomic disorders. Optic nerve and/or visual disturbances (flashing dark spots) have also been reported, particularly in those patients at higher than recommended doses. These adverse reactions are usually reversible. There are reports in the literature of abnormal visual evoked potentials in patients that suggest lasting optic nerve damage, but such reports are rare. Ototoxicity (hearing loss and tinnitus) has also been reported in post-marketing use.
Ongoing monitoring of the safety of paclitaxel has also resulted in occasional reports of convulsions, dizziness, and headache.
Arthralgia/Myalgia.
The frequency and severity of myalgia/arthralgia did not significantly correlate with the dose of paclitaxel treatment or the duration of administration. 60% of treated patients had arthralgia/myalgia; 8% of these patients had severe symptoms, a symptom that was usually transient, appearing 2-3 days after paclitaxel treatment and recovering after a few days. The frequency and severity of skeletal muscle symptoms remained constant throughout the treatment period.
Liver.
The frequency and severity of abnormal liver function did not significantly correlate with the dose of paclitaxel treatment or the duration of administration. In patients with normal liver function at baseline, the incidence of elevated bilirubin, alkaline phosphatase, and AST was 7%, 22%, and 19%, respectively. There was no cumulative hepatotoxicity with prolonged paclitaxel use. Ongoing monitoring of the safety of paclitaxel also includes occasional reports of hepatic necrosis and hepatic encephalopathy resulting in death.
Renal.
Among patients with Kaposi’s sarcoma treated with paclitaxel, five patients developed grade III or IV nephrotoxicity and one patient discontinued treatment due to suspected grade IV severity HIV nephropathy. Renal insufficiency with reversible blood creatinine elevation occurred in four other patients.
Patients treated with paclitaxel and cisplatin may have an elevated risk of renal failure during the combination of paclitaxel + cisplatin for the treatment of gynecologic cancers compared with cisplatin alone.
 Gastrointestinal (GI).
The reported incidence of nausea/vomiting, diarrhea, and mucositis in all patients was 52%, 38%, and 31%, respectively. These symptoms were usually mild to moderate. The incidence of mucositis was time-dependent, with a higher incidence at 24 hours of infusion than at 3 hours of infusion.
In patients with AIDS-associated Kaposi’s sarcoma with poor prognosis, the incidence of nausea/vomiting, diarrhea, and mucositis was 69%, 79%, and 28%, respectively. One-third of patients with Kaposi’s sarcoma had diarrhea before the start of the study.
In the phase III first-line clinical study in ovarian cancer, the incidence of nausea and vomiting was higher with paclitaxel combined with cisplatin than with paclitaxel monotherapy in ovarian and breast cancer. There was also a higher incidence of any degree of diarrhea compared to controls, but there was no difference in the incidence of severe diarrhea in these studies.
Ongoing monitoring of paclitaxel safety also reported occasional small bowel obstruction, intestinal perforation, pancreatitis, ischemic colitis, dehydration, esophagitis, constipation, and ascites. Neutropenic small bowel colitis (appendicitis) has been reported occasionally in patients treated with paclitaxel monotherapy and in combination with other chemotherapeutic agents, even in combination with G-CSF.
Injection site reactions.
Injection site reactions, including those secondary to extravasation, are usually mild and include local edema, pain, sclerosis, erythema, induration, skin discoloration, and puffiness at the injection site. These reactions occur more frequently with a 24-hour infusion compared to a 3-hour infusion. Recurrence of skin reactions at previously extravasated sites, called “memory revival”, caused by paclitaxel infusion at other sites has also been reported occasionally.
More serious events such as phlebitis, cellulitis, sclerosis, skin peeling, necrosis, and fibrosis have been reported occasionally during continuous monitoring of paclitaxel safety. In some cases, injection site skin reactions may occur during a prolonged infusion, or 1 week or 10 days after the infusion.
There is no specific treatment for extravasation. To prevent extravasation, close monitoring of the infusion site for possible leakage during the infusion is recommended.
Other clinical adverse reactions.
Alopecia can occur in the vast majority of patients (87%). Transient skin changes due to allergic reactions associated with paclitaxel have been reported, but no other skin toxicity has been significantly associated with paclitaxel treatment. Nail changes (hyperpigmentation or discoloration of the nail bed) were uncommon (2%). puffiness was reported in 21% of patients (17% of whom had no prior puffiness); only 1% had severe puffiness, but none required treatment interruption. Swelling was usually localized and associated with disease. Patients with normal baseline developed swelling in 5% of the regimens and it did not increase over time in the study.
Ongoing monitoring of the safety of paclitaxel also includes occasional occurrence of skin abnormalities related to radiation memory resuscitation, maculopapular rash, pruritus, Stevens-Johnson syndrome, and toxic epidermal necrolysis relaxation disorder. Ongoing monitoring of the safety of paclitaxel has also reported occasional reports of conjunctivitis, excessive tearing, anorexia, confusion, flash hallucinations, shadowing before the eyes, vertigo, and elevated blood creatinine.
Adverse reactions reported in ongoing monitoring of the safety of paclitaxel also include malaise and discomfort. In a phase III clinical study of paclitaxel 135 mg/m2 24-hour infusion combined with cisplatin as first-line treatment for ovarian cancer, 17% of patients experienced malaise, significantly higher than the 10% incidence with cyclophosphamide/cisplatin control therapy.
Accidental exposure.
Respiratory distress, chest pain, burning eyes, sore throat and nausea have been reported upon inhalation. Tingling sensation, burning and local redness occur with local exposure.
 The following list, organized by system organ, presents adverse events reported according to MedDRA preferred terminology and their incidence, with incidence categorized by the following definitions: very common (≥1/10), common (≥1/100, < 1/10), uncommon (≥1/1000, < 1/100), rare (≥1/10,000, < 1/ 1000), very rare (< 1/10000) and unknown (incidence cannot be estimated based on available data).
