TAXOL^® (paclitaxel) INJECTION
(Patient Information Included)

TAXOL^® (paclitaxel) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2–4% of patients receiving TAXOL in clinical trials. Fatal reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H₂ antagonists. (See DOSAGE AND ADMINISTRATION.) Patients who experience severe hypersensitivity reactions to TAXOL should not be rechallenged with the drug.

TAXOL therapy should not be given to patients with solid tumors who have baseline neutrophil counts of less than 1500 cells/mm³ and should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline neutrophil count is less than 1000 cells/mm³. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving TAXOL.

TAXOL (paclitaxel) Injection 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. TAXOL 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 purified Cremophor^® EL* (polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, USP.

^{*Cremophor® EL is the registered trademark of BASF Aktiengesellschaft.
Cremophor® EL is further purified by a Bristol-Myers Squibb Company proprietary process before use.}

Paclitaxel is a natural product with antitumor activity. TAXOL (paclitaxel) is obtained via a semi-synthetic process from Taxus baccata. The chemical name for paclitaxel is 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.

Paclitaxel has the following structural formula:

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 TAXOL, 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 TAXOL 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:

It appeared that with the 24-hour infusion of TAXOL, a 30% increase in dose (135 mg/m² versus 175 mg/m²) increased the C_MAX by 87%, whereas the AUC(0-∞) remained proportional. However, with a 3-hour infusion, for a 30% increase in dose, the C_MAX 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 TAXOL, 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 CL_T and volume of distribution were consistent with the findings in the Phase 3 study. The pharmacokinetics of TAXOL 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 TAXOL 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 TAXOL 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-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 PRECAUTIONS: 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 five 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.

The safety and efficacy of TAXOL followed by cisplatin in patients with advanced ovarian cancer and no prior chemotherapy were evaluated in two 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 II_B–C, III, or IV disease (optimally or non-optimally debulked) received either TAXOL 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 six courses. Although the protocol allowed further therapy, only 15% received both drugs for nine 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 TAXOL 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 six courses.

In both studies, patients treated with TAXOL (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.

FIGURE 1
SURVIVAL: Cc VERSUS Tc (INTERGROUP)

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

The adverse event profile for patients receiving TAXOL 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 TAXOL 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.

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 TAXOL or to no further chemotherapy following four 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 three different dose levels of doxorubicin (A) and to evaluate the effect of the addition of TAXOL 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 two divided doses on days 1 and 2), or 90 mg/m² (in two divided doses on days 1 and 2 with prophylactic G-CSF support and ciprofloxacin) every 3 weeks for four courses and either TAXOL 175 mg/m² as a 3-hour infusion every 3 weeks for four 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 TAXOL 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 TAXOL 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 TAXOL (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 TAXOL than other groups. Results of subset analyses are shown in Table 4.

These retrospective subgroup analyses suggest that the beneficial effect of TAXOL (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 TAXOL 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 TAXOL subsequent to AC was consistent with that seen in the pooled analysis of data from 812 patients (Table 10) treated with single-agent TAXOL in 10 clinical studies. These adverse events are described in the ADVERSE REACTIONS section in tabular (Tables 10 and 13) and narrative form.

In a Phase 3 open label randomized study conducted by the ECOG, 599 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).

Response rates, median time to progression, median survival, and one-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 TAXOL plus cisplatin arms for response rate and time to tumor progression. There was no statistically significant difference in survival between either TAXOL plus cisplatin arm and the cisplatin plus etoposide arm.

In the ECOG study, the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire had seven subscales that measured subjective assessment of treatment. Of the seven, the Lung Cancer Specific Symptoms subscale favored the TAXOL 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 TAXOL 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 TAXOL 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.

Data from two Phase 2 open label studies support the use of TAXOL (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.

