VA Class:AN900

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• PACLitaxel

Chemical Name:

• [2a R -[2aα,4β,4aβ,6β,9α(α R *,β S *),11α,1-2α,12aα,12bα]]-β-(Benzoylamino)-α-hydroxybenzenepropanoic acid 6, 12b- bis (acetyloxy)-12-(benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a-,12b-dodecahydro-4, 11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methano-1 H -cyclodeca[3,4]benz [1,2-b]oxet -9-yl ester

Molecular Formula:

• C₄₇H₅₁NO₁₄

Paclitaxel is a natural or semisynthetic diterpene antineoplastic agent extracted from the bark of the Western (Pacific) yew ( Taxus brevifolia ) or the needles and twigs of Taxus baccata .1,2,3,4,6,7,20,22,71,183

Paclitaxel is commercially available in 2 types of formulations: conventional paclitaxel (in a nonaqueous solution) and albumin-bound paclitaxel.1,354 The efficacy and safety of paclitaxel for each indication is based on research and clinical experience using a specific formulation.354 Albumin-bound paclitaxel currently is labeled for use only in the second-line therapy of metastatic breast cancer, first-line therapy of non-small cell lung cancer in combination with carboplatin, and first-line therapy of metastatic adenocarcinoma of the pancreas in combination with gemcitabine.354 The functional properties of paclitaxel may differ substantially according to formulation; therefore, albumin-bound paclitaxel may not be substituted for or used in combination with other formulations of paclitaxel.354

Ovarian Cancer

Paclitaxel is used alone or in combination therapy for the treatment of ovarian cancer.1,122,134

Adjuvant Therapy for Early-stage Ovarian Epithelial Cancer

The use of platinum-based therapy, such as carboplatin and paclitaxel, is being investigated for adjuvant treatment following surgery in poor-prognosis early-stage ovarian epithelial cancer†.134,293 (See Uses: Ovarian Cancer: Adjuvant Therapy for Early-stage Ovarian Epithelial Cancer in Carboplatin 10:00.)

First-line Therapy for Advanced Ovarian Epithelial Cancer

A platinum-containing agent in combination with paclitaxel is a preferred regimen for the initial treatment of advanced ovarian epithelial cancer.122,134

Carboplatin Versus Cisplatin

Randomized trials have demonstrated that carboplatin is as effective as but less toxic than cisplatin when used in combination with paclitaxel for the initial treatment of advanced ovarian cancer.249,294 Carboplatin in combination with paclitaxel† currently is a preferred regimen for the initial treatment of advanced ovarian epithelial cancer.122,134 (See Uses: Ovarian Cancer: First-line Therapy for Advanced Ovarian Epithelial Cancer in Carboplatin 10:00.)

Platinum-containing Agent With Paclitaxel Versus Platinum-containing Agent With Cyclophosphamide

Evidence from randomized trials indicates that combined paclitaxel and cisplatin therapy is superior to combined cyclophosphamide and cisplatin therapy for the initial treatment of advanced epithelial ovarian cancer.132,134,178,184,214

The current indication for the use of paclitaxel in combination with cisplatin for the initial treatment of advanced ovarian epithelial cancer is based principally on a comparative study in which 410 patients (386 evaluable patients) with suboptimally debulked (greater than 1 cm residual tumor mass) stage III or IV ovarian cancer who had no prior chemotherapy were randomized to receive paclitaxel 135 mg/m² (administered by 24-hour IV infusion) with cisplatin 75 mg/m² versus cyclophosphamide 750 mg/m² with cisplatin 75 mg/m².1,132 Among 216 evaluable patients with measurable disease, those receiving paclitaxel and cisplatin had an overall objective response of 73% (51% complete responses, 22% partial responses) compared with 60% (31% complete responses, 29% partial responses) for those receiving cisplatin and cyclophosphamide;132 the higher response rate for the combination of paclitaxel and cisplatin was maintained according to intention-to-treat analysis of 240 women with measurable disease (62 versus 48%).1 Patients receiving paclitaxel and cisplatin also had a longer median time to progression (evaluable patients: 18 versus 13 months; intention-to-treat analysis: 16.6 versus 13 months) and increased median overall survival (evaluable patients: 38 versus 24 months; intention-to-treat analysis: 35.5 versus 24.2 months) than those receiving cyclophosphamide and cisplatin.1,132 Higher frequencies of severe neutropenia (81 versus 58%), alopecia (55 versus 37%), asthenia (17 versus 10%), diarrhea (16 versus 8%), febrile neutropenia (15 versus 4%), myalgia/arthralgia (9 versus 2%), and hypersensitivity reactions (8 versus 1%) were observed in patients receiving paclitaxel and cisplatin compared with those receiving cyclophosphamide and cisplatin.1,132

In a confirmatory randomized trial involving 680 patients with advanced ovarian cancer, longer median survival (35.6 versus 25.9 months), longer median time to progression (15.3 versus 11.5 months), and higher response rates (59 versus 45%) were observed for combination therapy with paclitaxel (175 mg/m² administered as a 3-hour IV infusion) and cisplatin versus cyclophosphamide and cisplatin.1,178 Limited evidence from subset analysis suggests that the same patterns were observed in patients with non-optimally debulked disease.1 Higher frequencies of neurotoxicity (87 versus 52%, severe in 21 versus 2%), myalgia/arthralgia (60 versus 27%), and diarrhea (37 versus 29%) were observed in patients receiving paclitaxel and cisplatin compared with those receiving cyclophosphamide and cisplatin.1,178

At a follow-up of 6.5 years, the survival benefit associated with the paclitaxel and cisplatin regimen in both randomized trials has been maintained.295

Combination therapy with paclitaxel and cisplatin is preferable to either high-dose cisplatin or paclitaxel alone for the initial treatment of advanced ovarian cancer.64,179

Intraperitoneal Cisplatin and Paclitaxel

Combined IV and intraperitoneal therapy with IV paclitaxel, intraperitoneal cisplatin, and intraperitoneal paclitaxel† has been used for the treatment of optimally debulked stage III epithelial ovarian cancer.10001

The National Cancer Institute (NCI) recommends use of a combined IV and intraperitoneal regimen for eligible patients with advanced epithelial ovarian cancer because of a substantial survival benefit.10005 Based on clinical trials, NCI recommends that use of a regimen containing intraperitoneal cisplatin (100 mg/m²) and a taxane (either IV only or IV plus intraperitoneal) should be strongly considered following primary surgery in patients with optimally debulked stage III epithelial ovarian cancer.10001,10005 Although an optimal intraperitoneal chemotherapy regimen has not been established,10005 favorable results were observed following sequential administration of IV paclitaxel, intraperitoneal cisplatin, and intraperitoneal paclitaxel in the Gynecologic Oncology Group (GOG)-172 study.10001

In this randomized, phase 3 trial (GOG-172), 429 patients with previously untreated stage III epithelial ovarian cancer or primary peritoneal cancer, with no residual mass exceeding 1 cm in diameter following surgery, received either combined IV and intraperitoneal therapy or IV therapy.10001 All patients enrolled in this study had good baseline GOG performance status (0-2) and adequate bone marrow, renal, and hepatic function.10001 Most patients (88%) had ovarian cancer, and serous adenocarcinoma was the most common histologic type (79% of patients).10001 The primary end points of the study were progression-free survival and overall survival.10001 Combined IV and intraperitoneal therapy consisted of 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 8.10001 IV therapy consisted of IV paclitaxel 135 mg/m² by 24-hour infusion on day 1 followed by IV cisplatin 75 mg/m² on day 2.10001 Both regimens were repeated every 21 days for up to 6 cycles.10001 Patients who received combined IV and intraperitoneal therapy had longer median progression-free (23.8 versus 18.3 months) and overall (65.6 versus 49.7 months) survival compared with patients who received IV therapy.10001

Most (83%) of the patients receiving IV therapy completed 6 cycles of their assigned chemotherapy regimen; however, only 42% of patients receiving combined IV and intraperitoneal therapy completed 6 cycles of assigned chemotherapy; patients who could not complete the intraperitoneal regimen received IV therapy for the remaining treatment cycles.10001 The most common reason for discontinuance of intraperitoneal therapy was catheter-related complications.10001 Grade 3 or 4 leukopenia (76 versus 64%), GI effects (46 versus 24%), metabolic effects (27 versus 7%), fatigue (18 versus 4%), neurologic effects (19 versus 9%), infection (16 versus 6%), thrombocytopenia (12 versus 4%), and pain (11 versus 1%) occurred more frequently in patients receiving combined IV and intraperitoneal therapy than in those receiving IV therapy.10001 Although patients receiving combined IV and intraperitoneal therapy reported less improvement in abdominal discomfort before cycle 4, improvement in abdominal discomfort was similar in both treatment groups 1 year after completion of therapy.10002,10010 Among patients who received combined IV and intraperitoneal therapy, quality of life was worse during and shortly after completion of therapy (before cycle 4 and at 3-6 weeks following therapy) compared with those who received IV therapy.10001,10002 Quality of life scores were similar for the groups at 1 year after completion of treatment, except for greater persistence of moderate paresthesias in patients receiving combined IV and intraperitoneal therapy.10001,10002,10005

Retrospective review of baseline data (patient and disease characteristics) from two phase 3 clinical trials (including GOG-172) for patients receiving intraperitoneal therapy for optimally debulked stage III epithelial ovarian cancer suggested that extent of residual tumor mass, histology, and age were important predictors of survival in such patients.10004 Patients with clear cell histology appeared to derive less benefit from intraperitoneal therapy compared with those with serous histology (hazard ratio for progression-free and overall survival of 2.66 and 3.88, respectively).10004 In addition, each additional year of age was associated with a 1% increase in the risk of death.10004 Although patients enrolled in the studies had optimally debulked (1 cm or less residual tumor mass) disease, survival was greater in patients with only microscopic residual disease.10004

Retrospective analysis of data from patients receiving a modified IV and intraperitoneal regimen suggests that a reduced dosage of intraperitoneal cisplatin administered in conjunction with a shortened IV paclitaxel infusion time may result in less toxicity and produce a survival benefit similar to that reported in the GOG-172 study (67 months versus 65.6 months reported in GOG-172).10001,10008 The modified IV and intraperitoneal regimen consisted of IV paclitaxel 135 mg/m² by 3-hour infusion on day 1, followed by intraperitoneal cisplatin 75 mg/m² on day 2 and intraperitoneal paclitaxel 60 mg/m² on day 8 of each 21-day cycle.10008 Most patients (80%) completed 4 or more cycles of therapy and 55% completed 6 cycles.10008 The frequency of grade 3 or 4 neutropenia (12%), GI effects (8%), metabolic effects (5%), neurologic effects (6%), infection (2%), fatigue (2%), and thrombocytopenia (0%) in this series of patients receiving the modified IV and intraperitoneal regimen appeared to be lower than toxicity rates reported in the GOG-172 study.10008 By shortening the infusion time for IV paclitaxel to 3 hours, the modified regimen also may provide an outpatient alternative to inpatient administration over 24 hours.10008,10012 However, randomized controlled trials are needed to establish comparative safety and efficacy of this modified regimen.10008 The modified IV and intraperitoneal schedule containing the lower intraperitoneal cisplatin dosage and the 3-hour IV paclitaxel infusion also has been studied in conjunction with a third cytotoxic drug, but with evidence of excessive toxicity.10013,10014

Based on current evidence, combined IV and intraperitoneal therapy with IV paclitaxel, intraperitoneal cisplatin, and intraperitoneal paclitaxel is recommended (accepted) for use as initial adjuvant treatment of optimally debulked stage III epithelial ovarian cancer in patients with good performance status (GOG performance status of 0-2).10012

Second-line Therapy for Advanced Ovarian Epithelial Cancer

Paclitaxel is used alone or in combination therapy as second-line or subsequent therapy in patients with advanced ovarian epithelial cancer.134

Paclitaxel is used alone as second-line or subsequent therapy in patients with advanced ovarian epithelial cancer.1 In the treatment of advanced ovarian cancer refractory to prior chemotherapy, paclitaxel alone produces an objective response in about 35% (range: 16-48%) of patients.24,26,28,29,124,129,130,131,241,242 Patients whose cancer is resistant to platinum-containing therapy (defined as tumor progression while on platinum-containing therapy or tumor relapse within 6 months after completion of a platinum-containing regimen) who then receive paclitaxel therapy reportedly have had response rates of 14-35%.28,129,242

The current indication of paclitaxel monotherapy for recurrent or refractory ovarian cancer was initially based on data from 5 phase I and II clinical studies involving 189 patients, a multicenter randomized phase III study involving 407 patients, and interim analysis of experience from an additional 300 patients who received the drug under a treatment IND protocol.1,24,26,28,29,129,130 According to the manufacturer, patients in 2 of the phase II clinical studies receiving an initial dose of paclitaxel of 135-170 mg/m² administered by 24-hour IV infusion had objective response rates (complete or partial responses) of 22% and 30%.1 The median duration of overall response in these 2 studies was about 7 months, and the median survival was 8.1 and 15.9 months.1 Similar responses were observed in other clinical studies using higher initial doses of paclitaxel or concomitant administration of paclitaxel and filgrastim, a recombinant human granulocyte colony-stimulating factor (G-CSF).23,26,29,130

The response rates observed in these phase II studies were confirmed in a large case series in which 1000 patients with platinum-refractory ovarian cancer who received paclitaxel 135 mg/m² administered by 24-hour IV infusion had an overall objective response rate of 22%.131 According to the manufacturer, patients in a phase III study with a bifactorial design receiving paclitaxel 135 or 175 mg/m² as a 3- or 24-hour IV infusion had an overall objective response rate of 16.2% with 6 complete responses and 60 partial responses.1,24 The duration of response measured from the first day of treatment was 8.3 months (range: 3.2-21.6 months).1 Median time to disease progression was 3.7 months (range: 0.1 to longer than 25 months), and median survival was 11.5 months (range: 0.2 to longer than 26 months).1

Response rates did not differ significantly according to dose or infusion schedule.1,24 Patients receiving a paclitaxel dose of either 175 or 135 mg/m² had objective (partial or complete) response rates of 20 or 15%, respectively.24 Patients receiving paclitaxel doses by either 3- or 24-hour IV infusion had objective (partial or complete) response rates of 16 or 19%, respectively.24 Median time to disease progression was longer in patients receiving 175 mg/m² than in those receiving 135 mg/m² (4.2 versus 3.1 months) and similar in patients receiving paclitaxel by 3-hour IV infusion or 24-hour IV infusion (4 versus 3.7 months).1 No difference in survival was observed according to dose or infusion schedule.24 Median survival was 11.6 or 11 months in patients receiving paclitaxel 175 or 135 mg/m², respectively, and 11.7 or 11.2 months in patients receiving paclitaxel by 3- or 24-hour infusion, respectively.1 Although severity of myelosuppression was affected by dose, the most important factor was duration of infusion; the same paclitaxel doses administered by 24-hour IV infusion were more myelotoxic than those administered by 3-hour IV infusion.1,24 The results of this randomized study support the use of paclitaxel doses of 135 or 175 mg/m² administered by 3-hour IV infusion, but the power of the study was inadequate to determine whether a particular dosage schedule for paclitaxel produced superior efficacy.1

Paclitaxel also has been used in combination therapy with a platinum agent (carboplatin or cisplatin) as second-line or subsequent therapy† for advanced ovarian epithelial cancer.134,247,302,303 Analysis of combined data for 802 patients involved in parallel randomized, multicenter trials indicates that median survival and median progression-free survival are prolonged in patients receiving combination therapy with paclitaxel and a platinum agent (a regimen of paclitaxel and carboplatin in 80% of patients) rather than platinum-based therapy alone (a regimen of carboplatin alone in 71% of patients) for the treatment of relapsed platinum-sensitive ovarian cancer.302

Dosage and Other Considerations

Response rates for paclitaxel therapy vary with tumor histology, volume of residual tumor, and development of resistance to previous platinum-based chemotherapy.24,28,129,131

Current evidence suggests that increased dose intensity (amount of paclitaxel per unit time) may affect response to paclitaxel but that paclitaxel doses exceeding 175 mg/m² are more toxic and do not improve survival in patients with advanced ovarian cancer.64,181,182 In addition to dose effect, the effect of duration of infusion of paclitaxel has been studied in patients with ovarian cancer.24 Efficacy was similar but toxicity, particularly myelosuppression, was greater when paclitaxel alone was administered by 24-hour versus 3-hour infusion for the subsequent therapy of advanced ovarian cancer.1,24 Limited evidence suggests that subsequent therapy with prolonged infusion of paclitaxel (96-hour IV infusion) does not produce response in patients with advanced ovarian cancer that was resistant to previous therapy with the drug administered by 3-hour or 24-hour IV infusion.250

The effect of duration of infusion on the efficacy and toxicity of paclitaxel administered as a component of combination therapy also has not been fully established.137,138,178 Increased incidence and severity of neurotoxicity is associated with administration of paclitaxel by 3-hour IV infusion in combination therapy with cisplatin in patients with gynecologic cancers.64,137,178 In a large randomized trial, patients with advanced ovarian cancer receiving paclitaxel (175 mg/m² administered as a 3-hour IV infusion) and cisplatin had an increased incidence of severe neurosensory toxicity compared with those receiving cyclophosphamide and cisplatin.178 Prolonged paclitaxel infusions do not appear to offer benefit in the treatment of ovarian cancer.298 In a randomized trial comparing 96-hour infusion of paclitaxel 120 mg/m² with 24-hour infusion of paclitaxel 135 mg/m² (each in a combination regimen of paclitaxel and cisplatin) for suboptimal stage III or IV ovarian epithelial cancer, median survival rates were similar between the groups but the relative death rate was approximately 5% greater among patients receiving the prolonged infusion of paclitaxel.298

Maintenance therapy with paclitaxel for advanced ovarian cancer† is being investigated.134 In a randomized trial, patients receiving 12 months of single-agent paclitaxel therapy following complete response to induction therapy with platinum/paclitaxel therapy for advanced ovarian cancer experienced longer progression-free survival but greater neurotoxicity than those receiving 3 months of such therapy.299 Because the trial was terminated according to study design following a planned interim analysis that detected the difference in progression-free survival, and cross-over treatment was allowed, overall survival data may be unavailable.301 Whether maintenance therapy with paclitaxel is superior to treatment upon progression of disease is unclear, and a confirmatory randomized trial is needed.299,300,301 Until further evidence is available, clinicians should discuss maintenance paclitaxel therapy and offer it as an option for patients with advanced ovarian cancer that has a complete response to induction therapy.134,300,301

