Paclitaxel

Name: Paclitaxel

Adverse Effects

>10%

Neutropenia (78-100%)

Alopecia (55-96%)

Anemia (47-96%)

Arthralgia/myalgia (93%)

Diarrhea (90%)

Leukopenia (90%)

Nausea/vomiting (9-88%)

Opportunistic infections (76%)

Peripheral neuropathy (42-79%)

Thrombocytopenia (4-68%)

Mucositis (5-45%)

Hypersensitivity (2-45%)

Renal impairment (34%)

Hypotension (17%)

1-10%

Bradycardia (3%)

<1%

Grand mal seizures

Cardiac conduction abnormalities

Frequency Not Defined

Pyrexia

Dehydration

Pancytopenia

Congestive heart failure

Left ventricular dysfunction

Stevens-Johnson syndrome, toxic epidermal necrolysis, and extravasation

Pregnancy & Lactation

Pregnancy Category: D

Lactation: not known if excreted in breast milk, do not nurse

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Clinical pharmacology

Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.

Following intravenous administration of paclitaxel, paclitaxel plasma concentrations declined in a biphasic manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug. The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment.

Pharmacokinetic parameters of paclitaxel following 3- and 24-hour infusions of paclitaxel at dose levels of 135 and 175 mg/m² were determined in a Phase 3 randomized study in ovarian cancer patients and are summarized in the following table.

TABLE 1 : SUMMARY OF PHARMACOKINETIC PARAMETERS-MEAN VALUES

Dose (mg/m²) Infusion Duration (h) N (patients) Cmax (ng/mL) AUC (0-∞) (ng•h/mL) T-HALF (h) CLT (L/h/m²)
135 24 2 195 6300 52.7 21.7
175 24 4 365 7993 15.7 23.8
135 3 7 2170 7952 13.1 17.7
175 3 5 3650 15007 20.2 12.2
Cmax =Maximum plasma concentration
AUC0-∞ =Area under the plasma concentration-time curve from time 0 to infinity
CLT =Total body clearance

It appeared that with the 24-hour infusion of paclitaxel, a 30% increase in dose (135 mg/m² vs 175 mg/m²) increased the Cmax by 87%, whereas the AUC(0-∞) remained proportional. However, with a 3- hour infusion, for a 30% increase in dose, the Cmax and AUC(0-∞) were increased by 68% and 89%, respectively. The mean apparent volume of distribution at steady state, with the 24-hour infusion of paclitaxel, ranged from 227 to 688 L/m², indicating extensive extravascular distribution and/or tissue binding of paclitaxel.

The pharmacokinetics of paclitaxel were also evaluated in adult cancer patients who received single doses of 15 to 135 mg/m² given by 1-hour infusions (n=15), 30 to 275 mg/m² given by 6-hour infusions (n=36), and 200 to 275 mg/m² given by 24-hour infusions (n=54) in Phase 1 and 2 studies. Values for CL and volume of distribution were consistent with the findings in the Phase 3 study. The pharmacokinetics of paclitaxel in patients with AIDS-related Kaposi's sarcoma have not been studied.

In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 mcg/mL, indicate that between 89 to 98% of drug is bound; the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.

After intravenous administration of 15 to 275 mg/m² doses of paclitaxel as 1-, 6-, or 24-hour infusions, mean values for cumulative urinary recovery of unchanged drug ranged from 1.3% to 12.6% of the dose, indicating extensive non-renal clearance. In 5 patients administered a 225 or 250 mg/m² dose of radiolabeled paclitaxel as a 3-hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine. Total recovery of radioactivity ranged from 56% to 101% of the dose. Paclitaxel represented a mean of 5% of the administered radioactivity recovered in the feces, while metabolites, primarily 6α-hydroxypaclitaxel, accounted for the balance. In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to 2 minor metabolites, 3'-p-hydroxypaclitaxel and 6α, 3'-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6α- hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4. (See DRUG INTERACTIONS.)

The disposition and toxicity of paclitaxel 3-hour infusion were evaluated in 35 patients with varying degrees of hepatic function. Relative to patients with normal bilirubin, plasma paclitaxel exposure in patients with abnormal serum bilirubin ≤ 2 times upper limit of normal (ULN) administered 175 mg/m² was increased, but with no apparent increase in the frequency or severity of toxicity. In 5 patients with serum total bilirubin > 2 times ULN, there was a statistically nonsignificant higher incidence of severe myelosuppression, even at a reduced dose (110 mg/m²), but no observed increase in plasma exposure. (See PRECAUTIONS: Hepatic and DOSAGE AND ADMINISTRATION.) The effect of renal dysfunction on the disposition of paclitaxel has not been investigated.

Possible interactions of paclitaxel with concomitantly administered medications have not been formally investigated.

Clinical Studies

Ovarian Carcinoma

First-Line Data: The safety and efficacy of paclitaxel followed by cisplatin in patients with advanced ovarian cancer and no prior chemotherapy were evaluated in 2, Phase 3 multicenter, randomized, controlled trials. In an Intergroup study led by the European Organization for Research and Treatment of Cancer involving the Scandinavian Group NOCOVA, the National Cancer Institute of Canada, and the Scottish Group, 680 patients with Stage IIB-C, III, or IV disease (optimally or non optimally debulked) received either paclitaxel 175 mg/m² infused over 3 hours followed by cisplatin 75 mg/m² (Tc) or cyclophosphamide 750 mg/m² followed by cisplatin 75 mg/m² (Cc) for a median of 6 courses. Although the protocol allowed further therapy, only 15% received both drugs for 9 or more courses. In a study conducted by the Gynecological Oncology Group (GOG), 410 patients with Stage III or IV disease ( > 1 cm residual disease after staging laparotomy or distant metastases) received either paclitaxel 135 mg/m² infused over 24 hours followed by cisplatin 75 mg/m² or cyclophosphamide 750 mg/m² followed by cisplatin 75 mg/m² for 6 courses.

In both studies, patients treated with paclitaxel in combination with cisplatin had significantly higher response rate, longer time to progression, and longer survival time compared with standard therapy. These differences were also significant for the subset of patients in the Intergroup study with nonoptimally debulked disease, although the study was not fully powered for subset analyses (TABLES 2A and 2B). Kaplan- Meier survival curves for each study are shown in FIGURES 1 and 2.

TABLE 2A : EFFICACY IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA STUDIES

  Intergroup (non optimally debulked Subset) 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 (percent) 58   43 62   48
- p-valuec   0.016     0.04  
Time to Progression            
- median (months) 13.2   9.9 16.6   13
- p-valuec   0.006     0.0008  
- hazard ratio (HR) c   0.76     0.7  
- 95% Clc   0.62-0.92     0.56 - 0.86  
Survival            
- median (months) 29.5   21.9 35.5   24.2
- p-valuec   0.0057     0.0002  
- hazard ratioc   0.73     0.64  
- 95% Clc   0.58-0.91     0.5-0.81  
aPaclitaxel dose in mg/m²/infusion duration in hours; cyclophosphamide and cisplatin doses in mg/m².
bAmong patients with measurable disease only.
cUncertified for the Intergroup Study, Stratified for Study GOG-111.

TABLE 2B : EFFICACY IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA INTERGROUP STUDY

  T175/3a c75
(n=342)
  C750a c75
(n=338)
Clinical Responseb (n=162)   (n=161)
-rate (percent) 59   45
-p-valuec   0.014  
Time to Progression      
-median (months) 15.3   11.5
-p-valuec   0.0005  
-hazard ratioc   0.74  
-95% CIc   0.63-0.88  
Survival      
-median (months) 35.6   25.9
-p-valuec   0.0016  
-hazard ratioc   0.73  
-95% CIc   0.60-0.89  
aPaclitaxel dose in mg/m²/infusion duration in hours; cyclophosphamide and cisplatin doses in mg/m².
bAmong patients with measurable disease only.
cUnsatisfied.

FIGURE 1: SURVIVAL: Cc VERSUS Tc (INTERGROUP)

FIGURE 2: SURVIVAL: Cc VERSUS Tc (gog-111)

The adverse event profile for patients receiving paclitaxel in combination with cisplatin in these studies was qualitatively consistent with that seen for the pooled analysis of data from 812 patients treated with single-agent paclitaxel in 10 clinical studies. These adverse events and adverse events from the Phase 3 first-line ovarian carcinoma studies are described in the ADVERSE REACTIONS section in tabular ( TABLES 10 and 11 ) and narrative form.

Second-Line Data: Data from 5, Phase 1 and 2 clinical studies (189 patients), a multicenter randomized Phase 3 study (407 patients), as well as an interim analysis of data from more than 300 patients enrolled in a treatment referral center program were used in support of the use of paclitaxel in patients who have failed initial or subsequent chemotherapy for metastatic carcinoma of the ovary. Two of the Phase 2 studies (92 patients) utilized an initial dose of 135 to 170 mg/m² in most patients ( > 90%) administered over 24 hours by continuous infusion. Response rates in these 2 studies were 22% (95% CI, 11-37%) and 30% (95% CI, 18-46%) with a total of 6 complete and 18 partial responses in 92 patients. The median duration of overall response in these 2 studies measured from the first day of treatment was 7.2 months (range, 3.5-15.8 months) and 7.5 months (range, 5.3-17.4 months), respectively. The median survival was 8.1 months (range, 0.2-36.7 months) and 15.9 months (range, 1.8-34.5+ months).

The Phase 3 study had a bifactorial design and compared the efficacy and safety of paclitaxel, administered at 2 different doses (135 or 175 mg/m²) and schedules (3- or 24-hour infusion). The overall response rate for the 407 patients was 16.2% (95% CI, 12.8-20.2%), with 6 complete and 60 partial responses. Duration of response, measured from the first day of treatment was 8.3 months (range, 3.2-21.6 months). Median time to progression was 3.7 months (range, 0.1+ to 25.1+ months). Median survival was 11.5 months (range, 0.2 to 26.3+ months).

Response rates, median survival, and median time to progression for the 4 arms are given in the following table.

TABLE 3: EFFICACY IN THE PHASE 3 SECOND-LINE OVARIAN CARCINOMA STUDY

  175/3 (n=96) 175/24 n=106) 135/3 (n=99) 135/24 (n=106)
Response
-rate (percent) 14.6 21.7 15.2 13.2
-95% Confidence Interval (8.5-23.6) (14.5-31.0) (9.0-24.1) (7.7-21.5)
Time to Progression
-median (months) 4.4 4.2 3.4 2.8
-95% Confidence Interval (3.0-5.6) (3.5-5.1) (2.8-4.2) (1.9-4.0)
Survival
-median (months) 11.5 11.8 13.1 10.7
-95% Confidence Interval (8.4-14.4) (8.9-14.6) (9.1-14.6) (8.1-13.6)

Analyses were performed as planned by the bifactorial study design described in the protocol, by comparing the 2 doses (135 or 175 mg/m²) irrespective of the schedule (3 or 24 hours) and the 2 schedules irrespective of dose. Patients receiving the 175 mg/m² dose had a response rate similar to that for those receiving the 135 mg/m² dose: 18% versus 14% (p=0.28). No difference in response rate was detected when comparing the 3-hour with the 24-hour infusion: 15% versus 17% (p=0.50). Patients receiving the 175 mg/m² dose of paclitaxel had a longer time to progression than those receiving the 135 mg/m² dose: median 4.2 versus 3.1 months (p=0.03). The median time to progression for patients receiving the 3-hour versus the 24-hour infusion was 4.0 months versus 3.7 months, respectively. Median survival was 11.6 months in patients receiving the 175 mg/m² dose of paclitaxel and 11.0 months in patients receiving the 135 mg/m² dose (p=0.92). Median survival was 11.7 months for patients receiving the 3-hour infusion of paclitaxel and 11.2 months for patients receiving the 24- hour infusion (p=0.91). These statistical analyses should be viewed with caution because of the multiple comparisons made.

Paclitaxel remained active in patients who had developed resistance to platinum-containing therapy (defined as tumor progression while on, or tumor relapse within 6 months from completion of, a platinum-containing regimen) with response rates of 14% in the Phase 3 study and 31% in the Phase 1 and 2 clinical studies.

The adverse event profile in this Phase 3 study was consistent with that seen for the pooled analysis of data from 812 patients treated in 10 clinical studies. These adverse events and adverse events from the Phase 3 second-line ovarian carcinoma study are described in the ADVERSE REACTIONS section in tabular ( TABLES 10 and 12 ) and narrative form.

The results of this randomized study support the use of paclitaxel at doses of 135 to 175 mg/m², administered by a 3-hour intravenous infusion. The same doses administered by 24-hour infusion were more toxic. However, the study had insufficient power to determine whether a particular dose and schedule produced superior efficacy.

Breast Carcinoma

Adjuvant Therapy

A Phase 3 Intergroup study (Cancer and Leukemia Group B [CALGB], Eastern Cooperative Oncology Group [ECOG], North Central Cancer Treatment Group [NCCTG], and Southwest Oncology Group [SWOG]) randomized 3170 patients with node-positive breast carcinoma to adjuvant therapy with paclitaxel or to no further chemotherapy following 4 courses of doxorubicin and cyclophosphamide (AC). This multicenter trial was conducted in women with histologically positive lymph nodes following either a mastectomy or segmental mastectomy and nodal dissections. The 3 x 2 factorial study was designed to assess the efficacy and safety of 3 different dose levels of doxorubicin (A) and to evaluate the effect of the addition of paclitaxel administered following the completion of AC therapy. After stratification for the number of positive lymph nodes (1-3, 4-9, or 10+), patients were randomized to receive cyclophosphamide at a dose of 600 mg/m² and doxorubicin at doses of either 60 mg/m² (on day 1), 75 mg/m² (in 2 divided doses on days 1 and 2), or 90 mg/m² (in 2 divided doses on days 1 and 2 with prophylactic G- CSF support and ciprofloxacin) every 3 weeks for 4 courses and either paclitaxel 175 mg/m² as a 3-hour infusion every 3 weeks for 4 additional courses or no additional chemotherapy. Patients whose tumors were positive were to receive subsequent tamoxifen treatment (20 mg daily for 5 years); patients who received segmental mastectomies prior to study were to receive breast irradiation after recovery from treatment-related toxicities.

At the time of the current analysis, median follow-up was 30.1 months. Of the 2066 patients who were hormone receptor positive, 93% received tamoxifen. The primary analyses of disease-free survival and overall survival used multivariate Cox models, which included paclitaxel administration, doxorubicin dose, number of positive lymph nodes, tumor size, menopausal status, and estrogen receptor status as factors. Based on the model for disease-free survival, patients receiving AC followed by paclitaxel had a 22% reduction in the risk of disease recurrence compared to patients randomized to AC alone (Hazard Ratio [HR]=0.78, 95% CI, 0.67-0.91, p=0.0022). They also had a 26% reduction in the risk of death (HR=0.74, 95% CI, 0.60-0.92, p=0.0065). For disease-free survival and overall survival, p- values were not adjusted for interim analyses. Kaplan- Meier curves are shown in FIGURES 3 and 4. Increasing the dose of doxorubicin higher than 60 mg/m² had no effect on either disease-free survival or overall survival.

FIGURE 3: DISEASE-FREE SURVIVAL: AC VERSUS AC+T

FIGURE 4: SURVIVAL: AC VERSUS AC+T

Subset analyses. Subsets defined by variables of known prognostic importance in adjuvant breast carcinoma were examined, including number of positive lymph nodes, tumor size, hormone receptor status, and menopausal status. Such analyses must be interpreted with care, as the most secure finding is the overall study result. In general, a reduction in hazard similar to the overall reduction was seen with paclitaxel for both disease-free and overall survival in all of the larger subsets with one exception; patients with receptor-positive tumors had a smaller reduction in hazard (HR=0.92) for disease-free survival with paclitaxel than other groups. Results of subset analyses are shown in TABLE 4.

TABLE 4 : SUBSET ANALYSES-ADJUVANT BREAST CARCINOMA STUDY

Patient Subset Disease-Free Survival Overall Survival
No. of Patients No. of Recurrences Hazard Ratio
(95% Cl)
No. of Deaths Hazard Ratio
(95% Cl)
No. of Positive Nodes
1-3 1449 221 0.72
(0.55-0.94)
107 0.76
(0.52-1.12)
4-9 1310 274 0.78
(0.61-0.99)
148 0.66
(0.47-0.91)
10+ 360 129 0.93
(0.66-1.31)
87 0.9
(0.59-1.36)
Tumor Size
(cm)
≤ 2 1096 153 0.79
(0.57-1.08)
67 0.73
(0.45-1.18)
> 2 and ≤ 5 1611 358 0.79
(0.64-0.97)
201 0.74
(0.56-0.98)
> 5 397 111 0.75
(0.51-1.08)
72 0.73
(0.46-1.16)
Menopausal Status
Pre 1929 374 0.83
(0.67-1.01)
187 0.72
(0.54-0.97)
Post 1183 250 0.73
(0.57-0.93)
155 0.77
(0.56-1.06)
• Receptor Status
Positivea 2066 293 0.92
(0.73-1.16)
126 0.83
(0.59-1.18)
Negative / Unknownb 1055 331 0.68
(0.55-0.85)
216 0.71
(0.54-0.93)
aPositive for either estrogen or progesterone receptors.
bNegative or missing for both estrogen and progesterone receptors (both missing: n=15).