 Reported adverse drug events
(MedDRA terminology) System Organ Classification Incidence MedDRA terminology Infection and Infestation Very common infection1 Uncommon septic shock Unknown cryptococcal meningitis, sepsis, cerebral leukoencephalopathy, opportunistic infection, cytomegalovirus infection, Pneumocystis carinii infection, Mycobacterium avium complex infection, esophageal candidiasis, Cryptosporidium gastroenteritis, pneumonia, herpes simplex, urinary tract infection, upper respiratory tract Infection, sinusitis, rhinitis Blood and lymphatic system abnormalities very common bone marrow failure, hemorrhage, neutropenia, anemia, thrombocytopenia, leukopenia rare neutropenia with fever unknown acute myeloid leukemia, myelodysplastic syndrome, hematotoxicity, reduced platelet count immune system abnormalities very common allergic reactions, hot flashes uncommon respiratory distress, angioedema, generalized urticaria Unknown anaphylaxis, anaphylaxis-like reactions2 Metabolic and nutritional disorders unknown anorexia, tumor lysis syndrome Mental disorders unknown blurred state of consciousness Neurological abnormalities very common neurotoxicity3, peripheral neuropathy, visual evoked potential abnormalities unknown convulsive grand mal seizures, vegetative neuropathy, encephalopathy, convulsions, peripheral motor neuropathy, dizziness, ataxia, hypertonia, sensory abnormalities, headaches, Insomnia eye abnormalities unknown optic nerve abnormalities, flash dark spots, flash hallucinations, flying mosquitoes, macular edema ear and vagus abnormalities unknown deafness, ototoxicity, vertigo, tinnitus heart abnormalities very common ECG abnormalities common bradycardia uncommon myocardial infarction, cardiomyopathy, ventricular tachycardia, atrioventricular block, tachycardia unknown ventricular failure, heart failure4, congestive heart failure, atrial fibrillation, reduced ejection fraction , supraventricular tachycardia, conduction abnormalities, extrasystoles, sinus bradycardia, ECG repolarization abnormalities vascular abnormalities very common hypotension uncommon thrombosis, hypertension, thrombophlebitis unspecified shock, phlebitis respiratory, thoracic and mediastinal abnormalities unspecified respiratory failure, pulmonary embolism, pulmonary fibrosis, interstitial lung disease, radiation pneumonia, dyspnea, pleural effusion, rhinorrhea, cough gastrointestinal abnormalities very Common abdominal pain, diarrhea, vomiting, nausea Unknown intestinal obstruction, intestinal perforation, mesenteric vascular thrombosis, ischemic colitis, pancreatitis, pseudomembranous enterocolitis, neutropenic small bowel colitis, ascites, esophagitis, mucosal inflammation, constipation Hepatobiliary abnormalities Common elevated aspartate transaminase, elevated blood alkaline phosphatase, abnormal liver function Uncommon elevated blood bilirubin Unknown hepatic necrosis 2, hepatic encephalopathy 2 Skin and subcutaneous tissue abnormalities very common hair loss common skin abnormalities, nail abnormalities unknown Stevens-Johnson syndrome, toxic epidermal necrolysis loosening, erythema multiforme, exfoliative dermatitis, urticaria, skin necrosis, memory resuscitation, skin peeling, skin fibrosis, cellulitis, pruritus, rash, erythema, nail peeling, acne, cutaneous lupus erythematosus skeletal muscle, connective tissue and bone abnormalities very common arthralgia, muscle pain uncommon back pain unknown extremity pain, SLE renal and urinary tract abnormalities unknown renal failure, nephrotoxicity systemic abnormalities and administration site conditions common extravasation, injection site reactions, local edema, pain, sclerosis, tenderness, skin discoloration, chills, injury unknown dehydration, fever, edema, chest pain, hyperhidrosis, malaise, malaise examination unknown elevated blood creatinine1 infection. Deaths accounted for 1% of all patients.
2 Events reporting patient deaths.
3 Including CNS toxicity reported in clinical trials in pediatric patients (rare cases associated with death).
4 Patients previously treated with anthracyclines and then treated with trastuzumab in combination with paclitaxel had a higher incidence and severity of cardiac dysfunction than those treated with paclitaxel alone, but death was rare.
 [Contraindications
Paclitaxel is contraindicated in patients with a history of allergic reactions to paclitaxel or other drugs formulated with Cremophor EL (polyoxyethylene castor oil). Paclitaxel should not be used in patients with solid tumors with baseline neutrophil counts less than 1500 cells/mm3 or in patients with AIDS-associated Kaposi’s sarcoma with baseline neutrophil counts less than 1000 cells/mm3. It is contraindicated in pregnant and lactating women.
 【Caution】.
Precautions for clinical application.
Paclitaxel must be administered under the supervision of an internist experienced in chemotherapy. Effective control of complications is possible only when adequate diagnostic and therapeutic equipment is available.
Treatment should be preceded by adrenocorticosteroids (e.g., dexamethasone), diphenhydramine, and H2 receptor antagonists (e.g., cimetidine or ranitidine) (see [Dosage]). Patients should be monitored for injection site reactions (e.g., hematomas) when prophylactic medications (e.g., intramuscular diphenhydramine) are administered prior to paclitaxel therapy (see [Dosage]). Fatal allergic reactions can occur with or without premedication. Mild symptoms such as flushing, rash, skin reactions, dyspnea, hypotension, tachycardia, etc. may be treated without discontinuation. However, the incidence of severe anaphylactic reactions characterized by respiratory distress and hypotension requiring rescue, angioneurotic edema, and generalized urticaria, which may be caused by the action of histamine through paclitaxel treatment, accounts for 2% to 4% of patients receiving paclitaxel and requires immediate discontinuation of paclitaxel once it occurs and aggressive symptomatic treatment. This drug is contraindicated in anyone who has had a severe allergic reaction to paclitaxel.
When used in combination with platinum compounds, paclitaxel should be administered first.
Myelosuppression (mainly neutrophil deficiency), which is related to the dose and duration of infusion, is the main dose-limiting toxic reaction of the same regimen and may be severe and lead to the development of infections, for which reason it is important to monitor the occurrence of myelosuppression. The median time of trough in neutrophil count is on day 11. Paclitaxel should not be used in patients with solid tumors with neutrophil counts less than 1500/mm3 (less than 1000/mm3 in patients with Kaposi’s sarcoma), and blood counts should be checked frequently during the administration of paclitaxel until neutrophils rise to 1500/mm3 (more than 1000/mm3 in patients with Kaposi’s sarcoma) and platelet counts rise to >100, 000/mm3 before starting another treatment cycle of paclitaxel.
Hypotension, bradycardia, and hypertension can occur during paclitaxel therapy, but usually do not require treatment. Occasionally, paclitaxel therapy has to be interrupted or stopped due to the initial onset or recurrence of hypertension, as determined by the physician in charge of treatment. Monitoring of vital signs during paclitaxel therapy is recommended, especially during the first hour of paclitaxel infusion. Continuous cardiac monitoring is not required unless the patient develops severe conduction abnormalities. Severe conduction abnormalities occur in <1% of patients during paclitaxel therapy, and some patients require a cardiac pacemaker. Patients who develop significant conduction abnormalities during paclitaxel titration should be treated appropriately and given continuous ECG monitoring during subsequent continuation of paclitaxel therapy. Monitoring of cardiac function is recommended when congestive heart failure has occurred with paclitaxel in combination with adriamycin for previously untreated metastatic breast cancer (see [Adverse Reactions]).