Breast Cancer

Adjuvant Therapy for Breast Cancer

Adjuvant Therapy for Node-positive Breast Cancer

Paclitaxel is administered sequentially to standard doxorubicin-containing combination chemotherapy as adjuvant therapy for node-positive breast cancer, particularly in patients with hormone receptor-negative disease.1,122,215

The current indication for paclitaxel as adjuvant therapy is based on data from a multicenter, randomized trial involving 3170 patients with node-positive breast cancer.1,304 Following completion of 4 courses of doxorubicin and cyclophosphamide (AC), patients received paclitaxel (175 mg/m² as a 3-hour IV infusion once every 3 weeks for 4 courses) or no additional chemotherapy.1 Patients with hormone receptor-positive disease were assigned to receive tamoxifen, and patients who had received segmental mastectomies were assigned to receive radiation therapy following recovery from treatment-related toxicity.1 At a median follow-up of 30.1 months, patients receiving AC followed by adjuvant therapy with paclitaxel had a 22% reduction in the risk of disease recurrence and a 26% reduction in the risk of death compared with patients receiving AC alone.1 Subset analysis according to number of positive nodes, tumor size, menopausal status, and hormone receptor status suggests a similar effect of adjuvant paclitaxel on disease-free or overall survival in all of the larger subsets except for patients with hormone receptor-positive tumors, who experienced a smaller reduction in risk for disease recurrence or death.1

The study was also designed to assess the efficacy and toxicity of 3 dose levels of doxorubicin (60, 75, or 90 mg/m²).1 No effect on disease-free or overall survival was observed for doxorubicin doses exceeding 60 mg/m²; higher incidences of severe hematologic toxicities (including severe thrombocytopenia and platelet transfusions), infections, mucositis, and cardiovascular events were observed for higher doses of doxorubicin.1 Higher frequencies of severe (grade 3 or 4) toxicity, including neurosensory toxicity, myalgia/arthralgia, neurologic pain (5 versus 1%), flu-like symptoms (5 versus 3%), and hyperglycemia (3 versus 1%), were observed in patients receiving AC followed by paclitaxel compared with those receiving AC alone.1 Two deaths (0.1%) were attributed to treatment with adjuvant paclitaxel.1

In another randomized trial, involving 3060 patients with node-positive breast cancer, disease-free survival was longer in patients receiving paclitaxel (versus no additional therapy) following postoperative chemotherapy with doxorubicin and cyclophosphamide.305

Differing dosage schedules are being investigated for the use of paclitaxel as adjuvant therapy for node-positive breast cancer (e.g., increased dose density, concurrent versus sequential administration of doxorubicin and cyclophosphamide with paclitaxel).306 In a randomized trial, increased dose density of the doxorubicin, cyclophosphamide, and paclitaxel regimen with treatment every 2 weeks rather than every 3 weeks was associated with prolonged disease-free and overall survival, but no effect was observed for concurrent administration (doxorubicin/cyclophosphamide followed by paclitaxel) versus sequential administration (doxorubicin followed by paclitaxel and then cyclophosphamide).306 Further follow-up of this study and a confirmatory trial are needed to establish the effect of dose densification for this regimen.306,348

Adjuvant Therapy for Early-stage HER2-positive Breast Cancer

Paclitaxel-containing adjuvant therapy is used in conjunction with trastuzumab for the treatment of operable HER2-positive breast cancer†.215 In several large randomized trials, the addition of trastuzumab to standard adjuvant chemotherapy in patients with operable HER2-positive breast cancer reduced the risk of death and/or prolonged disease-free survival.307,308 See Adjuvant Therapy for Early-stage Breast Cancer under Uses: Breast Cancer, in Trastuzumab 10:00.

First-line Therapy for Advanced Breast Cancer

Paclitaxel and Gemcitabine

Paclitaxel is used in combination with gemcitabine for the initial treatment of metastatic breast cancer following failure of adjuvant chemotherapy; prior therapy in such patients should have included an anthracycline antineoplastic agent (e.g., doxorubicin) unless clinically contraindicated.352

The current indication for combination therapy with paclitaxel and gemcitabine for the first-line treatment of metastatic breast cancer is based on data from a randomized, multinational, phase III trial involving 529 patients who had prior adjuvant or neoadjuvant anthracycline therapy unless clinically contraindicated.352 Patients were randomized to receive either combination therapy with paclitaxel and gemcitabine (paclitaxel 175 mg/m² by 3-hour IV infusion followed by gemcitabine 1250 mg/m² by 30-minute IV infusion on day 1 and then the same dosage of gemcitabine on day 8) or paclitaxel alone (paclitaxel 175 mg/m² by 3-hour IV infusion on day 1) in 21-day cycles.352 Longer median time to disease progression (5.2 versus 2.9 months) and higher response rates (40.8 versus 22.1%) were observed in patients receiving paclitaxel and gemcitabine compared with those receiving paclitaxel monotherapy.352 In an interim analysis, a trend toward prolonged survival was noted among patients receiving combination therapy with paclitaxel and gemcitabine.352 Greater toxicity was reported in patients receiving combination therapy with paclitaxel and gemcitabine than in those receiving paclitaxel alone, including neutropenia (all: 69 versus 31%, severe: 48 versus 11%), anemia (69 versus 51%), thrombocytopenia (26 versus 7%), elevated serum ALT (SGPT) concentrations (18 versus 6%), and elevated serum AST (SGOT) concentrations (16 versus 5%).352

Paclitaxel With or Without Doxorubicin

Paclitaxel has been used alone or in combination with doxorubicin as first-line chemotherapy for metastatic breast cancer†.215

In a randomized trial with crossover, patients with metastatic breast cancer who had no previous chemotherapy with anthracyclines or taxanes received paclitaxel 200 mg/m²administered by 3-hour IV infusion or doxorubicin IV 75 mg/m² for 7 courses or until disease progression or unacceptable toxicity were observed; patients with disease progression were crossed over to therapy with the alternative agent.245 Although overall survival did not differ, lower response rates and shorter median progression-free survival were observed among patients receiving initial therapy with paclitaxel versus doxorubicin; arthralgia/myalgia and sensory neurotoxicity were associated with paclitaxel whereas mucositis, gastrointestinal toxicity, grade 4 neutropenia, febrile neutropenia, and cardiotoxicity were more frequently observed with doxorubicin.245

In a randomized, phase III, multicenter trial, patients with metastatic breast cancer receiving first-line therapy with doxorubicin and paclitaxel had higher response rates, longer median time to progression, and longer median survival than those receiving cyclophosphamide, doxorubicin, and fluorouracil (CAF).309 Neutropenia (including grade 3 or 4 neutropenia), arthralgia/myalgia, peripheral neuropathy, and diarrhea occurred more frequently in patients receiving doxorubicin and paclitaxel, whereas nausea and vomiting was more common in those receiving CAF.309 In another randomized trial, similar response rates, median progression-free survival, and median survival were observed for patients receiving doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line therapy for metastatic breast cancer.310

Results from a phase III trial comparing a combination of paclitaxel and doxorubicin to either agent alone (with subsequent crossover to the alternative agent) as first-line therapy for metastatic breast cancer showed a higher overall response rate and longer time to treatment failure with the combination regimen; however, overall survival and quality of life were similar for combination therapy compared with either agent alone.238 Results from a randomized study comparing paclitaxel monotherapy to a standard combination chemotherapy regimen (CMFP [cyclophosphamide, methotrexate, fluorouracil, and prednisolone]) showed a similar objective response rate, time to progression, and overall survival duration with the 2 regimens.236

The choice of single-agent or combination chemotherapy as first-line therapy for metastatic breast cancer may depend on the rate of disease progression, the presence of comorbid conditions, and clinician and patient preferences.215

Paclitaxel and Trastuzumab for HER2-positive Metastatic Breast Cancer

Paclitaxel is used in combination with trastuzumab (Herceptin^®, Genentech), a humanized anti-HER2 antibody, for the initial treatment of metastatic breast cancer in patients with tumors that overexpress the HER2 protein.215,244 (See First-line Therapy for Advanced Breast Cancer under Uses: Breast Cancer, in Trastuzumab 10:00.)

The current indication for combination therapy with paclitaxel and trastuzumab for the initial treatment of metastatic breast cancer is based on data from a randomized, controlled, multicenter trial involving 469 patients with 2+ or 3+ HER2-overexpressing breast tumors (based on a 0-3+ scale).244,351 Patients were randomized to receive chemotherapy alone or chemotherapy combined with trastuzumab (4 mg/kg IV loading dose followed by once-weekly doses of 2 mg/kg IV).244,351 Chemotherapy consisted of an anthracycline and cyclophosphamide unless patients had received prior adjuvant chemotherapy with an anthracycline, in which case chemotherapy consisted of paclitaxel 175 mg/m² administered by 3-hour IV infusion every 21 days for at least 6 cycles.244,351 Longer median time to disease progression (6.7 versus 2.5 months), higher overall response rate (38 versus 15%), and longer median duration of response (8.3 versus 4.3 months) were reported for combination therapy with paclitaxel and trastuzumab compared with paclitaxel alone in patients with metastatic breast cancer characterized by excess production of the HER2 protein.244

Second-line Therapy for Advanced Breast Cancer

Conventional Paclitaxel

Paclitaxel is used as monotherapy for the treatment of breast cancer in patients who have metastatic disease refractory to conventional combination chemotherapy or who have experienced relapse within 6 months of adjuvant chemotherapy; prior therapy in such patients should have included an anthracycline antineoplastic agent (e.g., doxorubicin) unless clinically contraindicated.1,122,215

The current indication for use of paclitaxel as a single agent in advanced breast cancer is based principally on data from a multicenter, randomized study involving 471 patients who were treated previously with 1 or 2 regimens of chemotherapy.1,42 For 454 evaluable patients in the study, overall response rate was 26%, median time to disease progression was 3.5 months, and median survival was 11.7 months.1 The median duration of response was 8.1 months.1 Patients receiving a paclitaxel dose of either 175 or 135 mg/m² administered as a 3-hour infusion had similar rates of objective (partial or complete) response of 28 or 22%, respectively.1,42 Median time to progression of disease was longer (4.2 versus 3 months) but median survival was similar (11.7 versus 10.5 months) for patients receiving paclitaxel doses of 175 or 135 mg/m², respectively.1,42

In this randomized study, 60% of patients had symptomatic disease with impaired performance status at study entry and 73% had visceral metastases.1,42 Overall, 30% of these patients had disease that progressed following adjuvant chemotherapy, 39% had metastatic disease refractory to conventional chemotherapy, and 31% of patients had disease that progressed or failed to respond in both settings.1 Of the patients in this study, 67% had received an anthracycline antineoplastic agent and 23% had disease considered resistant to this class of agents.1,42

Two uncontrolled phase II studies of paclitaxel therapy were conducted in a total of 53 patients with metastatic breast cancer who had been treated previously with a maximum of one regimen of antineoplastic therapy (including some patients who had received no prior chemotherapy).1,36,38 Treatment consisted of paclitaxel as a 24-hour IV infusion at initial doses of 250 mg/m² (with G-CSF support) or 200 mg/m², and overall objective response rates of 57 and 52% were observed.1 Dose reductions were required in patients who experienced severe hematologic (e.g., neutropenia) or nonhematologic (e.g., infection, neurotoxicity) toxicity;36,48 therefore, the median dose of paclitaxel per course was 203 mg/m² for both studies.48 Overall, response rates were not influenced by initial dose or dose intensity of paclitaxel or by concomitant administration of filgrastim.48,64

In another phase II study of patients whose disease was refractory to at least 2 regimens of antineoplastic therapy, including anthracycline therapy, an overall response rate of 30% (partial responses only) was observed with a paclitaxel dose of 200 mg/m² given as a 24-hour infusion with concomitant administration of filgrastim.1,49,64,125 In phase II studies that evaluated the use of a 3-hour infusion schedule, patients with metastatic breast cancer that was refractory to previous chemotherapy, including anthracyclines, who received paclitaxel doses of 175-225 mg/m² had overall response rates (partial or complete) of 18-38%.126,127,128

The optimal dosage regimen of paclitaxel when used as single-agent therapy in patients with metastatic breast cancer has not been established.36,44,45,124,246 The effect of dose on the efficacy and toxicity of paclitaxel has been studied in patients with metastatic breast cancer.267 In patients with metastatic breast cancer receiving paclitaxel administered as a 3-hour IV infusion, paclitaxel doses exceeding 175 mg/m² are associated with greater toxicity, particularly hematologic and neurosensory toxicity, but do not appear to increase response rate or prolong survival.267 The use of a weekly schedule of paclitaxel to increase dose density is being investigated.268,349 In a phase II study, an overall response rate of 53% was observed in patients with metastatic breast cancer receiving paclitaxel 100 mg/m² administered once weekly until disease progression (median of 14 infusions per patient); this regimen was notable for lack of myelosuppression although peripheral neuropathy prohibited dose escalation above paclitaxel 100 mg/m².268

The effect of duration of infusion on the efficacy and toxicity of paclitaxel has been studied in patients with metastatic breast cancer.44,64 Evidence from a randomized trial indicates that response rate is higher in patients with advanced breast cancer receiving high-dose paclitaxel (250 mg/m²) by 24- versus 3-hour IV infusion but event-free survival and survival are similar; hematologic toxicity, including febrile neutropenia, occurs more frequently with the 24-hour infusion of paclitaxel whereas severe neurotoxicity is more common with the 3-hour infusion.252 No difference in response rate, duration of response, or survival was observed in patients with metastatic breast cancer receiving paclitaxel 140 mg/m² by 96-hour IV infusion or paclitaxel 250 mg/m² by 3-hour IV infusion.253

Albumin-bound Paclitaxel

Albumin-bound paclitaxel is used as monotherapy for the treatment of breast cancer in patients who have metastatic disease refractory to conventional combination chemotherapy or who have experienced relapse within 6 months of adjuvant chemotherapy; prior therapy in such patients should have included an anthracycline antineoplastic agent (e.g., doxorubicin) unless clinically contraindicated.215,354

The current indication for use of albumin-bound paclitaxel as a single agent in advanced breast cancer is based principally on data from 2 single-arm open-label studies and a randomized trial.354,355

In a randomized trial involving 460 patients with metastatic breast cancer, patients received either albumin-bound paclitaxel 260 mg/m² by 30-minute IV infusion or paclitaxel 175 mg/m² by 3-hour IV infusion.354,355 Most patients in the study had visceral metastases, had received prior chemotherapy in the adjuvant and/or metastatic setting, and had received therapy with anthracyclines.354,355 Patients with metastatic breast cancer receiving albumin-bound paclitaxel had a higher rate of reconciled target lesion response (21.5%) than those receiving conventional paclitaxel (11.1%).354 The reconciled target lesion response rate was based on independent radiologic assessment of tumor response reconciled with the investigator assessment of response for the first 6 cycles of therapy.354 Compared with conventional paclitaxel, albumin-bound paclitaxel was associated with a lower incidence of grade 4 neutropenia (9 versus 22%) and hypersensitivity reactions (all: 4 versus 12%, severe: 0 versus 2%), but a higher frequency of sensory neuropathy (all: 71 versus 56%, severe: 10 versus 2%), asthenia (47 versus 39%), nausea (30 versus 22%), diarrhea (27 versus 15%), and vomiting (18 versus 10%).354

Objective responses to albumin-bound paclitaxel were observed in 2 phase II studies in patients with metastatic breast cancer.354,356 In one study, patients received albumin-bound paclitaxel 300 mg/m² by 30-minute IV infusion once every 3 weeks.354,356 In the other study, patients received albumin-bound paclitaxel 175 mg/m² by 30-minute IV infusion once every 3 weeks.354

Non-small Cell Lung Cancer

Adjuvant Therapy

Platinum-containing therapy, such as paclitaxel and carboplatin, is used in selected patients for the adjuvant treatment of completely resected non-small cell lung cancer†.217 In a randomized trial, patients receiving 4 cycles of paclitaxel and carboplatin therapy following surgery for stage IB non-small cell lung cancer had a higher overall survival rate at 4 years (71%) than those in an observation group (59%).311 Analysis of pooled data abstracted from randomized trials suggests that adjuvant chemotherapy prolongs survival in patients with resected non-small cell lung cancer.312

Therapy for Advanced Disease

Currently preferred regimens for the initial treatment of advanced non-small cell lung cancer in patients with good performance status include a platinum-containing agent in combination with another cytotoxic agent such as paclitaxel, docetaxel, gemcitabine, pemetrexed, or vinorelbine.359,363

Although the primary objective of treatment in patients with advanced non-small cell lung carcinoma is palliation, small improvements in survival have been demonstrated with the use of platinum-based chemotherapy.217,219

Conventional Paclitaxel and Carboplatin

Paclitaxel and carboplatin is used in the treatment of advanced non-small cell lung cancer†.122,217 Similar response rates and median survival were observed in a randomized trial in which patients received paclitaxel and carboplatin versus regimens of cisplatin in combination with paclitaxel, gemcitabine, or docetaxel for advanced non-small cell lung cancer.291 Paclitaxel and carboplatin (paclitaxel 225 mg/m² by 3-hour IV infusion on day 1 followed on the same day by carboplatin at the dose required to obtain an AUC of 6 mg/mL per minute) was less toxic than the other regimens and was selected as a reference regimen for further studies.291 However, another randomized trial showed a survival benefit in patients receiving cisplatin/paclitaxel rather than carboplatin/paclitaxel for advanced non-small cell lung cancer.315 In this study, paclitaxel 200 mg/m² by 3-hour IV infusion was administered with either cisplatin 80 mg/m² or carboplatin at the dose required to obtain an AUC of 6 mg/mL per minute.315 In another randomized trial, response rates, median survival, and 1- and 2-year survival rates were similar in patients receiving either paclitaxel/carboplatin or vinorelbine/cisplatin for advanced non-small cell lung cancer; grade 3 peripheral neuropathy occurred more frequently in patients receiving paclitaxel and carboplatin whereas grade 3 or 4 leukopenia and grade 3 nausea and vomiting were more frequent in patients receiving vinorelbine and cisplatin.292 Further study is needed to clarify the comparative efficacy of carboplatin and cisplatin in the treatment of non-small cell lung cancer.316

Weekly schedules of paclitaxel and carboplatin for the treatment of advanced non-small cell lung cancer are being investigated.313