These retrospective subgroup analyses suggest that the beneficial effect of paclitaxel is clearly established in the receptor-negative subgroup, but the benefit in receptor-positive patients is not yet clear. With respect to menopausal status, the benefit of paclitaxel is consistent (see TABLE 4 and FIGURES 5-8).

FIGURE 5: DISEASE-FREE SURVIVAL-RECEPTOR STATUS NEGATIVE/UNKNOWN AC VERSUS AC+T

FIGURE 6: DISEASE-FREE SURVIVAL-RECEPTOR STATUS POSITIVE AC VERSUS AC+T

FIGURE 7: DISEASE-FREE SURVIVAL-PREMENOPAUSAL AC VERSUS AC+T

FIGURE 8: DISEASE-FREE SURVIVAL-PREMENOPAUSAL AC VERSUS AC+T

The adverse event profile for the patients who received paclitaxel subsequent to AC was consistent with that seen in the pooled analysis of data from 812 patients ( TABLE 10 ) treated with single-agent paclitaxel in 10 clinical studies. These adverse events are described in the ADVERSE REACTIONS section in tabular ( TABLE 10 and 13 ) and narrative form.

After Failure Of Initial Chemotherapy

Data from 83 patients accrued in 3, Phase 2 open-label studies and from 471 patients enrolled in a Phase 3 randomized study were available to support the use of paclitaxel in patients with metastatic breast carcinoma.

Phase 2 open-label studies: Two studies were conducted in 53 patients previously treated with a maximum of 1 prior chemotherapeutic regimen. Paclitaxel was administered in these 2 trials as a 24- hour infusion at initial doses of 250 mg/m² (with G-CSF support) or 200 mg/m². The response rates were 57% (95% CI, 37-75%) and 52% (95% CI, 32- 72%), respectively. The third Phase 2 study was conducted in extensively pretreated patients who had failed anthracycline therapy and who had received a minimum of 2 chemotherapy regimens for the treatment of metastatic disease. The dose of paclitaxel was 200 mg/m² as a 24-hour infusion with G-CSF support. Nine of 30 patients achieved a partial response, for a response rate of 30% (95% CI, 15- 50%).

Phase 3 randomized study: This multicenter trial was conducted in patients previously treated with 1 or 2 regimens of chemotherapy. Patients were randomized to receive paclitaxel at a dose of either 175 mg/m² or 135 mg/m² given as a 3-hour infusion. In the 471 patients enrolled, 60% had symptomatic disease with impaired performance status at study entry, and 73% had visceral metastases. These patients had failed prior chemotherapy either in the adjuvant setting (30%), the metastatic setting (39%), or both (31%). Sixty-seven percent of the patients had been previously exposed to anthracyclines and 23% of them had disease considered resistant to this class of agents.

The overall response rate for the 454 evaluable patients was 26% (95% CI, 22-30%), with 17 complete and 99 partial responses. The median duration of response, measured from the first day of treatment, was 8.1 months (range, 3.4-18.1+ months). Overall for the 471 patients, the median time to progression was 3.5 months (range, 0.03-17.1 months). Median survival was 11.7 months (range, 0-18.9 months).

Response rates, median survival and median time to progression for the 2 arms are given in the following table.

TABLE 5 : EFFICACY IN BREAST CANCER AFTER FAILURE OF INITIAL CHEMOTHERAPY OR WITHIN 6 MONTHS OF ADJUVANT CHEMOTHERAPY

  175/3
(n=235)
135/3
(n=236)
Response
-rate (percent) 28 22
-p-value 0.135
Time to Progression
-median (months) 4.2 3.0
-p-value 0.027
Survival
-median (months) 11.7 10.5
-p-value 0.321

The adverse event profile of the patients who received single-agent paclitaxel in the Phase 3 study was consistent with that seen for the pooled analysis of data from 812 patients treated in 10 clinical studies. These adverse events and adverse events from the Phase 3 breast carcinoma study are described in the ADVERSE REACTIONS section in tabular ( TABLES 10 and 14 ) and narrative form.

Non-Small Cell Lung Carcinoma (NSCLC)

In a Phase 3 open-label randomized study conducted by the ECOG, 599 patients were randomized to either paclitaxel (T) 135 mg/m² as a 24-hour infusion in combination with cisplatin (c) 75 mg/m², paclitaxel (T) 250 mg/m² as a 24-hour infusion in combination with cisplatin (c) 75 mg/m² with G- CSF support, or cisplatin (c) 75 mg/m² on day 1, followed by etoposide (VP) 100 mg/m² on days 1, 2, and 3 (control).

Response rates, median time to progression, median survival, and 1-year survival rates are given in the following table. The reported p-values have not been adjusted for multiple comparisons. There were statistically significant differences favoring each of the paclitaxel plus cisplatin arms for response rate and time to tumor progression. There was no statistically significant difference in survival between either paclitaxel plus cisplatin arm and the cisplatin plus etoposide arm.

TABLE 6 : EFFICACY PARAMETERS IN THE PHASE 3 FIRST- LINE NSCLC STUDY

  T135/24 c75
(n=198)
T250/24 c75
(n=201)
VP100a c75
(n=200)
Response
-rate (percent) 25 23 12
p-valueb 0.001 < 0.001
Time to Progression
-median (months) 4.3 4.9 2.7
p-valueb 0.05 0.004
Survival
-median (months) 9.3 10.0 7.4
-p-valueb 0.12 0.08
1-Year Survival
-percent of patients 36 40 32
a Etoposide (VP) 100 mg/m² was administered IV on days 1, 2, and 3.
b Compared to cisplatin/etoposide.

In the ECOG study, the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire had 7 subscales that measured subjective assessment of treatment. Of the 7, the Lung Cancer Specific Symptoms subscale favored the paclitaxel 135 mg/m²/24 hour plus cisplatin arm compared to the cisplatin/etoposide arm. For all other factors, there was no difference in the treatment groups.

The adverse event profile for patients who received paclitaxel in combination with cisplatin in this study was generally consistent with that seen for the pooled analysis of data from 812 patients treated with single-agent paclitaxel in 10 clinical studies. These adverse events and adverse events from the Phase 3 first-line NSCLC study are described in the ADVERSE REACTIONS section in tabular ( TABLES 10 and 15 ) and narrative form.

AIDS-Related Kaposi's Sarcoma

Data from 2, Phase 2 open-label studies support the use of paclitaxel as second-line therapy in patients with AIDS-related Kaposi's sarcoma. Fifty-nine of the 85 patients enrolled in these studies had previously received systemic therapy, including interferon alpha (32%), DaunoXome® (31%), DOXIL® (2%), and doxorubicin containing chemotherapy (42%), with 64% having received prior anthracyclines.

Eighty-five percent of the pretreated patients had progressed on, or could not tolerate, prior systemic therapy.

In Study CA139-174, patients received paclitaxel at 135 mg/m² as a 3-hour infusion every 3 weeks (intended dose intensity 45 mg/m² /week). If no dose-limiting toxicity was observed, patients were to receive 155 mg/m² and 175 mg/m² in subsequent courses. Hematopoietic growth factors were not to be used initially. In Study CA139-281, patients received paclitaxel at 100 mg/m² as a 3-hour infusion every 2 weeks (intended dose intensity 50 mg/m²/week). In this study patients could be receiving hematopoietic growth factors before the start of paclitaxel therapy, or this support was to be initiated as indicated; the dose of paclitaxel was not increased. The dose intensity of paclitaxel used in this patient population was lower than the dose intensity recommended for other solid tumors.

All patients had widespread and poor-risk disease. Applying the ACTG staging criteria to patients with prior systemic therapy, 93% were poor risk for extent of disease (T1), 88% had a CD4 count < 200 cells/mm³ (I1), and 97% had poor risk considering their systemic illness (S1 ).

All patients in Study CA139-174 had a Karnofsky performance status of 80 or 90 at baseline; in Study CA139- 281, there were 26 (46%) patients with a Karnofsky performance status of 70 or worse at baseline.

TABLE 7 : EXTENT OF DISEASE AT STUDY ENTRYPercent of Patients

  Prior Systemic Therapy
(n=59)
Visceral ± edema ± oral ± cutaneous 42
Edema or lymph nodes ± oral ± cutaneous 41
Oral ± cutaneous 10
Cutaneous only 7

Although the planned dose intensity in the 2 studies was slightly different (45 mg/m²/week in Study CA139-174 and 50 mg/m²/week in Study CA139-281), delivered dose intensity was 38 to 39 mg/m²/week in both studies, with a similar range (20-24 to 51-61).

Efficacy: The efficacy of paclitaxel was evaluated by assessing cutaneous tumor response according to the amended ACTG criteria and by seeking evidence of clinical benefit in patients in 6 domains of symptoms and/or conditions that are commonly related to AIDS related Kaposi's sarcoma.

Cutaneous Tumor Response (Amended ACTG Criteria): The objective response rate was 59% (95% CI, 46-72%) (35 of 59 patients) in patients with prior systemic therapy. Cutaneous responses were primarily defined as flattening of more than 50% of previously raised lesions.

TABLE 8 : OVERALL BEST RESPONSE (AMENDED ACTG CRITERIA)Percent of Patients

  Prior Systemic Therapy
(n=59)
Complete response 3
Partial response 56
Stable disease 29
Progression 8
Early death/toxicity 3

The median time to response was 8.1 weeks and the median duration of response measured from the first day of treatment was 10.4 months (95% CI, 7.0-11.0 months) for the patients who had previously received systemic therapy. The median time to progression was 6.2 months (95% CI, 4.6-8.7 months).

Additional Clinical Benefit: Most data on patient benefit were assessed retrospectively (plans for such analyses were not included in the study protocols). Nonetheless, clinical descriptions and photographs indicated clear benefit in some patients, including instances of improved pulmonary function in patients with pulmonary involvement, improved ambulation, resolution of ulcers, and decreased analgesic requirements in patients with Kaposi's sarcoma (KS) involving the feet and resolution of facial lesions and edema in patients with KS involving the face, extremities, and genitalia.

Safety: The adverse event profile of paclitaxel administered to patients with advanced HIV disease and poor-risk AIDS- related Kaposi's sarcoma was generally similar to that seen in the pooled analysis of data from 812 patients with solid tumors. These adverse events and adverse events from the Phase 2 second-line Kaposi's sarcoma studies are described in the ADVERSE REACTIONS section in tabular ( TABLES 10 and 16 ) and narrative form. In this immunosuppressed patient population, however, a lower dose intensity of paclitaxel and supportive therapy including hematopoietic growth factors in patients with severe neutropenia are recommended. Patients with AIDS-related Kaposi's sarcoma may have more severe hematologic toxicities than patients with solid tumors.

Side effects

Pooled Analysis of Adverse Event Experiences from Single-Agent Studies

Data in the following table are based on the experience of 812 patients (493 with ovarian carcinoma and 319 with breast carcinoma) enrolled in 10 studies who received single- agent TAXOL. Two hundred and seventy-five patients were treated in 8, Phase 2 studies with TAXOL doses ranging from 135 to 300 mg/m2 administered over 24 hours (in 4 of these studies, G-CSF was administered as hematopoietic support). Three hundred and one patients were treated in the randomized Phase 3 ovarian carcinoma study which compared 2 doses (135 or 175 mg/m2) and 2 schedules (3 or 24 hours) of TAXOL. Two hundred and thirty-six patients with breast carcinoma received TAXOL (135 or 175 mg/m2) administered over 3 hours in a controlled study.

TABLE 10: SUMMARYa OF ADVERSE EVENTS IN PATIENTS WITH SOLID TUMORS RECEIVING SINGLE-AGENT TAXOL

  Percent of Patients
(n=812)
•Bone Marrow
   - Neutropenia < 2000/mm3 90
   < 500/mm3 52
   - Leukopenia < 4000/mm3 90
   < 1000/mm3 17
   - Thrombocytopenia < 100,000/mm3 20
   < 50,000/mm3 7
   - Anemia < 11g/dL 78
   < 8g/dL 16
   - Infections 30
   - Bleeding 14
   - Red Cell Transfusions 25
   - Platelet Transfusions 2
•Hypersensitivity Reactionb
   - All 41
   - Severe† 2
•Cardiovascular
   - Vital Sign Changesc  
   - Bradycardia (n=537) 3
   - Hypotension (n=532) 12
   - Significant Cardiovascular Events 1
•Abnormal ECG
   - All Pts 23
   - Pts with normal baseline (n=559) 14
•Peripheral Neuropathy
   - Any symptoms 60
   - Severe symptoms† 3
•Myalgia/Arthralgia
   - Any symptoms 60
   - Severe symptoms† 8
•Gastrointestinal
   - Nausea and vomiting 52
   - Diarrhea 38
   - Mucositis 31
•Alopecia 87
•Hepatic (Pts with normal baseline and on study data)  
   - Bilirubin elevations (n=765) 7
   - Alkaline phosphatase elevations (n=575) 22
   - AST (SCOT) elevations (n=591) 19
•Injection Site Reaction 13
a Based on worst course analysis.
b All patients received premedication.
c During the first 3 hours of infusion.
†Severe events are defined as at least Grade III toxicity.

None of the observed toxicities were clearly influenced by age.

Disease-Specific Adverse Event Experiences

First-Line Ovary in Combination: For the 1084 patients who were evaluable for safety in the Phase 3 first-line ovary combination therapy studies, TABLE 11 shows the incidence of important adverse events. For both studies, the analysis of safety was based on all courses of therapy (6 courses for the GOG-111 study and up to 9 courses for the Intergroup study).

TABLE 11: FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA STUDIES

  Percent of Patients
  Intergroup GOG-111
  T175/3b
c75c
(n=339)
C750c
c75c
(n=336)
T135/24b
c75c
(n=196)
C750c
c75c
(n=213)
•Bone Marrow
   - Neutropenia < 2000/mm3 91d 95d 96 92
< 500/mm3 33d 43d 81d 58d
   - Thrombocytopenia < 100,000/mm3e 21d 33d 26 30
< 50,000/mm3 3d 7d 10 9
   - Anemia < llg/dLf 96 97 88 86
< 8g/dL 3d 8d 13 9
   - Infections 25 27 21 15
   - Febrile Neutropenia 4 7 15d 4d
•Hypersensitivity Reaction
   - All 11d 6d 8d,g 1d,g
   - Severe† 1 1 3d,g - d,g
•Neurotoxicityh
   - Any symptoms 87d 52d 25 20
   - Severe symptoms† 21d 2d 3d - d
•Nausea and Vomiting
   - Any symptoms 88 93 65 69
   - Severe symptoms† 18 24 10 11
•Myalgia/Arthralgia
   - Any symptoms 60d 27d 9d 2d
   - Severe symptoms† 6d ld 1 -
•Diarrhea
   - Any symptoms 37d 29d 16d 8d
   - Severe symptoms† 2 3 4 1
•Asthenia
   - Any symptoms NC NC 17d 10d
   - Severe symptoms† NC NC 1 1
•Alopecia
   - Any symptoms 96d 89d 55d 37d
   - Severe symptoms† 51d 21d 6 8
aBased on worst course analysis.
bTAXOL (T) dose in mg/m2/infusion duration in hours.
cCyclophosphamide (C) or cisplatin (c) dose in mg/m2.
dp < 0.05 by Fisher exact test.
e < 130,000/mm3 in the Intergroup study.
f < 12 g/dL in the Intergroup study.
gAll patients received premedication.
hIn the GOG-111 study, neurotoxicity was collected as peripheral neuropathy and in the Intergroup study, neurotoxicity was collected as either neuromotor or neurosensory symptoms.
†Severe events are defined as at least Grade in toxicity.
NC Not Collected

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

TABLE 12: FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 SECOND-LINE OVARIAN CARCINOMA STUDY

  Percent of Patients
    175/24b
(n=105)
135/3b
(n=98)
135/24b
(n=105)
175/3b
(n=95)
•Bone Marrow
   - Neutropenia < 2000/mm3 78 98 78 98
< 500/mm3 27 75 14 67
   - Thrombocytopenia < 100,000/mm3 4 18 8 6
< 50,000/mm3 1 7 2 1
   - Anemia < 11 g/dL 84 90 68 88
< 8g/dL 11 12 6 10
Infections 26 29 20 18
•Hypersensitivity Reactionc
   - All 41 45 38 45
   - Severe† 2 0 2 1
•Peripheral Neuropathy
   - Any symptoms 63 60 55 42
   - Severe symptoms† 1 2 0 0
•Mucositis
   - Any symptoms 17 35 21 25
   - Severe symptoms† 0 3 0 2
aBased on worst course analysis.
bAXOL dose in mg/m2/infusion duration in hours.
cAll patients received premedication.
†Severe events are defined as at least Grade III toxicity.

Myelosuppression was dose and schedule related, with the schedule effect being more prominent. The development of severe hypersensitivity reactions (HSRs) was rare; 1% of the patients and 0.2% of the courses overall. There was no apparent dose or schedule effect seen for the HSRs. Peripheral neuropathy was clearly dose related, but schedule did not appear to affect the incidence.