There is evidence of enhanced toxicity of paclitaxel in patients with serum total bilirubin >2 times ULN. Caution should be exercised when using paclitaxel in these patients and dose adjustment needs to be considered (see [Dosage]).
Paclitaxel contains anhydrous ethanol. Therefore, in all patients, consideration should be given to the possible central nervous system effects and other effects of ethanol. Children may be more sensitive than adults to effects produced by ethanol (see [Pediatric Use]).
Precautions in preparation.
Paclitaxel is a cytotoxic anticancer drug and, like other potentially toxic compounds, care must be taken when preparing paclitaxel, which should be handled according to proper anticancer drug pick-up and disposal protocols. To minimize the risk of skin exposure, impermeable gloves should always be worn when handling vials containing paclitaxel injection. This includes all procedures in the clinic, pharmacy, storage room and home healthcare, including unpacking and visual inspection, delivery within the unit, and the dispensing and administration process.
In case of skin contact with paclitaxel solution, the skin should be washed immediately and thoroughly with soap and water and rinsed thoroughly with water as soon as paclitaxel comes into contact with mucous membranes.
Reproductive System.
Due to the possibility of gene mutation caused by this product, both male and female patients should use effective contraceptive measures during treatment and for 6 months after the end of treatment. Because this product may reduce male fertility, consider early sperm withdrawal for subsequent reproduction if reproductive needs arise.
Do not use if the inner bottle seal is broken or missing.
[For Pregnant and Lactating Women].
Pregnant women.
Paclitaxel may harm the fetus when used in pregnant women. Studies have shown that paclitaxel is embryotoxic to rabbits and can reduce fertility in rats. The use of paclitaxel at 3.0 mg/kg/day (approximately 0.2 of the maximum recommended human dose per mg/m2 unit) during organogenesis in rabbits was able to cause embryonic and fetal toxicity as evidenced by intrauterine mortality, increased ablation, and increased fetal death. Toxicity to female rabbits was likewise found at this dose. At 1.0 mg/kg/day of paclitaxel (approximately 1/15th of the maximum recommended human dose at mg/m2), no teratogenic effects were found. At higher doses, extensive fetal deaths prevented evaluation of teratogenicity. Pre-mating and intra-mating doses of paclitaxel equal to or exceeding 1 mg/kg/day (equivalent to 0.04 of the maximum recommended human dose on a mg/m2 basis) in female and male rats produced fertility impairment. This dose of paclitaxel causes a decrease in fertility and reproductive indices, as well as an increase in embryonic and fetal toxicity.
It has not been studied in pregnant women. It is contraindicated in pregnant women. If paclitaxel is used in a pregnant woman or if a patient becomes pregnant during the application of this drug, the patient should be informed immediately of this potential hazard and women of childbearing potential who are receiving paclitaxel should be advised to avoid pregnancy.
Use in nursing women.
It is not known whether this product is secreted through human milk. Intravenous infusion of carbon-14-labeled paclitaxel to rats 9 to 10 days postpartum resulted in higher radioactivity concentrations in the emulsion than in plasma, with a parallel decrease in plasma concentrations. It is contraindicated in lactating women. Because many drugs are secreted through human milk and because of the potential for serious adverse reactions in breastfed infants, interruption of breastfeeding while receiving paclitaxel is recommended.
 Pediatric Use]
The safety and efficacy of paclitaxel in children have not been established.
Central nervous system (CNS) toxicity has been reported in a clinical trial in pediatric patients (rarely causing death). In this study, paclitaxel was infused intravenously at doses of 350 to 420 mg/m2 for more than 3 hours. The high-dose ethanol component of paclitaxel preparations infused over a short period of time may be the most significant cause of central nervous system (CNS) toxicity. This effect may be enhanced by the combined use of antihistamines. Although the direct effects produced by paclitaxel itself cannot be ignored, the high doses used in this study (more than 2 times higher than the recommended adult dose) must be taken into account when evaluating the safety of paclitaxel use in this population.
 [Geriatric use].
In eight clinical studies evaluating the safety and efficacy of paclitaxel for advanced ovarian cancer, breast cancer, or non-small cell lung cancer, paclitaxel was used in 2228 patients, and in the adjuvant breast cancer study, paclitaxel was used in 1570 patients after randomization grouping. Of these 3798 patients, 649 (17%) were ≥65 years old, including 49 (1%) ≥75 years old. In most studies, severe myelosuppression was more common in older patients; in some studies, severe neuropathy was more common in older patients. The incidence of cardiovascular events was higher in elderly patients treated with paclitaxel in 2 clinical studies of non-small cell lung cancer. Efficacy estimates appeared to be similar in older and younger patients; however, because of the small number of older patients studied, relative efficacy cannot be reliably derived. In one study of first-line treatment of ovarian cancer, the median survival rate was lower in older patients than in younger patients, but no other efficacy parameters indicated that the younger patient group was better. Table 9 shows the incidence of grade IV neutropenia and severe neurotoxicity in patients of different ages in the clinical trial.
 Table 9: Adverse reactions occurring in elderly patients treated with paclitaxel in clinical trials
Indication
(study/treatment protocol) Patients [number of occurrences/total (%)] Neutropenia
(Class IV) Peripheral neuropathy
(Grade III/IV) Age (years) Age (years)³65<65³65<65 Ovarian cancer First-line/T175/3 c75 a34/83
(41)78/252 (31)24/84 (29)*b46/255 (18)b first-line/T135/24 c75 a48/61
(79)106/129 (82)3/62
(5)2/134
(1)2nd line/III T175/3c5/19
(26)21/76
(28)1/19
(5)0/76
(0)2nd line/III T175/24c21/25
(84)57/79
(72)0/25
(0)2/80
(3)Second line/phase III T135/3c4/16
(25)10/81
(12)0/17
(0)0/81
(0)2nd line/III T135/24c17/22
(77)53/83
(64)0/22
(0)0/83
(0)2nd line III combined 47/82 (57)*141/319 (44)1/83
(1)2/320
(1)Breast cancer adjuvant treatment AC, sequential T d56/102 (55)734/1468 (50)5/102
(5)e46/1468 (3)e breast cancer that failed initial treatment Stage III/T175/3 c7/24
(29)56/200 (28)3/25
(12)12/204 (6)Stage III/T135/3 c7/20
(35)37/207 (18)0/20
(0)6/209
(3)Non-small cell lung cancer T135/24 c75 a58/71
(82)86/124 (69)9/71
(13)f16/124 (13)f stage III/T175/3 c80 a37/89 (42)*56/267 (21)11/91 (12)*11/271 (4)* p<0.05
a Paclitaxel dose (mg/m2)/infusion time (hours); cisplatin dose (mg/m2).
b Peripheral neuropathy in ovarian cancer first-line treatment studies classified in this category of neurotoxicity (see Table 3).
c Paclitaxel dose (mg/m2)/infusion time (hours).
d Adriamycin and cyclophosphamide (AC) for 4 courses followed by paclitaxel (T) at a dose of 175 mg/m2/3 hours every 3 weeks for 4 courses.
ePeripheral neuropathy in the adjuvant breast cancer study was reported as sensory neurotoxicity (see Table 5).
fPeripheral neuropathy in the non-small cell lung cancer (NSCLC) study was reported as sensory neurotoxicity (see Table 7).