Conventional Paclitaxel and Cisplatin

Paclitaxel and cisplatin is used in the treatment of advanced non-small cell lung cancer.1,122,217 Combination chemotherapy with paclitaxel and cisplatin is associated with higher response rates and similar survival compared with other cisplatin-containing regimens (e.g., cisplatin with etoposide, cisplatin with teniposide).217,219,221,222,225,234,254

The current indication for the use of paclitaxel in combination with cisplatin for the initial treatment of advanced non-small cell lung cancer is based on a comparative study in which 599 patients with stage IIIB or IV non-small cell lung cancer who had not received previous chemotherapy were randomized to receive paclitaxel at a dose of 135 or 250 mg/m² administered by 24-hour IV infusion followed by IV cisplatin 75 mg/m² versus IV cisplatin 75/mg/m² with IV etoposide 100 mg/m².1,254 Patients receiving the higher dose of paclitaxel received concomitant administration of granulocyte colony-stimulating factor [G-CSF]).1,254 Patients receiving paclitaxel (135 or 250 mg/m²) combined with cisplatin had higher response rates (25 or 23%, respectively, versus 12%) but similar median survival (9.3 or 10 months, respectively, versus 7.4 months) compared with those receiving combination therapy with etoposide and cisplatin.1 Longer time to progression of disease was observed in patients receiving the higher dose of paclitaxel combined with cisplatin compared with etoposide and cisplatin (4.9 versus 2.7 months).1 Quality of life assessed by the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire showed a more favorable score in the Lung Cancer Specific Symptoms subscale for patients receiving the lower dose of paclitaxel combined with cisplatin compared with etoposide and cisplatin.1

Similar response rates and median survival were observed in patients receiving paclitaxel doses of either 250 or 135 mg/m², but greater toxicity occurred in patients receiving the higher dose, including arthralgia/myalgia (42 versus 21%), severe neurosensory toxicity (28 versus 13%), and severe hypersensitivity reactions (4 versus 1%).1,254 Although patients received concomitant administration of G-CSF with the higher dose of paclitaxel, severe neutropenia was common in patients receiving paclitaxel 250 or 135 mg/m² with cisplatin (65 or 74%, respectively) and occurred more frequently than in patients receiving etoposide with cisplatin (55%).1,254 Other adverse effects that occurred more frequently in patients receiving paclitaxel 250 or 135 mg/m² by 24-hour IV infusion followed by cisplatin than in those receiving etoposide with cisplatin included arthralgia/myalgia (42 or 21%, respectively, versus 9%) and severe neurosensory toxicity (28 or 13%, respectively, versus 8%).1

Conventional Paclitaxel and Gemcitabine

Paclitaxel also is used in non-platinum-based combination regimens for the treatment of advanced non-small cell lung cancer†.122,217 In a phase III randomized trial, efficacy and toxicity were similar in patients with advanced non-small cell lung cancer receiving initial treatment with paclitaxel/gemcitabine or paclitaxel/carboplatin.314 Treatment consisted of paclitaxel 200 mg/m² as a 3-hour IV infusion on day 1 followed by either gemcitabine (1000 mg/m² as a 30-minute IV infusion on days 1 and 8) or carboplatin (at the dose required to obtain an AUC of 6 mg/mL per minute as a 1-hour IV infusion on day 1) with treatment cycles repeated every 3 weeks for up to 6 cycles.314 Treatment-related toxicity was mild in both groups.314

Albumin-bound Paclitaxel and Carboplatin

Albumin-bound paclitaxel in combination with carboplatin is used for the initial treatment of advanced non-small cell lung cancer in patients who are not candidates for curative surgery or radiation therapy.354 Combination chemotherapy with albumin-bound paclitaxel and carboplatin is associated with higher response rates and similar survival compared with conventional paclitaxel and carboplatin.354,358,360

The current indication for albumin-bound paclitaxel in combination with carboplatin is based principally on the results of a randomized, multicenter, open-label trial in patients with previously untreated advanced non-small cell lung cancer.354,358 In this study, 1052 patients with stage IIIB or IV non-small cell lung cancer were randomized to receive either albumin-bound paclitaxel (100 mg/m² by 30-minute IV infusion) on days 1, 8, and 15 followed by IV carboplatin (at the dose required to obtain an AUC of 6 mg/mL per minute) on day 1 of each 21-day cycle or conventional paclitaxel (200 mg/m² by 3-hour IV infusion) followed by IV carboplatin (at the dose required to obtain an AUC of 6 mg/mL per minute) on day 1 of each 21-day cycle.354,358 Treatment was continued until disease progression or unacceptable toxicity occurred.354,358 Patients receiving albumin-bound paclitaxel combined with carboplatin had higher overall response rates (33 versus 25%) but similar median overall survival (12.1 versus 11.2 months) and progression-free survival (6.3 versus 5.8 months) compared with those receiving conventional paclitaxel combined with carboplatin.354,358 Albumin-bound paclitaxel therapy was associated with higher overall response rates (41 versus 24%) compared with conventional paclitaxel therapy in patients with squamous cell histology and was as effective as conventional paclitaxel in patients with nonsquamous cell histology (response rate of 26 versus 25% in patients with nonsquamous cell histology receiving therapy with albumin-bound paclitaxel or conventional paclitaxel, respectively).354,358 Grade 3 or greater thrombocytopenia (18 versus 9%) and anemia (27 versus 7%) occurred more frequently in patients receiving albumin-bound paclitaxel, whereas grade 3 or greater neutropenia (58 versus 47%) and sensory neuropathy (12 versus 3%) occurred more frequently in those receiving conventional paclitaxel.358

Conventional Paclitaxel

Paclitaxel appears to be one of the most active single agents in patients with non-small cell lung carcinoma who have not received prior chemotherapy.23,45,53 In phase II studies of patients with advanced non-small cell lung carcinoma who had not received prior chemotherapy, objective response rates of 21-24% (0-4% complete responses, 20-21% partial responses) and 1-year survival rates of approximately 40% have been observed with paclitaxel alone at doses of 200-250 mg/m² administered by 24-hour infusion every 3 weeks.45,53,54,55,221,225 Response rates of 10-26% have been observed in additional phase II studies of patients who had not received previous chemotherapy for advanced disease with paclitaxel doses of 135-225 mg/m² administered over shorter periods of infusion (i.e., 1 or 3 hours).255,256,257 Limited evidence suggests that paclitaxel is not active against disease refractory to platinum-containing chemotherapy.63,258

Intrapleural injections of paclitaxel have been used for the treatment of malignant pleural effusions† in a limited number of patients with non-small cell lung cancer.235

AIDS-related Kaposi's Sarcoma

Paclitaxel alone is used for the palliative treatment of advanced or refractory AIDS-related (epidemic) Kaposi's sarcoma.1,120,122 Use of a liposomal anthracycline (doxorubicin or daunorubicin) is a first-line therapy of choice for advanced AIDS-related Kaposi's sarcoma (see Uses: AIDS-related Kaposi's Sarcoma in Doxorubicin 10:00 or Daunorubicin 10:00).120,122

Although the comparative efficacy of paclitaxel versus other treatments for advanced AIDS-related Kaposi's sarcoma (e.g., liposomal doxorubicin; liposomal daunorubicin; combination therapy with conventional doxorubicin, bleomycin, and a vinca alkaloid [ vinblastine or vincristine]) has not been established, paclitaxel has shown substantial activity in patients with advanced disease (e.g., extensive mucocutaneous disease, lymphedema, symptomatic visceral disease).116,117,118,216 Objective responses to paclitaxel therapy have been reported in patients with poor prognostic factors,123 including low baseline helper/inducer (CD4⁺, T4⁺) T-cell counts (less than 200/mm³), visceral involvement (e.g., pulmonary disease), or history of opportunistic infection, as well as in patients who have received prior systemic chemotherapy.1,117,118,119,216 However, the depressed immunologic status of the patient limits the therapeutic benefit of systemic chemotherapy, and there currently are no data showing unequivocal evidence of improved survival with any treatment for AIDS-related Kaposi's sarcoma; new therapies are continually being evaluated.120

The current indication for use of paclitaxel in advanced AIDS-related Kaposi's sarcoma is based on limited data from 2 uncontrolled phase II studies involving 59 patients who previously had received systemic therapy, including interferon alfa (32%), liposomal daunorubicin (31%), liposomal doxorubicin (2%), and/or conventional doxorubicin-containing chemotherapy (42%); 64% of the patients had received previous chemotherapy with anthracycline agents.1 Most of these patients experienced progression of disease during, or could not tolerate, previous systemic therapy for AIDS-related Kaposi's sarcoma.1 According to the manufacturer, the overall objective response rate was 59% (3% complete responses, 56% partial responses).1 A cutaneous (i.e., objective) response was defined principally as flattening of the size of all previously raised lesions by at least 50%.1,23 The median duration of response measured from the first day of treatment was 10.4 months (range: 7-11 months).1 Median time to disease progression was 6.2 months (range: 4.6-8.7 months).1

Retrospective analysis of the data showed that some patients receiving paclitaxel as second-line therapy for AIDS-related Kaposi's sarcoma experienced additional clinical benefits, including improvement of pulmonary function in those with pulmonary involvement, increased ambulation, resolution of ulcers, decreased analgesic requirements for pain caused by foot lesions, and resolution of facial lesions.1 Rapid, substantial improvement in tumor-associated lymphedema also has been observed in patients receiving paclitaxel for advanced AIDS-related Kaposi's sarcoma.1,116,118

The optimum dosage regimen for paclitaxel in the treatment of AIDS-related Kaposi's sarcoma has not been established.116,117,118,119,121,216 In the first phase II study, paclitaxel was administered IV over 3 hours at an initial dosage of 135 mg/m² once every 3 weeks.1,117 The paclitaxel dose was to be increased by 20 mg/m² for each subsequent cycle of therapy to a maximum dose of 175 mg/m²; however, at least 12 of 29 patients required dose reduction to less than 135 mg/m² because of dose-limiting toxicity, particularly neutropenia.1,117 Patients in this study initially did not receive concomitant therapy with granulocyte colony-stimulating factor (i.e., filgrastim), but the study protocol was later modified to allow concomitant administration of filgrastim to reduce the severity of paclitaxel-associated myelosuppression.1,117,121,216 In the second phase II study, paclitaxel was administered IV over 3 hours at a dosage of 100 mg/m² once every 2 weeks.1,118 Concomitant administration of a granulocyte colony-stimulating factor (G-CSF) was initiated as clinically indicated, and most of the patients in this study were already receiving G-CSF prior to the initiation of paclitaxel therapy.1,118 The dose intensity of paclitaxel per week was 38-39 mg/m² for both studies.1

Although direct comparison of data from these uncontrolled phase II studies is not possible, a higher incidence of hematologic toxicity was reported in patients receiving paclitaxel 135 mg/m² compared with that reported in patients receiving paclitaxel 100 mg/m², including severe neutropenia (76 versus 35%), febrile neutropenia (55 versus 9%), and opportunistic infections (76 versus 54%).1,121 The higher incidence of hematologic toxicity in patients receiving paclitaxel 135 mg/m² may have been at least partially secondary to the delayed administration of G-CSF in these patients.64,121 The manufacturer recommends concomitant administration of a granulocyte colony-stimulating factor (e.g., filgrastim) as clinically indicated in patients with AIDS-related Kaposi's sarcoma to reduce the severity of myelosuppression associated with paclitaxel therapy.1,116,118

The incidence of nonhematologic toxicity also appears to be higher in patients receiving higher doses of paclitaxel.1,121 Certain adverse effects occurred more frequently in patients receiving the higher dose of paclitaxel (135 versus 100 mg/m²) for AIDS-related Kaposi's sarcoma, including arthralgia and/or myalgia (93 versus 48%), peripheral neuropathy (79 versus 46%), and hypersensitivity reaction (14 versus 9%).1,121

Other schedules of paclitaxel therapy have been investigated in patients with AIDS-related Kaposi's sarcoma.216 Some responses have been reported in patients with advanced AIDS-related Kaposi's sarcoma receiving paclitaxel administered by continuous 96-hour infusion (initial dosage of 105 mg/m² with or without filgrastim) following progression of disease or absence of response with administration of the drug by 3-hour infusion.216 Further study is needed to determine the optimal dosage and schedule of paclitaxel for the treatment of advanced AIDS-related Kaposi's sarcoma.117,216

Optimal therapy for the treatment of advanced AIDS-related Kaposi's sarcoma has not been established.116,120 The potential effects of systemic chemotherapy on the patient's immune and hematologic status must be considered in the management of AIDS-related Kaposi's sarcoma.116,120

Pancreatic Cancer

Albumin-bound paclitaxel in combination with gemcitabine is used as first-line therapy in patients with metastatic adenocarcinoma of the pancreas.354 Combination chemotherapy with albumin-bound paclitaxel and gemcitabine is associated with higher response rates and prolonged overall and progression-free survival compared with gemcitabine monotherapy.354,361

The current indication for albumin-bound paclitaxel in combination with gemcitabine is based principally on the results of a randomized, multicenter, open-label trial in patients with previously untreated metastatic adenocarcinoma of the pancreas.354,361 In this study, 861 patients with metastatic adenocarcinoma of the pancreas were randomized (stratified according to performance status, presence of liver metastases, and geographic region) to receive either albumin-bound paclitaxel (125 mg/m² administered IV over 30-40 minutes) followed by gemcitabine (1 g/m² administered IV over 30-40 minutes) on days 1, 8, and 15 of each 28-day cycle or gemcitabine (1 g/m² IV over 30-40 minutes) alone once weekly for 7 weeks followed by a treatment-free week, and then once weekly for 3 consecutive weeks (days 1, 8, and 15) of each subsequent 28-day cycle.354,361 Median overall survival was prolonged in patients receiving albumin-bound paclitaxel combined with gemcitabine compared with those receiving gemcitabine alone (8.5 versus 6.7 months);354,361 1-year survival was reported in 35% of patients receiving combined therapy and 22% of those receiving gemcitabine alone.361 Median progression-free survival also was prolonged in patients receiving albumin-bound paclitaxel combined with gemcitabine compared with those receiving gemcitabine alone (5.5 versus 3.7 months).354,361 The median time to treatment failure was 5.1 months in patients receiving combined therapy and 3.6 months in those receiving gemcitabine monotherapy.361 Patients receiving albumin-bound paclitaxel combined with gemcitabine had higher overall response rates (23 versus 7%);354,361 one patient receiving combined therapy achieved a complete response compared with none of those receiving gemcitabine alone.361 Subgroup analysis suggested that combined therapy consistently had a greater effect than gemcitabine monotherapy on overall and progression-free survival in patients with more advanced disease (i.e., those with poor performance status, presence of liver metastasis, more than 3 sites of metastatic disease, or carbohydrate antigen [CA] 19-9 level of 59 or more times the upper limit of normal).361 Compared with gemcitabine monotherapy, combined therapy was associated with a higher incidence of grade 3 or greater neutropenia (38 versus 27%), leukopenia (31 versus 16%), thrombocytopenia (13 versus 9%), febrile neutropenia (3 versus 1%), fatigue (17 versus 7%), peripheral neuropathy (17 versus 1%), and diarrhea (6 versus 1%).361

Small Cell Lung Cancer

Paclitaxel is an active agent in the treatment of small cell lung cancer†.108,122

In phase II studies of patients with previously untreated extensive-stage small cell lung cancer, objective response rates of 35-41% (mostly partial responses) have been observed with paclitaxel alone (using a regimen of paclitaxel 250 mg/m² by 24-hour IV infusion every 3 weeks).97,98 Responses to paclitaxel (175 mg/m² by 3-hour IV infusion every 3 weeks) used alone or in combination therapy have been reported in patients with advanced small cell lung cancer that has relapsed following one or more previous chemotherapy regimens.228,230 In phase I and II studies, combination therapy with paclitaxel (e.g., cisplatin, etoposide, and paclitaxel; carboplatin, etoposide, and paclitaxel) has produced high response rates in patients with limited- or extensive-stage small cell lung cancer;101,103,229,317,320 however, randomized studies to date have not demonstrated a survival benefit from adding paclitaxel to standard combination regimens.318,319

In a randomized trial, response rates and median survival were similar but toxicity was greater when paclitaxel was added to etoposide and cisplatin for previously untreated extensive-stage small cell lung cancer.318 Another randomized trial was terminated early because excessive toxicity and toxicity-related mortality occurred when paclitaxel was added to etoposide/cisplatin for the initial treatment of limited-stage or extensive-stage small cell lung cancer.319 Based on experience in these randomized trials, the addition of paclitaxel to standard regimens for the treatment of small-cell lung cancer is not recommended.318,319

Concomitant administration of granulocyte colony-stimulating factor (G-CSF) has been used in some patients with small cell lung cancer to reduce the severity of myelosuppression associated with paclitaxel therapy;98,100,101 however, use of G-CSF generally is not required when paclitaxel is administered by short IV infusion (e.g., 1 or 3 hours).64

Because the current prognosis for patients with small cell lung cancer is unsatisfactory regardless of stage and despite considerable diagnostic and therapeutic advances, all patients with this cancer are candidates for inclusion in clinical trials at the time of diagnosis.108

Esophageal Cancer

Paclitaxel has been used alone or in combination therapy for the treatment of esophageal cancer†.111,122 Like cisplatin, paclitaxel is active against both histologic types of esophageal cancer (i.e., squamous cell carcinoma and adenocarcinoma).110,114

In a phase II study of patients with advanced esophageal cancer who had not received prior chemotherapy, an objective response rate of 32% (2% complete responses, 30% partial responses) has been observed with paclitaxel alone using an initial paclitaxel dosage of 250 mg/m² administered as a 24-hour IV infusion every 3 weeks.111 Response rates did not differ significantly according to histologic type; patients with adenocarcinoma and squamous cell carcinoma of the esophagus had objective response rates of 34 and 28%, respectively.111 Concomitant administration of granulocyte colony-stimulating factor was used to reduce the severity of myelosuppression associated with paclitaxel therapy, particularly with longer infusion schedules and higher doses of the drug.111

The use of paclitaxel in combination with other antineoplastic agents (e.g., cisplatin, fluorouracil) for the treatment of advanced esophageal cancer is being investigated.113 The use of paclitaxel-containing regimens (with or without radiation therapy) prior to surgical resection is being investigated for the treatment of esophageal cancer.112,231,321 Optimal therapy for esophageal cancer has not been established, and new therapies are continually being evaluated.109,110 Because the prognosis for most patients with esophageal cancer remains poor, all newly diagnosed patients should be considered for enrollment in clinical trials comparing various treatment modalities.64,109