^{DaunoXome®is a registered trademark of Gilead Sciences, Inc.
DOXIL® is a registered trademark of ALZA Corporation.}

In Study CA139-174 patients received TAXOL 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 TAXOL 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 TAXOL therapy, or this support was to be initiated as indicated; the dose of TAXOL was not increased. The dose intensity of TAXOL 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.

Although the planned dose intensity in the two 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 38–39 mg/m²/week in both studies, with a similar range (20–24 to 51–61).

TAXOL is indicated as first-line and subsequent therapy for the treatment of advanced carcinoma of the ovary. As first-line therapy, TAXOL is indicated in combination with cisplatin.

TAXOL is indicated for the adjuvant treatment of node-positive breast cancer administered sequentially to standard doxorubicin-containing combination chemotherapy. In the clinical trial, there was an overall favorable effect on disease-free and overall survival in the total population of patients with receptor-positive and receptor-negative tumors, but the benefit has been specifically demonstrated by available data (median follow-up 30 months) only in the patients with estrogen and progesterone receptor-negative tumors. (See CLINICAL STUDIES: Breast Carcinoma.)

TAXOL is indicated 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.

TAXOL, in combination with cisplatin, is indicated for the first-line treatment of non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy.

TAXOL is indicated for the second-line treatment of AIDS-related Kaposi’s sarcoma.

TAXOL is contraindicated in patients who have a history of hypersensitivity reactions to TAXOL or other drugs formulated in Cremophor^® EL (polyoxyethylated castor oil).

TAXOL should not be used in patients with solid tumors who have baseline neutrophil counts of <1500 cells/mm³ or in patients with AIDS-related Kaposi’s sarcoma with baseline neutrophil counts of <1000 cells/mm³.

Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2–4% of patients receiving TAXOL in clinical trials. Fatal reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H₂ antagonists. (See DOSAGE AND ADMINISTRATION.) Patients who experience severe hypersensitivity reactions to TAXOL should not be rechallenged with the drug.

Bone marrow suppression (primarily neutropenia) is dose-dependent and is the dose-limiting toxicity. Neutrophil nadirs occurred at a median of 11 days. TAXOL should not be administered to patients with baseline neutrophil counts of less than 1500 cells/mm³ (<1000 cells/mm³ for patients with KS). Frequent monitoring of blood counts should be instituted during TAXOL treatment. Patients should not be re-treated with subsequent cycles of TAXOL until neutrophils recover to a level >1500 cells/mm³ (>1000 cells/mm³ for patients with KS) and platelets recover to a level >100,000 cells/mm³.

Severe conduction abnormalities have been documented in <1% of patients during TAXOL therapy and in some cases requiring pacemaker placement. If patients develop significant conduction abnormalities during TAXOL infusion, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with TAXOL.

TAXOL can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel during the period of organogenesis to rabbits at doses of 3.0 mg/kg/day (about 0.2 the daily maximum recommended human dose on a mg/m² basis) caused embryo- and fetotoxicity, as indicated by intrauterine mortality, increased resorptions, and increased fetal deaths. Maternal toxicity was also observed at this dose. No teratogenic effects were observed at 1.0 mg/kg/day (about 1/15 the daily maximum recommended human dose on a mg/m² basis); teratogenic potential could not be assessed at higher doses due to extensive fetal mortality.

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

Contact of the undiluted concentrate with plasticized polyvinyl chloride (PVC) equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC infusion bags or sets, diluted TAXOL solutions should preferably be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

TAXOL should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns. Use of filter devices such as IVEX-2^® filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

^{IVEX-2®is the registered trademark of the Millipore Corporation.}

In a Phase 1 trial using escalating doses of TAXOL (110–200 mg/m²) and cisplatin (50 or 75 mg/m²) given as sequential infusions, myelosuppression was more profound when TAXOL was given after cisplatin than with the alternate sequence (ie, TAXOL before cisplatin). Pharmacokinetic data from these patients demonstrated a decrease in paclitaxel clearance of approximately 33% when TAXOL was administered following cisplatin.