 [Drug interactions].
In a phase I trial using incremental doses of paclitaxel (110 to 200 mg/m2) and cisplatin (50 or 75 mg/m2) as a sequential titration, myelosuppression was more severe in the former when paclitaxel was given after cisplatin compared with paclitaxel given before cisplatin. Pharmacokinetic data from these patients demonstrated that paclitaxel clearance was reduced by approximately 20% when cisplatin was administered after paclitaxel.
The cytochrome P450 isoenzymes CYP2C8 and CYP3A4 promote the metabolism of paclitaxel. The pharmacokinetics of paclitaxel is also altered when paclitaxel is combined with known substrates, inducers (e.g., rifampin, carbamazepine, phenytoin, efavirenz, nevirapine) or inhibitors (e.g., erythromycin, fluoxetine, gemfibrozil) of CYP2C8 and CYP3A4, and caution should be exercised.
Interactions between paclitaxel and substrates of CYP3A4, as well as protease inhibitors (ritonavir, saquinavir, indinavir, and nafinavir) that are substrates/or inhibitors of CYP3A4, have not been confirmed by clinical studies.
Many drugs (ketoconazole, isobodine, valium, quinidine, dexamethasone, cyclosporine, teniposide, pediposide, perphenazine) can inhibit the metabolism of paclitaxel to 6α-hydroxypaclitaxel in vitro, but are used at concentrations beyond the normal therapeutic dose in vivo. Testosterone, 17α-ethinyl estradiol, retinoic acid, and the CYP2C8-specific inhibitor, acanthin, were also able to inhibit the production of 6α-hydroxypaclitaxel in vitro.
Reports in the literature suggest that when paclitaxel is combined with adriamycin, it may increase the blood concentration of adriamycin (and its active metabolite, adriamycinone). An effect of dosing sequence was found, characterized by greater neutropenia and stomatitis when paclitaxel was administered “before” adriamycin and when the infusion time was longer than the recommended infusion time (24 hours for paclitaxel and 48 hours for adriamycin).
Paclitaxel and vaccines: Because this product may inhibit normal defense mechanisms, its combination with a live virus vaccine may enhance replication of the vaccine virus and/or increase the adverse effects of that vaccine. Administration of live vaccines to patients using this product may result in severe infection. The patient’s antibody response to the vaccine may be reduced. Live vaccines should be avoided and expert advice sought.
Concomitant use of paclitaxel with live vaccines increases the risk of fatal systemic vaccine disease. Concomitant use of live vaccines in immunosuppressed medicated patients is therefore not recommended.
 [Drug overdose].
There are no drugs available for the treatment of paclitaxel overdose. The most significant predictable complications of overdose include myelosuppression, peripheral neurotoxicity, and mucositis.
Overdose of paclitaxel in pediatric patients may result in acute alcoholism (possibly related to receiving too much paclitaxel soluble medium containing ethanol).
 [Clinical Trials].
Clinical studies:
Ovarian cancer
First-line information: Two multicenter, randomized controlled phase III clinical studies confirmed the safety and efficacy of tamsulosin in combination with cisplatin in patients with chemotherapy-free advanced ovarian cancer. A European Agency for Research and Treatment of Cancer-sponsored international collaborative group study included 680 patients with stage II B-C, III, or IV (after managerially desired or non-ideal tumor cytoreduction) from the Scandinavian Collaboration NOCOVA, the National Cancer Institute of Canada, and the Scottish Collaboration, receiving 75 mg/ m2 of cisplatin in combination with 175 mg/ m2 of tysol sustained infusion over 3 hours or receive 75 mg/ m2 of cisplatin in combination with 750 mg/ m2 of cyclophosphamide for a median of six cycles. Despite the availability of further treatment options, only 15% of patients received nine or more cycles of combination drug therapy. In a study sponsored by the Gynecologic Oncology Group (GOG), 410 patients with stage III or IV disease (residual foci greater than 1 cm after staged surgery or with distant metastases) received 75 mg/ m2 of cisplatin combined with 135 mg/ m2 of teso over a 24-hour infusion or 75 mg/ m2 of cisplatin combined with 750 mg/ m2 of cyclophosphamide, both for six weeks.
In both studies, patients treated with tamsulosin (paclitaxel) in combination with cisplatin demonstrated significantly higher remission rates, longer time to disease progression, and longer survival compared to standard therapy. Although the studies did not have sufficient statistical power for stratified analysis, significant differences were also seen in the subgroup of patients classified as non-ideal post-tumor cytoreductive surgery (debutked) in the collaborative group study. Figures 1 and 2 show the Kaplan-Meier survival curves for each study.
Table 10
Efficacy of Phase III First-Line Ovarian Cancer Studies
 Collaborative group
(subgroup after suboptimal tumor cytoreduction) GOG-111 T175/3a
c75
(n = 218) C750a
c75
(n = 227) T135/24a
c75
(n = 196) C750a
c75
(n = 214) Clinical responseb N = 153 N = 153 N = 113 N = 127 – Rate (%) 58 4362 48 – P-valuec 0.016 0.04 Time to disease progression – Median time to disease progression (months) 13.2 9.916.6 13.0 -P-valuec 0.0060 0.0008 -Hazard ratio (HR)c 0.76 0.70 -95% confidence intervalc 0.62-0.92 0.56-0.86 Survival -Median (months) 29.5 21.935.5 24.2 -P-valuec 0.0057 0.0002 -Hazard ratio (HR)c 0.73 0.64 -95% confidence intervalc 0.58-0.91 0.50-0.81 aTyrosin dose in mg/m2/infusion time in hours; cyclophosphamide and cisplatin Dose in mg/m2
bOnly patients with measurable lesions were included
cThe Collaborative Group study was not stratified, whereas stratification was performed in the GOG-111 study.