Adjuvant Breast: For the Phase 3 adjuvant breast carcinoma study, the following table shows the incidence of important severe adverse events for the 3121 patients (total population) who were evaluable for safety as well as for a group of 325 patients (early population) who, per the study protocol, were monitored more intensively than other patients.

TABLE 13: FREQUENCYa OF IMPORTANT SEVEREb ADVERSE EVENTS IN THE PHASE 3 ADIUVANT RREAST CARCINOMA STUDY

  Percent of Patients
  Early Population Total Population
  ACc
(n=166)
ACc followed by Td
(n=159)
ACc
(n=1551)
ACcfollowed by Td
(n=1551)
•Bone Marrowe
   - Neutropenia < 500/mm3 79 76 48 50
   - Thrombocytopenia < 50,000/mm3 27 25 11 11
   - Anemia < 8 g/dL 17 21 8 8
   - Infections 6 14 5 6
   - Fever Without Infection - 3 < 1 1
•Hypersensitivity Reactionf 1 4 1 2
•Cardiovascular Events 1 2 1 2
•Neuromotor Toxicity 1 1 < 1 1
•Neurosensory Toxicity - 3 < 1 3
•Myalgia/Arthralgia - 2 < 1 2
•Nausea/Vomiting 13 18 8 9
•Mucositis 13 4 6 5
aBased on worst course analysis.
bSevere events are defined as at least Grade III toxicity.
cPatients received 600 mg/m2 cyclophosphamide and doxorubicin (AC) at doses of either 60 mg/m2, 75 mg/m2, or 90 mg/m2 (with prophylactic G-CSF support and ciprofloxacin), every 3 weeks for 4 courses.
dTAXOL (T) following 4 courses of AC at a dose of 175 mg/m2/3 hours every 3 weeks for 4 courses.
eThe incidence of febrile neutropenia was not reported in this study.
fAll patients were to receive premedication.

The incidence of an adverse event for the total population likely represents an underestimation of the actual incidence given that safety data were collected differently based on enrollment cohort. However, since safety data were collected consistently across regimens, the safety of the sequential addition of TAXOL (paclitaxel) following AC therapy may be compared with AC therapy alone. Compared to patients who received AC alone, patients who received AC followed by TAXOL experienced more Grade III/IV neurosensory toxicity, more Grade III/IV myalgia/arthralgia, more Grade III/IV neurologic pain (5% vs 1%), more Grade III/IV flu-like symptoms (5% vs 3%), and more Grade III/IV hyperglycemia (3% vs 1%). During the additional 4 courses of treatment with TAXOL, 2 deaths (0.1%) were attributed to treatment. During TAXOL treatment, Grade IV neutropenia was reported for 15% of patients, Grade II/III neurosensory toxicity for 15%, Grade II/III myalgias for 23%, and alopecia for 46%.

The incidences of severe hematologic toxicities, infections, mucositis, and cardiovascular events increased with higher doses of doxorubicin.

Breast Cancer After Failure of Initial Chemotherapy: For the 458 patients who received single-agent TAXOL in the Phase 3 breast carcinoma study, the following table shows the incidence of important adverse events by treatment arm (each arm was administered by a 3-hour infusion).

TABLE 14: FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE PHASE 3 STUDY OF BREAST CANCER AFTER FAILURE OF INITIAL CHEMOTHERAPY OR WITHIN 6 MONTHS OF ADJUVANT CHEMOTHERAPY

  Percent of Patients
  175/3b
(n=229)
135/3b
(n=229)
•Bone Marrow
   - Neutropenia < 2000/mm3 90 81
   < 500/mm3 28 19
   - Thrombocytopenia < 100,000/mm3 11 7
   < 50,000/mm3 3 2
   - Anemia < llg/dL 55 47
   < 8g/dL 4 2
   - Infections 23 15
   - Febrile Neutropenia 2 2
•Hypersensitivity Reactionc
   - All 36 31
   - Severe† 0 < 1
•Peripheral Neuropathy
   - Any symptoms 70 46
   - Severe symptoms† 7 3
•Mucositis
   - Any symptoms 23 17
   - Severe symptoms† 3 < 1
aBased on worst course analysis.
bTAXOL dose in mg/m2/infusion duration in hours.
cAll patients received premedication.
†Severe events are defined as at least Grade III toxicity.

Myelosuppression and peripheral neuropathy were dose related. There was one severe hypersensitivity reaction (HSR) observed at the dose of 135 mg/m2.

First-Line NSCLC in Combination: In the study conducted by the Eastern Cooperative Oncology Group (ECOG), patients were randomized to either TAXOL (T) 135 mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2, TAXOL (T) 250 mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2 with G-CSF support, or cisplatin (c) 75 mg/m2 on day 1, followed by etoposide (VP) 100 mg/m2 on days 1, 2, and 3 (control).

The following table shows the incidence of important adverse events.

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

  Percent of Patients
  T135/24b
c75
(n=195)
T250/240c
c75
(n=197)
VP100d
c75
(n=196)
•Bone Marrow
   - Neutropenia < 2000/mm3 89 86 84
   < 500/mm3 74e 65 55
   - Thrombocytopenia < normal 48 68 62
   < 50,000/mm3 6 12 16
   - Anemia < normal 94 96 95
   < 8g/dL 22 19 28
   - Infections 38 31 35
•Hypersensitivity Reactionf
   - All 16 27 13
   - Severe† 1 4e 1
•Arthralgial Myalgia
   - Any symptoms 21e 42e 9
   - Severe symptoms† 3 11 1
•Nausea/Vomiting
   - Any symptoms 85 87 81
   - Severe symptoms† 27 29 22
•Mucositis
   - Any symptoms 18 28 16
   - Severe symptoms† 1 4 2
•Newomotor Toxicity
   - Any symptoms 37 47 44
   - Severe symptoms† 6 12 7
•Newosensory Toxicity
   - Any symptoms 48 61 25
   - Severe symptoms† 13 28e 8
•Cardiovascular Events
   - Any symptoms 33 39 24
   - Severe symptoms† 13 12 8
aBased on worst course analysis.
bTAXOL (T) dose in mg/m /infusion duration in hours; cisplatin (c) dose in mg/m .
c TAXOL dose in mg/m2/infusion duration in hours with G-CSF support; cisplatin dose in mg/m2.
dEtoposide (VP) dose in mg/m2 was administered IV on days 1,2, and 3; cisplatin dose in mg/m2.
e p < 0.05.
fAll patients received premedication.
†Severe events are defined as at least Grade III toxicity.

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

Kaposi's Sarcoma: The following table shows the frequency of important adverse events in the 85 patients with KS treated with 2 different single-agent TAXOL (paclitaxel) regimens.

TABLE 16: FREQUENCYa OF IMPORTANT ADVERSE EVENTS IN THE AIDS-RELATED KAPOSFS SARCOMA STUDIES

  Percent of Patients
  Study CA139-174
TAXOL 135/3b q 3 wk
(n=29)
Study CA139-281
TAXOL 100/3b q 2 wk
(n=56)
Bone Marrow
   - Neutropenia < 2000/mm3 100 95
< 500/mm3 76 35
   - Thrombocytopenia < 100,000/mm3 52 27
< 50,000/mm3 17 5
   - Anemia < 11 g/dL 86 73
< 8g/dL 34 25
   - Febrile Neutropenia 55 9
Opportunistic Infection
   - Any 76 54
   - Cytomegalovirus 45 27
   - Herpes Simplex 38 11
   - Pneumocystis carinii 14 21
   - M. avium intracellulare 24 4
   - Candidiasis, esophageal 7 9
   - Cryptosporidiosis 7 7
   - Cryptococcal meningitis 3 2
   - Leukoencephalopathy   2
Hypersensitivity Reactionc
   - All 14 9
Cardiovascular
   - Hypotension 17 9
   - Bradycardia 3  
Peripheral Neuropathy
   - Any 79 46
   - Severe† 10 2
Myalgia/Arthralgia
   - Any 93 48
   - Severe† 14 16
Gastrointestinal
   - Nausea and Vomiting 69 70
   - Diarrhea 90 73
   - Mucositis 45 20
Renal (creatinine elevation)
   - Any 34 18
   - Severe† 7 5
Discontinuation for drug toxicity 7 16
aBased on worst course analysis.
bTAXOL dose in mg/m /infusion duration in hours.
cAll patients received premedication.
†Severe events are defined as at least Grade III toxicity.

As demonstrated in this table, toxicity was more pronounced in the study utilizing TAXOL (paclitaxel) at a dose of 135 mg/m2 every 3 weeks than in the study utilizing TAXOL at a dose of 100 mg/m2 every 2 weeks. Notably, severe neutropenia (76% vs 35%), febrile neutropenia (55% vs 9%), and opportunistic infections (76% vs 54%) were more common with the former dose and schedule. The differences between the 2 studies with respect to dose escalation and use of hematopoietic growth factors, as described above, should be taken into account. (See Clinical Studies: AIDS-Related Kaposi's Sarcoma.) Note also that only 26% of the 85 patients in these studies received concomitant treatment with protease inhibitors, whose effect on paclitaxel metabolism has not yet been studied.

Adverse Event Experiences by Body System

Unless otherwise noted, the following discussion refers to the overall safety database of 812 patients with solid tumors treated with single-agent TAXOL in clinical studies. Toxicities that occurred with greater severity or frequency in previously untreated patients with ovarian carcinoma or NSCLC who received TAXOL in combination with cisplatin or in patients with breast cancer who received TAXOL after doxorubicin/cyclophosphamide in the adjuvant setting and that occurred with a difference that was clinically significant in these populations are also described. The frequency and severity of important adverse events for the Phase 3 ovarian carcinoma, breast carcinoma, NSCLC, and the Phase 2 Kaposi's sarcoma studies are presented above in tabular form by treatment arm. In addition, rare events have been reported from postmarketing experience or from other clinical studies. The frequency and severity of adverse events have been generally similar for patients receiving TAXOL for the treatment of ovarian, breast, or lung carcinoma or Kaposi's sarcoma, but patients with AIDS-related Kaposi's sarcoma may have more frequent and severe hematologic toxicity, infections (including opportunistic infections, see TABLE 16), and febrile neutropenia. These patients require a lower dose intensity and supportive care. (See Clinical Studies: AIDS-Related Kaposi's Sarcoma.) Toxicities that were observed only in or were noted to have occurred with greater severity in the population with Kaposi's sarcoma and that occurred with a difference that was clinically significant in this population are described. Elevated liver function tests and renal toxicity have a higher incidence in KS patients as compared to patients with solid tumors.

Hematologic: Bone marrow suppression was the major dose-limiting toxicity of TAXOL. Neutropenia, the most important hematologic toxicity, was dose and schedule dependent and was generally rapidly reversible. Among patients treated in the Phase 3 second-line ovarian study with a 3-hour infusion, neutrophil counts declined below 500 cells/mm3 in 14% of the patients treated with a dose of 135 mg/m2 compared to 27% at a dose of 175 mg/m2 (p=0.05). In the same study, severe neutropenia ( < 500 cells/mm3) was more frequent with the 24-hour than with the 3-hour infusion; infusion duration had a greater impact on myelosuppression than dose. Neutropenia did not appear to increase with cumulative exposure and did not appear to be more frequent nor more severe for patients previously treated with radiation therapy.

In the study where TAXOL was administered to patients with ovarian carcinoma at a dose of 135 mg/m2/24 hours in combination with cisplatin versus the control arm of cyclophosphamide plus cisplatin, the incidences of grade IV neutropenia and of febrile neutropenia were significantly greater in the TAXOL plus cisplatin arm than in the control arm. Grade IV neutropenia occurred in 81% on the TAXOL plus cisplatin arm versus 58% on the cyclophosphamide plus cisplatin arm, and febrile neutropenia occurred in 15% and 4% respectively. On the TAXOL/cisplatin arm, there were 35/1074 (3%) courses with fever in which Grade IV neutropenia was reported at some time during the course. When TAXOL followed by cisplatin was administered to patients with advanced NSCLC in the ECOG study, the incidences of Grade IV neutropenia were 74% (TAXOL 135 mg/m2/24 hours followed by cisplatin) and 65% (TAXOL 250 mg/m2/24 hours followed by cisplatin and G-CSF) compared with 55% in patients who received cisplatin/etoposide.

Fever was frequent (12% of all treatment courses). Infectious episodes occurred in 30% of all patients and 9% of all courses; these episodes were fatal in 1% of all patients, and included sepsis, pneumonia and peritonitis. In the Phase 3 second-line ovarian study, infectious episodes were reported in 20% and 26% of the patients treated with a dose of 135 mg/m2 or 175 mg/m2 given as 3-hour infusions, respectively. Urinary tract infections and upper respiratory tract infections were the most frequently reported infectious complications. In the immunosuppressed patient population with advanced HIV disease and poor-risk AIDS-related Kaposi's sarcoma, 61% of the patients reported at least one opportunistic infection. (See Clinical Studies: AIDS-Related Kaposi's Sarcoma.) The use of supportive therapy, including G-CSF, is recommended for patients who have experienced severe neutropenia. (See DOSAGE AND ADMINISTRATION.)

Thrombocytopenia was reported. Twenty percent of the patients experienced a drop in their platelet count below 100,000 cells/mm3 at least once while on treatment; 7% had a platelet count < 50,000 cells/mm3 at the time of their worst nadir. Bleeding episodes were reported in 4% of all courses and by 14% of all patients, but most of the hemorrhagic episodes were localized and the frequency of these events was unrelated to the TAXOL dose and schedule. In the Phase 3 second-line ovarian study, bleeding episodes were reported in 10% of the patients; no patients treated with the 3-hour infusion received platelet transfusions. In the adjuvant breast carcinoma trial, the incidence of severe thrombocytopenia and platelet transfusions increased with higher doses of doxorubicin.

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

Hypersensitivity Reactions (HSRs): In clinical trials, all patients received premedication prior to TAXOL administration (see WARNINGS and PRECAUTIONS: Hypersensitivity Reactions). The frequency and severity of HSRs were not affected by the dose or schedule of TAXOL administration. In the Phase 3 second-line ovarian study, the 3-hour infusion was not associated with a greater increase in HSRs when compared to the 24-hour infusion. Hypersensitivity reactions were observed in 20% of all courses and in 41% of all patients. These reactions were severe in less than 2% of the patients and 1% of the courses. No severe reactions were observed after course 3 and severe symptoms occurred generally within the first hour of TAXOL infusion. The most frequent symptoms observed during these severe reactions were dyspnea, flushing, chest pain, and tachycardia. Abdominal pain, pain in the extremities, diaphoresis, and hypertension were also noted.

The minor hypersensitivity reactions consisted mostly of flushing (28%), rash (12%), hypotension (4%), dyspnea (2%), tachycardia (2%), and hypertension (1%). The frequency of hypersensitivity reactions remained relatively stable during the entire treatment period.

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

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

Significant cardiovascular events possibly related to single-agent TAXOL (paclitaxel) occurred in approximately 1% of all patients. These events included syncope, rhythm abnormalities, hypertension, and venous thrombosis. One of the patients with syncope treated with TAXOL at 175 mg/m2 over 24 hours had progressive hypotension and died. The arrhythmias included asymptomatic ventricular tachycardia, bigeminy, and complete AV block requiring pacemaker placement. Among patients with NSCLC treated with TAXOL in combination with cisplatin in the Phase 3 study, significant cardiovascular events occurred in 12 to 13%. This apparent increase in cardiovascular events is possibly due to an increase in cardiovascular risk factors in patients with lung cancer.

Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 23% of all patients. Among patients with a normal ECG prior to study entry, 14% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, sinus tachycardia, and premature beats. Among patients with normal ECGs at baseline, prior therapy with anthracyclines did not influence the frequency of ECG abnormalities.

Cases of myocardial infarction have been reported. Congestive heart failure, including cardiac dysfunction and reduction of left ventricular ejection fraction or ventricular failure, has been reported typically in patients who have received other chemotherapy, notably anthracyclines. (See PRECAUTIONS: DRUG INTERACTIONS.)

Atrial fibrillation and supraventricular tachycardia have been reported.

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

Pleural effusion and respiratory failure have been reported.

Neurologic: The assessment of neurologic toxicity was conducted differently among the studies as evident from the data reported in each individual study (see TABLES 10-16). Moreover, the frequency and severity of neurologic manifestations were influenced by prior and/or concomitant therapy with neurotoxic agents.

In general, the frequency and severity of neurologic manifestations were dose-dependent in patients receiving single-agent TAXOL. Peripheral neuropathy was observed in 60% of all patients (3% severe) and in 52% (2% severe) of the patients without pre-existing neuropathy. The frequency of peripheral neuropathy increased with cumulative dose. Paresthesia commonly occurs in the form of hyperesthesia. Neurologic symptoms were observed in 27% of the patients after the first course of treatment and in 34 to 51% from course 2 to 10. Peripheral neuropathy was the cause of TAXOL discontinuation in 1% of all patients. Sensory symptoms have usually improved or resolved within several months of TAXOL discontinuation. Pre-existing neuropathies resulting from prior therapies are not a contraindication for TAXOL therapy.