The metabolism of TAXOL is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering TAXOL concomitantly with known substrates or inhibitors of the cytochrome P450 isoenzymes CYP2C8 and CYP3A4. (See CLINICAL PHARMACOLOGY.)

Potential interactions between TAXOL, a substrate of CYP3A4, and protease inhibitors (ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of CYP3A4, have not been evaluated in clinical trials.

Reports in the literature suggest that plasma levels of doxorubicin (and its active metabolite doxorubicinol) may be increased when paclitaxel and doxorubicin are used in combination.

TAXOL therapy should not be administered to patients with baseline neutrophil counts of less than 1500 cells/mm³. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving TAXOL. Patients should not be re-treated with subsequent cycles of TAXOL until neutrophils recover to a level >1500 cells/mm³ and platelets recover to a level >100,000 cells/mm³. In the case of severe neutropenia (<500 cells/mm³ for seven days or more) during a course of TAXOL therapy, a 20% reduction in dose for subsequent courses of therapy is recommended.

For patients with advanced HIV disease and poor-risk AIDS-related Kaposi’s sarcoma, TAXOL, at the recommended dose for this disease, can be initiated and repeated if the neutrophil count is at least 1000 cells/mm³.

Patients with a history of severe hypersensitivity reactions to products containing Cremophor^® EL (eg, cyclosporin for injection concentrate and teniposide for injection concentrate) should not be treated with TAXOL. In order to avoid the occurrence of severe hypersensitivity reactions, all patients treated with TAXOL should be premedicated with corticosteroids (such as dexamethasone), diphenhydramine and H₂ antagonists (such as cimetidine or ranitidine). Minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia do not require interruption of therapy. However, severe reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria require immediate discontinuation of TAXOL and aggressive symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with TAXOL.

Hypotension, bradycardia, and hypertension have been observed during administration of TAXOL, but generally do not require treatment. Occasionally TAXOL infusions must be interrupted or discontinued because of initial or recurrent hypertension. Frequent vital sign monitoring, particularly during the first hour of TAXOL infusion, is recommended. Continuous cardiac monitoring is not required except for patients with serious conduction abnormalities. (See WARNINGS.)

Although the occurrence of peripheral neuropathy is frequent, the development of severe symptomatology is unusual and requires a dose reduction of 20% for all subsequent courses of TAXOL.

TAXOL contains dehydrated alcohol USP, 396 mg/mL; consideration should be given to possible CNS and other effects of alcohol. (See PRECAUTIONS: Pediatric Use.)

There is limited evidence that the myelotoxicity of TAXOL may be exacerbated in patients with serum total bilirubin >2 times ULN (see CLINICAL PHARMACOLOGY). Extreme caution should be exercised when administering TAXOL to such patients, with dose reduction as recommended in DOSAGE AND ADMINISTRATION, Table 17.

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 rarely.

Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been received as part of the continuing surveillance of TAXOL safety. In some cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to ten days.

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

The carcinogenic potential of TAXOL (paclitaxel) has not been studied.

Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). Paclitaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.

Administration of paclitaxel prior to and during mating produced impairment of fertility in male and female rats at doses equal to or greater than 1 mg/kg/day (about 0.04 the daily maximum recommended human dose on a mg/m² basis). At this dose, paclitaxel caused reduced fertility and reproductive indices, and increased embryo- and fetotoxicity. (See WARNINGS.)

Pregnancy “Category D.” (See WARNINGS.)

It is not known whether the drug is excreted in human milk. Following intravenous administration of carbon-14 labeled TAXOL to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving TAXOL therapy.

The safety and effectiveness of TAXOL (paclitaxel) in pediatric patients have not been established.

There have been reports of central nervous system (CNS) toxicity (rarely associated with death) in a clinical trial in pediatric patients in which TAXOL was infused intravenously over 3 hours at doses ranging from 350 mg/m² to 420 mg/m². The toxicity is most likely attributable to the high dose of the ethanol component of the TAXOL vehicle given over a short infusion time. The use of concomitant antihistamines may intensify this effect. Although a direct effect of the paclitaxel itself cannot be discounted, the high doses used in this study (over twice the recommended adult dosage) must be considered in assessing the safety of TAXOL for use in this population.