 Table 11
Efficacy of the Phase III First-line Ovarian Cancer Collaborative Group Studies
 T175/3a
c75
(n = 342) C750a
c75
(n = 338) Clinical responsebN = 162 N = 161 -Rate (percentage) 59 45 -P valuec 0.014 Time to disease progression -Median time (months) 15.3 11.5 -P valuec 0.0005 -Hazard (HR)c 0.74 -95% confidence intervalc 0.63-0.88 Survival -Median time (months) 35.6 25.9 -P-valuec 0.0016 -Hazard (HR)c 
  -95% confidence intervalc 0.60-0.89 aTyrosin dose in mg/m2/infusion time in hours; cyclophosphamide and cisplatin dose in mg/m2
bIncluding only patients with measurable lesions
cUnstratified studies
 
 
 
 The adverse events that occurred in patients treated with the combination of tamsulosin and cisplatin in these studies were qualitatively consistent with the information obtained from the analysis of 812 patients treated with tamsulosin monotherapy in 10 additional clinical studies. These adverse events, as well as those derived from phase III clinical studies of first-line ovarian cancer treatment, are described in the adverse events section in both tabular (Tables 2 and 3) and narrative form.
Second-line information: information from five phase I and II clinical studies (189 patients), one multicenter randomized phase III clinical study (407 patients), and interim analysis information from more than 300 patients enrolled in a Treatment Referral Center program supported the use of tamsulosin in patients with metastatic ovarian cancer who failed initial or subsequent chemotherapy. The majority of patients (>90%) in the two phase II clinical studies (92 patients) used an initial dose of 135-170 mg/m2 as a continuous input over 24 hours. Remission rates in the two studies were 22% (95% confidence interval 11-37%) and 30% (95% confidence interval 18-46%), respectively, with a total of 6 complete and 18 partial remissions among the 92 patients. The median remission periods calculated from the first day of treatment were 7.2 months (from 3.5 to 15.8 months) and 7.5 months (from 5.3 to 17.4 months) in these two studies, respectively. Median survival was 8.1 months (from 0.2 to 36.7 months) and 15.9 months (from 1.8 to 34.5 months).
A two-factor design was developed for the phase III clinical study comparing the safety and efficacy of tamsulosin treatment at two different doses (135 or 175 mg/m2) and different dosing regimens (3 or 24-hour infusion). 407 patients had an overall remission rate of 16.2% (95% confidence interval 12.8-20.2%), with 6 in complete remission and 60 in partial remission. The duration of remission from the first day of treatment was 8.3 months (from 3.2 to 21.6 months). The median time to disease progression was 3.7 months (from 0.1 to 25.1 months). The median survival was 11.5 months (from 0.2 to 26.3 months). The remission rate, median survival, and median time to disease progression for the four regimen groups in this study are presented in the following table.
 Table 12
Efficacy of the phase III second-line ovarian cancer study
 175/3
(n = 96) 175/24
(n = 106) 135/3
(n = 99) 135/24
(n = 106) Remission – rate (%) 14.621.715.213.2-95% confidence interval8.5-23.614.5-31.09.0-24.17.7-21.5 Time to disease progression – median time (months) 4.44. 23.42.8-95% confidence interval3.0-5.63.5-5.12.8-4.21.9-4.0 Survival -median time (months)11.511.813.110.7-95% confidence interval8.4-14.48.9- 14.69.1-14.68.1-13.6
 Analyses were performed using a planned design two-factor study comparing two different doses (135 or 175 mg/m2) without regard to dosing regimen (3 or 24-hour infusion) and comparing two dosing regimens without regard to dose. Patients receiving the 175 mg/m2 dose had similar remission rates to those receiving the 135 mg/m2 dose: 18% and 14% (P = 0.28). There was no difference in remission rates between patients when comparing the 3-hour and 24-hour infusions: 15% and 17% (P = 0.50). Patients treated with the 175 mg/m2 dose of tamsulosin had a longer time to disease progression in the former compared with patients receiving the 135 mg/m2 dose: median values were 4.2 and 3.1 months (P = 0.03). median time to disease progression was 4.0 and 3.7 months for patients at the 3-hour and 24-hour infusions, respectively. The median survival was 11.6 months for patients receiving the 175 mg/m2 dose of tamsulosin and 11.0 months for patients receiving the 135 mg/m2 dose (P = 0.92). Median survival was 11.7 months for patients receiving a 3-hour infusion of Tysol compared with 11.2 months for patients receiving a 24-hour infusion (P = 0.91). Due to the multiple comparison model, the results of these statistical analyses must be treated with caution.
For patients who were resistant to platinum-containing therapy (defined as tumor progression during treatment with platinum-containing therapy or tumor recurrence within 6 months of treatment), tamsulosin remained effective, with a remission rate of 14% in the phase III study and 31% in the phase I and II clinical studies.
The adverse events that occurred in this phase III study were in essence consistent with the information obtained from the analysis of 812 patients treated with tamsulosin monotherapy in 10 other clinical studies. These adverse events, as well as those originating from the phase III clinical study of second-line ovarian cancer treatment, are described in the adverse reactions section in both tabular (Tables 2 and 4) and narrative form.
The results of this randomized study confirm the use of Tysol at doses of 135-175 mg/m2 administered as a 3-hour intravenous infusion. A 24-hour infusion of the same dose was more toxic. However, this study did not have sufficient statistical certainty to indicate which dose and dosing regimen would achieve better efficacy.
Breast Cancer
Adjuvant Therapy
A phase III collaborative group study (Cancer and Leukemia Study Group B [CALGB], Eastern Cooperative Oncology Group [ECOG], Northern Center Cancer Treatment Group [NCCTG], Southwest Oncology Group [SWOG]) randomized 3170 patients with lymph node-positive breast cancer to either the observation group after four courses of adriamycin and cyclophosphamide (AC regimen) or the adjuvant treatment with Tysol group. Female patients enrolled in this multicenter study were those with positive lymph nodes on pathological examination after mastectomy or partial mastectomy plus lymph node dissection. A 3×2 chi-square analysis was designed to evaluate the efficacy and safety of different adriamycin dose levels and to evaluate the effect of sequential tylosin administration after completion of the AC regimen. After stratification by the number of positive lymph nodes (1-3, 4-9, 10+), patients were randomized to receive 600 mg/m2 of cyclophosphamide combined with adriamycin, with adriamycin administration regimens of 60 mg/m2 (day 1), 75 mg/m2 (given in two divided doses on days 1 and 2), or 90 mg/m2 (given in two divided doses on days 1 and 2 and pre-treated with ciprofloxacin and G-CSF support) , repeated every three weeks for a total of four courses of therapy; in addition, patients received or did not receive four additional courses of Tysol 175 mg/m2 continuous 3-hour infusion every three weeks, respectively. Receptor-positive patients were thereafter also treated with tamoxifen (20 mg daily for 5 years); patients who underwent local mastectomy prior to the study were to receive radiotherapy after recovery from treatment-related toxic effects.