In the Intergroup first-line ovarian carcinoma study (see TABLE 11), neurotoxicity included reports of neuromotor and neurosensory events. The regimen with TAXOL 175 mg/m2 given by 3-hour infusion plus cisplatin 75 mg/m2 resulted in greater incidence and severity of neurotoxicity than the regimen containing cyclophosphamide and cisplatin, 87% (21% severe) versus 52% (2% severe), respectively. The duration of grade III or IV neurotoxicity cannot be determined with precision for the Intergroup study since the resolution dates of adverse events were not collected in the case report forms for this trial and complete follow-up documentation was available only in a minority of these patients. In the GOG first-line ovarian carcinoma study, neurotoxicity was reported as peripheral neuropathy. The regimen with TAXOL 135 mg/m2 given by 24-hour infusion plus cisplatin 75 mg/m2 resulted in an incidence of neurotoxicity that was similar to the regimen containing cyclophosphamide plus cisplatin, 25% (3% severe) versus 20% (0% severe), respectively. Cross-study comparison of neurotoxicity in the Intergroup and GOG trials suggests that when TAXOL is given in combination with cisplatin 75 mg/m2, the incidence of severe neurotoxicity is more common at a TAXOL dose of 175 mg/m2 given by 3-hour infusion (21%) than at a dose of 135 mg/m2 given by 24-hour infusion (3%).

In patients with NSCLC, administration of TAXOL followed by cisplatin resulted in a greater incidence of severe neurotoxicity compared to the incidence in patients with ovarian or breast cancer treated with single-agent TAXOL. Severe neurosensory symptoms were noted in 13% of NSCLC patients receiving TAXOL 135 mg/m2 by 24-hour infusion followed by cisplatin 75 mg/m2 and 8% of NSCLC patients receiving cisplatin/etoposide (see TABLE 15).

Other than peripheral neuropathy, serious neurologic events following TAXOL administration have been rare ( < 1%) and have included grand mal seizures, syncope, ataxia, and neuroencephalopathy.

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

Convulsions, dizziness, and headache have been reported.

Arthralgia/Myalgia: There was no consistent relationship between dose or schedule of TAXOL and the frequency or severity of arthralgia/myalgia. Sixty percent of all patients treated experienced arthralgia/myalgia; 8% experienced severe symptoms. The symptoms were usually transient, occurred 2 or 3 days after TAXOL administration, and resolved within a few days. The frequency and severity of musculoskeletal symptoms remained unchanged throughout the treatment period.

Hepatic: No relationship was observed between liver function abnormalities and either dose or schedule of TAXOL administration. Among patients with normal baseline liver function 7%, 22%, and 19% had elevations in bilirubin, alkaline phosphatase, and AST (SGOT), respectively. Prolonged exposure to TAXOL was not associated with cumulative hepatic toxicity.

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

Renal: Among the patients treated for Kaposi's sarcoma with TAXOL, 5 patients had renal toxicity of grade III or IV severity. One patient with suspected HIV nephropathy of grade IV severity had to discontinue therapy. The other 4 patients had renal insufficiency with reversible elevations of serum creatinine.

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

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

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

patients with Kaposi's sarcoma complained of diarrhea prior to study start. (See Clinical Studies: AIDS-Related Kaposi's Sarcoma.)

In the first-line Phase 3 ovarian carcinoma studies, the incidence of nausea and vomiting when TAXOL was administered in combination with cisplatin appeared to be greater compared with the database for single-agent TAXOL in ovarian and breast carcinoma. In addition, diarrhea of any grade was reported more frequently compared to the control arm, but there was no difference for severe diarrhea in these studies.

Intestinal obstruction, intestinal perforation, pancreatitis, ischemic colitis, dehydration, esophagitis, constipation, and ascites have been reported. Neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, was observed in patients treated with TAXOL alone and in combination with other chemotherapeutic agents.

Injection Site Reaction: Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. These reactions have been observed more frequently with the 24-hour infusion than with the 3-hour infusion. Recurrence of skin reactions at a site of previous extravasation following administration of TAXOL at a different site, ie, "recall," has been reported.

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

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

Other Clinical Events: Alopecia was observed in almost all (87%) of the patients. Transient skin changes due to TAXOL-related hypersensitivity reactions have been observed, but no other skin toxicities were significantly associated with TAXOL administration. Nail changes (changes in pigmentation or discoloration of nail bed) were uncommon (2%). Edema was reported in 21% of all patients (17% of those without baseline edema); only 1% had severe edema and none of these patients required treatment discontinuation. Edema was most commonly focal and disease-related. Edema was observed in 5% of all courses for patients with normal baseline and did not increase with time on study.

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

Reports of asthenia and malaise have been received as part of the continuing surveillance of TAXOL safety. In the Phase 3 trial of TAXOL 135 mg/m2 over 24 hours in combination with cisplatin as first-line therapy of ovarian cancer, asthenia was reported in 17% of the patients, significantly greater than the 10% incidence observed in the control arm of cyclophosphamide/cisplatin.

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

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

Read the entire FDA prescribing information for Taxol (paclitaxel)

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Paclitaxel Description

Paclitaxel Injection, USP is a clear colorless to slightly yellow viscous solution. It is supplied as a nonaqueous solution intended for dilution with a suitable parenteral fluid prior to intravenous infusion. Paclitaxel is available in 30 mg (5 mL), 100 mg (16.7 mL), and 300 mg (50 mL) multidose vials. Each mL of sterile nonpyrogenic solution contains 6 mg Paclitaxel, 527 mg of Polyoxyl 35 Castor Oil, NF, 49.7% (v/v) Dehydrated Alcohol, USP and 2 mg Citric Acid, USP.

Paclitaxel is a natural product with antitumor activity. Paclitaxel is obtained via an extraction process from Taxus X media ‘Hicksii’. The chemical name for Paclitaxel is (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-1,2a,3,4,4a,6,9,10,11,12,12a,12b-Dodecahydro-4,6,9,11,12,-12b-hexahydroxy-4a,8,13,13-tetramethyl-7,11-methano-5H-cyclodeca [3,4] benz [1,2-b] oxet-5-one 6,12b-diacetate, 12-benzoate, 9-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.

Paclitaxel has the following structural formula:

Paclitaxel is a white to off-white crystalline powder with the empirical formula C47H51NO14 and a molecular weight of 853.9. It is highly lipophilic, insoluble in water, and melts at around 216-217°C.

Paclitaxel - Clinical Pharmacology

Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, Paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.

Following intravenous administration of Paclitaxel, Paclitaxel plasma concentrations declined in a biphasic manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug. The later phase is due, in part, to a relatively slow efflux of Paclitaxel from the peripheral compartment.

Pharmacokinetic parameters of Paclitaxel following 3- and 24-hour infusions of Paclitaxel at dose levels of 135 and 175 mg/m2 were determined in a Phase 3 randomized study in ovarian cancer patients and are summarized in the following table:

Table 1. Summary of Pharmacokinetic Parameters – Mean Values

Dose
(mg/m2)

Infusion
Duration
(h)

N
(patients)

Cmax 
(ng/mL)

AUC (0-∞)
(ng•h/mL)

T-HALF
(h)

CLT 
(L/h/m2)

135

24

2

195

6300

52.7

21.7

175

24

4

365

7993

15.7

23.8

135

3

7

2170

7952

13.1

17.7

175

3

5

3650

15007

20.2

12.2

Cmax = Maximum plasma concentration

AUC (0-∞) = Area under the plasma concentration-time curve from time 0 to infinity

CLT = Total body clearance

It appeared that with the 24-hour infusion of Paclitaxel, a 30% increase in dose (135 mg/m2 versus 175 mg/m2) increased the Cmax by 87%, whereas the AUC (0-∞) remained proportional. However, with a 3-hour infusion, for a 30% increase in dose, the Cmax and AUC (0-∞) were increased by 68% and 89%, respectively. The mean apparent volume of distribution at steady state, with the 24-hour infusion of Paclitaxel, ranged from 227 to 688 L/m2, indicating extensive extravascular distribution and/or tissue binding of Paclitaxel.

The pharmacokinetics of Paclitaxel were also evaluated in adult cancer patients who received single doses of 15-135 mg/m2 given by 1-hour infusions (n=15), 30-275 mg/m2 given by 6-hour infusions (n=36), and 200-275 mg/m2 given by 24-hour infusions (n=54) in Phase 1 & 2 studies. Values for CLT and volume of distribution were consistent with the findings in the Phase 3 study. The pharmacokinetics of Paclitaxel in patients with AIDS-related Kaposi’s sarcoma have not been studied.

In vitro studies of binding to human serum proteins, using Paclitaxel concentrations ranging from 0.1 to 50 μg/mL, indicate that between 89%-98% of drug is bound; the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of Paclitaxel.

After intravenous administration of 15-275 mg/m2 doses of Paclitaxel Injection, USP as 1-, 6-, or 24-hour infusions, mean values for cumulative urinary recovery of unchanged drug ranged from 1.3% to 12.6% of the dose, indicating extensive non-renal clearance. In five patients administered a 225 or 250 mg/m2 dose of radiolabeled Paclitaxel as a 3-hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine. Total recovery of radioactivity ranged from 56% to 101% of the dose. Paclitaxel represented a mean of 5% of the administered radioactivity recovered in the feces, while metabolites, primarily 6α-hydroxyPaclitaxel, accounted for the balance. In vitro studies with human liver microsomes and tissue slices showed that Paclitaxel was metabolized primarily to 6α-hydroxyPaclitaxel by the cytochrome P450 isozyme CYP2C8; and to two minor metabolites, 3’-p-hydroxyPaclitaxel and 6α, 3’-p-dihydroxy-Paclitaxel, by CYP3A4. In vitro, the metabolism of Paclitaxel to 6α-hydroxyPaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxyPaclitaxel in vitro. The pharmacokinetics of Paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4. (See PRECAUTIONS: Drug Interactions section.)

The disposition and toxicity of Paclitaxel 3-hour infusion were evaluated in 35 patients with varying degrees of hepatic function. Relative to patients with normal bilirubin, plasma Paclitaxel exposure in patients with abnormal serum bilirubin ≤2 times upper limit of normal (ULN) administered 175 mg/m2 was increased, but with no apparent increase in the frequency or severity of toxicity. In 5 patients with serum total bilirubin >2 times ULN, there was a statistically nonsignificant higher incidence of severe myelosuppression, even at a reduced dose (110 mg/m2), but no observed increase in plasma exposure. (See PRECAUTIONS: Hepatic and DOSAGE AND ADMINISTRATION.) The effect of renal or hepatic dysfunction on the disposition of Paclitaxel has not been investigated.

Possible interactions of Paclitaxel with concomitantly administered medications have not been formally investigated.

Clinical Studies

Ovarian Carcinoma:

First-Line Data: The safety and efficacy of Paclitaxel followed by cisplatin in patients with advanced ovarian cancer and no prior chemotherapy were evaluated in 2, Phase 3 multicenter, randomized, controlled trials. In an Intergroup study led by the European Organization for Research and Treatment of Cancer involving the Scandinavian Group NOCOVA, the National Cancer Institute of Canada, and the Scottish Group, 680 patients with Stage IIB–C, III, or IV disease (optimally or non-optimally debulked) received either Paclitaxel 175 mg/m2 infused over 3 hours followed by cisplatin 75 mg/m2 (Tc) or cyclophosphamide 750 mg/m2 followed by cisplatin 75 mg/m2 (Cc) for a median of 6 courses. Although the protocol allowed further therapy, only 15% received both drugs for 9 or more courses. In a study conducted by the Gynecological Oncology Group (GOG), 410 patients with Stage III or IV disease (>1 cm residual disease after staging laparotomy or distant metastases) received either Paclitaxel 135 mg/m2 infused over 24 hours followed by cisplatin 75 mg/m2 or cyclophosphamide 750 mg/m2 followed by cisplatin 75 mg/m2 for 6 courses.

In both studies, patients treated with Paclitaxel in combination with cisplatin had significantly higher response rate, longer time to progression, and longer survival time compared with standard therapy. These differences were also significant for the subset of patients in the Intergroup study with non-optimally debulked disease, although the study was not fully powered for subset analyses (Tables 2A and 2B). Kaplan- Meier survival curves for each study are shown in Figures 1 and 2.

Table 2A. Efficacy in the Phase 3 First-Line Ovarian Carcinoma Studies

Intergroup (non-optimally
debulked subset)

GOG-111

T175/3a 
c75
(n=218)

C750a 
c75
(n=227)

T135/24a 
c75
(n=196)

C750a 
c75
(n=214)

• Clinical Responseb

- rate (percent)

- p-valuec

(n=153)

58

0.016

(n=153)

43

(n=113)

62

0.04

(n=127)

48

• Time to Progression

- median (months)

- p-valuec

- hazard ratio (HR)c

- 95% CIc

 

13.2

0.0060

0.76

0.62–0.92

 

9.9

 

16.6

0.0008

0.70

0.56–0.86

 

13.0

• Survival

- median (months)

- p-valuec

- hazard ratio (HR)c

- 95% CIc

 

29.5

0.0057

73

0.58-0.91

 

21.9

 

35.5

0.0002

0.64

0.50-0.81

 

24.2

a   Paclitaxel dose in mg/m2/infusion duration in hours; cyclophosphamide and cisplatin doses in mg/m2.

b   Among patients with measurable disease only.

c   Unstratified for the Intergroup Study, Stratified for Study GOG-111.

Table 2B. Efficacy in the Phase 3 First-Line Ovarian Carcinoma Intergroup Study

T175/3a

c75

(n=342)

C750a

c75

(n=338)

• Clinical Responseb

- rate (percent)

- p-valuec

(n=162)

59

0.014

(n=161)

45

• Time to Progression

- median (months)

- p-valuec

- hazard ratio (HR)c

- 95% CIc

 

15.3

0.0005

0.74

0.63–0.88

 

11.5

• Survival

- median (months)

- p-valuec

- hazard ratio (HR)c

- 95% CIc

 

35.6

0.0016

0.73

0.60–0.89

 

25.9

a Paclitaxel dose in mg/m2/infusion duration in hours; cyclophosphamide and cisplatin doses in mg/m2.

b Among patients with measurable disease only.

c Unstratified.

Figure 1. Survival: Cc Versus Tc (Intergroup)

 

Figure 2. Survival: Cc Versus Tc (GOG-111)

 

The adverse event profile for patients receiving Paclitaxel in combination with cisplatin in these studies was qualitatively consistent with that seen for the pooled analysis of data from 812 patients treated with single-agent Paclitaxel in 10 clinical studies. These adverse events and adverse events from the Phase 3 first-line ovarian carcinoma studies are described in the ADVERSE REACTIONS section in tabular (Tables 10 and 11) and narrative form.

Second-Line Data: Data from five Phase 1 & 2 clinical studies (189 patients), a multicenter randomized Phase 3 study (407 patients), as well as an interim analysis of data from more than 300 patients enrolled in a treatment referral center program were used in support of the use of Paclitaxel in patients who have failed initial or subsequent chemotherapy for metastatic carcinoma of the ovary. Two of the Phase 2 studies (92 patients) utilized an initial dose of 135 to 170 mg/m2 in most patients (>90%) administered over 24 hours by continuous infusion. Response rates in these two studies were 22% (95% CI: 11% to 37%) and 30% (95% CI: 18% to 46%) with a total of 6 complete and 18 partial responses in 92 patients. The median duration of overall response in these two studies measured from the first day of treatment was 7.2 months (range: 3.5-15.8 months) and 7.5 months (range: 5.3-17.4 months), respectively. The median survival was 8.1 months (range: 0.2-36.7 months) and 15.9 months (range: 1.8-34.5+ months).

The Phase 3 study had a bifactorial design and compared the efficacy and safety of Paclitaxel, administered at two different doses (135 or 175 mg/m2 and schedules (3- or 24-hour infusion). The overall response rate for the 407 patients was 16.2% (95% CI: 12.8% to 20.2%), with 6 complete and 60 partial responses. Duration of response, measured from the first day of treatment was 8.3 months (range: 3.2-21.6 months). Median time to progression was 3.7 months (range: 0.1+ - 25.1+ months). Median survival was 11.5 months (range: 0.2-26.3+ months).

Response rates, median survival, and median time to progression for the 4 arms are given in the following table.

Table 3. Efficacy in the Phase 3 Second-Line Ovarian Carcinoma Study

175/3

(n=96)

175/24

(n=106)

135/3

(n=99)

135/24

(n=106)

• Response

- rate (percent)

- 95% Confidence Interval

14.6

(8.5-23.6)

21.7

(14.5-31.0)

15.2

(9.0-24.1)

13.2

(7.7-21.5)

• Time to Progression

- median (months)

- 95% Confidence Interval

4.4

(3.0-5.6)

4.2

(3.5-5.1)

3.4

(2.8-4.2)

2.8

(1.9-4.0)

• Survival

- median (months)

- 95% Confidence Interval

11.5

(8.4-14.4)

11.8

(8.9-14.6)

13.1

(9.1-14.6)

10.7

(8.1-13.6)

Analyses were performed as planned by the bifactorial study design described in the protocol, by comparing the two doses (135 or 175 mg/m2) irrespective of the schedule (3 or 24 hours) and the two schedules irrespective of dose. Patients receiving the 175 mg/m2 dose had a response rate similar to that for those receiving the 135 mg/m2 dose: 18% vs. 14% (p=0.28). No difference in response rate was detected when comparing the 3-hour with the 24-hour infusion: 15% vs. 17% (p=0.50). Patients receiving the 175 mg/m2 dose of Paclitaxel had a longer time to progression than those receiving the 135 mg/m2 dose: median 4.2 vs. 3.1 months (p=0.03). The median time to progression for patients receiving the 3-hour vs. the 24-hour infusion was 4.0 months vs. 3.7 months, respectively. Median survival was 11.6 months in patients receiving the 175 mg/m2 dose of Paclitaxel and 11.0 months in patients receiving the 135 mg/m2 dose (p=0.92). Median survival was 11.7 months for patients receiving the 3-hour infusion of Paclitaxel and 11.2 months for patients receiving the 24 hour infusion (p=0.91). These statistical analyses should be viewed with caution because of the multiple comparisons made.