Of 2228 patients who received TAXOL in eight clinical studies evaluating its safety and effectiveness in the treatment of advanced ovarian cancer, breast carcinoma, or NSCLC, and 1570 patients who were randomized to receive TAXOL in the adjuvant breast cancer study, 649 patients (17%) were 65 years or older and 49 patients (1%) were 75 years or older. In most studies, severe myelosuppression was more frequent in elderly patients; in some studies, severe neuropathy was more common in elderly patients. In two clinical studies in NSCLC, the elderly patients treated with TAXOL had a higher incidence of cardiovascular events. Estimates of efficacy appeared similar in elderly patients and in younger patients; however, comparative efficacy cannot be determined with confidence due to the small number of elderly patients studied. In a study of first-line treatment of ovarian cancer, elderly patients had a lower median survival than younger patients, but no other efficacy parameters favored the younger group. Table 9 presents the incidences of Grade IV neutropenia and severe neuropathy in clinical studies according to age.

(See Patient Information Leaflet.)

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 eight Phase 2 studies with TAXOL 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 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.

None of the observed toxicities were clearly influenced by age.

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, 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.

There is no known antidote for TAXOL (paclitaxel) overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, peripheral neurotoxicity, and mucositis. Overdoses in pediatric patients may be associated with acute ethanol toxicity (see PRECAUTIONS: Pediatric Use).

TAXOL is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised in handling TAXOL. The use of gloves is recommended. If TAXOL solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. If TAXOL contacts mucous membranes, the membranes should be flushed thoroughly with water. Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration (see PRECAUTIONS: Injection Site Reaction).

TAXOL (paclitaxel) Injection must be diluted prior to infusion. TAXOL should be diluted in 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, 5% Dextrose and 0.9% Sodium Chloride Injection, USP, or 5% Dextrose in Ringer’s Injection to a final concentration of 0.3 to 1.2 mg/mL. The solutions are physically and chemically stable for up to 27 hours at ambient temperature (approximately 25° C) and room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. No significant losses in potency have been noted following simulated delivery of the solution through IV tubing containing an in-line (0.22 micron) filter.

Data collected for the presence of the extractable plasticizer DEHP [di-(2-ethylhexyl)phthalate] show that levels increase with time and concentration when dilutions are prepared in PVC containers. Consequently, the use of plasticized PVC containers and administration sets is not recommended. TAXOL solutions should be prepared and stored in glass, polypropylene, or polyolefin containers. Non-PVC containing administration sets, such as those which are polyethylene-lined, should be used.

TAXOL should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns. Use of filter devices such as IVEX-2^® filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

The Chemo Dispensing Pin^™ device or similar devices with spikes should not be used with vials of TAXOL since they can cause the stopper to collapse resulting in loss of sterile integrity of the TAXOL solution.

^{Chemo Dispensing Pin™ is a trademark of B. Braun Medical Incorporated}

Unopened vials of TAXOL (paclitaxel) Injection are stable until the date indicated on the package when stored between 20°–25° C (68°–77° F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration components in the TAXOL vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation. There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25° C) and lighting conditions for up to 27 hours.

NDC 0015-3475-30       30 mg/5 mL multidose vial individually packaged in a carton.
NDC 0015-3476-30     100 mg/16.7 mL multidose vial individually packaged in a carton.
NDC 0015-3479-11     300 mg/50 mL multidose vial individually packaged in a carton.