At the time of the current analysis, the median follow-up period was 30.1 months. 93% of the 2066 hormone receptor-positive patients were treated with tamoxifen. The primary analysis of disease-free survival and overall survival was performed using a multifactorial Cox model, which included factors such as tamsulosin treatment, adriamycin dose, number of positive lymph nodes, tumor size, menopausal status, and estrogen receptor status. Based on a disease-free survival model, patients treated with sequential tylosin therapy with the AC regimen had a 22% lower risk of recurrence (hazard ratio [HR]=0.78, 95% confidence interval 0.67-0.91, P=0.0022) than the randomized group of patients receiving chemotherapy with the AC regimen alone. The risk of death was reduced by 26% (hazard ratio [HR]=0.74, 95% confidence interval 0.60-0.92, P=0.0065). For disease-free survival and overall survival, P values for the analysis were not adjusted. Figure 3 and Figure 4 show Kaplan-Meier survival curves. Increasing the adriamycin dose beyond 60 mg/m2 had no effect on disease-free survival or overall survival.　　　　　　　　　　　　
 
 Stratified analysis
Stratification studies were performed by known significant prognostic factors for breast cancer, including number of positive lymph nodes, tumor size, hormone receptor status, and menopausal status. This analysis needs to be interpreted with caution, as the results of the entire study are the most reliable outcome. In general, in all but one of the large strata, the reduction in risk of disease-free survival and overall survival with tamsulosin (paclitaxel) use was similar to that seen in the overall study; the reduction in risk of disease-free survival and overall survival with tamsulosin use was smaller in receptor-positive patients (HR=0.92) compared with the other groups. Table 13 shows the results of the stratified analysis.
Table 13
Stratified analysis-adjuvant breast cancer treatment study
Patient stratification Disease-free survival Overall survival Number of patients Number of recurrences Hazard
(95% Confidence Interval) Number of Deaths Hazard
(95% confidence interval) Number of positive lymph nodes 1-314492210.72
(0.55-0.94)1070.76
(0.52-1.12)4-913102740.78
(0.61-0.99)1480.66
(0.47-0.91)10+3601290.93
(0.66-1.31)970.90
(0.59-1.36)Tumor size (cm) ≤210961530.79
(0.57-1.08)670.73
(0.45-1.18)>2 and ≤516113580.79
(0.64-0.97)2010.74
(0.56-0.98)>53971110.75
(0.51-1.08)720.73
(0.46-1.16)Menopausal status Premenopausal 19293740.83
(0.67-1.01)1870.72
(0.54-0.97)Postmenopausal11832500.73
(0.57-0.93)1550.77
(0.56-1.06)Receptor status Positivea20662930.92
(0.73-1.16)1260.83
(0.59-1.18) Negative or unknownb10553310.68
(0.55-0.85)2160.71
(0.54-0.93)a Positive for estrogen or progesterone receptors.
b Negative or absent for both estrogen and progesterone receptors (both absent: n = 15).
 These retrospective subgroup analyses suggest that the benefit of Tysol is clearly shown in the receptor-negative subgroup, while in receptor-positive patients the benefit is unclear. In contrast, the benefit of tamsulosin use was consistent across menopausal status (see Table 13 and Figures 5-8).
 Figure 5. DFS-receptor-negative or unknown
 
 
 
Patients treated with tamsulosin after the AC regimen were consistent with the information from the pooled analysis of 812 patients in 10 additional clinical studies (Table 2) that employed tamsulosin monotherapy in terms of overall adverse events. These adverse events are elucidated graphically (Tables 2 and 5) and narratively in the section on adverse events.
After failure of initial chemotherapy
Data from 83 patients in three phase II open clinical studies and 471 patients in one phase III randomized clinical study support the use of tamsulosin in patients with metastatic breast cancer.
Phase II open clinical studies: 53 patients in two studies had received up to one prior chemotherapy regimen. In both studies tamsulosin was administered at an initial dose of 250 mg/m2 (G-CSF support) or 200 mg/m2 as a 24-hour continuous infusion. Remission rates were 57% (95% confidence interval: 37-75%) and 52% (95% confidence interval: 32-72%), respectively. The third phase II clinical study was all in patients who had failed multiple anthracycline chemotherapy regimens and were treated with a minimum of two chemotherapy regimens. Tysol was administered at a dose of 200 mg/m2 24-hour continuous infusion and supported with G-CSF. 9 of 30 patients achieved partial remission, for a remission rate of 30% (95% confidence interval: 15-50%).
Phase III randomized clinical study: This multicenter study enrolled patients who had received one or two prior chemotherapy treatments. Patients were randomized to two groups receiving a 3-hour continuous infusion of tamsulosin (paclitaxel) at doses of 175 mg/m2 and 135 mg/m2. 60% of the 471 patients enrolled had symptoms affecting physical status scores at enrollment, and 73% had visceral metastases. All of these patients had a history of chemotherapy failure, which included adjuvant therapy (30%) and treatment for metastases (39%), or both (31%). 67% of patients had a history of anthracycline use, and 23% were considered resistant to this class of drugs.
The overall remission rate for the 454 evaluable patients was 26% (95% confidence interval: 22-30%), with 17 in complete remission and 99 in partial remission. The median remission period calculated from the first day of treatment was 8.1 months (from 3.4-18.1 months). 471 patients had an overall median time to disease progression of 3.5 months (from 0.03-17.1 months) and a median survival of 11.7 months (from 0-18.9 months).
The table below gives the remission rate, median survival, and median time to disease progression for both groups.
 Table 14
Efficacy in breast cancer that failed initial chemotherapy or recurred within 6 months of adjuvant chemotherapy
 175/3
(n=235) 135/3
(n=236) Remission rate – rate (percentage) 28 22 – P value 0.135 Time to disease progression – median (months) 4.2 3.0 – P value 0.027 Survival – median (months) 11.7 10.5 – P value 0.321 
 
 The overall adverse events that occurred in patients treated with Tysol monotherapy in the Phase III clinical study were consistent with the pooled analysis information obtained in the 812 patients treated in the other 10 clinical studies. These adverse events, as well as those originating from the Phase III breast cancer clinical studies, are presented in the adverse events section in both tabular (Tables 2 and 6) and narrative form.