Paclitaxel remained active in patients who had developed resistance to platinum-containing therapy (defined as tumor progression while on, or tumor relapse within 6 months from completion of, a platinum-containing regimen) with response rates of 14% in the Phase 3 study and 31% in the Phase 1 & 2 clinical studies.

The adverse event profile in this Phase 3 study was consistent with that seen for the pooled analysis of data from 812 patients treated in 10 clinical studies. These adverse events and adverse events from the Phase 3 second-line ovarian carcinoma study are described in the ADVERSE REACTIONS section in tabular (Tables 10 and 12) and narrative form.

The results of this randomized study support the use of Paclitaxel Injection, USP at doses of 135 to 175 mg/m2, administered by a 3-hour intravenous infusion. The same doses administered by 24-hour infusion were more toxic. However, the study had insufficient power to determine whether a particular dose and schedule produced superior efficacy.

Breast Carcinoma:

Adjuvant Therapy

A Phase 3 Intergroup study (Cancer and Leukemia Group B [CALGB], Eastern Cooperative Oncology Group [ECOG], North Central Cancer Treatment Group [NCCTG], and Southwest Oncology Group [SWOG]) randomized 3170 patients with node-positive breast carcinoma to adjuvant therapy with Paclitaxel or to no further chemotherapy following 4 courses of doxorubicin and cyclophosphamide (AC). This multicenter trial was conducted in women with histologically positive lymph nodes following either a mastectomy or segmental mastectomy and nodal dissections. The 3 x 2 factorial study was designed to assess the efficacy and safety of 3 different dose levels of doxorubicin (A) and to evaluate the effect of the addition of Paclitaxel administered following the completion of AC therapy. After stratification for the number of positive lymph nodes (1–3, 4–9, or 10+), patients were randomized to receive cyclophosphamide at a dose of 600 mg/m2 and doxorubicin at doses of either 60 mg/m2 (on day 1), 75 mg/m2 (in 2 divided doses on days 1 and 2), or 90 mg/m2 (in 2 divided doses on days 1 and 2 with prophylactic G-CSF support and ciprofloxacin) every 3 weeks for 4 courses and either Paclitaxel 175 mg/m2 as a 3-hour infusion every 3 weeks for 4 additional courses or no additional chemotherapy. Patients whose tumors were positive were to receive subsequent tamoxifen treatment (20 mg daily for 5 years); patients who received segmental mastectomies prior to study were to receive breast irradiation after recovery from treatment-related toxicities.

At the time of the current analysis, median follow-up was 30.1 months. Of the 2066 patients who were hormone receptor positive, 93% received tamoxifen. The primary analyses of disease-free survival and overall survival used multivariate Cox models, which included Paclitaxel administration, doxorubicin dose, number of positive lymph nodes, tumor size, menopausal status, and estrogen receptor status as factors. Based on the model for disease-free survival, patients receiving AC followed by Paclitaxel had a 22% reduction in the risk of disease recurrence compared to patients randomized to AC alone (Hazard Ratio [HR]=0.78, 95% CI, 0.67–0.91, p=0.0022). They also had a 26% reduction in the risk of death (HR=0.74, 95% CI, 0.60–0.92, p=0.0065). For disease-free survival and overall survival, p-values were not adjusted for interim analyses. Kaplan-Meier curves are shown in Figures 3 and 4. Increasing the dose of doxorubicin higher than 60 mg/m2 had no effect on either disease-free survival or overall survival.

Figure 3. Disease-Free Survival: AC Versus AC+T

 

Figure 4. Survival: AC Versus AC+T

 

Subset analyses: Subsets defined by variables of known prognostic importance in adjuvant breast carcinoma were examined, including number of positive lymph nodes, tumor size, hormone receptor status, and menopausal status. Such analyses must be interpreted with care, as the most secure finding is the overall study result. In general, a reduction in hazard similar to the overall reduction was seen with Paclitaxel for both disease-free and overall survival in all of the larger subsets with one exception; patients with receptor-positive tumors had a smaller reduction in hazard (HR=0.92) for disease-free survival with Paclitaxel than other groups. Results of subset analyses are shown in Table 4.

Table 4. Subset Analyses Adjuvant Breast Carcinoma Study

Patient Subset

 

Disease-Free Survival

Overall Survival

No. of

Patients

No. of

Recurrences

Hazard Ratio

(95% CI)

No. of

Deaths

Hazard Ratio

(95% CI)

• No. of Positive Nodes

1-3

 

4-9

 

10+

 

1449

 

1310

 

360

 

221

 

274

 

129

 

0.72

(0.55-0.94)

0.78

(0.61-0.99)

0.93

(0.66-1.31)

 

107

 

148

 

87

 

0.76

(0.52-1.12)

0.66

(0.47-0.91)

0.90

(0.59-1.36)

• Tumor Size (cm)

≤2

 

>2 and ≤5

 

>5

 

1096

 

1611

 

397

 

 

153

 

358

 

111

 

 

0.79

(0.57-1.08)

0.79

(0.64-0.97)

0.75

(0.51-1.08)

 

67

 

201

 

72

 

0.73

(0.45-1.18)

0.74

(0.56-0.98)

0.73

(0.46-1.16)

• Menopausal Status

Pre

 

Post

 

1929

 

1183

 

374

 

250

 

0.83

(0.67-1.01)

0.73

(0.57-0.93)

 

187

 

155

 

0.72

(0.54-0.97)

0.77

(0.56-1.06)

• Receptor Status

Positivea

 

Negative/Unknownb

 

2066

 

1055

 

293

 

331

 

0.92

(0.73-1.16)

0.68

(0.55-0.85)

 

126

 

216

 

0.83

(0.59-1.18)

0.71

(0.54-0.93)

a   Positive for either estrogen or progesterone receptors.

b   Negative or missing for both estrogen and progesterone receptors (both missing: n=15).

These retrospective subgroup analyses suggest that the beneficial effect of Paclitaxel is clearly established in the receptor-negative subgroup, but the benefit in receptor-positive patients is not yet clear. With respect to menopausal status, the benefit of Paclitaxel is consistent (see Table 4 and Figures 5–8).

Figure 5. Disease-Free Survival: Receptor Status Negative/Unknown AC Versus AC+T

Figure 6. Disease-Free Survival: Receptor Status Positive AC Versus AC+T

Figure 7. Disease-Free Survival: Premenopausal AC Versus AC+T

Figure 8. Disease-Free Survival: Postmenopausal AC Versus AC+T

 

The adverse event profile for the patients who received Paclitaxel subsequent to AC was consistent with that seen in the pooled analysis of data from 812 patients (Table 10) treated with single-agent Paclitaxel in 10 clinical studies. These adverse events are described in the ADVERSE REACTIONS section in tabular (Tables 10 and 13) and narrative form.

After Failure of Initial Chemotherapy: Data from 83 patients accrued in three Phase 2 open label studies and from 471 patients enrolled in a Phase 3 randomized study were available to support the use of Paclitaxel in patients with metastatic breast carcinoma.

Phase 2 Open Label Studies: Two studies were conducted in 53 patients previously treated with a maximum of one prior chemotherapeutic regimen. Paclitaxel was administered in these two trials as a 24-hour infusion at initial doses of 250 mg/m2 (with G-CSF support) or 200 mg/m2. The response rates were 57% (95% CI: 37% to 75%) and 52% (95% CI: 32% to 72%), respectively. The third Phase 2 study was conducted in extensively pretreated patients who had failed anthracycline therapy and who had received a minimum of two chemotherapy regimens for the treatment of metastatic disease. The dose of Paclitaxel was 200 mg/m2 as a 24-hour infusion with G-CSF support. Nine of 30 patients achieved a partial response, for a response rate of 30% (95% CI: 15% to 50%).

Phase 3 Randomized Study: This multicenter trial was conducted in patients previously treated with one or two regimens of chemotherapy. Patients were randomized to receive Paclitaxel at a dose of either 175 mg/m2 or 135 mg/m2 given as a 3-hour infusion. In the 471 patients enrolled, 60% had symptomatic disease with impaired performance status at study entry, and 73% had visceral metastases. These patients had failed prior chemotherapy either in the adjuvant setting (30%), the metastatic setting (39%), or both (31%). Sixty-seven percent of the patients had been previously exposed to anthracyclines and 23% of them had disease considered resistant to this class of agents.

The overall response rate for the 454 evaluable patients was 26% (95% CI: 22% to 30%), with 17 complete and 99 partial responses. The median duration of response, measured from the first day of treatment, was 8.1 months (range: 3.4-18.1+ months). Overall for the 471 patients, the median time to progression was 3.5 months (range: 0.03-17.1 months). Median survival was 11.7 months (range: 0-18.9 months).

Response rates, median survival and median time to progression for the 2 arms are given in the following table.

Table 5. Efficacy in Breast Cancer after Failure of Initial Chemotherapy or Within 6 Months of Adjuvant Chemotherapy

 

175/3

(n=235)

 

135/3

(n=236)

•  Response

    - rate (percent)

    - p-value

28

0.135

22

•  Time to Progression

    - median (months)

    - p-value

4.2

0.027

3.0

•  Survival

    - median (months)

    - p-value

11.7

0.321

10.5

The adverse event profile of the patients who received single-agent Paclitaxel Injection, USP, in the Phase 3 study was consistent with that seen for the pooled analysis of data from 812 patients treated in 10 clinical studies. These adverse events and adverse events from the Phase 3 breast carcinoma study are described in the ADVERSE REACTIONS section in tabular (Tables 10 and 14) and narrative form.

Non-Small Cell Lung Carcinoma (NSCLC)

In a Phase 3 open-label randomized study conducted by the ECOG, 599 patients were randomized to either Paclitaxel (T) 135 mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2, Paclitaxel (T) 250 mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2 with G-CSF support, or cisplatin (c) 75 mg/m2 on day 1, followed by etoposide (VP) 100 mg/m2 on days 1, 2, and 3 (control). Response rates, median time to progression, median survival, and 1-year survival rates are given in the following table. The reported p-values have not been adjusted for multiple comparisons. There were statistically significant differences favoring each of the Paclitaxel plus cisplatin arms for response rate and time to tumor progression. There was no statistically significant difference in survival between either Paclitaxel plus cisplatin arm and the cisplatin plus etoposide arm.

Table 6. Efficacy Parameters in the Phase 3 First-Line NSCLC Study

 

T135/24

c75

(n=198)

T250/24

c75

(n=201)

VP100a

c75

(n=200)

•  Response

    - rate (percent)

    - p-valueb

25

0.001

23

<0.001

12

•  Time to Progression

    - median (months)

    - p-valueb

4.3

0.05

4.9

0.004

2.7

•  Survival

    - median (months)

    - p-value b

9.3

0.12

10.0

0.08

7.4

•  1-Year Survival

    - percent of patients

36

40

32

a   Etoposide (VP) 100 mg/m2 was administered IV on days 1, 2, and 3.

b   Compared to cisplatin/etoposide.

In the ECOG study, the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire had 7 subscales that measured subjective assessment of treatment. Of the 7, the Lung Cancer Specific Symptoms subscale favored the Paclitaxel 135 mg/m2/24 hour plus cisplatin arm compared to the cisplatin/etoposide arm. For all other factors, there was no difference in the treatment groups.

The adverse event profile for patients who received Paclitaxel in combination with cisplatin in this study was generally consistent with that seen for the pooled analysis of data from 812 patients treated with single-agent Paclitaxel in 10 clinical studies. These adverse events and adverse events from the Phase 3 first-line NSCLC study are described in the ADVERSE REACTIONS section in tabular (Tables 10 and 15) and narrative form.

AIDS-Related Kaposi’s Sarcoma

Data from 2, Phase 2 open-label studies support the use of Paclitaxel as second-line therapy in patients with AIDS-related Kaposi’s sarcoma. Fifty-nine of the 85 patients enrolled in these studies had previously received systemic therapy, including interferon alpha (32%), DaunoXome® (31%), DOXIL® (2%), and doxorubicin containing chemotherapy (42%), with 64% having received prior anthracyclines. Eighty-five percent of the pretreated patients had progressed on, or could not tolerate, prior systemic therapy.1

In Study CA139-174, patients received Paclitaxel at 135 mg/m2 as a 3-hour infusion every 3 weeks (intended dose intensity 45 mg/m2/week). If no dose-limiting toxicity was observed, patients were to receive 155 mg/m2 and 175 mg/m2 in subsequent courses. Hematopoietic growth factors were not to be used initially. In Study CA139-281, patients received Paclitaxel at 100 mg/m2 as a 3-hour infusion every 2 weeks (intended dose intensity 50 mg/m2/week). In this study patients could be receiving hematopoietic growth factors before the start of Paclitaxel therapy, or this support was to be initiated as indicated; the dose of Paclitaxel was not increased. The dose intensity of Paclitaxel used in this patient population was lower than the dose intensity recommended for other solid tumors.

All patients had widespread and poor-risk disease. Applying the ACTG staging criteria to patients with prior systemic therapy, 93% were poor risk for extent of disease (T1), 88% had a CD4 count <200 cells/mm3 (I1), and 97% had poor risk considering their systemic illness (S1).

All patients in Study CA139-174 had a Karnofsky performance status of 80 or 90 at baseline; in Study CA139-281, there were 26 (46%) patients with a Karnofsky performance status of 70 or worse at baseline.

Table 7. Extent of Disease at Study Entry Percent of Patients

 

Prior Systemic Therapy

(n=59)

Visceral ± edema ± oral ± cutaneous

42

Edema or lymph nodes ± oral ± cutaneous

41

Oral ± cutaneous

10

Cutaneous only

7

Although the planned dose intensity in the 2 studies was slightly different (45 mg/m2/week in Study CA139-174 and 50 mg/m2/week in Study CA139-281), delivered dose intensity was 38 to 39 mg/m2/week in both studies, with a similar range (20–24 to 51–61).

Efficacy: The efficacy of Paclitaxel was evaluated by assessing cutaneous tumor response according to the amended ACTG criteria and by seeking evidence of clinical benefit in patients in 6 domains of symptoms and/or conditions that are commonly related to AIDS-related Kaposi’s sarcoma.

Cutaneous Tumor Response (Amended ACTG Criteria): The objective response rate was 59% (95% CI, 46–72%) (35 of 59 patients) in patients with prior systemic therapy. Cutaneous responses were primarily defined as flattening of more than 50% of previously raised lesions.

Table 8. Overall Best Response (Amended ACTG Criteria) Percent of Patients

 

Prior Systemic Therapy

(n=59)

Complete response

3

Partial response

56

Stable disease

29

Progression

8

Early death/toxicity

3

The median time to response was 8.1 weeks and the median duration of response measured from the first day of treatment was 10.4 months (95% CI, 7.0–11.0 months) for the patients who had previously received systemic therapy. The median time to progression was 6.2 months (95% CI, 4.6–8.7 months).

Additional Clinical Benefit: Most data on patient benefit were assessed retrospectively (plans for such analyses were not included in the study protocols). Nonetheless, clinical descriptions and photographs indicated clear benefit in some patients, including instances of improved pulmonary function in patients with pulmonary involvement, improved ambulation, resolution of ulcers, and decreased analgesic requirements in patients with Kaposi’s sarcoma (KS) involving the feet and resolution of facial lesions and edema in patients with KS involving the face, extremities, and genitalia.

Safety: The adverse event profile of Paclitaxel administered to patients with advanced HIV disease and poor-risk AIDS-related Kaposi’s sarcoma was generally similar to that seen in the pooled analysis of data from 812 patients with solid tumors. These adverse events and adverse events from the Phase 2 second-line Kaposi’s sarcoma studies are described in the ADVERSE REACTIONS section in tabular (Tables 10 and 16) and narrative form. In this immunosuppressed patient population, however, a lower dose intensity of Paclitaxel and supportive therapy including hematopoietic growth factors in patients with severe neutropenia are recommended. Patients with AIDS-related Kaposi’s sarcoma may have more severe hematologic toxicities than patients with solid tumors.

Contraindications

Paclitaxel Injection, USP is contraindicated in patients who have a history of hypersensitivity reactions to Paclitaxel or other drugs formulated in Polyoxyl 35 Castor Oil, NF.

Paclitaxel Injection, USP should not be used in patients with solid tumors who have baseline neutrophil counts of <1,500 cells/mm3 or in patients with AIDS-related Kaposi’s sarcoma with baseline neutrophil counts of <1,000 cells/mm3.