Store the vials in original cartons between 20°–25° C (68°–77° F). Retain in the original package to protect from light.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published^1–7. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

• Recommendations for the safe handling of parenteral antineoplastic drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, US Government Printing Office, Washington, DC 20402.
• AMA Council Report. Guidelines for handling parenteral antineoplastics. JAMA 1985; 253 (11): 1590-1592.
• National Study Commission on Cytotoxic Exposure—Recommendations for handling cytotoxic agents. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.
• Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia 1983; 1:426-428.
• Jones RB, et al: Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA-A Cancer Journal for Clinicians 1983; Sept/Oct 258-263.
• American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47:1033-1049.
• Controlling occupational exposure to hazardous drugs. (OSHA WORK-PRACTICE GUIDELINES.) Am J Health-Syst Pharm 1996; 53:1669-1685.

TAXOL^® Injection
(generic name = paclitaxel)

What is TAXOL?

TAXOL is a prescription cancer medicine. It is injected into a vein and it is used to treat different types of tumors. The tumors include advanced ovary and breast cancer. The tumors also include certain lung cancers (non-small cell) in people who cannot have surgery or radiation therapy. TAXOL may also be used to treat AIDS-related Kaposi’s sarcoma.

What is cancer?

Under normal conditions, the cells in your body divide and grow in an orderly, controlled way. Cell division and growth are necessary for the human body to perform its functions and to repair itself, when necessary. Cancer cells are different from normal cells because they are not able to control their own growth. The reasons for this abnormal growth are not yet fully understood.

A tumor is a mass of unhealthy cells that are dividing and growing fast and in an uncontrolled way. When a tumor invades surrounding healthy body tissue it is known as a malignant tumor. A malignant tumor can spread (metastasize) from its original site to other parts of the body if not found and treated early.

How does TAXOL work?

TAXOL is a type of medical treatment called chemotherapy. The purpose of chemotherapy is to kill cancer cells or prevent their growth.

All cells, whether they are healthy cells or cancer cells, go through several stages of growth. During one of the stages, the cell starts to divide. TAXOL may stop the cells from dividing and growing, so they eventually die. In addition, normal cells may also be affected by TAXOL causing some of the side effects. (See What are the possible side effects of TAXOL? below.)

Who should not take TAXOL?

Patients who have a history of hypersensitivity (allergic reactions) to TAXOL or other drugs containing Cremophor^® EL* (polyoxyethylated castor oil), like cyclosporine or teniposide, should not be given TAXOL. In addition, TAXOL should not be given to patients with dangerously low white blood cell counts.

How is TAXOL given?

TAXOL is injected into a vein [intravenous (IV) infusion]. Before you are given TAXOL, you will have to take certain medicines (premedications) to prevent or reduce the chance you will have a serious allergic reaction. Such reactions have occurred in a small number of patients while receiving TAXOL and have been rarely fatal. (See What are the possible side effects of TAXOL? below.)

What are the possible side effects of TAXOL?

Most patients taking TAXOL will experience side effects, although it is not always possible to tell whether such effects are caused by TAXOL, another medicine they may be taking, or the cancer itself. Important side effects are described below; however, some patients may experience other side effects that are less common. Report any unusual symptoms to your doctor.

Important side effects observed in studies of patients taking TAXOL were as follows:

—allergic reactions. Allergic reactions can vary in degrees of severity. They may cause death in rare cases. When a severe allergic reaction develops, it usually occurs at the time the medicine is entering the body (during TAXOL infusion). Allergic reactions may cause trouble breathing, very low blood pressure, sudden swelling, and/or hives or rash. The likelihood of a serious allergic reaction is lowered by the use of several kinds of medicines that are given to you before the TAXOL infusion.

—heart and blood vessel (cardiovascular) effects. TAXOL may cause a drop in heart rate (bradycardia) and low blood pressure (hypotension). The patient usually does not notice these changes. These changes usually do not require treatment. Your heart function, including blood pressure and pulse, will be monitored while you are receiving the medicine. You should notify your doctor if you have a history of heart disease.