Non-Small Cell Lung Cancer (NSCLC)
In a phase III open randomized study conducted by ECOG, 599 patients were randomized to either tamsulosin 135 mg/m2 24-hour continuous infusion combined with cisplatin 75 mg/m2, tamsulosin 250 mg/m2 24-hour continuous infusion combined with cisplatin 75 mg/m2 and G-CSF supportive therapy, or cisplatin 75 mg/m2 on day one combined with first, second, and third day pedialyte ethoside (VP) 100 mg/m2 (control group).
The table below gives the remission rate, median time to disease progression, median survival, and 1-year survival rate. The reported P values were not adjusted for multiple references, and the teso combined with cisplatin group was significantly better than the control group in terms of remission rate, and time to disease progression. There was no statistically significant difference in survival between the teso combined with cisplatin regimen group and the cisplatin combined with pedialyte glycosides regimen group.
 Table 15
Phase III first-line non-small cell lung cancer study efficacy parameters
 T135/24
c75
(n=198) T250/24
c75
(n=201) VP100a
c75
(n=200) Remission rate – rate (%) 252312 – P valueb0.001<0.001 Time to disease progression – median (months) 4.34.92.7 – P valueb0.050.004 Survival – median (months) 9.310.07.4 – P valueb0.120.08 One-year survival – % of patients 364032a 1st, 2nd, 3rd day intravenous administration of pedialyte glycosides 100 mg/m2
b Compared with cisplatin/pegylated glycosides
 In the ECOG study, the Functional Assessment of Oncology Therapy-Lung (FACT-L) Quality of Life Questionnaire score had seven subcategories to measure subjective assessment of treatment. In one of the seven lung cancer specific symptom subcategories, the Tysol 135 mg/m2/24 hours combined with cisplatin regimen was superior to the cisplatin/pegylated glycosides regimen. In the other subcategories, there was no difference between treatment groups.
The overall adverse events that occurred in patients treated with tamsulosin in combination with cisplatin in this study were consistent with the pooled analysis information obtained in 812 patients treated with tamsulosin monotherapy in 10 other clinical studies. These adverse events, as well as those originating from the phase III first-line non-small cell lung cancer studies, are set forth in the adverse reactions section in tabular (Tables 2 and 7) and narrative form.
AIDS-associated Carcinosarcoma
Information from two phase II open studies supports tamsulosin as second-line treatment for AIDS-associated Karls Sarcoma. Fifty-nine of the 85 patients participating in these studies had received prior systemic therapy, including alpha interferon (32%), Daunoxome (31%), esterosomal adriamycin (Doxil) (2%), and chemotherapy containing adriamycin (42%), and 64% had received prior anthracycline therapy. Of those who had been treated, 85% had disease progression or were intolerant of prior systemic therapy.
In the CA139-174 study, patients received a 3-hour continuous infusion of tamsulosin 135 mg/m2 every three weeks (planned dose intensity of 45 mg/m2/week). In the absence of dose-limiting toxicity, patients will receive subsequent therapy with tysol at 155 mg/m2 and 175 mg/m2. Hematopoietic growth factors were not used at the beginning of treatment. In the CA139-281 study, patients received a 3-hour continuous infusion of Tysol 100 mg/m2 every two weeks (planned dose intensity of 50 mg/m2/week). In this study, patients could be treated with hematopoietic growth factor prior to thaumaturgic therapy or start this supportive therapy when needed, but the dose of thaumaturgic was not increased. The dose intensity of tamsulosin in this patient population was lower than that recommended in solid tumors.
All patients had extensive disease and a poor prognosis. Using ACTG staging criteria for pre-treated patients, 93% of patients had high-risk disease (T1), 88% had CD4 counts less than 200 cells/mm3 (I1), and 97% were at high risk due to the presence of systemic disease (S1).
All patients in the CA139-174 study had a Karlsberg functional score of 80 or 90 at baseline; 26 patients (46%) in the CA139-281 study had a Karlsberg functional score of 70 or worse at baseline.
 Table 16
Extent of disease at study entry
Percentage of Patients
 Before systemic therapy
(n = 59) Visceral ± swelling ± oral ± skin 42 swelling or lymph nodes ± oral ± skin 41 oral ± skin 10 skin only 7
 Although there was a slight difference in dose intensity between the two study schedules (45 mg/m2/week in study CA139-174 and 50 mg/m2/week in study CA139-281), however, the actual dose intensity used in both studies was 38-39 mg/m2/week, with a similar range (20-24 to 51-61).
Efficacy: Evidence of patient benefit was obtained to evaluate the efficacy of tamsulosin based on remission of somatic surface tumors as evaluated by modified ACTG criteria, and based on six symptoms and/or states commonly associated with AIDS-associated karst sarcoma.
Remission of body surface tumors (modified ACTG criteria): an objective remission rate of 59% (95% confidence interval 46%-72%) for patients who had received prior systemic therapy (35 of 59 patients). Body surface remission was defined as flattening of more than 50% of the previously raised skin lesions.
 Table 17
Overall best remission (modified ACTG criteria)
Percentage of patients
 Prior systemic therapy complete remission3 partial remission56 stable disease29 disease progression8 early death/toxicity3
 Patients with prior systemic therapy had a median remission time of 8.1 weeks and a median remission period of 10.4 months (95% confidence interval: 7.0-11.0 months) from the first day of treatment. The median time to disease progression was 6.2 months (95% confidence interval: 4.6-8.7 months).
Additional clinical benefit: Most of the information on patient benefit came from retrospective analyses (protocols for such analyses were not included in the study protocol). However, clinical descriptions and photographs show clear benefits in a subset of patients, including improved lung function in patients with lung involvement, improved mobility, regression of ulcers, reduced need for pain medication in patients with foot carcinosarcoma, improvement in facial injuries, and improvement in swelling of the extremities and external genitalia.
Safety: Adverse events occurring with tamsulosin treatment in patients with progressive HIV and poor prognosis AIDS-associated Karls Sarcoma were, in general, consistent with the pooled analysis of data from 812 patients with solid tumors in 10 additional clinical studies. These adverse events, as well as those originating from the phase II second-line Karls Sarcoma study, are described in the adverse events section in both tabular (Tables 2 and 8) and narrative form. However, in this immunosuppressed patient population, low-dose strength tamsulosin is recommended and supportive therapy including hematopoietic growth factor is used in neutropenic patients. hematologic toxicity may be more severe in patients with AIDS-associated karst sarcoma compared to patients with solid tumors.