Bladder Cancer

Paclitaxel is an active agent in the treatment of transitional cell bladder cancer†.168,232 Paclitaxel has been used alone and in combination therapy for the treatment of advanced or metastatic bladder cancer.168,232

In a phase II study of 26 patients with advanced transitional cell bladder cancer who had not received prior chemotherapy, objective responses occurred in 42% (27% complete responses, 15% partial responses) of patients receiving paclitaxel 250 mg/m² by 24-hour IV infusion every 21 days.168 Concomitant administration of granulocyte colony-stimulating factor (i.e., filgrastim) was used to reduce the severity of myelosuppression associated with paclitaxel therapy.168 Only partial responses have been reported in a small number of patients receiving paclitaxel alone169,170 or in combination with other antineoplastic agents171 for advanced or metastatic bladder cancer refractory to previous chemotherapy and/or radiation therapy. A low response rate (10%, partial responses only) was observed in patients receiving paclitaxel 80 mg/m² by 1-hour IV infusion once weekly for 4 weeks for previously treated advanced urothelial cancer.322

Because paclitaxel is eliminated principally via hepatic metabolism, it may be a reasonable alternative in patients with advanced transitional cell urothelial cancer who have renal impairment and cannot tolerate the renal toxicity associated with cisplatin-based regimens.169,175,248 Paclitaxel also may be a useful alternative for the treatment of advanced or metastatic bladder cancer in patients with poor performance status who cannot tolerate standard platinum-based regimens.248

Combination therapy with paclitaxel followed by carboplatin has been investigated as an active regimen in patients with advanced bladder cancer.232 Although high response rates were observed in earlier phase II studies of paclitaxel and carboplatin for previously untreated advanced bladder cancer,174,224 lower response rates were reported for this combination in a later phase II study323 and another phase II study involving patients with cisplatin-treated disease.324 Limited evidence from a small randomized trial that did reach full enrollment suggests that response rates and survival are similar but toxicity is lesser in patients receiving paclitaxel/carboplatin versus cisplatin, methotrexate, vinblastine, and doxorubicin (M-VAC).104 In this study, paclitaxel 225 mg/m² by 3-hour IV infusion was administered on day 1 followed by carboplatin at the dose required to obtain an AUC of 6 mg/mL per minute administered over 30 minutes; this cycle was administered every 3 weeks for a maximum of 6 cycles.104 Combination therapy with paclitaxel and carboplatin may be a reasonable option for the treatment of advanced bladder cancer in patients with renal dysfunction.325 The use of weekly dosing schedules of paclitaxel and carboplatin for patients with advanced bladder cancer is being investigated.326

The use of paclitaxel in combination therapy with other antineoplastic agents (e.g., cisplatin, ifosfamide, gemcitabine) is being evaluated for the palliative treatment of advanced or metastatic bladder cancer.172,173,327,328,329 New chemotherapy regimens are continually being evaluated for the treatment of bladder cancer.232

Head and Neck Cancer

Paclitaxel is an active agent in the treatment of head and neck cancer†.122,213

Paclitaxel is used in combination with cisplatin for the palliative treatment of advanced head and neck cancer.122 In a randomized trial involving patients with locally advanced, recurrent, or metastatic head and neck cancer, similar response rates and survival were observed in those receiving cisplatin and paclitaxel (paclitaxel 175 mg/m² by 3-hour IV infusion on day 1 followed by cisplatin 75 mg/m² IV on day 1) versus those receiving cisplatin and fluorouracil (cisplatin 100 mg/m² on day 1 and fluorouracil 1000 mg/m² per 24 hours by continuous IV infusion day 1 through 4).330 Hematologic toxicities and stomatitis were more common in the patients receiving cisplatin and fluorouracil, but the frequency of neurotoxicity was similar between the groups.330 The use of paclitaxel in combination with other antineoplastic agents is being investigated.93,208,209,210,212

Paclitaxel has been used alone for the treatment of advanced head and neck cancer.80,96 In phase II studies of patients with advanced or unresectable locally advanced squamous cell carcinoma of the head and neck, objective response rates of 36-40% (7-12% complete responses, 24-33% partial responses) have been observed with paclitaxel alone using a regimen of paclitaxel 250 mg/m² as a 24-hour IV infusion administered every 3 weeks.80,96 Long-term follow-up for one of these studies indicates a median survival of 9.2 months with paclitaxel monotherapy in patients with advanced head and neck cancer.180

The effect of dose on the efficacy and toxicity of paclitaxel has been studied in patients with advanced head and neck cancer.260 Results of a randomized clinical trial indicate that response rates and duration of survival are similar when paclitaxel doses of 200 mg/m² (with granulocyte colony-stimulating factor [G-CSF]) or 135 mg/m²(without G-CSF) are administered by 24-hour infusion followed by cisplatin 75 mg/m² with treatment cycles administered every 3 weeks; however, unacceptably high rates of hematologic toxicity occurred and neither regimen is recommended for use in the treatment of advanced head and neck cancer.260 Concomitant administration of granulocyte colony-stimulating factor has been used in patients with squamous cell carcinoma of the head and neck to reduce the severity of myelosuppression associated with paclitaxel therapy, particularly with high doses of the drug.80,88,93,94,96,209,260

Paclitaxel also has been administered by IV infusion over shorter periods (e.g., 1 or 3 hours) in patients with head and neck cancer.87,88,208,209,210,212,261,262 The effect of duration of infusion on the efficacy and toxicity of paclitaxel has been studied in patients with advanced head and neck cancer.262 Interim analysis from a randomized study shows that toxicity is greater in patients with recurrent or metastatic squamous cell carcinoma of the head and neck receiving paclitaxel 175 mg/m² administered by 24-hour IV infusion versus 3-hour IV infusion.262 Paclitaxel has been administered by IV infusion over longer periods in patients with head and neck cancer; low response rates were observed for a regimen of paclitaxel 120 or 140 mg/m² by 96-hour IV infusion in patients with advanced squamous cell carcinoma of the head and neck.331

In addition to its antitumor activity, in vitro studies indicate that paclitaxel is a radiosensitizer, and the use of paclitaxel in combination with radiation therapy is being investigated in patients with advanced head and neck cancer.91,95,207 Paclitaxel-containing therapy has been used with concurrent radiation therapy in the treatment of advanced head or neck cancer.86,90,94,332 Paclitaxel-containing therapy is being investigated as induction therapy preceding surgery and/or radiation therapy, or concurrent chemotherapy and radiation therapy, in the treatment of locally advanced squamous cell carcinoma of the head and neck.90,333 The prognosis for patients with advanced head and neck cancer generally is poor; the optimal timing and regimens of chemotherapy used alone or in the combined modality treatment of advanced head and neck cancer have not been established, and new therapies are continually being evaluated.82,83,84,85,213

Cervical Cancer

Paclitaxel is an active agent in the treatment of cervical cancer†.122,271 (See Uses: Cervical Cancer in Cisplatin 10:00 for an overview of therapy for cervical cancer.)

Paclitaxel and Radiation Therapy for Locally Advanced Cervical Cancer

The use of paclitaxel as a radiation sensitizer is being investigated in patients with locally advanced cervical cancer†.275 Additional comparative studies are needed to determine the optimum chemotherapy regimens and schedules to be used concurrently with radiation therapy for the treatment of locally advanced cervical cancer.270,272,277,278

Paclitaxel for Advanced Cervical Cancer

Paclitaxel is an active agent in the treatment of metastatic or recurrent cervical cancer†.271,273,274,275,276 Objective response rates of 17-25% have been observed in patients receiving paclitaxel as a single agent for advanced squamous cell carcinoma of the cervix.273,274 An objective response rate of 31% was reported in patients receiving paclitaxel alone for advanced nonsquamous cervical cancer.334

Paclitaxel and Cisplatin for Advanced Cervical Cancer

Paclitaxel and cisplatin is used in the treatment of advanced cervical cancer.122,271 Objective responses of 40-45% for combination therapy with cisplatin and paclitaxel have been reported in patients who previously had not received chemotherapy for advanced or recurrent cervical cancer.279,280 In a randomized trial involving patients with advanced squamous cell cervical cancer, response rate was higher (36 versus 19%) and progression-free survival was longer (4.8 versus 2.8 months) in those receiving paclitaxel and cisplatin than in those receiving cisplatin alone; overall survival was similar between the groups (9.7 versus 8.8 months).335 In this study, patients received either paclitaxel and cisplatin (paclitaxel 135 mg/m² by 24-hour IV infusion followed immediately by IV cisplatin 50 mg/m²) or single-agent cisplatin (same dosage of cisplatin used for combination therapy) every 3 weeks.335

Endometrial Cancer

Paclitaxel is used in the treatment of endometrial cancer†.122,336

Paclitaxel is an active agent that has been used in the treatment of advanced or recurrent endometrial cancer.337,338 Paclitaxel and carboplatin, with or without radiation therapy, is used in the palliative treatment of advanced or recurrent endometrial cancer.122,339 In a randomized trial, similar response rates, progression-free survival, and overall survival were observed for patients receiving doxorubicin and cisplatin versus doxorubicin and paclitaxel (with filgrastim) for advanced endometrial cancer.340 In another randomized trial, higher response rate and prolonged progression-free and overall survival but greater neurotoxicity was observed with the addition of paclitaxel to doxorubicin and cisplatin for advanced endometrial cancer.341 A phase III randomized trial comparing doxorubicin, cisplatin, paclitaxel and filgrastim (G-CSF) versus carboplatin and paclitaxel for advanced endometrial cancer is under way.342

The use of adjuvant radiation therapy and chemotherapy with cisplatin and paclitaxel following surgery for high-risk endometrial cancer confined to the uterus is being investigated.343

Other Uses

Paclitaxel is used in the treatment of gastric cancer†.122 Paclitaxel is used in the treatment of relapsed or refractory testicular cancer†.122

Reconstitution and Administration

Paclitaxel is administered by IV infusion.1,3,13,20,21,354 Paclitaxel also has been administered intraperitoneally†.10001,10008

Paclitaxel is commercially available in 2 types of formulations: conventional paclitaxel (in a nonaqueous solution)1 and albumin-bound paclitaxel.354 The properties of paclitaxel may differ according to formulation, and the dosage and reconstitution instructions for paclitaxel are specific to formulation.354 Albumin-bound paclitaxel may not be substituted for or used in combination with other formulations of paclitaxel.354

Caution should be exercised in handling and preparing solutions of conventional or albumin-bound paclitaxel.1,354 Because dermatologic reactions (e.g., tingling, burning, erythema) may occur with accidental exposure to the drug, the manufacturers recommend the use of protective gloves during preparation and administration of paclitaxel.1,354 Skin accidentally exposed to the drug should be washed immediately and thoroughly with soap and water.1,354 If the drug comes into contact with mucous membranes, thorough flushing with water should be used immediately.1,354 Dyspnea, chest pain, ocular burning, sore throat, and nausea have been reported upon inhalation, and inadvertent inhalation should be avoided during preparation and administration of paclitaxel solutions.1,354

Paclitaxel for injection concentrate, diluted solutions of conventional paclitaxel, and reconstituted suspensions of albumin-bound paclitaxel should be inspected visually for particulate matter and discoloration whenever solution and container permit.1,354

Medication errors have occurred that involved confusion between paclitaxel (Taxol^®) and docetaxel (Taxotere^®).290 To avoid medication errors, the prescriber should print both the brand and generic names for paclitaxel on the prescription order form.290 If a handwritten prescription is difficult to read, the pharmacist should confirm the drug name with the prescriber.290 If the prescription is confirmed verbally, the drug names should be spelled out.290 Pharmacy labels and preprinted order forms should list both the generic and brand names using upper- and lower-case fonts (i.e., PACLItaxel and TaxOL).290 Two pharmacists should provide independent confirmation that the correct drug is being administered before chemotherapy is dispensed, and two nurses should confirm that the correct drug has been dispensed for the correct patient before administering the medication.290

IV Administration

Adverse local effects have occurred following extravasation of paclitaxel during administration, and the injection site should be monitored closely during infusion of conventional or albumin-bound paclitaxel for possible infiltration of the drug.1,354 (See Cautions: Local Effects.)

Conventional Paclitaxel

Paclitaxel for injection concentrate must be diluted prior to IV infusion .1,20 For IV infusion, the manufacturer recommends diluting the concentrate 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

Undiluted paclitaxel for injection concentrate should not be placed in plasticized polyvinyl chloride (PVC) equipment or devices used to prepare solutions for infusion.1 To minimize exposure of the patient to leached DEHP, diluted paclitaxel solutions preferably should be stored in glass or polypropylene bottles or in plastic (polypropylene or polyolefin) bags and administered through polyethylene-lined administration sets.1,11,12,20,45 Leaching of unacceptable amounts of DEHP has been reported with some administration sets labeled as not containing PVC (probably because of pumping segments made of heavily plasticized PVC);195 therefore, compatibility of administration sets with paclitaxel solutions should be verified prior to their use.189 (See Chemistry and Stability: Stability.)

Because a small number of fibers (within acceptable USP limits) have been detected in paclitaxel solutions prepared from the commercially available for injection concentrate,7,20,45 a hydrophilic, microporous inline filter with a pore size not exceeding 0.22 µm is necessary during administration of paclitaxel solutions.1,7,20,45 The manufacturer reports that 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 (See Chemistry and Stability: Stability.) The Chemo Dispensing Pin^® device or similar devices with spikes should not be used with vials of paclitaxel; this type of device can cause the stopper to collapse and contaminate the paclitaxel solution.1

Albumin-bound Paclitaxel

Albumin-bound paclitaxel in the form of lyophilized powder must be reconstituted to an injectable suspension prior to IV infusion.354 Using aseptic technique, 20 mL of 0.9% sodium chloride injection should be injected slowly (over a minimum period of 1 minute) into the vial containing the lyophilized paclitaxel.354 The flow from the sterile syringe should be injected onto the inside wall of the vial; injection of 0.9% sodium chloride injection directly onto the lyophilized cake should be avoided because it causes foaming.354 Once injection of the 20 mL of 0.9% sodium chloride injection into the vial is complete, the vial should be allowed to sit for a minimum of 5 minutes to ensure thorough wetting of the lyophilized cake/powder.354 The vial then should be swirled and/or inverted gently for at least 2 minutes until the cake/powder is completely dissolved; foaming should be avoided.354 If foaming or clumping occurs, the reconstituted paclitaxel suspension should be allowed to stand for at least 15 minutes until foam subsides.354

The reconstituted suspension has a final paclitaxel concentration of 5 mg/mL.354 The exact dosing volume of the injectable suspension should be calculated using the following formula: dosing volume in mL equals total dose in mg divided by 5 mg/mL.354 Before the dosing volume is withdrawn from the vial, the suspension should be inspected.354 The reconstituted paclitaxel suspension should appear milky and homogeneous with no visible particulates.354 If particulates are visible or settling has occurred, the vial should be inverted gently to ensure complete resuspension of the particles in solution.354 Then the appropriate dosing volume of paclitaxel suspension should be withdrawn from the vial and injected into an empty sterile PVC IV bag.354 Unlike conventional paclitaxel, DEHP-free containers or administration sets are not required for the preparation or administration of albumin-bound paclitaxel suspension.354 Unlike conventional paclitaxel, the use of an inline filter is not recommended for the IV infusion of albumin-bound paclitaxel suspension.354

The injection site should be monitored closely during the infusion for possible infiltration of the drug.354 According to the manufacturer, limiting the infusion of albumin-bound paclitaxel to 30 minutes as directed reduces the likelihood of infusion-related reactions.354

Intraperitoneal Instillation

Conventional Paclitaxel

For intraperitoneal† administration in the Gynecologic Oncology Group (GOG)-172 study in patients with advanced epithelial ovarian cancer, the paclitaxel 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 an additional liter of warmed saline solution.344,10005 Following peritoneal infusion, the 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

Various implanted access ports and connecting catheters have been used for intraperitoneal administration of chemotherapeutic agents.10017 The intraperitoneal catheter may be placed at the time of primary (cytoreductive) surgery as long as contamination of the peritoneal cavity has not occurred.344,10017 Timing of placement of the intraperitoneal catheter (at the time of primary surgery versus delayed insertion) does not appear to affect tolerance of intraperitoneal therapy or treatment completion rates.344,10017 The intraperitoneal catheter should be removed as soon as intraperitoneal therapy is completed to avoid catheter-related complications.344,10011 Further study is needed to optimize techniques for intraperitoneal therapy to minimize the risk of complications (e.g., infection, catheter obstruction, catheter retraction, bowel perforation, pain, leakage, port access problems).344,345,10005,10017 Specialized sources should be consulted for guidance on how to administer intraperitoneal therapy.345,10005

Supportive therapy should include premedication to prevent hypersensitivity reactions to paclitaxel.344,10005

Dosage

Paclitaxel is commercially available in 2 types of formulations: conventional paclitaxel (in a nonaqueous solution)1 and albumin-bound paclitaxel.354 The functional properties of paclitaxel may differ according to formulation, and the dosage instructions for paclitaxel are specific to formulation.354 Albumin-bound paclitaxel may not be substituted for or used in combination with other formulations of paclitaxel.354 Clinicians should consult the respective 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

Dosage of albumin-bound paclitaxel is expressed in terms of paclitaxel.