Adverse Reactions

Pooled Analysis of Adverse Event Experiences from Single-Agent Studies: Data in the following table are based on the experience of 812 patients (493 with ovarian carcinoma and 319 with breast carcinoma) enrolled in 10 studies who received single-agent Paclitaxel Injection, USP. Two hundred and seventy-five patients were treated in eight Phase 2 studies with Paclitaxel doses ranging from 135 to 300 mg/m2 administered over 24 hours (in four of these studies, G-CSF was administered as hematopoietic support). Three hundred and one patients were treated in the randomized Phase 3 ovarian carcinoma study which compared two doses (135 or 175 mg/m2) and two schedules (3 or 24 hours) of Paclitaxel. Two hundred and thirty-six patients with breast carcinoma received Paclitaxel (135 or 175 mg/m2) administered over 3 hours in a controlled study.

Table 10. Summarya of Adverse Events in Patients with Solid Tumors Receiving Single-Agent Paclitaxel

 

Percent of Patients

(n=812)

•  Bone Marrow

    - Neutropenia                                        <2,000/mm3

                                                                 <500/mm3

    - Leukopenia                                         <4,000/mm3

                                                                 <1,000/mm3

    - Thrombocytopenia                              <100,000/mm3

                                                                 <50,000/mm3

    - Anemia                                               <11 g/dL

                                                                 <8 g/dL

    - Infections

    - Bleeding

    - Red Cell Transfusions

    - Platelet Transfusions

90

52

90

17

20

7

78

16

30

14

25

2

•  Hypersensitivity Reactionb

    - All

    - Severe†

41

2

•  Cardiovascular

    - Vital Sign Changesc

       - Bradycardia (n=537)

       - Hypotension (n=532)

    - Significant Cardiovascular Events

3

12

1

•  Abnormal ECG

    - All Pts

    - Pts with normal baseline (n=559)

23

14

•  Peripheral Neuropathy

    - Any symptoms

    - Severe symptoms†

60

3

•  Myalgia/Arthralgia

    - Any symptoms

    - Severe symptoms†

60

8

•  Gastrointestinal

    - Nausea and vomiting

    - Diarrhea

    - Mucositis

52

38

31

•  Alopecia

87

•  Hepatic (Pts with normal baseline and on study data)

    - Bilirubin elevations (n=765)

    - Alkaline phosphatase elevations (n=575)

    - AST (SGOT) elevations (n=591)

7

22

19

•  Injection Site Reaction

13

a   Based on worst course analysis.

b   All patients received premedication.

c   During the first 3 hours of infusion.

†   Severe events are defined as at least Grade III toxicity.

None of the observed toxicities were clearly influenced by age.

Disease-Specific Adverse Event Experiences

First-Line Ovary in Combination: For the 1084 patients who were evaluable for safety in the Phase 3 first-line ovary combination therapy studies, Table 11 shows the incidence of important adverse events. For both studies, the analysis of safety was based on all courses of therapy (6 courses for the GOG-111 study and up to 9 courses for the Intergroup study).

Table 11. Frequencya of Important Adverse Events in the Phase 3 First-Line Ovarian Carcinoma Studies

 

Percent of Patients

Intergroup

GOG-111

T175/3b

c75c

(n=339)

C750c

c75c

(n=336)

T135/24b

c75c

(n=196)

C750c

c75c

(n=213)

•  Bone Marrow

    - Neutropenia                    <2,000/mm3

                                             <500/mm3

    - Thrombocytopenia          <100,000/mm3e

                                             <50,000/mm3

    - Anemia                           <11 g/dLf

                                             <8 g/dL

    - Infections

    - Febrile Neutropenia

91d

33d

21d

3d

96

3d

25

4

95d

43d

33d

7d

97

8d

27

7

96

81d

26

10

88

13

21

15d

92

58d

30

9

86

9

15

4d

•  Hypersensitivity Reaction

    - All

    - Severe†

11d

1

6d

1

8d,g

3d,g

1d,g

–d,g

•  Neurotoxicityh

    - Any symptoms

    - Severe symptoms†

87d

21d

52d

2d

25

3d

20

–d

•  Nausea and Vomiting

    - Any symptoms

    - Severe symptoms†

88

18

93

24

65

10

69

11

•  Myalgia/Arthralgia

    - Any symptoms

    - Severe symptoms†

60d

6d

27d

1d

9d

1

2d

•  Diarrhea

    - Any symptoms

    - Severe symptoms†

37d

2

29d

3

16d

4

8d

1

•  Asthenia

    - Any symptoms

    - Severe symptoms†

NC

NC

NC

NC

17d

1

10d

1

•  Alopecia

    - Any symptoms

    - Severe symptoms†

96d

51d

89d

21d

55d

6

37d

8

a   Based on worst course analysis.

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

c   Cyclophosphamide (C) or cisplatin (c) dose in mg/m2.

d   p<0.05 by Fisher exact test.

e   <130,000/mm3 in the Intergroup study.

f   <12 g/dL in the Intergroup study.

g   All patients received premedication.

h   In the GOG-111 study, neurotoxicity was collected as peripheral neuropathy and in the Intergroup study, neurotoxicity was collected as either neuromotor or neurosensory symptoms.

†   Severe events are defined as at least Grade III toxicity.

NC Not Collected

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

Table 12. Frequencya of Important Adverse Events in the Phase 3 Second-Line Ovarian Carcinoma Study

 

Percent of Patients

175/3b

(n=95)

175/24b

(n=105)

135/3b

(n=98)

135/24b

(n=105)

•  Bone Marrow

    - Neutropenia                   <2,000/mm3

                                            <500/mm3

    - Thrombocytopenia         <100,000/mm3

                                            <50,000/mm3

    - Anemia                          <11 g/dL

                                            <8 g/dL

    - Infections

78

27

4

1

84

11

26

98

75

18

7

90

12

29

78

14

8

2

68

6

20

98

67

6

1

88

10

18

•  Hypersensitivity Reactionc

    - All

    - Severe†

41

2

45

0

38

2

45

1

•  Peripheral Neuropathy

    - Any symptoms

    - Severe symptoms†

63

1

60

2

55

0

42

0

•  Mucositis

    - Any symptoms

    - Severe symptoms†

17

0

35

3

21

0

25

2

a   Based on worst course analysis.

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

c   All patients received premedication.

†   Severe events are defined as at least Grade III toxicity.

Myelosuppression was dose and schedule related, with the schedule effect being more prominent. The development of severe hypersensitivity reactions (HSRs) was rare; 1% of the patients and 0.2% of the courses overall. There was no apparent dose or schedule effect seen for the HSRs. Peripheral neuropathy was clearly dose-related, but schedule did not appear to affect the incidence.

Adjuvant Breast: For the Phase 3 adjuvant breast carcinoma study, the following table shows the incidence of important severe adverse events for the 3121 patients (total population) who were evaluable for safety as well as for a group of 325 patients (early population) who, per the study protocol, were monitored more intensively than other patients.

Table 13. Frequencya of Important Severeb Adverse Events in the Phase 3 Adjuvant Breast Carcinoma Study

 

Percent of Patients

Early Population

Total Population

ACc

(n=166)

ACc

followed

by Td

(n=159)

ACc

(n=1551)

ACc

followed

by Td

(n=1570)

•  Bone Marrowe

    - Neutropenia                        <500/mm3

    - Thrombocytopenia              <50,000/mm3

    - Anemia                               <8 g/dL

    - Infections

    - Fever Without Infection

79

27

17

6

76

25

21

14

3

48

11

8

5

<1

50

11

8

6

1

•  Hypersensitivity Reactionf

1

4

1

2

•  Cardiovascular Events

1

2

1

2

•  Neuromotor Toxicity

1

1

<1

1

•  Neurosensory Toxicity

3

<1

3

•  Myalgia/Arthralgia

2

<1

2

•  Nausea/Vomiting

13

18

8

9

•  Mucositis

13

4

6

5

a   Based on worst course analysis.

b   Severe events are defined as at least Grade III toxicity.

c   Patients received 600 mg/m2 cyclophosphamide and doxorubicin (AC) at doses of either 60 mg/m2, 75 mg/m2, or 90 mg/m2 (with prophylactic G-CSF support and ciprofloxacin), every 3 weeks for 4 courses.

d   Paclitaxel (T) following 4 courses of AC at a dose of 175 mg/m2/3 hours every 3 weeks for 4 courses.

e   The incidence of febrile neutropenia was not reported in this study.

f   All patients were to receive premedication.

The incidence of an adverse event for the total population likely represents an underestimation of the actual incidence given that safety data were collected differently based on enrollment cohort. However, since safety data were collected consistently across regimens, the safety of the sequential addition of Paclitaxel following AC therapy may be compared with AC therapy alone. Compared to patients who received AC alone, patients who received AC followed by Paclitaxel experienced more Grade III/IV neurosensory toxicity, more Grade III/IV myalgia/arthralgia, more Grade III/IV neurologic pain (5% vs 1%), more Grade III/IV flu-like symptoms (5% vs 3%), and more Grade III/IV hyperglycemia (3% vs 1%). During the additional 4 courses of treatment with Paclitaxel, 2 deaths (0.1%) were attributed to treatment. During Paclitaxel treatment, Grade IV neutropenia was reported for 15% of patients, Grade II/III neurosensory toxicity for 15%, Grade II/III myalgias for 23%, and alopecia for 46%.

The incidences of severe hematologic toxicities, infections, mucositis, and cardiovascular events increased with higher doses of doxorubicin.

Breast Cancer After Failure of Initial Chemotherapy: For the 458 patients who received single-agent Paclitaxel in the Phase 3 breast carcinoma study, the following table shows the incidence of important adverse events by treatment arm (each arm was administered by a 3-hour infusion).

Table 14. Frequencya of Important Adverse Events in the Phase 3 Study of Breast Cancer after Failure of Initial Chemotherapy or Within 6 Months of Adjuvant Chemotherapy

 

Percent of Patients

175/3b

(n=229)

135/3b

(n=229)

•  Bone Marrow

    - Neutropenia                                    <2,000/mm3

                                                             <500/mm3

    - Thrombocytopenia                          <100,000/mm3

                                                             <50,000/mm3

    - Anemia                                           <11 g/dL

                                                             <8 g/dL

    - Infections

    - Febrile Neutropenia

90

28

11

3

55

4

23

2

81

19

7

2

47

2

15

2

•  Hypersensitivity Reactionc

    - All

    - Severe†

36

0

31

<1

•  Peripheral Neuropathy

    - Any symptoms

    - Severe symptoms†

70

7

46

3

•  Mucositis

    - Any symptoms

    - Severe symptoms†

23

3

17

<1

a   Based on worst course analysis.

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

c   All patients received premedication.

†   Severe events are defined as at least Grade III Toxicity.

Myelosuppression and peripheral neuropathy were dose related. There was one severe hypersensitivity reaction (HSR) observed at the dose of 135 mg/m2.

First-Line NSCLC in Combination: In the study conducted by the Eastern Cooperative Oncology Group (ECOG), patients were randomized to either Paclitaxel (T) 135 mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2, Paclitaxel (T) 250 mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2 with G-CSF support, or cisplatin (c) 75 mg/m2 on day 1, followed by etoposide (VP) 100 mg/m2 on days 1, 2, and 3 (control).

The following table shows the incidence of important adverse events.

Table 15. Frequencya of Important Adverse Events in the Phase 3 Study for First-Line NSCLC

 

Percent of Patients

T135/24b

c75

(n=195)

T250/24c

c75

(n=197)

VP100d

c75

(n=196)

•  Bone Marrow

    - Neutropenia                              <2,000/mm3

                                                       <500/mm3

    - Thrombocytopenia                    <normal

                                                       <50,000/mm3

    - Anemia                                     <normal

                                                       <8 g/dL

    - Infections

89

74e

48

6

94

22

38

86

65

68

12

96

19

31

84

55

62

16

95

28

35

•  Hypersensitivity Reactionf

    - All

    - Severe†

16

1

27

4e

13

1

•  Arthralgia/Myalgia

    - Any symptoms

    - Severe symptoms†

21e

3

42e

11

9

1

•  Nausea/Vomiting

    - Any symptoms

    - Severe symptoms†

85

27

87

29

81

22

•  Mucositis

    - Any symptoms

    - Severe symptoms†

18

1

28

4

16

2

•  Neuromotor Toxicity

    - Any symptoms

    - Severe symptoms†

37

6

47

12

44

7

•  Neurosensory Toxicity

    - Any symptoms

    - Severe symptoms†

48

13

61

28e

25

8

•  Cardiovascular Events

    - Any symptoms

    - Severe symptoms†

33

13

39

12

24

8

a   Based on worst course analysis.

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

c   Paclitaxel dose in mg/m2/infusion duration in hours with G-CSF support; cisplatin dose in mg/m2.

d   Etoposide (VP) dose in mg/m2 was administered IV on days 1, 2, and 3; cisplatin dose in mg/m2.

e   p<0.05.

f   All patients received premedication.

†   Severe events are defined as at least Grade III Toxicity.

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

Kaposi’s Sarcoma: The following table shows the frequency of important adverse events in the 85 patients with KS treated with 2 different single-agent Paclitaxel regimens.

Table 16. Frequencya of Important Adverse Events in the Aids-Related Kaposi’s Sarcoma Studies

 

Percent of Patients

Study CA139-174

Paclitaxel 135/3b

q 3 wk

(n=29)

Study CA139-281

Paclitaxel 100/3b

q 2 wk

(n=56)

•  Bone Marrow

    - Neutropenia                          <2,000/mm3

                                                   <500/mm3

    - Thrombocytopenia                <100,000/mm3

                                                   <50,000/mm3

    - Anemia                                 <11 g/dL

                                                   <8 g/dL

    - Febrile Neutropenia

100

76

52

17

86

34

55

95

35

27

5

73

25

9

•  Opportunistic Infection

    - Any

    - Cytomegalovirus

    - Herpes Simplex

    - Pneumocystis carinii

    - M. avinum intracellulare

    - Candidiasis, esophageal

    - Cryptosporidiosis

    - Cryptococcal meningitis

    - Leukoencephalopathy

76

45

38

14

24

7

7

3

54

27

11

21

4

9

7

2

2

•  Hypersensitivity Reactionc

    - All

14

9

•  Cardiovascular

    - Hypotension

    - Bradycardia

17

3

9

•  Peripheral Neuropathy

    - Any

    - Severe†

79

10

46

2

•  Myalgia/Arthralgia

    - Any

    - Severe†

93

14

48

16

•  Gastrointestinal

    - Nausea and Vomiting

    - Diarrhea

    - Mucositis

69

90

45

70

73

20

•  Renal (creatinine elevation)

    - Any

    - Severe†

34

7

18

5

•  Discontinuation for drug toxicity

7

16

a   Based on worst course analysis.

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

c   All patients received premedication.

†   Severe events are defined as at least Grade III toxicity.

As demonstrated in this table, toxicity was more pronounced in the study utilizing Paclitaxel at a dose of 135 mg/m2 every 3 weeks than in the study utilizing palcitaxel at a dose of 100 mg/m2 every 2 weeks. Notably, severe neutropenia (76% vs 35%), febrile neutropenia (55% vs 9%), and opportunistic infections (76% vs 54%) were more common with the former dose and schedule. The differences between the 2 studies with respect to dose escalation and use of hematopoietic growth factors, as described above, should be taken into account. (See CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma.) Note also that only 26% of the 85 patients in these studies received concomitant treatment with protease inhibitors, whose effect on Paclitaxel metabolism has not yet been studied.

Adverse Event Experiences by Body System:

The following discussion refers to the overall safety database of 812 patients with solid tumors treated with single-agent Paclitaxel in clinical studies. Toxicities that occurred with greater severity or frequency in previously untreated patients with ovarian carcinoma or NSCLC who received Paclitaxel in combination with cisplatin or in patients with breast cancer who received Paclitaxel after doxorubicin/cyclophosphamide in the adjuvant setting and that occurred with a difference that was clinically significant in these populations are also described.

The frequency and severity of important adverse events for the Phase 3 ovarian carcinoma, breast carcinoma, NSCLC, and the Phase 2 Kaposi’s sarcoma carcinoma studies are presented above in tabular form by treatment arm. In addition, rare events have been reported from postmarketing experience or from other clinical studies. The frequency and severity of adverse events have been generally similar for patients receiving Paclitaxel for the treatment of ovarian, breast, or lung carcinoma or Kaposi’s sarcoma, but patients with AIDS-related Kaposi’s sarcoma may have more frequent and severe hematologic toxicity, infections (including opportunistic infections, see Table 16), and febrile neutropenia. These patients require a lower dose intensity and supportive care. (See CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma.) Toxicities that were observed only in or were noted to have occurred with greater severity in the population with Kaposi’s sarcoma and that occurred with a difference that was clinically significant in this population are described. Elevated liver function tests and renal toxicity have a higher incidence in KS patients as compared to patients with solid tumors.