 
 Pharmacology and Toxicology]
Pharmacological effects
Paclitaxel is a novel anti-microtubule drug that stabilizes microtubules by promoting the polymerization of microtubulin dimers and inhibiting their depolymerization, thereby inhibiting the normal dynamic reorganization of the microtubule network, which is essential for cell function during interphase and mitosis. In addition, paclitaxel can cause abnormal arrangement of microtubule “bundles” throughout the cell cycle and during mitosis when multiple stellate bodies are produced, thus affecting tumor cell division.
Toxicological studies
Genotoxicity: In vitro human lymphocyte chromosome aberration test and in vivo mouse micronucleus test were positive for paclitaxel, while Ames test and CHO/HGPRT gene mutation test were negative for paclitaxel.
Reproductive toxicity: In the rat fertility and early embryonic development toxicity assay, paclitaxel at doses of 1 mg/kg/day (in mg/m2, approximately 0.04 times the maximum recommended human dose) and above showed impairment of fertility in males and females, resulting in reduced fertility and fertility index. Embryo-fetal toxicity was seen in pregnant rabbits given paclitaxel 3 mg/kg/day (at mg/m2, approximately 0.2 times the maximum recommended human dose) during the organogenesis period, as evidenced by intrauterine death, increased embryo resorption, and increased fetal death at this dose, which can cause maternal toxicity. No teratogenic effect was seen with paclitaxel 1.0 mg/kg/day (about 1/15 of the maximum recommended human dose in mg/m2), and higher doses caused widespread fetal death, and teratogenicity could not be evaluated.
Carcinogenicity: The carcinogenicity of paclitaxel has not been studied.
 Pharmacokinetics]
When administered intravenously, the concentration of paclitaxel in plasma shows a biphasic decreasing curve. Its first rapid decreasing phase indicates that the drug is distributed to the peripheral compartment and is eliminated. The latter phase indicates a relatively low rate of drug efflux out of the peripheral compartment.
The pharmacokinetic parameters of paclitaxel after intravenous administration were determined in a phase III clinically randomized study in ovarian cancer patients with a paclitaxel dose of 135 mg/m2 in a 3-hour drip or a dose of 175 mg/m224 in a 2-hour drip. The results are shown in Table 18.
 Table 18: Non-atrial pharmacokinetic parameters of paclitaxel single dose intravenous titration (mean values)
Dose
(mg/m2) Duration of titration (h) N
(number of cases) Cmax (ng/ml) AUC0-∞
(ng-h/ml)T1/2
(h)CL
(L/h/m2)135242195630052.721.7175244365799315.723.8135372170795213.117.71753536501500720.212.2
 CMAX = the area of decrease in the blood concentration time curve during the period when the peak plasma drug concentration AUC0-∞ = 0 to infinity.
CLT = total clearance.
 The results showed that increasing the dose from 135 mg/m2 to 175 mg/m2 (30% increase in dose) increased the peak drug concentration (Cmax) by 87% while the area under the curve (AUC0-∞) increased proportionally when paclitaxel was given as a 24-hour intravenous drip. However, with a 3-hour intravenous drip, the dose was also increased by 30%, and the peak concentration and area under the curve were increased by 68% and 89%, respectively. With a 24-hour intravenous drip of paclitaxel, the mean volume of distribution values at steady state ranged from 227 to 688 L/m2, indicating a large extravascular/ or large tissue binding of paclitaxel.
The pharmacokinetics of paclitaxel were evaluated in phase I and phase II clinical trials in adult cancer patients. The doses used were: single doses of 15-135 mg/m2 as a 1-hour intravenous drip (n=15), 30-275 mg/m2 as a 6-hour intravenous drip (n=36), and 200-275 mg/m2 as a 24-hour intravenous drip (n=54). The data obtained in terms of total clearance and volume of distribution were consistent with the findings of the phase III clinical study. Pharmacokinetic studies with paclitaxel in patients with AIDS-associated Kaposi’s sarcoma have not been performed.
In vitro studies of protein binding of human serum using paclitaxel concentrations ranging from 0.1 to 50 μg/ml showed protein binding rates between 89% and 98%, and the protein binding of paclitaxel was not affected by cimetidine, ranitidine, dexamethasone, or diphenhydramine.
The distribution of paclitaxel in humans has not been fully elucidated. The mean (and SD) of the cumulative total amount of prototype drug obtained in the urine after dosing paclitaxel 15 to 275 mg/m2 as a 1-hour, 6-hour, or 24-hour intravenous dose ranged from 1.3% (0.5%) to 12.6% (16.2%) of the administered dose, suggesting that a substantial amount of clearance was nonrenal. In five patients with 3-hour infusions of radiolabeled paclitaxel at doses of 225 to 250 mg/m2, by 120 hours, an average of 71% of the radioactivity appeared in the feces and 14% in the urine. Total radioactive clearance was 56% to 101% of the dose. An average of 5% of radiolabeled paclitaxel appeared in the feces, with the remainder being metabolites, primarily 6α-hydroxypaclitaxel. In vitro studies of human liver microsomes and tissue sections showed that paclitaxel was metabolized by CYP2C8, mainly to 6α-hydroxypaclitaxel, and by CYP3A4 to two minor metabolites, 3′-p-hydroxypaclitaxel and 6α-3′-p-dihydroxy-paclitaxel.
The in vivo course and toxicity of a 3-hour infusion of paclitaxel were evaluated in 35 patients with varying degrees of liver function. Compared to patients with normal bilirubin, paclitaxel concentrations in plasma were increased at a dose of 175 mg/m2 in patients with abnormal but ≤2 times the upper limit of normal (ULN) serum bilirubin, but the incidence of toxicity was not significantly increased and the severity was not significantly increased. In the five patients with total serum bilirubin>2 times ULN, the incidence of severe myelosuppression was higher even at reduced doses (110 mg/m2), although the difference was not statistically significant, but plasma concentrations were not elevated. Studies on the effect of renal insufficiency on the in vivo course of paclitaxel have not been performed.
Possible drug interactions between concomitant paclitaxel and other drugs have not been formally studied.
 Storage】Store under 25℃, protected from light and airtight.
Package】Transparent I-type glass vial, 1 pc/box
Expiration date】24 months.
Execution Standard】Imported drug registration standard is JX20150265
Approval number】Imported drug registration certificate number is H20171227
Manufacturer
Company Name: Bristol-Myers Squibb S.R.L.
Address: PIAZZALE DELL’ INDUSTRIA, 40-46, 00144 ROMA
Country: ITALY
 Name of manufacturer: Corden Pharma Latina S.P.A.
Address: Via Del Murillo Km. 2.800, Sermoneta, Latina, Italy
Country: Italy
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