Conventional or albumin-bound paclitaxel should not be administered to patients with baseline neutrophil counts less than 1500/mm³.1,354 In patients with HIV infection, conventional paclitaxel should not be administered if baseline neutrophil counts are less than 1000/mm³.1 To monitor the occurrence of paclitaxel-induced bone marrow suppression, mainly neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed in all patients receiving paclitaxel.1,354

Conventional Paclitaxel

All patients should be premedicated before administration of conventional paclitaxel to prevent severe hypersensitivity reactions.1,21,22

For patients receiving paclitaxel for the treatment of solid tumors, the manufacturer recommends the following premedication regimen: oral dexamethasone 20 mg administered approximately 12 and 6 hours before paclitaxel; IV diphenhydramine hydrochloride (or similar antihistamine) 50 mg administered 30-60 minutes before paclitaxel; and either IV cimetidine hydrochloride (300 mg of cimetidine) or ranitidine hydrochloride (50 mg of ranitidine) administered 30-60 minutes before paclitaxel.1,22

For patients with HIV infection who are receiving conventional paclitaxel for the treatment of AIDS-related Kaposi's sarcoma, the manufacturer recommends the following premedication regimen: oral dexamethasone 10 mg administered approximately 12 and 6 hours before paclitaxel; IV diphenhydramine hydrochloride (or similar antihistamine) 50 mg administered 30-60 minutes before paclitaxel; and either IV cimetidine hydrochloride (300 mg of cimetidine) or ranitidine hydrochloride (50 mg of ranitidine) administered 30-60 minutes before paclitaxel.1,22 This is the same premedication regimen as for other patients receiving paclitaxel with the exception of a reduced dose of oral dexamethasone (10 mg).1

Concomitant administration of filgrastim is used to reduce the severity of myelosuppression in patients receiving paclitaxel therapy, particularly those who are at high risk for febrile neutropenia.1 Because of immunosuppression in patients with advanced HIV disease, the manufacturer recommends concomitant administration of a granulocyte colony-stimulating factor (e.g., filgrastim) as clinically indicated to reduce the severity of myelosuppression associated with paclitaxel in patients with AIDS-related Kaposi's sarcoma.1

Albumin-bound Paclitaxel

Unlike conventional paclitaxel, which requires premedication prior to administration to prevent severe hypersensitivity reactions, premedication generally is not required prior to administration of albumin-bound paclitaxel.354 However, premedication may be necessary in patients who experienced a hypersensitivity reaction during a previous course of therapy with the drug.354

Ovarian Cancer

Conventional Paclitaxel as First-line Therapy for Advanced Ovarian Epithelial Cancer

When used in combination therapy with cisplatin for the initial treatment of advanced ovarian cancer, there are 2 recommended paclitaxel-containing regimens.1 Differences in toxicity should be considered when selecting the appropriate regimen for a patient.1 One recommended regimen is conventional paclitaxel 175 mg/m² administered by 3-hour IV infusion followed by cisplatin 75 mg/m² IV with cycles repeated every 3 weeks.1 Another recommended regimen is conventional paclitaxel 135 mg/m² administered by 24-hour IV infusion followed by cisplatin 75 mg/m² IV with cycles repeated every 3 weeks.1

Intraperitoneal Conventional Paclitaxel and Cisplatin as First-line Therapy for Advanced Ovarian Epithelial Cancer

When combined therapy with IV and intraperitoneal conventional paclitaxel and intraperitoneal cisplatin† has been used for the initial adjuvant treatment of optimally debulked stage III epithelial ovarian cancer, 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 IV and intraperitoneal regimens are being investigated.10008,10012,10013,10014 (See Uses: Ovarian Cancer.)

Conventional Paclitaxel as Second-line or Subsequent Therapy for Advanced Ovarian Epithelial Cancer

When used as monotherapy in patients with metastatic carcinoma of the ovary that failed to respond to first-line or subsequent chemotherapy, the recommended regimen is conventional paclitaxel 135 or 175 mg/m² infused IV over 3 hours and repeated every 3 weeks as tolerated.1 Optimal dosage of paclitaxel has not been established in this patient population.1

Breast Cancer

Conventional Paclitaxel as Adjuvant Therapy for Node-positive Breast Cancer

For the adjuvant therapy of node-positive breast cancer, conventional paclitaxel 175 mg/m² is administered as a 3-hour IV infusion once every 3 weeks for 4 courses following the completion of doxorubicin-containing combination chemotherapy.1 In a large randomized trial on which this indication is based, patients received 4 courses of doxorubicin and cyclophosphamide followed by adjuvant therapy with paclitaxel.1,304

Conventional or Albumin-bound Paclitaxel as Second-line Therapy for Advanced Breast Cancer

For metastatic breast cancer that is refractory to initial chemotherapy or breast cancer that has relapsed within 6 months of adjuvant therapy, conventional paclitaxel 175 mg/m² is administered as a 3-hour IV infusion once every 3 weeks.1

For metastatic breast cancer that is refractory to combination chemotherapy or breast cancer that has relapsed within 6 months of adjuvant therapy, albumin-bound paclitaxel 260 mg/m² is administered as a 30-minute IV infusion once every 3 weeks.354

Non-small Cell Lung Cancer

Conventional Paclitaxel and Cisplatin

When used in combination therapy with cisplatin for the initial treatment of advanced non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy, the recommended regimen is conventional paclitaxel 135 mg/m² administered by 24-hour IV infusion followed by cisplatin 75 mg/m² IV with cycles repeated every 3 weeks.1,254 A regimen of conventional paclitaxel 175 mg/m² administered by 3-hour IV infusion followed by cisplatin 80 mg/m² IV with cycles repeated every 3 weeks also has been used in patients with advanced non-small cell lung cancer.234

Albumin-bound Paclitaxel and Carboplatin

When used in combination therapy with carboplatin for the initial treatment of advanced non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy, the recommended regimen is albumin-bound paclitaxel 100 mg/m² administered by 30-minute IV infusion on days 1, 8, and 15 and IV carboplatin at the dose required to obtain an area under the concentration-time curve (AUC) of 6 mg/mL per minute on day 1 of each 21-day cycle.354

AIDS-related Kaposi's Sarcoma

Conventional Paclitaxel

For patients with advanced HIV infection, paclitaxel therapy should be initiated only if the neutrophil count is at least 1000/mm³.1

For patients with AIDS-related Kaposi's sarcoma that has failed to respond to first-line or subsequent chemotherapy, there are 2 recommended paclitaxel regimens.1 One recommended regimen is conventional paclitaxel 135 mg/m² administered by 3-hour IV infusion once every 3 weeks.1 Another recommended regimen is conventional paclitaxel 100 mg/m² administered by 3-hour IV infusion once every 2 weeks.1 Both of these regimens achieve a dose intensity of 45-50 mg/m² per week.1 In phase II studies, greater toxicity was observed with the higher-dose schedule, and patients with poor performance status were treated with paclitaxel 100 mg/m² once every 2 weeks.1

Pancreatic Cancer

Albumin-bound Paclitaxel and Gemcitabine

When used in combination therapy with gemcitabine for the initial treatment of metastatic adenocarcinoma of the pancreas, the recommended regimen is albumin-bound paclitaxel 125 mg/m² administered IV over 30-40 minutes followed by gemcitabine 1 g/m² administered IV over 30-40 minutes on days 1, 8, and 15 of each 28-day cycle.354

Dosage Modification for Toxicity and Contraindications for Continued Therapy with Conventional Paclitaxel

Hematologic Toxicity

For patients receiving conventional paclitaxel, repeat cycles of the drug should be withheld until platelet counts exceed 100,000/mm³ and neutrophil counts are at least 1500/mm³ in patients with solid tumors or are at least 1000/mm³ in patients with advanced AIDS-related Kaposi's sarcoma.1

For patients receiving conventional paclitaxel who experience severe neutropenia (neutrophil count less than 500/mm³ for at least 7 days), a 20% reduction in the dose of conventional paclitaxel is recommended for subsequent courses of therapy.1

The incidence and severity of hematologic toxicity (i.e., neutropenia) have been shown to increase with dose and duration of infusion for conventional paclitaxel.1 The use of supportive therapy, such as G-CSF, with administration of conventional paclitaxel is recommended for patients who have experienced severe neutropenia.1

Sensitivity Reactions

Mild symptoms (e.g., flushing, skin reactions, dyspnea, hypotension, tachycardia) do not require interruption of therapy.1 If signs or symptoms of a severe reaction (e.g., hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, generalized urticaria) occur during administration of paclitaxel, the infusion should be discontinued immediately and aggressive symptomatic therapy instituted as necessary.1 Such therapy may include epinephrine, IV fluids, and additional doses of antihistamine (e.g., diphenhydramine) and corticosteroid as clinically indicated.20,21,23,64

Further therapy with conventional paclitaxel should not be undertaken in any patient who experienced a severe hypersensitivity reaction during a previous course of therapy with the drug.1 It is not known whether patients who have exhibited hypersensitivity to conventional paclitaxel can tolerate subsequent therapy with albumin-bound paclitaxel.354

Hepatic Toxicity

In patients with preexisting hepatic impairment, dose reduction is recommended depending on the degree of hepatic impairment for the first course of therapy with conventional paclitaxel.1 Further dose reduction may be required during subsequent courses of paclitaxel therapy based on hepatic toxicity.1 (See Dosage of Conventional Paclitaxel in Hepatic Impairment under Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Cardiovascular Toxicity

If a patient develops substantial conduction abnormalities during administration of paclitaxel, appropriate therapy should be initiated and continuous cardiac monitoring should be performed during subsequent therapy with the drug.1,25 Paclitaxel infusions occasionally must be interrupted or discontinued because of initial or recurrent hypertension.1,74

Neurologic Toxicity

For patients who experience severe peripheral neuropathy while receiving conventional paclitaxel, the manufacturer recommends a 20% reduction in the dose for subsequent courses of therapy.1 The incidence and severity of neurotoxicity increase with paclitaxel dose.1

Dosage Modification for Toxicity and Contraindications for Continued Therapy with Albumin-bound Paclitaxel for Breast Cancer

Hematologic Toxicity

For patients receiving albumin-bound paclitaxel, repeat cycles of the drug should be withheld until neutrophil counts exceed 1500/mm³ and platelet counts exceed 100,000/mm³.354

For patients who experience severe neutropenia (neutrophil count less than 500/mm³ for at least 7 days) while receiving albumin-bound paclitaxel for breast cancer, the manufacturer recommends a reduction in dose to albumin-bound paclitaxel 220 mg/m² for subsequent courses of therapy.354 For patients who experience recurrence of severe neutropenia, further reduction in dose to albumin-bound paclitaxel 180 mg/m² is recommended.354

Sensitivity Reactions

Further therapy with paclitaxel should not be undertaken in any patient who experienced a severe hypersensitivity reaction during a previous course of therapy with the drug.354 It is not known whether patients who have exhibited hypersensitivity to conventional paclitaxel can tolerate subsequent therapy with albumin-bound paclitaxel.354

Hepatic Toxicity

In patients with preexisting hepatic impairment, dose reduction is recommended depending on the degree of hepatic impairment for the first course of therapy with albumin-bound paclitaxel.354 Further dose reduction may be required during subsequent courses of albumin-bound paclitaxel therapy based on hepatic toxicity.354 (See Dosage of Albumin-bound Paclitaxel in Hepatic Impairment under Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Neurologic Toxicity

Sensory neuropathy associated with albumin-bound paclitaxel is dose and schedule dependent.354 In patients with breast cancer, the incidence and severity of sensory neuropathy associated with albumin-bound paclitaxel increased with cumulative dose of the drug.354

For patients who experience grade 1 or 2 sensory neuropathy while receiving albumin-bound paclitaxel, dosage modification generally is not required.354

For patients with breast cancer who experience severe sensory neuropathy while receiving albumin-bound paclitaxel, treatment should be withheld until resolution to grade 1 or 2 severity followed by reduction in dose to albumin-bound paclitaxel 220 mg/m² for subsequent courses of therapy.354 For patients who experience recurrence of severe sensory neuropathy, treatment should be withheld until resolution to grade 1 or 2 severity followed by further reduction in dose to albumin-bound paclitaxel 180 mg/m² for subsequent courses of therapy.354

Dosage Modification for Toxicity and Contraindications for Continued Therapy with Albumin-bound Paclitaxel for Non-small Cell Lung Cancer

Hematologic Toxicity

For patients receiving albumin-bound paclitaxel, repeat cycles of the drug should be withheld until neutrophil counts are at least 1500/mm³ and platelet counts are at least 100,000/mm³.354

For patients who experience severe neutropenia (neutrophil count less than 500/mm³ for at least 7 days) or thrombocytopenia (platelet count less than 50,000/mm³) while receiving albumin-bound paclitaxel for non-small cell lung cancer, the manufacturer recommends dose reduction upon resumption of therapy.354

For patients with non-small cell lung cancer who experience severe neutropenia or febrile neutropenia (neutrophil count less than 500/mm³ with fever exceeding 38°C) while receiving albumin-bound paclitaxel and carboplatin, treatment should be delayed until neutrophil counts are at least 1500/mm³ on day 1 or at least 500/mm³ on day 8 or 15 of the cycle; treatment may then be resumed at a permanently reduced dose of albumin-bound paclitaxel 75 mg/m² and a target carboplatin AUC of 4.5 mg/mL per minute.354 Following a second episode of severe neutropenia or febrile neutropenia, treatment should again be delayed; treatment may be resumed at a permanently reduced dose of albumin-bound paclitaxel 50 mg/m² and a target carboplatin AUC of 3 mg/mL per minute.354 Albumin-bound paclitaxel and carboplatin should be discontinued following a third episode of severe neutropenia or febrile neutropenia.354

If initiation of a repeat cycle of therapy for non-small cell lung cancer is delayed by more than 7 days because the patient's neutrophil count is less than 1500/mm³, permanent dose reduction of albumin-bound paclitaxel to 75 mg/m² and a target carboplatin AUC of 4.5 mg/mL per minute is recommended.354 Following a second such treatment delay, permanent dose reduction of albumin-bound paclitaxel to 50 mg/m² and a target carboplatin AUC of 3 mg/mL per minute is recommended.354 Albumin-bound paclitaxel and carboplatin should be discontinued following a third such delay.354

For patients with non-small cell lung cancer who experience severe thrombocytopenia while receiving albumin-bound paclitaxel and carboplatin, treatment should be delayed until platelet counts are at least 100,000/mm³ on day 1 or at least 50,000/mm³ on day 8 or 15 of the cycle; treatment may then be resumed at a permanently reduced dose of albumin-bound paclitaxel 75 mg/m² and a target carboplatin AUC of 4.5 mg/mL per minute.354 Albumin-bound paclitaxel and carboplatin should be discontinued following a second episode of severe thrombocytopenia.354

Sensitivity Reactions

Further therapy with paclitaxel should not be undertaken in any patient who experienced a severe hypersensitivity reaction during a previous course of therapy with the drug.354 It is not known whether patients who have exhibited hypersensitivity to conventional paclitaxel can tolerate subsequent therapy with albumin-bound paclitaxel.354

Hepatic Toxicity

In patients with preexisting hepatic impairment, dose reduction is recommended depending on the degree of hepatic impairment for the first course of therapy with albumin-bound paclitaxel.354 Further dose reduction may be required during subsequent courses of albumin-bound paclitaxel therapy based on hepatic toxicity.354 (See Dosage of Albumin-bound Paclitaxel in Hepatic Impairment under Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Neurologic Toxicity

Sensory neuropathy associated with albumin-bound paclitaxel is dose and schedule dependent.354

For patients who experience grade 1 or 2 peripheral neuropathy while receiving albumin-bound paclitaxel, dosage modification generally is not required.354

For patients with non-small cell lung cancer who experience grade 3 or 4 peripheral neuropathy while receiving albumin-bound paclitaxel and carboplatin, treatment should be withheld until resolution to grade 1 or less followed by a permanent reduction in dose to albumin-bound paclitaxel 75 mg/m² and a target carboplatin AUC of 4.5 mg/mL per minute.354 Following a second episode of grade 3 or 4 peripheral neuropathy, treatment should again be withheld until resolution to grade 1 or less; treatment may then be resumed at a permanently reduced dose of albumin-bound paclitaxel 50 mg/m² and a target carboplatin AUC of 3 mg/mL per minute.354 Albumin-bound paclitaxel and carboplatin should be discontinued following a third episode of grade 3 or 4 peripheral neuropathy.354

Dosage Modification for Toxicity and Contraindications for Continued Therapy with Albumin-bound Paclitaxel for Pancreatic Cancer

When dosage modification is necessary for patients receiving albumin-bound paclitaxel and gemcitabine for pancreatic cancer, dosage of albumin-bound paclitaxel should be reduced in decrements of 25 mg/m² (i.e., 1 dose level) and dosage of gemcitabine should be reduced in decrements of 200 mg/m² (i.e., 1 dose level); however, if a dose of albumin-bound paclitaxel 75 mg/m² or gemcitabine 600 mg/m² requires further reduction, both drugs should be discontinued.354

Hematologic Toxicity

For patients receiving albumin-bound paclitaxel, repeat cycles of the drug should be withheld until neutrophil counts are at least 1500/mm³ and platelet counts are at least 100,000/mm³.354 See Table 1 for recommended dosage modifications for hematologic toxicity occurring either within a cycle or at the start of a repeat cycle of albumin-bound paclitaxel and gemcitabine therapy in patients with pancreatic cancer.