Hematologic: Bone marrow suppression was the major dose-limiting toxicity of Paclitaxel. Neutropenia, the most important hematologic toxicity, was dose and schedule dependent and was generally rapidly reversible. Among patients treated in the Phase 3 second line ovarian study with a 3-hour infusion, neutrophil counts declined below 500 cells/mm3 in 14% of the patients treated with a dose of 135 mg/m2 compared to 27% at a dose of 175 mg/m2 (p=0.05). In the same study, severe neutropenia (<500 cells/mm3) was more frequent with the 24-hour than with the 3-hour infusion; infusion duration had a greater impact on myelosuppression than dose. Neutropenia did not appear to increase with cumulative exposure and did not appear to be more frequent nor more severe for patients previously treated with radiation therapy.

In the study where Paclitaxel was administered to patients with ovarian carcinoma at a dose of 135 mg/m2/24 hours in combination with cisplatin versus the control arm of cyclophosphamide plus cisplatin, the incidences of grade IV neutropenia and of febrile neutropenia were significantly greater in the Paclitaxel plus cisplatin arm than in the control arm. Grade IV neutropenia occurred in 81% on the Paclitaxel plus cisplatin arm versus 58% on the cyclophosphamide plus cisplatin arm, and febrile neutropenia occurred in 15% and 4% respectively. On the Paclitaxel/cisplatin arm, there were 35/1074 (3%) courses with fever in which Grade IV neutropenia was reported at some time during the course. When Paclitaxel followed by cisplatin was administered to patients with advanced NSCLC in the ECOG study, the incidences of Grade IV neutropenia were 74% (Paclitaxel 135 mg/m2/24 hours followed by cisplatin) and 65% (Paclitaxel 250 mg/m2/24 hours followed by cisplatin and G-CSF) compared with 55% in patients who received cisplatin/etoposide.

Fever was frequent (12% of all treatment courses). Infectious episodes occurred in 30% of all patients and 9% of all courses; these episodes were fatal in 1% of all patients, and included sepsis, pneumonia and peritonitis. In the Phase 3 second-line ovarian study, infectious episodes were reported in 20% and 26% of the patients treated with a dose of 135 mg/m2 or 175 mg/m2 given as a 3-hour infusion respectively. Urinary tract infections and upper respiratory tract infections were the most frequently reported infectious complications. In the immunosuppressed patient population with advanced HIV disease and poor-risk AIDS-related Kaposi’s sarcoma, 61% of the patients reported at least one opportunistic infection. (See CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma.) The use of supportive therapy, including G-CSF, is recommended for patients who have experienced severe neutropenia. (See DOSAGE AND ADMINISTRATION.)

Thrombocytopenia was reported. Twenty percent of the patients experienced a drop in their platelet count below 100,000 cells/mm3 at least once while on treatment; 7% had a platelet count <50,000 cells/mm3 at the time of their worst nadir. Bleeding episodes were reported in 4% of all courses and by 14% of all patients but most of the hemorrhagic episodes were localized and the frequency of these events was unrelated to the Paclitaxel Injection, USP dose and schedule. In the Phase 3 second-line ovarian study, bleeding episodes were reported in 10% of the patients; no patients treated with the 3-hour infusion received platelet transfusions. In the adjuvant breast carcinoma trial, the incidence of severe thrombocytopenia and platelet transfusions increased with higher doses of doxorubicin.

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

Hypersensitivity Reactions (HSRs): All patients received premedication prior to Paclitaxel (see WARNINGS and PRECAUTIONS: Hypersensitivity Reactions sections). The frequency and severity of HSRs were not affected by the dose or schedule of Paclitaxel administration. In the Phase 3 second-line ovarian study, the 3-hour infusion was not associated with a greater increase in HSRs when compared to the 24-hour infusion. Hypersensitivity reactions were observed in 20% of all courses and in 41% of all patients. These reactions were severe in less than 2% of the patients and 1% of the courses. No severe reactions were observed after course 3 and severe symptoms occurred generally within the first hour of Paclitaxel infusion. The most frequent symptoms observed during these severe reactions were dyspnea, flushing, chest pain, and tachycardia. Abdominal pain, pain in the extremities, diaphoresis, and hypertension were also noted.

The minor hypersensitivity reactions consisted mostly of flushing (28%), rash (12%), hypotension (4%), dyspnea (2%), tachycardia (2%), and hypertension (1%). The frequency of hypersensitivity reactions remained relatively stable during the entire treatment period.

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

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

Significant cardiovascular events possibly related to single-agent Paclitaxel occurred in approximately 1% of all patients. These events included syncope, rhythm abnormalities, hypertension and venous thrombosis. One of the patients with syncope treated with Paclitaxel at 175 mg/m2 over 24 hours had progressive hypotension and died. The arrhythmias included asymptomatic ventricular tachycardia, bigeminy and complete AV block requiring pacemaker placement. Among patients with NSCLC treated with Paclitaxel in combination with cisplatin in the Phase 3 study, significant cardiovascular events occurred in 12 to 13%. This apparent increase in cardiovascular events is possibly due to an increase in cardiovascular risk factors in patients with lung cancer.

Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 23% of all patients. Among patients with a normal ECG prior to study entry, 14% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, sinus tachycardia, and premature beats. Among patients with normal ECGs at baseline, prior therapy with anthracyclines did not influence the frequency of ECG abnormalities.

Cases of myocardial infarction have been reported. Congestive heart failure, including cardiac dysfunction and reduction of left ventricular ejection fraction or ventricular failure, has been reported typically in patients who have received other chemotherapy, notably anthracyclines. (See PRECAUTIONS: Drug Interactions section.)

Atrial fibrillation and supraventricular tachycardia have been reported.

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

Pleural effusion and respiratory failure have been reported.

Neurologic: The assessment of neurologic toxicity was conducted differently among the studies as evident from the data reported in each individual study (see Tables 10-16). Moreover, the frequency and severity of neurologic manifestations were influenced by prior and/or concomitant therapy with neurotoxic agents.

In general, the frequency and severity of neurologic manifestations were dose-dependent in patients receiving single-agency Paclitaxel. Peripheral neuropathy was observed in 60% of all patients (3% severe) and in 52% (2% severe) of the patients without pre-existing neuropathy. The frequency of peripheral neuropathy increased with cumulative dose. Paresthesia commonly occurs in the form of hyperesthesia. Neurologic symptoms were observed in 27% of the patients after the first course of treatment and in 34%-51% from course 2 to 10. Peripheral neuropathy was the cause of Paclitaxel discontinuation in 1% of all patients. Sensory symptoms have usually improved or resolved within several months of Paclitaxel discontinuation. Pre-existing neuropathies resulting from prior therapies are not a contraindication for Paclitaxel therapy.

In the Intergroup first-line ovarian carcinoma study (see Table 11), neurotoxicity included reports of neuromotor and neurosensory events. The regimen with Paclitaxel 175 mg/m2 given by 3-hour infusion plus cisplatin 75 mg/m2 resulted in greater incidence and severity of neurotoxicity than the regimen containing cyclophosphamide and cisplatin, 87% (21% severe) versus 52% (2% severe), respectively. The duration of grade III or IV neurotoxicity cannot be determined with precision for the Intergroup study since the resolution dates of adverse events were not collected in the case report forms for this trial and complete follow-up documentation was available only in a minority of these patients. In the GOG first-line ovarian carcinoma study, neurotoxicity was reported as peripheral neuropathy. The regimen with Paclitaxel 135 mg/m2 given by 24-hour infusion plus cisplatin 75 mg/m2 resulted in an incidence of neurotoxicity that was similar to the regimen containing cyclophosphamide plus cisplatin, 25% (3% severe) versus 20% (0% severe), respectively. Cross-study comparison of neurotoxicity in the Intergroup and GOG trials suggests that when Paclitaxel is given in combination with cisplatin 75 mg/m2, the incidence of severe neurotoxicity is more common at a Paclitaxel dose of 175 mg/m2 given by 3-hour infusion (21%) than at a dose of 135 mg/m2 given by 24-hour infusion (3%).

In patients with NSCLC, administration of Paclitaxel followed by cisplatin resulted in a greater incidence of severe neurotoxicity compared to the incidence in patients with ovarian or breast cancer treated with single-agent Paclitaxel. Severe neurosensory symptoms were noted in 13% of NSCLC patients receiving Paclitaxel 135 mg/m2 by 24-hour infusion followed by cisplatin 75 mg/m2 and 8% of NSCLC patients receiving cisplatin/etoposide (see Table 15).

Other than peripheral neuropathy, serious neurologic events following Paclitaxel administration have been rare (<1%) and have included grand mal seizures, syncope, ataxia, and neuroencephalopathy.

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

Convulsions, dizziness, and headache have been reported.

Arthralgia/Myalgia: There was no consistent relationship between dose or schedule of Paclitaxel and the frequency or severity of arthralgia/myalgia. Sixty percent of all patients treated experienced arthralgia/myalgia; 8% experienced severe symptoms. The symptoms were usually transient, occurred two or three days after Paclitaxel administration, and resolved within a few days. The frequency and severity of musculoskeletal symptoms remained unchanged throughout the treatment period.

Hepatic: No relationship was observed between liver function abnormalities and either dose or schedule of Paclitaxel administration. Among patients with normal baseline liver function 7%, 22%, and 19% had elevations in bilirubin, alkaline phosphatase, and AST (SGOT), respectively. Prolonged exposure to Paclitaxel was not associated with cumulative hepatic toxicity.

Hepatic necrosis and hepatic encephalopathy leading to death have reported.

Renal: Among the patients treated for Kaposi’s sarcoma with Paclitaxel, 5 patients had renal toxicity of grade III or IV severity. One patient with suspected HIV nephropathy of grade IV severity had to discontinue therapy. The other 4 patients had renal insufficiency with reversible elevations of serum creatinine.

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

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

In patients with poor-risk AIDS-related Kaposi’s sarcoma, nausea/vomiting, diarrhea, and mucositis were reported by 69%, 79%, and 28% of patients, respectively. One-third of 43 patients with Kaposi’s sarcoma complained of diarrhea prior to study start. (See CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma.)

In the first-line Phase 3 ovarian carcinoma studies, the incidence of nausea and vomiting when Paclitaxel was administered in combination with cisplatin appeared to be greater compared with the database for single-agent Paclitaxel in ovarian and breast carcinoma. In addition, diarrhea of any grade was reported more frequently compared to the control arm, but there was no difference for severe diarrhea in these studies.

Intestinal obstruction, intestinal perforation, pancreatitis, ischemic colitis, and dehydration have been reported. Neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, were observed in patients treated with Paclitaxel alone and in combination with other chemotherapeutic agents.

Injection Site Reaction: Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. These reactions have been observed more frequently with the 24-hour infusion than with the 3-hour infusion. Recurrence of skin reactions at a site of previous extravasation following administration of Paclitaxel at a different site, i.e., “recall”, has been reported.

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

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

Other Clinical Events: Alopecia was observed in almost all (87%) of the patients. Transient skin changes due to Paclitaxel Injection, USP-related hypersensitivity reactions have been observed, but no other skin toxicities were significantly associated with Paclitaxel administration. Nail changes (changes in pigmentation or discoloration of nail bed) were uncommon (2%). Edema was reported in 21% of all patients (17% of those without baseline edema); only 1% had severe edema and none of these patients required treatment discontinuation. Edema was most commonly focal and disease-related. Edema was observed in 5% of all courses for patients with normal baseline and did not increase with time on study.

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

Reports of asthenia and malaise have been received as part of the continuing surveillance of Paclitaxel safety. In the Phase 3 trial of Paclitaxel 135 mg/m2 over 24 hours in combination with cisplatin as first-line therapy of ovarian cancer, asthenia was reported in 17% of the patients, significantly greater than the 10% incidence observed in the control arm of cyclophosphamide/cisplatin.

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

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

What should I discuss with my healthcare provider before receiving paclitaxel?

You should not receive this medication if you are allergic to paclitaxel, or to other medications that contain an ingredient called Cremophor EL (polyoxyethylated castor oil). This includes cyclosporine and teniposide.

To make sure paclitaxel is safe for you, tell your doctor if you have:

  • HIV, AIDS, or Kaposi's sarcoma;

  • heart disease;

  • high blood pressure; or

  • liver disease.

Do not receive paclitaxel if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

It is not known whether paclitaxel passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using paclitaxel.

Paclitaxel dosing information

Usual Adult Dose for Ovarian Cancer:

For previously untreated patients with cancer of the ovary:
175 mg/m2 IV over 3 hours every 3 weeks followed by cisplatin
OR
135 mg/m2 IV over 24 hours every 3 weeks followed by cisplatin

For patients previously treated for cancer of the ovary:
175 mg/m2 IV over 3 hours every 3 weeks
OR
135 mg/m2 IV over 3 hours every 3 weeks

Comment:
-All patients should be premedicated prior to receiving this drug to prevent severe hypersensitivity reactions. Consult the manufacturer product information or local protocol for premedication guidelines.

Uses: As subsequent therapy for the treatment of advanced carcinoma of the ovary; as first-line therapy in combination with cisplatin

Usual Adult Dose for Breast Cancer:

After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy:
175 mg/m2 IV over 3 hours every 3 weeks

Comment:
-All patients should be premedicated prior to receiving this drug to prevent severe hypersensitivity reactions. Consult the manufacturer product information or local protocol for premedication guidelines.

Use: For the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy; prior therapy should have included an anthracycline unless clinically contraindicated

Usual Adult Dose for Breast Cancer -- Adjuvant:

For adjuvant treatment of node-positive breast cancer:
175 mg/m2 IV over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing chemotherapy

Comment:
-All patients should be premedicated prior to receiving this drug to prevent severe hypersensitivity reactions. Consult the manufacturer product information or local protocol for premedication guidelines.

Use: For the adjuvant treatment of node-positive breast cancer administered sequentially to standard doxorubicin-containing combination chemotherapy

Usual Adult Dose for Non-Small Cell Lung Cancer:

135 mg/m2 IV over 24 hours followed by cisplatin every 3 weeks

Comment:
-All patients should be premedicated prior to receiving this drug to prevent severe hypersensitivity reactions. Consult the manufacturer product information or local protocol for premedication guidelines.

Use: For the first-line treatment of non-small cell lung cancer in combination with cisplatin in patients who are not candidates for potentially curative surgery and/or radiation therapy

Usual Adult Dose for Kaposi's Sarcoma:

For patients with AIDS-Related Kaposi's Sarcoma:
135 mg/m2 IV over 3 hours every 3 weeks
OR
100 mg/m2 IV over 3 hours every 2 weeks

Note: In patients with advanced HIV disease:
1) Reduce the dose of dexamethasone as one of the premedication drugs (consult the manufacturer product information).
2) Initiate or repeat treatment with this drug only if the neutrophil count is at least 1000 cells/mm3.
3) Reduce the dose of subsequent courses of this drug by 20% for patients who experience severe neutropenia (a neutrophil count less than 500 cells/mm3 for a week or longer).
4) Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.

Comment:
-All patients should be premedicated prior to receiving this drug to prevent severe hypersensitivity reactions. Consult the manufacturer product information or local protocol for premedication guidelines.

Use: For the second-line treatment of AIDS-related Kaposi's sarcoma

Paclitaxel Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.

