PACLITAXEL INJECTION USP

Rx ONLY

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 polyoxyethylated castor oil and 49.7% (v/v) dehydrated alcohol.

Paclitaxel is a natural product with antitumor activity. Paclitaxel is obtained via a semi-synthetic process from Taxus baccata.

The chemical name for paclitaxel is (2α^R,4-^S,4α^S,6^R,9^S,11^S,12^S,12α^R,12β^S)-1,2α,3,4,4a,6,9,10,11,12,12α,12β-Dodecahydro-4,6,9,11,12,12β-hexahydroxy-4α,8,13,13-tetramethyl-7, 11-methano-5H-cyclodeca[3,4]-benz[1,2-^b]oxet-5-one 6,12β-deacetate, 12-benzoate, 9-ester with (2^R,3^S)-N-benzoyl-3-phenylisoserine.

Paclitaxel has the following structural formula:

Paclitaxel is a white to off-white crystalline powder with the molecular formula C₄₇H₅₁NO₁₄ and a molecular weight of 853.91. It is highly lipophilic, insoluble in water, and melts at around 216° to 217°C.

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 injection, 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:

It appeared that with the 24-hour infusion of paclitaxel, 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 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 & 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 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 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-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporine, 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.

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 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 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 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 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 six 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.

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% Cl: 11% to 37%) and 30% (95% Cl: 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 to 15.8 months) and 7.5 months (range: 5.3 to 17.4 months), respectively. The median survival was 8.1 months (range: 0.2 to 36.7 months) and 15.9 months (range: 1.8 to 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% Cl: 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 to 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.

Analyses were performed as planned by the bifactorial study design described 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 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.

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 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 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 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 paclitaxel 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 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% Cl 0.67 to 0-91, p=0.0022). They also had a 26% reduction in the risk of death (HR = 0.74, 95% Cl 0.60 to 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.

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.

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: Subset Analyses-Adjuvant Breast Carcinoma Study and Figures 5 to 8).

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 rnedian duration of response, measured from the first day of treatment, was 8.1 months (range: 3.4 to 18.1, months). Overall for the 471 patients, the median time to progression was 3.5 months (range: 0.03 to 17.1 months). Median survival was 11.7 months (range: 0 to 18.9 months).

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

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.

 In a Phase 3 open label randomized study conducted by the ECOG, 599 patients were randomized to either paclitaxel (P) 135 mg/m² as a 24-hour infusion in combination with cisplatin (c) 75 mg/m², paclitaxel (P) 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 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.

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 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.

Data from two 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.

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 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 six 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% to 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.

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 to 11 months) for the patients who had previously received systemic therapy. The median time to progression was 6.2 months (95% CI: 4.6 to 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 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.

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

Paclitaxel 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.)

Paclitaxel 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.

Paclitaxel, 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.

Paclitaxel is indicated for the second-line treatment of AIDS-related Kaposi's sarcoma.

Paclitaxel is contraindicated in patients who have a history of hypersensitivity reactions to paclitaxel or other drugs formulated in polyoxyethylated castor oil.

Paclitaxel 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% to 4% of patients receiving paclitaxel 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 paclitaxel 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. Paclitaxel 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 paclitaxel treatment. Patients should not be re-treated with subsequent cycles of paclitaxel 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 paclitaxel therapy and in some cases requiring pacemaker placement. If patients develop significant conduction abnormalities during paclitaxel infusion, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with paclitaxel.

Paclitaxel can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel during the period of organogenesis to rabbits at doses of 3 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 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 paclitaxel is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.

Women of 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 paclitaxel solutions should preferably be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

Paclitaxel 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.

Paclitaxel therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 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 paclitaxel. Patients should not be re-treated with subsequent cycles of paclitaxel 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 paclitaxel 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, paclitaxel, 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 polyoxyethylated castor oil (eg, cyclosporine for injection concentrate and teniposide for injection concentrate) shouId not be treated with paclitaxel. In order to avoid the occurrence of severe hypersensitivity reactions, all patients treated with paclitaxel 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 paclitaxel and aggressive symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with paclitaxel.

Hypotension, bradycardia, and hypertension have been observed during administration of paclitaxel, but generally do not require treatment. Occasionally paclitaxel infusions must be interrupted or discontinued because of initial or recurrent hypertension. Frequent vital sign monitoring, particularly during the first hour of paclitaxel 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 paclitaxel.

Paclitaxel 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 paclitaxel may be exacerbated in patients with serum total bilirubin >2 times ULN (see CLINICAL PHARMACOLOGY). Extreme caution should be exercised when administering paclitaxel to such patients, with dose reduction as recommended in DOSAGE AND ADMINISTRATION, Table 17: Recommendations for Dosing in Patients With Hepatic Impairment Based on Clinical Trial Dataa .

Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted 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, 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 paclitaxel safety. In some cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to ten days.

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

The carcinogenic potential of 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.)

It is not known whether the drug is excreted in human milk. Following intravenous administration of carbon-14 labeled paclitaxel 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 paclitaxel therapy.

The safety and effectiveness of 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 paclitaxel 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 paclitaxel 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 paclitaxel for use in this population.

Of 2228 patients who received paclitaxel 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 paclitaxel 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 paclitaxel 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.)

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

None of the observed toxicities were clearly influenced by age.

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