For patients with pancreatic cancer who experience grade 3 or 4 febrile neutropenia while receiving albumin-bound paclitaxel and gemcitabine, therapy should be withheld until fever resolves and neutrophil count reaches or exceeds 1500/mm³; albumin-bound paclitaxel and gemcitabine may then be resumed at 1 dose level lower than the previous dosage.354

Sensitivity Reactions

Further therapy with paclitaxel should not be undertaken in any patient who experienced a severe hypersensitivity reaction during a previous course of therapy with the drug.354 It is not known whether patients who have exhibited hypersensitivity to conventional paclitaxel can tolerate subsequent therapy with albumin-bound paclitaxel.354

Hepatic Toxicity

In patients with preexisting hepatic impairment, dose reduction is recommended depending on the degree of hepatic impairment for the first course of therapy with albumin-bound paclitaxel.354 Further dose reduction may be required during subsequent courses of albumin-bound paclitaxel therapy based on hepatic toxicity.354 (See Dosage of Albumin-bound Paclitaxel in Hepatic Impairment under Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Neurologic Toxicity

Sensory neuropathy associated with albumin-bound paclitaxel is dose and schedule dependent.354

For patients who experience grade 1 or 2 peripheral neuropathy while receiving albumin-bound paclitaxel, dosage modification generally is not required.354

For patients with pancreatic cancer who experience grade 3 or 4 peripheral neuropathy while receiving albumin-bound paclitaxel and gemcitabine, treatment with albumin-bound paclitaxel should be withheld until resolution to grade 1 or less; the drug may then be resumed at 1 dose level lower than the previous dosage.354 No modification of gemcitabine dosage is required.354

Dermatologic Toxicity

For patients with pancreatic cancer who experience grade 2 or 3 cutaneous toxicity while receiving albumin-bound paclitaxel and gemcitabine, the dose of albumin-bound paclitaxel and gemcitabine should be reduced by 1 dose level.354 If cutaneous toxicity persists, treatment should be discontinued.354

GI Toxicity

For patients with pancreatic cancer who experience grade 3 mucositis or diarrhea while receiving albumin-bound paclitaxel and gemcitabine, treatment should be withheld until resolution to grade 1 or less; albumin-bound paclitaxel and gemcitabine may then be resumed at 1 dose level lower than the previous dosage.354

Pulmonary Toxicity

For patients with pancreatic cancer who develop signs and symptoms of pneumonitis while receiving albumin-bound paclitaxel and gemcitabine, therapy should be interrupted during evaluation of suspected pneumonitis.354 Albumin-bound paclitaxel and gemcitabine should be permanently discontinued in patients diagnosed with pneumonitis.354

Dosage in Renal and Hepatic Impairment

The effect of renal impairment on the disposition of paclitaxel has not been fully established.1,20,23,354 Reduction of paclitaxel dosage in patients with impaired renal function does not appear to be necessary.20,23,124

Paclitaxel is metabolized mainly in the liver, and increased toxicity may occur in patients with hepatic impairment.1,354

Dosage of Conventional Paclitaxel in Hepatic Impairment

Toxicity associated with paclitaxel, particularly grade 3 or 4 myelosuppression, may be exacerbated in patients with serum total bilirubin concentrations greater than 2 times the upper limit of normal.1 Paclitaxel should be used with extreme caution in patients with hepatic impairment, and dosage reduction is recommended depending on the degree of hepatic impairment.1,362 Such patients should be monitored closely for the development of profound myelosuppression.1

For patients receiving conventional paclitaxel as a 24-hour IV infusion for ovarian or non-small cell lung cancer, the usual dose of 135 mg/m² may be administered for the first course of therapy in those who have serum transaminase concentrations less than 2 times the upper limit of normal and serum bilirubin concentrations up to 1.5 mg/dL; for patients with elevated serum transaminase concentrations less than 10 times the upper limit of normal and serum bilirubin concentrations up to 1.5 mg/dL, a reduced dose of paclitaxel 100 mg/m² is recommended; for patients with elevated serum transaminase concentrations less than 10 times the upper limit of normal and serum bilirubin concentrations of 1.6-7.5 mg/dL, a reduced dose of paclitaxel 50 mg/m² is recommended.1 For patients with elevated serum transaminase concentrations at least 10 times the upper limit of normal or serum bilirubin concentrations exceeding 7.5 mg/dL, paclitaxel therapy is not recommended.1

For patients receiving conventional paclitaxel as a 3-hour IV infusion for ovarian or breast cancer, the usual dose of 175 mg/m² may be administered for the first course of therapy in those who have serum transaminase concentrations less than 10 times the upper limit of normal and serum bilirubin concentrations up to 1.25 times the upper limit of normal; for patients with serum transaminase concentrations less than 10 times the upper limit of normal and serum bilirubin concentrations of 1.26-2 times the upper limit of normal, a reduced dose of paclitaxel 135 mg/m² is recommended; for patients with serum transaminase concentrations less than 10 times the upper limit of normal and serum bilirubin concentrations of 2.01-5 times the upper limit of normal, a reduced dose of paclitaxel 90 mg/m² is recommended.1 For patients with elevated serum transaminase concentrations at least 10 times the upper limit of normal or serum bilirubin concentrations exceeding 5 times the upper limit of normal, paclitaxel therapy is not recommended.1

Further reduction of paclitaxel dosage for subsequent courses of therapy should be based on patient tolerance.1

Dosage of Albumin-bound Paclitaxel in Hepatic Impairment

Patients should be monitored closely since toxicity associated with paclitaxel may be exacerbated in patients with hepatic impairment.354 Paclitaxel should be used with caution in patients with hepatic impairment, and dosage reduction is recommended depending on the degree of hepatic impairment.354 No adjustment of the initial dosage is required in patients with mild hepatic impairment.354

Breast Cancer

For patients receiving albumin-bound paclitaxel for breast cancer, the usual dose of 260 mg/m² may be administered for the first course of therapy in those who have mild hepatic impairment (AST concentrations less than 10 times the upper limit of normal and elevated serum bilirubin concentrations up to 1.25 times the upper limit of normal).354

For patients with moderate hepatic impairment (AST concentrations less than 10 times the upper limit of normal and serum bilirubin concentrations of 1.26-2 times the upper limit of normal), a reduced initial dose of albumin-bound paclitaxel 200 mg/m² is recommended.354 For patients with severe hepatic impairment (AST concentrations less than 10 times the upper limit of normal and serum bilirubin concentrations of 2.01-5 times the upper limit of normal), a reduced initial dose of albumin-bound paclitaxel 130 mg/m² is recommended.354 If the 130-mg/m² dose of albumin-bound paclitaxel is tolerated, the dose may be increased to 200 mg/m² in subsequent cycles.354 For patients with serum AST concentrations exceeding 10 times the upper limit of normal or serum bilirubin concentrations exceeding 5 times the upper limit of normal, albumin-bound paclitaxel therapy is not recommended.354 Further reduction of albumin-bound paclitaxel dosage for subsequent courses of therapy should be based on patient tolerance.354

Non-small Cell Lung Cancer

For patients receiving albumin-bound paclitaxel for non-small cell lung cancer, the usual dose of 100 mg/m² may be administered for the first course of therapy in those who have mild hepatic impairment (AST concentrations less than 10 times the upper limit of normal and elevated serum bilirubin concentrations up to 1.25 times the upper limit of normal).354

For patients with moderate hepatic impairment (AST concentrations less than 10 times the upper limit of normal and serum bilirubin concentrations of 1.26-2 times the upper limit of normal), a reduced initial dose of albumin-bound paclitaxel 75 mg/m² is recommended.354 For patients with severe hepatic impairment (AST concentrations less than 10 times the upper limit of normal and serum bilirubin concentrations of 2.01-5 times the upper limit of normal), a reduced initial dose of albumin-bound paclitaxel 50 mg/m² is recommended.354 If the 50-mg/m² dose of albumin-bound paclitaxel is tolerated, the dose may be increased to 75 mg/m² in subsequent cycles.354 For patients with serum AST concentrations exceeding 10 times the upper limit of normal or serum bilirubin concentrations exceeding 5 times the upper limit of normal, albumin-bound paclitaxel therapy is not recommended.354 Patients with serum bilirubin concentrations exceeding the upper limit of normal were excluded from clinical studies evaluating use of the drug in non-small cell lung cancer.354 Further reduction of albumin-bound paclitaxel dosage for subsequent courses of therapy should be based on patient tolerance.354

Pancreatic Cancer

For patients receiving albumin-bound paclitaxel for pancreatic cancer, the usual dose of 125 mg/m² may be administered for the first course of therapy in those who have mild hepatic impairment (AST concentrations less than 10 times the upper limit of normal and elevated serum bilirubin concentrations up to 1.25 times the upper limit of normal).354 For patients with AST concentrations less than 10 times the upper limit of normal and serum bilirubin concentrations of 1.26-5 times the upper limit of normal, AST concentrations exceeding 10 times the upper limit of normal, or serum bilirubin concentrations exceeding 5 times the upper limit of normal, albumin-bound paclitaxel therapy is not recommended.354 Patients with serum bilirubin concentrations exceeding the upper limit of normal were excluded from clinical studies evaluating use of the drug in pancreatic cancer.354 Further reduction of albumin-bound paclitaxel dosage for subsequent courses of therapy should be based on patient tolerance.354

Hematologic Effects and Infectious Complications

The major and dose-limiting adverse effect of paclitaxel is bone marrow suppression, manifested by neutropenia, leukopenia, thrombocytopenia, and anemia.1,22,25,26,28,29,184,354 The frequency and severity of hematologic toxicity increase with higher dose,1,184,354 especially at conventional paclitaxel doses exceeding 190 mg/m².35,64 Paclitaxel-induced neutropenia does not appear to increase with cumulative exposure and does not appear to be more frequent or more severe in patients who have received prior radiation therapy.1 In clinical studies, myelosuppression was more profound when paclitaxel was given after cisplatin rather than with the alternative sequence (i.e., paclitaxel before cisplatin), apparently because plasma clearance of paclitaxel was decreased by approximately 33% when the drugs were administered in this sequence.1,25

Neutropenia and Leukopenia

Paclitaxel-induced neutropenia, which is dose and schedule dependent, generally is rapidly reversible.1,25,26,28,29,184,354

Conventional Paclitaxel

Neutropenia (neutrophil count less than 2000/mm³) occurred in 90% of patients with ovarian or breast cancer and in 95-100% of patients with AIDS-related Kaposi's sarcoma receiving paclitaxel as a single agent in clinical trials.1 Severe neutropenia (neutrophil count less than 500/mm³) occurred in 52% of patients during paclitaxel monotherapy for ovarian or breast cancer.1 In a phase III clinical trial of patients with metastatic ovarian cancer receiving subsequent therapy with paclitaxel alone at a dose of 135 or 175 mg/m² administered as an infusion over 3 hours, severe neutropenia occurred in 14 or 27%, respectively.1 In patients with AIDS-related Kaposi's sarcoma receiving paclitaxel 100 or 135 mg/m² by 3-hour IV infusion, severe neutropenia occurred in 35 or 76%, respectively.1

In a randomized trial in patients receiving initial treatment for advanced ovarian cancer, grade 4 neutropenia occurred in 81%, and febrile neutropenia occurred in 15%, of patients receiving paclitaxel 135 mg/m² by 24-hour IV infusion followed by cisplatin; episodes of fever associated with grade 4 neutropenia were reported in approximately 3% of courses.1 In another randomized trial in patients receiving initial treatment for advanced ovarian cancer, grade 4 neutropenia occurred in 33%, and febrile neutropenia occurred in 4%, of patients receiving paclitaxel 175 mg/m² by 3-hour IV infusion followed by cisplatin.1 In patients with node-positive breast cancer receiving cyclophosphamide and doxorubicin followed by paclitaxel, grade 4 neutropenia was reported in 76% of patients but it occurred during the period of paclitaxel therapy in only 15% of patients.1 In patients with non-small cell lung cancer receiving initial treatment with paclitaxel 135 mg/m² by 24-hour IV infusion followed by cisplatin, neutropenia occurred in 89% of patients and was severe in 74% of patients.1

The onset of neutropenia usually occurs by 8-10 days3,25 and neutrophil nadirs generally occur at a median of 10-12 days following paclitaxel administration;1,25 neutrophil counts commonly recover by 15-21 days after administration.3,25 Subsequent paclitaxel courses of therapy generally do not result in lower neutrophil nadirs than the initial course, suggesting that the drug may not be irreversibly toxic to stem cells.3,28,29 Some data suggest that the addition of filgrastim to paclitaxel therapy may reduce the duration and severity of neutropenia and/or allow dose intensification.26,27,184 There also is some evidence that shorter paclitaxel infusion times (e.g., 3 hours) may result in a lower frequency and severity of neutropenia.20,24,184,198 In a phase III trial of subsequent therapy for patients with metastatic ovarian cancer, neutropenia, including severe neutropenia, occurred more frequently in patients receiving paclitaxel doses by 24-hour infusion than in those receiving the drug by 3-hour infusion; duration of infusion had a greater effect on paclitaxel-induced myelosuppression than did the amount of dose (135 versus 175 mg/m²).1

Leukopenia (less than 4000/mm³) occurred in 90% of patients with ovarian or breast cancer receiving paclitaxel as a single agent in clinical trials and was severe (less than 1000/mm³) in 17% of patients.1

Albumin-bound Paclitaxel

Neutropenia (neutrophil count less than 2000/mm³) occurred in 80%, severe neutropenia (neutrophil count less than 500/mm³) occurred in 9%, and febrile neutropenia occurred in 2% of patients receiving albumin-bound paclitaxel for metastatic breast cancer.354 In a phase III clinical trial of patients with advanced non-small cell lung cancer receiving therapy with albumin-bound paclitaxel 100 mg/m² by 30-minute IV infusion in combination with carboplatin, grade 3 or 4 neutropenia occurred in 47% of patients.354,358 In patients with metastatic pancreatic cancer receiving albumin-bound paclitaxel 125 mg/m² by 30- to 40-minute IV infusion in combination with gemcitabine, grade 3 or 4 neutropenia occurred in 38% of patients.354

Infectious Complications

Conventional Paclitaxel

Fever was associated with 12% of all paclitaxel treatment courses in patients with solid tumors receiving the drug as a single agent.1 Among patients receiving paclitaxel monotherapy for ovarian or breast cancer, at least one episode of infection was reported in 30% of patients, and 9% of all treatment courses were associated with an infectious episode.1 These infectious episodes, including sepsis, pneumonia, and peritonitis, were fatal in 1% of all patients.1 In a phase III trial of paclitaxel as subsequent therapy for patients with metastatic ovarian cancer, infectious episodes occurred in 20 or 26% of patients receiving paclitaxel 135 or 175 mg/m², respectively, by 3-hour infusion.1 Urinary and respiratory tract infections were the most frequently reported infectious complications.1

In patients with node-positive breast cancer receiving cyclophosphamide and doxorubicin followed by paclitaxel, severe infection was reported in 14% of patients.1 In patients with non-small cell lung cancer receiving initial treatment with paclitaxel 135 mg/m² by 24-hour IV infusion followed by cisplatin, infections occurred in 38% of patients.1

Among patients receiving paclitaxel for AIDS-related Kaposi's sarcoma, at least one episode of opportunistic infection was reported in 61% of patients.1 In patients with AIDS-related Kaposi's sarcoma, febrile neutropenia (neutrophil count less than 500/mm³ with fever exceeding 38°C and IV anti-infectives and/or hospitalization required) occurred in 55% of patients receiving paclitaxel 135 mg/m² and in 9% of those receiving paclitaxel 100 mg/m².1

Albumin-bound Paclitaxel

Infection was reported in 24% of patients receiving albumin-bound paclitaxel for metastatic breast cancer.354 Oral candidiasis, respiratory tract infections, and pneumonia were the most frequently reported infectious complications.354 In patients with metastatic breast cancer, febrile neutropenia occurred in 2% of patients receiving albumin-bound paclitaxel as a single agent.354

Among patients receiving albumin-bound paclitaxel combined with gemcitabine for pancreatic cancer, pyrexia was reported in 41% of patients and urinary tract infections were reported in 11% of patients.354 Other infections reported in less than 10% of patients were oral candidiasis and pneumonia.354 In patients with pancreatic cancer, sepsis (irrespective of neutrophil count) occurred in 5% of patients receiving albumin-bound paclitaxel combined with gemcitabine; biliary obstruction or the presence of a biliary stent appear to be risk factors for sepsis.354

Thrombocytopenia

Conventional Paclitaxel

Thrombocytopenia (platelet count less than 100,000/mm³) developed less frequently than neutropenia,1,25,28,29 with at least one episode occurring in 20% of patients with ovarian or breast cancer receiving paclitaxel alone as subsequent therapy in clinical trials, and was severe (platelet count less than 50,000/mm³) in 7% of patients.1 In patients with AIDS-related Kaposi's sarcoma receiving paclitaxel 135 or 100 mg/m², thrombocytopenia occurred in 52 or 27% of patients, and was severe in 17 or 5%, respectively.1

In randomized trials for the initial treatment of advanced ovarian cancer, thrombocytopenia (platelet count less than 130,000/mm³) was reported in 21% of patients receiving paclitaxel 175 mg/m² by 3-hour IV infusion followed by cisplatin, and thrombocytopenia (platelet count less than 100,000/mm³) was reported in 26% of patients receiving paclitaxel 135 mg/m² by 24-hour IV infusion followed by cisplatin.1 In patients with node-positive breast cancer receiving cyclophosphamide and doxorubicin followed by paclitaxel, severe thrombocytopenia (platelet count less than 50,000/mm³) was reported in 25% of patients.1 In patients with non-small cell lung cancer receiving initial treatment with paclitaxel 135 mg/m² by 24-hour IV infusion followed by cisplatin, thrombocytopenia occurred in 48% of patients and was severe (platelet count less than 50,000/mm³) in 6% of patients.1

Platelet nadirs usually occur 8 or 9 days after administration of the drug.35 Bleeding episodes occurred in 14% of patients with ovarian or breast cancer receiving paclitaxel alone as subsequent therapy and in 4% of all treatment courses, but most episodes were localized, and the frequency of such events was unrelated to paclitaxel dose or schedule; 2% of patients received platelet transfusions.1 In a phase III clinical trial of subsequent therapy for metastatic ovarian carcinoma, bleeding episodes were reported in 10% of patients receiving paclitaxel (135 or 175 mg/m²) by 3-hour infusion; none of the patients who were treated with the 3-hour infusion received platelet transfusions.1

Albumin-bound Paclitaxel

Thrombocytopenia (platelet count less than 100,000/mm³) occurred in 2%, and was severe (platelet count less than 50,000/mm³) in less than 1%, of patients receiving albumin-bound paclitaxel for metastatic breast cancer.354 Bleeding was reported in 2% of patients.354 In a phase III clinical trial of patients with advanced non-small cell lung cancer receiving therapy with albumin-bound paclitaxel 100 mg/m² by 30-minute IV infusion in combination with carboplatin, grade 3 or 4 thrombocytopenia occurred in 18% of patients; epistaxis occurred in 7% of patients.354,358 In patients with metastatic pancreatic cancer receiving albumin-bound paclitaxel 125 mg/m² by 30- to 40-minute IV infusion in combination with gemcitabine, grade 3 or 4 thrombocytopenia occurred in 13% of patients; epistaxis occurred in 15% of patients.354

Anemia

Conventional Paclitaxel

Anemia (hemoglobin less than 11 g/dL) occurred in 78% of patients with ovarian or breast cancer receiving paclitaxel monotherapy in clinical trials and was severe (less than 8 g/dL) in 16% of patients.1 No consistent relationship between paclitaxel dose or schedule and the frequency of anemia was observed.1 Anemia occurred in 69% of patients with a baseline hemoglobin of 11 g/dL or higher at study entry, and 7% had severe anemia.1 Among patients receiving paclitaxel alone as subsequent therapy for ovarian or breast cancer, packed red blood cell transfusions were administered to 25% of all patients and to 12% of patients with a baseline hemoglobin of 11 g/dL or higher.1 In patients with AIDS-related Kaposi's sarcoma receiving paclitaxel 135 or 100 mg/m², anemia occurred in 86 or 73% of patients, and was severe in 34 or 25%, respectively.1