—infections due to low white blood cell count. Among the body’s defenses against bacterial infections are white blood cells. Between your TAXOL treatment cycles, you will often have blood tests to check your white blood cell counts. TAXOL usually causes a brief drop in white blood cells. If you have a fever (temperature above 100.4° F) or other sign of infection, tell your doctor right away. Sometimes serious infections develop that require treatment in the hospital with antibiotics. Serious illness or death could result if such infections are not treated when white blood cell counts are low.

—hair loss. Complete hair loss, or alopecia, almost always occurs with TAXOL. This usually involves the loss of eyebrows, eyelashes, and pubic hair, as well as scalp hair. It can occur suddenly after treatment has begun, but usually happens 14 to 21 days after treatment. Hair generally grows back after you’ve finished your TAXOL treatment.

—joint and muscle pain. You may get joint and muscle pain a few days after your TAXOL treatment. These symptoms usually disappear in a few days. Although pain medicine may not be necessary, tell your doctor if you are uncomfortable.

—irritation at the injection site. TAXOL sometimes causes irritation at the site where it enters the vein. Reactions may include discomfort, redness, swelling, inflammation (of the surrounding skin or of the vein itself), and ulceration (open sores). These reactions are usually caused by the IV (intravenous) fluid leaking into the surrounding area. If you notice anything unusual at the site of the injection (needle), either during or after treatment, tell your doctor right away.

—low red blood cell count. Red blood cells deliver oxygen to tissues throughout all parts of the body and take carbon dioxide from the tissues by using a protein called hemoglobin. A lowering of the volume of red blood cells may occur following TAXOL treatment causing anemia. Some patients may need a blood transfusion to treat the anemia.

Patients can feel tired, tire easily, appear pale, and become short of breath. Contact your doctor if you experience any of these symptoms following TAXOL treatment.

—mouth or lip sores (mucositis). Some patients develop redness and/or sores in the mouth or on the lips. These symptoms might occur a few days after the TAXOL treatment and usually decrease or disappear within one week. Talk with your doctor about proper mouth care and other ways to prevent or reduce your chances of developing mucositis.

—numbness, tingling, or burning in the hands and/or feet (neuropathy). These symptoms occur often with TAXOL and usually get better or go away without medication within several months of completing treatment. However, if you are uncomfortable, tell your doctor so that he/she can decide the best approach for relief of your symptoms.

—stomach upset and diarrhea. Some patients experience nausea, vomiting, and/or diarrhea following TAXOL use. If you experience nausea or stomach upset, tell your doctor. Diarrhea will usually disappear without treatment; however, if you experience severe abdominal or stomach area pain and/or severe diarrhea, tell your doctor right away.

Talk with your doctor or other healthcare professional to discuss ways to prevent or reduce some of these side effects. Because this leaflet does not include all possible side effects that can occur with TAXOL, it is important to talk with your doctor about other possible side effects.

Can I take TAXOL if I am pregnant or nursing a baby?

TAXOL could harm the fetus when given to a pregnant woman. Women should avoid becoming pregnant while they are undergoing treatment with TAXOL. Tell your doctor if you become pregnant or plan to become pregnant while taking TAXOL.

Because studies have shown TAXOL to be present in the breast milk of animals receiving the drug, it may be present in human breast milk as well. Therefore, nursing a baby while taking TAXOL is NOT recommended.

_______________________
_{This medicine was prescribed for your particular condition. This summary does not include everything there is to know about TAXOL. Medicines are sometimes prescribed for purposes other than those uled in a Patient Information Leaflet. If you have questions or concerns, or want more information about TAXOL, your doctor and pharmacist have the complete prescribing information upon which this guide is based. You may want to read it and discuss it with your doctor. Remember, no written summary can replace careful discussion with your doctor.}

Bristol-Myers Squibb Company
Princeton, NJ 08543 USA

*Cremophor^® EL is the registered trademark of BASF Aktiengesellschaft.
 Cremophor^® EL is further purified by a Bristol-Myers Squibb Company proprietary process before use.

This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.

1109663B1
Issue Date: January 2000
Based on package insert dated March 2003