  • Conventional paclitaxel: Premedicate all patients before paclitaxel administration, including intraperitoneal† administration,344 10005 to prevent severe hypersensitivity reactions.1 21 22 Oral dexamethasone 20 mg (10 mg for HIV-infected patients) administered approximately 12 and 6 hours before paclitaxel as well as IV diphenhydramine hydrochloride (or similar antihistamine) 50 mg and either IV cimetidine hydrochloride (300 mg of cimetidine) or ranitidine hydrochloride (50 mg of ranitidine) administered 30–60 minutes before paclitaxel can be given.1 22

  • Albumin-bound paclitaxel: Premedication generally not required, but may be necessary in patients who experienced a hypersensitivity reaction during a previous course.354

Administration

Administer conventional and albumin-bound paclitaxel by IV infusion.1 3 13 20 21 354 Conventional paclitaxel also administered intraperitoneally†.10001 10008

Handle cautiously (by trained nonpregnant personnel); use protective equipment (e.g., gloves) and wash hands after removal of the gloves.1 354

Immediately treat accidental contact with skin by thoroughly washing with soap and water; immediately treat accidental contact with mucous membranes by thoroughly washing with water.1 354 Dyspnea, chest pain, ocular burning, sore throat, and nausea reported upon inhalation.1

IV Administration

Conventional Paclitaxel

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion.1

Contact of undiluted paclitaxel for injection concentrate with plasticized polyvinyl chloride (PVC) equipment or devices used to prepare solutions for infusion is not recommended.1 Diethylhexyl phthalate (DEHP) can be leached from PVC containers.1

Diluted paclitaxel solutions preferably should be stored in glass or polypropylene containers or in plastic (polypropylene or polyolefin) bags and administered through polyethylene-lined administration sets.1

A hydrophilic, microporous inline filter with a pore size ≤0.22 mcm is necessary during administration.1 7 20 45 Use of filter devices such as IVEX-2 filters, which incorporate short inlet and outlet PVC-coated tubing, has not resulted in significant leaching of DEHP.1 45 195

Do not use a Chemo Dispensing Pen or similar device; these devices may cause the stopper to collapse and contaminate the solution (resulting in loss of sterility).1

Dilution of Conventional Paclitaxel

The concentrate for injection must be diluted prior to administration.1 20

Dilute in 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, or 5% dextrose in Ringer’s injection to a final paclitaxel concentration of 0.3–1.2 mg/mL.1

Rate of Administration of Conventional Paclitaxel

Infuse appropriate dose IV over 3 or 24 hours, depending on the treatment regimen.1

Albumin-bound Paclitaxel

Administer by IV infusion; do not use inline filters.354

Reconstitution of Albumin-bound Paclitaxel

Add 20 mL of 0.9% sodium chloride injection to a vial containing 100 mg of paclitaxel lyophilized powder; slowly inject the diluent onto the inside wall of the vial.354 Allow the vial to sit for ≥5 minutes (to ensure wetting of cake/powder); then, gently swirl and/or invert vial for ≥2 minutes.354 Handle in such a manner to avoid foaming.354 Resulting preparation contains 5 mg/mL.354

Withdraw appropriate dose from vial and transfer to an empty sterile PVC IV bag.354 DEHP-free containers and administration sets not needed.354

Rate of Administration of Albumin-bound Paclitaxel

Infuse appropriate dose IV over 30 minutes.354 Limiting infusion duration to 30 minutes reduces risk of infusion-related reactions.354

Intraperitoneal Instillation

In patients with advanced epithelial ovarian cancer (GOG-172 study), dose was diluted in 1 L of 0.9% sodium chloride solution that was warmed to 37°C and infused through a surgically implanted peritoneal catheter, followed by intraperitoneal infusion of 1 L of warmed saline solution.344 10005 Following peritoneal infusion, patient was asked to roll into a different position every 15 minutes for the next 2 hours to disperse the drug throughout the peritoneal cavity.10005

Consult specialized sources for guidance on how to administer intraperitoneal therapy.345 10005 Further study needed to optimize techniques for intraperitoneal therapy to minimize risk of complications (e.g., infection, catheter obstruction, catheter retraction, bowel perforation, pain, leakage, port access problems).344 345 10005 10017

Dosage

Consult manufacturer's labeling and published protocols for formulation-specific regimens and specific dosages, methods of administration, and administration sequence of other antineoplastic agents used in combination regimens.354 362

Adults

Ovarian Cancer IV (Conventional Paclitaxel)

Previously untreated patients: 175 mg/m2 given over 3 hours followed by cisplatin 75 mg/m2 in repeated 3-week cycles.1 Alternatively, 135 mg/m2 given over 24 hours followed by cisplatin 75 mg/m2 in repeated 3-week cycles.1

Previously treated patients: 135 mg/m2 or 175 mg/m2 given over 3 hours in repeated 3-week cycles.1

Reduce dose by 20% for subsequent cycles in patients who experience severe neutropenia (ANC <500/mm3 for >7 days) or severe peripheral neuropathy.1

IV and Intraperitoneal (Conventional Paclitaxel)†

Previously untreated patients with optimally debulked disease: IV paclitaxel 135 mg/m2 by 24-hour infusion on day 1, followed by intraperitoneal cisplatin 100 mg/m2 on day 2 and intraperitoneal paclitaxel 60 mg/m2 on day 8, has been administered every 21 days for up to 6 cycles.10001

Modified regimens (e.g., with shorter IV infusion times that may permit outpatient administration) are being investigated.10008 10012 10013 10014

Breast Cancer IV (Conventional Paclitaxel)

Adjuvant therapy: 175 mg/m2 given over 3 hours in repeated 3-week cycles for 4 cycles administered sequentially to doxorubicin-containing chemotherapy.1

Treatment after failure of initial therapy for metastatic disease or relapse within 6 months of adjuvant therapy: 175 mg/m2 given over 3 hours in repeated 3-week cycles.1

Reduce dose by 20% for subsequent cycles in patients who experience severe neutropenia (ANC <500/mm3 for >7 days) or severe peripheral neuropathy.1

IV (Albumin-bound Paclitaxel)

Treatment after failure of initial therapy for metastatic disease or relapse within 6 months of adjuvant therapy: 260 mg/m2 every 3 weeks.354

Reduce dose to 220 mg/m2 for subsequent cycles in patients who experience severe neutropenia (ANC <500/mm3 for >7 days) or severe sensory neuropathy.354 Reduce dose to 180 mg/m2 if severe neutropenia or severe sensory neuropathy recurs.354 For grade 3 sensory neuropathy, withhold therapy until resolution to grade 1 or 2; when therapy is resumed, reduce dose.354

Non-small Cell Lung Cancer (NSCLC) IV (Conventional Paclitaxel)

135 mg/m2 given over 24 hours followed by cisplatin 75 mg/m2 in repeated 3-week cycles.1 254 Alternatively, 175 mg/m2 given over 3 hours followed by cisplatin 80 mg/m2 in repeated 3-week cycles has been used.234

Reduce dose by 20% for subsequent cycles in patients who experience severe neutropenia (ANC <500/mm3 for >7 days) or severe peripheral neuropathy.1

IV (Albumin-bound Paclitaxel)

100 mg/m2 given over 30 minutes on days 1, 8, and 15, followed by carboplatin (target AUC 6 mg/mL per minute) on day 1 of each 21-day cycle.354

Table 1. Dosage Modification for Toxicity in Patients Receiving Albumin-bound Paclitaxel and Carboplatin for NSCLC354

Toxicity

Episode

Albumin-bound Paclitaxel and Carboplatin Dosage Modification

Febrile neutropenia (ANC <500/mm3 with fever >38°C)

or

delay of next cycle by >7 days for ANC <1500/mm3

or

ANC <500/mm3 for >7 days

First

Withhold both drugs until ANC ≥1500/mm3 and platelets ≥100,000/mm3 on day 1 or ANC ≥500/mm3 and platelets ≥50,000/mm3 on day 8 or 15 of the cycle; upon resumption, permanently reduce albumin-bound paclitaxel dose to 75 mg/m2 and carboplatin target AUC to 4.5 mg/mL per minute

 

Second

Withhold both drugs until ANC ≥1500/mm3 and platelets ≥100,000/mm3 on day 1 or ANC ≥500/mm3 and platelets ≥50,000/mm3 on day 8 or 15 of the cycle; upon resumption, permanently reduce albumin-bound paclitaxel dose to 50 mg/m2 and carboplatin target AUC to 3 mg/mL per minute

 

Third

Discontinue both drugs

Thrombocytopenia (platelet count <50,000/mm3)

First

Withhold both drugs until ANC ≥1500/mm3 and platelets ≥100,000/mm3 on day 1 or ANC ≥500/mm3 and platelets ≥50,000/mm3 on day 8 or 15 of the cycle; upon resumption, permanently reduce albumin-bound paclitaxel dose to 75 mg/m2 and carboplatin target AUC to 4.5 mg/mL per minute

 

Second

Discontinue both drugs

Severe (grade 3 or 4) peripheral neuropathy

First

Withhold both drugs until neuropathy is grade 1 or less; upon resumption, permanently reduce albumin-bound paclitaxel dose to 75 mg/m2 and carboplatin target AUC to 4.5 mg/mL per minute

 

Second

Withhold both drugs until neuropathy is grade 1 or less; upon resumption, permanently reduce albumin-bound paclitaxel dose to 50 mg/m2 and carboplatin target AUC to 3 mg/mL per minute

 

Third

Discontinue both drugs

AIDS-related Kaposi’s Sarcoma IV (Conventional Paclitaxel)

135 mg/m2 given over 3 hours in repeated 3-week cycles.1 Alternatively, 100 mg/m2 over 3 hours in repeated 2-weeks cycles.1 The regimen given every 3 weeks is more toxic than the regimen given every 2 weeks; patients with poor performance status have been treated with paclitaxel 100 mg/m2.1

Reduce dose by 20% for subsequent cycles in patients who experience severe neutropenia (ANC <500/mm3 for >7 days); initiate granulocyte colony stimulating factor (G-CSF) as indicated.1

Pancreatic Cancer IV (Albumin-bound Paclitaxel)

125 mg/m2 given over 30–40 minutes followed by gemcitabine 1 g/m2 IV over 30–40 minutes on days 1, 8, and 15 of each 28-day cycle.354

When dosage modification is necessary, reduce dose of albumin-bound paclitaxel in decrements of 25 mg/m2 (i.e., 1 dose level) and gemcitabine in decrements of 200 mg/m2 (i.e., 1 dose level); however, if a dose of albumin-bound paclitaxel 75 mg/m2 or a dose of gemcitabine 600 mg/m2 requires further reduction, discontinue both drugs.354

Table 2. Dosage Modification for Hematologic Toxicity in Patients Receiving Albumin-bound Paclitaxel and Gemcitabine for Pancreatic Cancer354

Cycle Day and Cell Counts (cells/mm3)

Albumin-bound Paclitaxel and Gemcitabine Dosage Modification

Day 1:

ANC <1500 or platelet count <100,000

Delay start of cycle until recovery

Day 8:

ANC 500 to <1000 or platelet count 50,000 to <75,000

Reduce dose of both drugs by 1 dose level

ANC <500 or platelet count <50,000

Withhold day 8 dose of both drugs

Day 15 (when day 8 doses were reduced or given without modification):

ANC 500 to <1000 or platelet count 50,000 to <75,000

Reduce dose of both drugs by 1 dose level from day 8

ANC <500 or platelet count <50,000

Withhold day 15 dose of both drugs

Day 15 (when day 8 doses were withheld):

ANC ≥1000 or platelet count ≥75,000

Reduce dose of both drugs by 1 dose level from day 1

ANC 500 to <1000 or platelet count 50,000 to <75,000

Reduce dose of both drugs by 2 dose levels from day 1

ANC <500 or platelet count <50,000

Withhold day 15 dose of both drugs

Table 3. Dosage Modification for Other Toxicities in Patients Receiving Albumin-bound Paclitaxel and Gemcitabine for Pancreatic Cancer354

Toxicity

Albumin-bound Paclitaxel and Gemcitabine Dosage Modification

Febrile neutropenia (grade 3 or 4)

Withhold both drugs until fever resolves and ANC is ≥1500/mm3; upon resumption, reduce dose of both drugs by 1 dose level

Severe (grade 3 or 4) peripheral neuropathy

Withhold albumin-bound paclitaxel until neuropathy is grade 1 or less; upon resumption, reduce albumin-bound paclitaxel dose by 1 dose level. No gemcitabine dose reduction required

Dermatologic toxicity (grade 2 or 3)

Reduce dose of both drugs by 1 dose level. Discontinue both drugs if toxicity persists

GI toxicity (grade 3 mucositis or diarrhea)

Withhold both drugs until GI toxicity is grade 1 or less; upon resumption, reduce dose of both drugs by 1 dose level

Special Populations

Hepatic Impairment

Increased risk of toxicity, particularly grade 3 or 4 myelosuppression.1 354 Adjust dosage as follows and closely monitor patients.1 354

Ovarian Cancer IV (Conventional Paclitaxel)

See Table 4 for recommended initial doses; base further dose reductions in subsequent courses on individual tolerance.1 362 Differences in criteria for bilirubin concentrations between the 3- and 24- hour infusions are due to differences in clinical trial design.1 362

Table 4. Recommended Initial Doses of Conventional Paclitaxel for Ovarian Cancer in Patients with Hepatic Impairment1362

Transaminase Concentration

Bilirubin Concentration

Recommended Initial Dose (for 3- or 24-Hour Infusion)

<2 times ULN

and

≤1.5 mg/dL

135 mg/m2 over 24 hours

2 to <10 times ULN

and

≤1.5 mg/dL

100 mg/m2 over 24 hours

<10 times ULN

and

1.6–7.5 mg/dL

50 mg/m2 over 24 hours

≥10 times ULN

or

>7.5 mg/dL

Not recommended

<10 times ULN

and

≤1.25 times ULN

175 mg/m2 over 3 hours

<10 times ULN

and

1.26–2 times ULN

135 mg/m2 over 3 hours

<10 times ULN

and

2.01–5 times ULN

90 mg/m2 over 3 hours

≥10 times ULN

or

>5 times ULN

Not recommended

Breast Cancer IV (Conventional Paclitaxel)

See Table 5 for recommended initial doses; base further dose reductions in subsequent courses on individual tolerance.1

Table 5. Recommended Initial Doses of Conventional Paclitaxel for Breast Cancer in Patients with Hepatic Impairment1362

Transaminase Concentration

Bilirubin Concentration

Recommended Initial Dose (for 3-Hour Infusion)

<10 times ULN

and

≤1.25 times ULN

175 mg/m2

<10 times ULN

and

1.26–2 times ULN

135 mg/m2

<10 times ULN

and

2.01–5 times ULN

90 mg/m2

≥10 times ULN

or

>5 times ULN

Not recommended

IV (Albumin-bound Paclitaxel)

See Table 6 for recommended initial doses; base further dose reductions in subsequent courses on individual tolerance.354

Table 6. Recommended Initial Doses of Albumin-bound Paclitaxel for Breast Cancer in Patients with Hepatic Impairment354

AST Concentration

Bilirubin Concentration

Recommended Initial Dose (for 30-Minute Infusion)

<10 times ULN

and

≤1.25 times ULN

260 mg/m2

<10 times ULN

and

1.26–2 times ULN

200 mg/m2

<10 times ULN

and

2.01–5 times ULN

130 mg/m2; may increase to 200 mg/m2 in subsequent courses based on tolerance

>10 times ULN

or

>5 times ULN

Not recommended

Non-small Cell Lung Cancer (NSCLC) IV (Conventional Paclitaxel)

See Table 7 for recommended initial doses; base further dose reductions in subsequent courses on individual tolerance.1

Table 7. Recommended Initial Doses of Conventional Paclitaxel for NSCLC in Patients with Hepatic Impairment1362

Transaminase Concentration

Bilirubin Concentration

Recommended Initial Dose (for 24-Hour Infusion)

<2 times ULN

and

≤1.5 times ULN

135 mg/m2

2 to <10 times ULN

and

≤1.5 times ULN

100 mg/m2

<10 times ULN

and

1.6–7.5 times ULN

50 mg/m2

≥10 times ULN

or

>7.5 times ULN

Not recommended

IV (Albumin-bound Paclitaxel)

Patients with serum bilirubin concentrations exceeding the ULN were excluded from clinical studies of albumin-bound paclitaxel for NSCLC.354

See Table 8 for recommended initial doses; base further dose reductions in subsequent courses on individual tolerance.354

Table 8. Recommended Initial Doses of Albumin-bound Paclitaxel for NSCLC in Patients with Hepatic Impairment354

AST Concentration

Bilirubin Concentration

Recommended Initial Dose (for 30-Minute Infusion)

<10 times ULN

and

≤1.25 times ULN

100 mg/m2

<10 times ULN

and

1.26–2 times ULN

75 mg/m2

<10 times ULN

and

2.01–5 times ULN

50 mg/m2

>10 times ULN

or

>5 times ULN

Not recommended

AIDS-related Kaposi’s Sarcoma IV (Conventional Paclitaxel)

Data not available to make dosage recommendations.1

Pancreatic Cancer IV (Albumin-bound Paclitaxel)

Patients with serum bilirubin concentrations exceeding the ULN were excluded from clinical studies in pancreatic cancer.354

If AST <10 times ULN and bilirubin ≤1.25 times ULN, give usual initial dose of 125 mg/m2 over 30–40 minutes.354 Base further dose reductions in subsequent courses on individual tolerance.354

Not recommended if AST >10 times ULN, bilirubin >5 times ULN, or AST <10 times ULN and bilirubin 1.26–5 times ULN.354

Renal Impairment

Conventional paclitaxel: Reduction of dosage does not appear to be necessary.20 23 124

Paclitaxel Pharmacokinetics

Absorption

Conventional paclitaxel: Exhibits nonlinear pharmacokinetic behavior when administered over short periods (i.e., 3 hours).35 183 186 196

Albumin-bound paclitaxel: Increase in AUC proportional to increase in dose for doses of 80–375 mg/m2.354 Duration of infusion does not affect pharmacokinetics.354

Special Populations

Conventional paclitaxel: Plasma paclitaxel exposure increased with abnormal serum bilirubin concentrations ≤2 times ULN.1

Albumin-bound paclitaxel: Plasma paclitaxel exposure following 260- or 200-mg/m2 dose in patients with mild or moderate hepatic impairment, respectively, was similar to exposure observed in patients with normal hepatic function.354 364

Distribution

Extent

Widely distributed.1 45 183 184

Conventional paclitaxel is detected in ascitic fluid;20 45 does not penetrate the CNS.20 45 183 184 186 199

Not known whether paclitaxel is distributed into human milk.1 354

Following administration of albumin-bound paclitaxel, concentration of drug in tumor cells is increased compared with concentration achieved following an equivalent dose of conventional paclitaxel.357

Plasma Protein Binding

88–98%.1 20 354

Elimination

Metabolism

Metabolized by CYP2C8 and, to a lesser extent, by CYP3A4.1 202 354

Elimination Route

Excreted principally in feces as metabolites and unchanged drug.184 196 197 205 246

Minimal urinary excretion.183 184 196 197 198 205

Half-life

Conventional paclitaxel: Average elimination half-life: 5.8 hours for 6- to 24-hour infusions,186 2.33 hours for 3-hour infusions.246

Albumin-bound paclitaxel: 27 hours.354

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