In randomized trials for the initial treatment of advanced ovarian cancer, anemia (hemoglobin less than 12 g/dL) was reported in 96% of patients receiving paclitaxel 175 mg/m² by 3-hour IV infusion followed by cisplatin, and anemia (hemoglobin less than 11 g/dL) was reported in 88% of patients receiving paclitaxel 135 mg/m² by 24-hour IV infusion followed by cisplatin.1 In patients with node-positive breast cancer receiving cyclophosphamide and doxorubicin followed by paclitaxel, severe anemia (hemoglobin less than 8 g/dL) was reported in 21% of patients.1 In patients receiving paclitaxel 135 mg/m² by 24-hour IV infusion followed by cisplatin for the initial treatment of advanced non-small cell lung cancer, anemia occurred in 94% of patients and was severe (hemoglobin less than 8 g/dL) in 22% of patients.1

Albumin-bound Paclitaxel

Anemia (hemoglobin less than 11 g/dL) occurred in 33%, and was severe (hemoglobin less than 8 g/dL) in 1%, of patients receiving albumin-bound paclitaxel for metastatic breast cancer.354

Anemia of grade 3 or 4 severity occurred in 28% of patients receiving albumin-bound paclitaxel combined with carboplatin for non-small cell lung cancer.354

Eosinophilia

Eosinophilia was reported in 40% of patients receiving a paclitaxel dose of 135 mg/m² for AIDS-related Kaposi's sarcoma.117

Sensitivity Reactions

Conventional Paclitaxel

Anaphylaxis and severe hypersensitivity reactions have occurred in 2-4% of patients receiving conventional paclitaxel in clinical trials.1 Paclitaxel frequently causes hypersensitivity reactions, and all patients receiving the conventional formulation of the drug should be premedicated to prevent severe reactions.1,3,20,21,22 (See Dosage and Administration: Dosage.) Fatal hypersensitivity reactions have occurred in patients receiving conventional paclitaxel despite premedication.1

In clinical trials involving use of paclitaxel alone as subsequent therapy for ovarian or breast cancer, 20% of all courses of paclitaxel therapy were associated with hypersensitivity reactions; reactions occurred in 41% of patients despite premedication and were severe in 2%.1 The frequency and severity of hypersensitivity reactions were not affected by the dose or schedule of paclitaxel administration in patients receiving the drug alone as subsequent therapy for ovarian cancer.1 The frequency and severity of hypersensitivity reactions were not affected by dose in patients receiving the drug alone as subsequent therapy for breast cancer.1 In patients with AIDS-related Kaposi's sarcoma receiving paclitaxel 135 or 100 mg/m², hypersensitivity reactions occurred in 14 or 9% of patients, respectively.1

In randomized trials for the initial treatment of advanced ovarian cancer, hypersensitivity reactions were reported in 11% of patients receiving paclitaxel 175 mg/m² by 3-hour IV infusion followed by cisplatin and in 8% of patients receiving paclitaxel 135 mg/m² by 24-hour IV infusion followed by cisplatin.1 In patients with node-positive breast cancer receiving cyclophosphamide and doxorubicin followed by paclitaxel, severe hypersensitivity reactions were reported in 4% of patients; all patients were designated to receive premedication.1 In patients with non-small cell lung cancer receiving initial treatment with paclitaxel 135 mg/m² by 24-hour IV infusion followed by cisplatin, hypersensitivity reactions occurred in 16% of patients and were severe in 1%.1

The most frequent manifestations of minor hypersensitivity reactions were flushing (28%), rash (12%), hypotension (4%), dyspnea (2%), tachycardia (2%), and hypertension (1%), as observed in patients receiving paclitaxel alone as subsequent therapy for ovarian or breast cancer.1 Rarely, chills and back pain have been reported in association with hypersensitivity reactions in patients receiving paclitaxel.1 The frequency of hypersensitivity reactions remained relatively stable during the entire treatment period.1

Severe reactions, which generally occur within the first hour of paclitaxel infusion, are characterized by dyspnea and hypotension requiring treatment, flushing, chest pains, tachycardia, angioedema, and generalized urticaria, and are probably histamine mediated.1,21 Delayed onset of urticarial rash, 7-10 days following completion of a course of therapy, has been observed in patients receiving paclitaxel for AIDS-related Kaposi's sarcoma.117 Discontinuance of paclitaxel therapy and aggressive management of symptoms are required in patients experiencing severe hypersensitivity reactions.1 (See Dosage Modification for Toxicity and Contraindications for Continued Therapy: Sensitivity Reactions in Dosage and Administration: Dosage.)

The exact cause of the hypersensitivity reactions is not known, but they may result from the polyoxyl 35 castor oil (Cremophor^® EL, polyethoxylated castor oil) in the paclitaxel for injection concentrate or from paclitaxel itself.3,20,21,184 (For information on hypersensitivity reactions associated with this vehicle, see Cautions: Sensitivity Reactions, in Cyclosporine 92:44.)

Other cutaneous reactions associated with hypersensitivity to paclitaxel, including acral erythema,147 generalized pustular dermatosis,148 and bullous fixed drug eruption,149 have been reported.

Albumin-bound Paclitaxel

Hypersensitivity reactions occurred in 4% of patients receiving albumin-bound paclitaxel for metastatic breast cancer; no severe hypersensitivity reactions were reported.354 Hypersensitivity reactions, which were grade 1 or 2 in severity, occurred on the day that albumin-bound paclitaxel was administered and consisted of dyspnea in 1%, and flushing, hypotension, chest pain, or arrhythmia, each in less than 1% of patients.354 However, severe and sometimes fatal hypersensitivity reactions have been reported during postmarketing experience in patients receiving albumin-bound paclitaxel.354 The use of albumin-bound paclitaxel in patients who have experienced hypersensitivity reactions to conventional paclitaxel has not been studied.354

Nervous System Effects

The frequency and severity of adverse neurologic effects were dose dependent in patients receiving therapy with conventional or albumin-bound paclitaxel.1,354 The frequency and severity of neurologic toxicity in patients receiving paclitaxel were influenced by prior and/or concomitant therapy with neurotoxic agents.1

Peripheral Neuropathy

Conventional Paclitaxel

Peripheral neuropathy was reported in 60% of all patients receiving paclitaxel alone as subsequent therapy for ovarian or breast cancer in clinical trials,1 and in 52% of patients without preexisting neuropathy.1 Among patients receiving paclitaxel alone as subsequent therapy for ovarian or breast cancer, paclitaxel-induced neuropathy was severe in 3% of patients (2% of patients without preexisting neuropathy) and required discontinuance of the drug in 1% of patients.1 The frequency and severity of peripheral neuropathy increased with the higher dose but did not appear to be affected by the schedule of paclitaxel administration in patients receiving the drug alone as subsequent therapy for ovarian cancer.1 The frequency and severity of peripheral neuropathy increased with the higher dose in patients receiving the drug alone as subsequent therapy for breast cancer.1 In patients with AIDS-related Kaposi's sarcoma receiving paclitaxel 135 or 100 mg/m², peripheral neuropathy occurred in 79 or 46% of patients, and was severe in 10 or 2%, respectively.1

Comparison across studies in patients with ovarian cancer suggests that higher incidences of neurotoxicity and severe neurotoxicity occur when paclitaxel 175 mg/m² by 3-hour IV infusion is followed by cisplatin.1 In randomized trials for the initial treatment of advanced ovarian cancer, neuromotor or neurosensory toxicity was reported in 87% (severe in 21%) of patients receiving paclitaxel 175 mg/m² by 3-hour IV infusion followed by cisplatin, and peripheral neuropathy was reported in 25% (severe in 3%) of patients receiving paclitaxel 135 mg/m² by 24-hour IV infusion followed by cisplatin.1 In patients with node-positive breast cancer receiving cyclophosphamide and doxorubicin followed by paclitaxel, grade 2 or 3 neurosensory toxicity occurred during the period of paclitaxel therapy in 15% of patients.1 In patients with advanced non-small cell lung cancer receiving initial treatment with paclitaxel 135 mg/m² by 24-hour IV infusion followed by cisplatin, neuromotor toxicity occurred in 37% of patients and was severe in 6%; neurosensory toxicity occurred in 48% of patients and was severe in 13%.1 This incidence of severe neurotoxicity in patients with non-small cell lung cancer receiving paclitaxel followed by cisplatin is higher than the incidence (severe peripheral neuropathy in 3%) reported in patients with ovarian or breast cancer receiving paclitaxel alone.1

The neuropathy usually is sensory in nature and is characterized by paresthesia with numbness and tingling in a stocking-and-glove distribution.3,20,25,26,30,184 Perioral numbness also has been reported,3,20,30 and many patients experience burning pain (often associated with hyperesthesia), particularly in the feet.3,20,25,30 The onset may be rapid, occurring within a few days.30 Pruritus preceding the onset of peripheral neuropathy has been reported in patients receiving high doses of paclitaxel by 3-hour IV infusion; paclitaxel-induced pruritus was relieved by treatment with tricyclic antidepressant therapy.165 One patient experienced a “recall” reaction of severe peripheral neuropathy following extravasation of paclitaxel.72

The frequency and severity of peripheral neuropathy are dose dependent1,3,20,22,25,30,184 and increase with cumulative dose;1,3,20,22,25,184 toxicity may be dose limiting3,20,22,184 or require dose modification.1

The frequency and severity of paclitaxel-induced neurotoxicity increase with dose,1,25,30 especially at doses exceeding 190 mg/m².30,35 Among patients receiving paclitaxel alone as subsequent therapy for ovarian or breast cancer, neurologic manifestations were apparent in 27% of patients following the initial course of therapy and in 34-51% of patients receiving 2-10 courses of therapy;1 such manifestations tended to worsen with increasing exposure to the drug.1,30 Sensory manifestations usually improve or resolve within several months after discontinuance of paclitaxel.1,3,20,25,30 Infrequently, motor neuron toxicity also has occurred in patients receiving the drug.3,20,30

Preexisting neuropathies resulting from previous therapies are not a contraindication to paclitaxel therapy;1 however, the incidence of paclitaxel-related neurotoxicity appears to be increased in patients with preexisting neuropathy or other risk factors for neuropathy.184

Albumin-bound Paclitaxel

Sensory neuropathy occurred in 71%, and was severe in 10 %, of patients receiving albumin-bound paclitaxel for metastatic breast cancer.354 The frequency of sensory neuropathy increased with the cumulative dose of albumin-bound paclitaxel.354 In the randomized trial comparing albumin-bound paclitaxel with conventional paclitaxel for metastatic breast cancer, 24 (10%) of 229 patients receiving albumin-bound paclitaxel developed grade 3 peripheral neuropathy, and none developed grade 4 peripheral neuropathy.354 Of these 24 patients, amelioration of symptoms at a median of 22 days was documented in 14 patients; 10 patients resumed treatment at a reduced dose of albumin-bound paclitaxel, and 2 patients discontinued therapy with the drug.354 Improvement was not documented in the other 10 patients, and 4 of these patients discontinued therapy with albumin-bound paclitaxel.354

Peripheral neuropathy occurred in 48%, and was severe in 3%, of patients receiving albumin-bound paclitaxel combined with carboplatin for non-small cell lung cancer.354 In the randomized trial comparing albumin-bound paclitaxel combined with carboplatin with conventional paclitaxel combined with carboplatin for non-small cell lung cancer, 3% of patients receiving albumin-bound paclitaxel combined with carboplatin developed grade 3 peripheral neuropathy and none developed grade 4 peripheral neuropathy.354 Grade 3 peripheral neuropathy improved to grade 1 or resolved in 59% of these patients following interruption or discontinuance of albumin-bound paclitaxel therapy.354 In comparison, severe (grade 3 or 4) peripheral neuropathy occurred in 12% of patients receiving conventional paclitaxel combined with carboplatin.354

Peripheral neuropathy occurred in 54%, and was severe in 17%, of patients receiving albumin-bound paclitaxel combined with gemcitabine for metastatic pancreatic cancer.354 In the randomized trial comparing albumin-bound paclitaxel combined with gemcitabine with gemcitabine monotherapy for pancreatic cancer, 17% of patients receiving albumin-bound paclitaxel developed grade 3 peripheral neuropathy, and none developed grade 4 peripheral neuropathy.354 The median time to onset of grade 3 peripheral neuropathy was 140 days following albumin-bound paclitaxel administration.354 Amelioration of grade 3 peripheral neuropathy to grade 1 severity or less at a median of 29 days following discontinuance of the drug was reported.354 Albumin-bound paclitaxel was resumed at a reduced dosage in 44% of patients with grade 3 peripheral neuropathy.354

Other Nervous System Effects

Conventional Paclitaxel

Rarely, seizures (including tonoclonic seizures),1,3,20,28 syncope,1 ataxia,1 and neuroencephalopathy1,73 have occurred during or immediately following administration of paclitaxel. Autonomic neuropathy resulting in paralytic ileus has been reported rarely in patients receiving paclitaxel.1 A case of acute and temporary worsening of parkinsonian syndrome following paclitaxel infusion has been reported in a geriatric patient with Parkinson's disease.140

The formulation of conventional paclitaxel contains ethyl alcohol, and some adverse neurologic effects of paclitaxel appear to be related to the effects of alcohol, particularly when high doses of conventional paclitaxel are administered over short infusion periods (e.g., 3 hours).1,141 CNS toxicity, rarely fatal, has been reported in pediatric patients receiving high doses of conventional paclitaxel by 3-hour IV infusion.1 (See Cautions: Pediatric Precautions.) Ethanol intoxication has been reported in a patient receiving high doses of conventional paclitaxel (348 mg/m²) by 3-hour IV infusion.141

Albumin-bound Paclitaxel

In patients receiving albumin-bound paclitaxel combined with gemcitabine for pancreatic cancer, depression occurred in 12%, and was severe in less than 1%, of patients.354 Headache occurred in 14%, and was severe in less than 1%, of patients receiving albumin-bound paclitaxel combined with gemcitabine for pancreatic cancer.354

Cranial nerve palsies, vocal cord paresis, and autonomic neuropathy resulting in paralytic ileus have been reported in patients receiving albumin-bound paclitaxel.354

Cardiovascular Effects

Hypotension and Bradycardia

Conventional Paclitaxel

Hypotension1,26 and bradycardia1,25,26,28,31 are the most common adverse cardiovascular effects of paclitaxel. During the first 3 hours of paclitaxel IV infusion in clinical trials of paclitaxel used alone as subsequent therapy for ovarian or breast cancer, hypotension occurred in 12% of all patients and 3% of all treatment courses, and bradycardia occurred in 3% of all patients and 1% of all treatment courses.1 In a phase III trial of patients receiving paclitaxel alone as subsequent therapy for metastatic ovarian cancer, the frequency of hypotension or bradycardia did not appear to be influenced by paclitaxel dose or schedule.1 The frequency of hypotension or bradycardia did not appear to be influenced by prior anthracycline therapy.1 In a phase II study in patients receiving paclitaxel 135 mg/m² by 3-hour IV infusion for AIDS-related Kaposi's sarcoma, hypotension and bradycardia occurred in 17 and 3% of all patients, respectively.1 Hypotension was reported in 9% of patients receiving paclitaxel 100 mg/m² by 3-hour IV infusion for AIDS-related Kaposi's sarcoma.1

In patients with advanced non-small cell lung cancer receiving initial treatment with paclitaxel 135 mg/m² by 24-hour IV infusion followed by cisplatin, adverse cardiovascular effects occurred in 33% of patients and were severe in 13%.1

Most episodes of bradycardia and hypotension associated with paclitaxel were asymptomatic1,25,26,28,31 and did not require further treatment or discontinuance of the drug, although hypotension associated with severe hypersensitivity reactions to the drug may require intervention.1 Chest pain is a frequent manifestation of a severe hypersensitivity reaction.1 (See Cautions: Sensitivity Reactions.) Atypical chest pain also has been reported during paclitaxel infusion and may be another manifestation of a hypersensitivity reaction.3

Albumin-bound Paclitaxel

During the 30-minute IV infusion, hypotension occurred in 5%, and bradycardia occurred in less than 1%, of patients receiving albumin-bound paclitaxel for metastatic breast cancer.354 Most episodes of hypotension or bradycardia were asymptomatic and did not require treatment or discontinuance of the paclitaxel infusion.354

Hypertension

Hypertension, often associated with a hypersensitivity reaction, has been observed in patients during administration of conventional paclitaxel.1,74 Hypertension also has been reported in patients receiving albumin-bound paclitaxel.354

ECG Abnormalities

ECG abnormalities in patients receiving conventional or albumin-bound paclitaxel generally were asymptomatic, were not dose limiting, and did not require therapeutic intervention.1,354

Conventional Paclitaxel

ECG abnormalities were present in 23% of all paclitaxel-treated patients during clinical trials of the drug as a single agent for the subsequent therapy of ovarian or breast cancer, developing in 14% of patients with normal baseline ECGs during therapy with the drug.1 The most frequent ECG abnormalities included nonspecific repolarization, sinus bradycardia, sinus tachycardia, and premature beats.1 Among patients with normal baseline ECGs, prior therapy with anthracyclines did not influence the frequency of ECG abnormalities.1

Albumin-bound Paclitaxel

ECG abnormalities were observed in 60% of all patients receiving albumin-bound paclitaxel for metastatic breast cancer and developed in 35% of patients with normal baseline ECGs.354 The most frequent ECG abnormalities included nonspecific repolarization, sinus bradycardia, and sinus tachycardia.354

Arrhythmias, Conduction Abnormalities, and Other Severe Cardiovascular Effects

Conventional Paclitaxel

Severe adverse cardiovascular effects occurred in about 1% of all patients receiving paclitaxel alone as subsequent therapy for ovarian or breast cancer in clinical trials.1,31 These effects included arrhythmias (e.g., asymptomatic ventricular tachycardia,1,25,31 bigeminy,1,31 syncope,1 hypertension,1 and venous thrombosis.1,144 In one patient treated with paclitaxel 175 mg/m² over 24 hours, syncope was accompanied by progressive hypotension and resulted in death.1 Severe conduction abnormalities, such as complete atrioventricular (AV) block requiring pacemaker insertion, have occurred in less than 1% of patients receiving paclitaxel.1,31 Atrial fibrillation and supraventricular tachycardia have been reported rarely in patients receiving paclitaxel.1 Junctional tachycardia has been reported in patients receiving paclitaxel.146 A higher incidence of severe adverse cardiovascular effects (12-13%) was reported in patients with advanced non-small cell lung cancer receiving paclitaxel in combination with cisplatin; difference in the cardiovascular risk factors in this patient population may have contributed to this increase.1

Rarely, vascular toxicity, including myocardial infarction, has been reported in patients receiving paclitaxel.1,3,25,31,145,164 In one case, fatal myocardial infarction not preceded by an arrhythmia occurred during paclitaxel infusion in a patient with atherosclerotic cardiovascular disease.3,25,31 A patient with no history of cardiac disease experienced acute myocardial infarction while receiving paclitaxel therapy for metastatic breast cancer and subsequently died; previous radiation therapy to the left breast may have increased the risk of myocardial infarction in this patient.145 In another patient, sudden death occurred 7 days following completion of paclitaxel infusion; the immediate cause of death was determined to be acute pulmonary edema, which was probably caused by acute heart failure.142 Cerebrovascular infarction occurred 36 hours following completion of paclitaxel infusion in a patient with metastatic ovarian cancer; although the mechanism is not clear, it has been suggested that administration of paclitaxel precipitated thrombus formation in a patient predisposed to thromboembolic disorder by underlying disease.164

Albumin-bound Paclitaxel

Severe adverse cardiovascular effects occurred in about 3% of patients receiving albumin-bound paclitaxel for metastatic breast cancer.354 These effects included chest pain, cardiac arrest, cardiac ischemia, myocardial infarction, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary embolism, and hypertension.354 Cerebrovascular events (strokes) and transient ischemic attacks also have been reported in patients receiving albumin-bound paclitaxel for metastatic breast cancer.354 Other adverse cardiovascular effects reported in patients receiving albumin-bound paclitaxel include tachycardia and AV block.354

Congestive Heart Failure and Cardiomyopathy

Conventional Paclitaxel

Congestive heart failure, with progressive deterioration and death in at least one patient, has been reported in patients receiving paclitaxel who had also received previous chemotherapy, including anthracyclines.1,75,143 Although congestive heart failure has been associated with anthracycline therapy, suspected paclitaxel-induced myocardial damage detected by electron microscopy has been reported.143 Cardiomyopathy associated with acute renal failure has been reported in a patient receiving paclitaxel for AIDS-related Kaposi's sarcoma; although this may have been a complication of the underlying disease, a causal relationship with the administration of paclitaxel could not be ruled out.117

Albumin-bound Paclitaxel

Congestive heart failure and left ventricular dysfunction have been reported in patients receiving albumin-bound paclitaxel, generally in those who previously received cardiotoxic drugs such as anthracyclines or had a history of cardiac disease.354

Edema

Conventional Paclitaxel

In clinical trials of paclitaxel as a single agent for the subsequent therapy of ovarian or breast cancer, edema occurred in 21% of all patients receiving paclitaxel, 17% of patients without baseline edema, and 5% of treatment courses in patients without baseline edema.1 Severe edema occurred in 1% of patients receiving subsequent therapy with paclitaxel alone for ovarian or breast cancer, and none of these patients required discontinuance of the drug.1 Edema in patients receiving paclitaxel commonly was focal and disease related; frequency of edema did not increase with length of time spent in the study.1

Albumin-bound Paclitaxel

Edema occurred in 10% of patients receiving albumin-bound paclitaxel for metastatic breast cancer, and none had severe edema.354 Peripheral edema occurred in 10% of patients receiving albumin-bound paclitaxel combined with carboplatin for non-small cell lung cancer, and none had severe edema.354 In patients receiving albumin-bound paclitaxel combined with gemcitabine for pancreatic cancer, peripheral edema occurred in 46%, and was severe in 3%, of patients.354

GI Effects

The most common GI toxicities associated with paclitaxel therapy are nausea and vomiting, diarrhea, and mucositis; these adverse effects usually are mild to moderate in severity.1,354 Intestinal obstruction,1,354 intestinal perforation,1,76,77,354 pancreatitis,1,78,354 ischemic colitis,1,354 and dehydration1,354 have occurred in patients receiving paclitaxel. Neutropenic enterocolitis (typhlitis) has been reported rarely in patients receiving conventional paclitaxel (alone or in combination therapy) despite concomitant administration of granulocyte colony-stimulating factor.1,79

Conventional Paclitaxel

Nausea and vomiting1,25,28,29 occurred in 52% of patients with ovarian or breast cancer and in 69% of patients with AIDS-related Kaposi's sarcoma receiving paclitaxel monotherapy in clinical trials.1 Higher incidences of nausea and vomiting are reported in clinical trials of combination therapy with paclitaxel and cisplatin for the initial treatment of advanced ovarian cancer (65 and 88%) or non-small cell lung cancer (85 and 87%).1 In patients with node-positive breast cancer receiving cyclophosphamide and doxorubicin followed by paclitaxel, severe nausea and vomiting was reported in 18% of patients.1

Diarrhea1,25,28,29 and mucositis1,25,26,28,29 occurred in 38 and 31%, respectively, of patients receiving paclitaxel alone as subsequent therapy for ovarian or breast cancer.1 In patients with AIDS-related Kaposi's sarcoma receiving paclitaxel, diarrhea and mucositis occurred in 79 and 28% of patients, respectively; one-third of patients with AIDS-related Kaposi's sarcoma reported diarrhea before initiation of paclitaxel therapy.1 In randomized trials for the initial treatment of advanced ovarian cancer, diarrhea was reported in 37% of patients receiving paclitaxel 175 mg/m² by 3-hour IV infusion followed by cisplatin and in 16% of patients receiving paclitaxel 135 mg/m² by 24-hour IV infusion followed by cisplatin.1 In patients with node-positive breast cancer receiving cyclophosphamide and doxorubicin followed by paclitaxel, severe mucositis was reported in 4% of patients.1 In patients with non-small cell lung cancer receiving initial treatment with paclitaxel 135 mg/m² by 24-hour IV infusion followed by cisplatin, mucositis occurred in 18% of patients and was severe in 1%.1

Paclitaxel-induced mucositis is characterized by diffuse ulceration of the lips, oral cavity, and pharynx; dysphagia and pain reflecting esophageal involvement may occur.3 In clinical trials of paclitaxel as a single agent for the subsequent therapy for ovarian or breast cancer, mucositis was schedule dependent and occurred more frequently in patients receiving paclitaxel by 24-hour infusion than in those receiving the drug by 3-hour infusion.1

Anorexia and taste perversion have been reported with use of paclitaxel.25

Albumin-bound Paclitaxel

Nausea occurred in 30% and was severe in 3%, diarrhea occurred in 26% and was severe in less than 1%, and vomiting occurred in 18% and was severe in 4% of patients receiving albumin-bound paclitaxel for metastatic breast cancer.354 Mucositis was reported in 7% of patients receiving albumin-bound paclitaxel for metastatic breast cancer and was severe in less than 1%.354

In the randomized trial comparing albumin-bound paclitaxel combined with gemcitabine with gemcitabine monotherapy for pancreatic cancer, nausea occurred in 54% and was severe in 6%, diarrhea occurred in 44% and was severe in 6%, and vomiting occurred in 36% and was severe in 6% of patients receiving albumin-bound paclitaxel.354 Mucositis was reported in 10% of patients receiving albumin-bound paclitaxel combined with gemcitabine for pancreatic cancer and was severe in 1%.354 Decreased appetite, dehydration, and dysgeusia were reported in 36, 21, and 16%, respectively, of patients receiving albumin-bound paclitaxel combined with gemcitabine.354

Dermatologic Effects

Conventional Paclitaxel

Alopecia occurred in 87% of patients receiving paclitaxel alone as subsequent therapy for ovarian or breast cancer in clinical trials.1,3,20,22,25,26,28,184 In randomized trials for the initial treatment of advanced ovarian cancer, alopecia was reported in 96% of patients receiving paclitaxel 175 mg/m² by 3-hour IV infusion followed by cisplatin and in 55% of patients receiving paclitaxel 135 mg/m² by 24-hour IV infusion followed by cisplatin.1 In patients with node-positive breast cancer receiving cyclophosphamide and doxorubicin followed by paclitaxel, alopecia occurred during the period of paclitaxel therapy in 46% of patients.1

Alopecia, which usually is complete, generally occurs 14-21 days after administration of paclitaxel with a sudden onset, often occurring in a single day.3,20,22 In addition, patients often experience a loss of all body hair including axillary, pubic, and extremity hair and eyelashes and eyebrows.3,20,22,25,28 Paclitaxel-induced alopecia is reversible,3,20,22,28 usually within 6-8 weeks after treatment,20 and patients receiving multiple courses of therapy often experience hair regrowth after 5-7 cycles.28

Transient skin changes have been observed in patients with paclitaxel-induced hypersensitivity reactions.1 (See Cautions: Sensitivity Reactions.) Nail changes (changes in pigmentation, discoloration of nail bed) occurred in 2% of patients receiving paclitaxel monotherapy for ovarian or breast cancer.1 Severe nail changes, including dark discoloration of hands and/or feet followed by nail raising and paronychia with exudation and subungual hemorrhage, partial or complete loss of nails, or pain in the nail beds, have been reported in patients receiving paclitaxel on a weekly schedule for metastatic breast cancer.349,350 Radiation recall dermatitis associated with paclitaxel,1,32,115,153,154,155,166 resulting in extensive desquamation and necrosis in one patient with metastatic breast cancer,32 has been reported in several patients. Maculopapular rash, pruritus, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely in patients receiving paclitaxel.1

Albumin-bound Paclitaxel

Alopecia occurred in 90% of patients receiving albumin-bound paclitaxel for metastatic breast cancer.354 Nail changes, such as changes in pigmentation or discoloration of the nail bed, were uncommon in patients receiving albumin-bound paclitaxel.354

In a randomized trial comparing albumin-bound paclitaxel combined with gemcitabine with gemcitabine monotherapy for pancreatic cancer, alopecia occurred in 50% of patients receiving albumin-bound paclitaxel.354 Rash was reported in 30% of patients receiving albumin-bound paclitaxel combined with gemcitabine for pancreatic cancer and was severe in 2%.354

Skin abnormalities related to radiation recall, generalized or maculopapular rash, erythema, pruritus, photosensitivity reactions, Stevens-Johnson syndrome, and toxic epidermal necrolysis also have been reported in patients receiving albumin-bound paclitaxel.354

Local Effects

Specific treatment for paclitaxel-induced extravasation reactions currently is unknown, and the injection site should be monitored closely for possible infiltration of the drug during infusion of conventional or albumin-bound paclitaxel.1,354

Conventional Paclitaxel

Injection site reactions occurred in 13% of patients receiving paclitaxel alone as subsequent therapy for ovarian or breast cancer in clinical studies.1 Injection site reactions, including reactions secondary to extravasation, usually were mild and were characterized by erythema, tenderness, skin discoloration, or swelling at the injection site.1 Such reactions have been observed more frequently in patients receiving paclitaxel by 24-hour infusion than in those receiving the drug by 3-hour infusion.1 Recurrence of skin reactions at a previous site of extravasation (i.e., “recall” reactions) following administration of paclitaxel at a different injection site has been reported rarely.1,159,160

Rarely, severe local effects of paclitaxel, such as phlebitis,1 cellulitis,1,157 induration,1,157 skin exfoliation,1 necrosis,1,157,158 and fibrosis1 have been reported. In some patients, the onset of injection site reaction occurred during prolonged infusion of paclitaxel;1 delayed onset of injection site reactions, 3-13 days following completion of paclitaxel infusion, also has been reported.1,157,158

Albumin-bound Paclitaxel

Injection site reactions occurred in less than 1% of patients receiving albumin-bound paclitaxel for metastatic breast cancer.354

Musculoskeletal Effects

Arthralgia and/or myalgia usually were transient, occurred 2 or 3 days after administration of conventional or albumin-bound paclitaxel, and resolved within a few days.1,354

Conventional Paclitaxel

Arthralgia and/or myalgia1,22,25,26,29 occurred in 60% of patients receiving paclitaxel alone as subsequent therapy for ovarian or breast cancer in clinical trials and was severe in 8% of patients.1 In patients with AIDS-related Kaposi's sarcoma receiving paclitaxel 135 or 100 mg/m², arthralgia and/or myalgia occurred in 93 or 48% of patients, and was severe in 14 or 16%, respectively.1

In randomized trials for the initial treatment of advanced ovarian cancer, myalgia or arthralgia was reported in 60% of patients receiving paclitaxel 175 mg/m² by 3-hour IV infusion followed by cisplatin and in 9% of patients receiving paclitaxel 135 mg/m² by 24-hour IV infusion followed by cisplatin.1 In patients with node-positive breast cancer receiving cyclophosphamide and doxorubicin followed by paclitaxel, grade 2 or 3 myalgias occurred during the period of paclitaxel therapy in 23% of patients.1 In patients with advanced non-small cell lung cancer receiving initial treatment with paclitaxel 135 mg/m² by 24-hour IV infusion followed by cisplatin, arthralgia/myalgia occurred in 21% of patients and was severe in 3%.1

In clinical trials of patients with ovarian or breast cancer, the frequency and severity of arthralgia and/or myalgia did not appear to be dose or schedule dependent and did not vary throughout the treatment period.1

Albumin-bound Paclitaxel

Myalgia and/or arthralgia occurred in 44%, and was severe in 8%, of patients receiving albumin-bound paclitaxel for metastatic breast cancer.354 In a phase III clinical trial of patients with advanced non-small cell lung cancer receiving therapy with albumin-bound paclitaxel 100 mg/m² by 30-minute IV infusion in combination with carboplatin, arthralgia or myalgia occurred in 13 or 10% of patients, respectively, and was severe in less than 1% of patients.354,358 In patients with advanced pancreatic cancer receiving albumin-bound paclitaxel 125 mg/m² by 30- to 40-minute IV infusion in combination with gemcitabine, arthralgia, myalgia, or extremity pain occurred in 11, 10, or 11% of patients, respectively, and was severe in 1% of patients.354

Hepatic Effects

Hepatic necrosis and hepatic encephalopathy resulting in death have occurred rarely in patients receiving conventional paclitaxel1 and may occur in patients receiving albumin-bound paclitaxel.354 Fatal hepatic coma occurred following administration of conventional paclitaxel in a patient with breast cancer and hepatic metastases.156

Conventional Paclitaxel

Abnormalities in liver function test results have occurred in patients receiving paclitaxel for ovarian or breast cancer but do not appear to be dose or schedule related.1 In patients with normal baseline hepatic function, increased serum alkaline phosphatase concentrations occurred in 22%, increased serum AST (SGOT) concentrations occurred in 19%, and increased serum bilirubin concentrations occurred in 7% of patients receiving paclitaxel monotherapy for ovarian or breast cancer.1 Prolonged exposure to paclitaxel has not been associated with cumulative hepatic toxicity.1

Albumin-bound Paclitaxel

Among patients with normal baseline hepatic function, increased serum AST (SGOT) concentrations occurred in 39%, increased serum alkaline phosphatase concentrations occurred in 36%, and increased serum bilirubin concentrations occurred in 7%, of patients receiving albumin-bound paclitaxel for metastatic breast cancer in a randomized trial.354 Elevations in serum GGT concentrations (grade 3 or 4) occurred in 14% of patients receiving albumin-bound paclitaxel.354

Renal Effects

Conventional Paclitaxel

Renal toxicity, including acute renal failure, has been reported in patients with HIV infection receiving paclitaxel.1,117 In patients with AIDS-related Kaposi's sarcoma receiving paclitaxel 135 or 100 mg/m² by 3-hour IV infusion, elevation of serum creatinine occurred in 34 or 18% of patients, and was severe in 7 or 5%, respectively.1 Elevations of serum creatinine generally were reversible; however, discontinuance of paclitaxel therapy was required in one patient suspected of having severe HIV nephropathy.1

Albumin-bound Paclitaxel

Elevations of serum creatinine occurred in 11%, and were severe in 1%, of patients receiving albumin-bound paclitaxel for metastatic breast cancer.354 No interruptions, delay, or reductions in dose of albumin-bound paclitaxel were required for renal toxicity.354

Respiratory Effects

Lung fibrosis has been reported rarely in patients receiving conventional paclitaxel1 and may occur in patients receiving albumin-bound paclitaxel.354

Conventional Paclitaxel

Radiation pneumonitis1 and interstitial pneumonia161 have been reported in patients receiving paclitaxel and concurrent radiation therapy. Possible radiation recall pneumonitis has been reported in a patient who received paclitaxel 12 days following completion of radiation therapy for metastatic adenocarcinoma of the lung.166 Adverse respiratory effects associated with hypersensitivity to paclitaxel, including pneumonitis150 and transient pulmonary infiltrates,151,162 also have been reported. Pulmonary embolism has been reported rarely in patients receiving paclitaxel.1

Albumin-bound Paclitaxel

Dyspnea was reported in 12%, and cough in 7%, of patients receiving albumin-bound paclitaxel for metastatic breast cancer.354 Pneumothorax has been reported in less than 1% of patients following treatment with albumin-bound paclitaxel for metastatic breast cancer.354 Cough was reported in 17% of patients receiving albumin-bound paclitaxel combined with gemcitabine for pancreatic cancer.354

Pneumonitis, interstitial pneumonia, pulmonary embolism, and radiation pneumonitis have been reported in patients receiving albumin-bound paclitaxel.354 Pneumonitis was reported in 4% of patients, and was fatal in 2 of 17 patients, following treatment with albumin-bound paclitaxel combined with gemcitabine for pancreatic cancer.354

Ocular Effects

Conventional Paclitaxel

Optic nerve disturbances and visual disturbances have been reported following administration of paclitaxel, particularly in patients receiving high doses.1,152 Rare reports of abnormalities in visual evoked potentials suggest persistent damage of the optic nerve related to paclitaxel.1,152 Other visual disturbances reported in association with paclitaxel infusion (e.g., scintillating scotomata, photopsia) generally appear to be reversible.1,152,163 Conjunctivitis and increased lacrimation have been reported rarely in patients receiving paclitaxel.1

Albumin-bound Paclitaxel

Ocular or visual disturbances occurred in 13% of 366 patients receiving albumin-bound paclitaxel for metastatic breast cancer in single-arm studies or a randomized trial.354 Severe ocular or visual disturbances occurred in 1% of patients and consisted of keratitis and blurred vision in patients receiving high doses (300 or 375 mg/m²) of albumin-bound paclitaxel.354 These adverse ocular effects generally have been reversible; however, rare reports of abnormal visual evoked potentials in patients receiving conventional paclitaxel suggest that persistent damage of the optic nerve may occur.354 Reduced visual acuity due to cystoid macular edema has been reported in patients receiving albumin-bound paclitaxel or other taxanes; following discontinuance of therapy, cystoid macular edema improves and visual acuity may return to baseline.354 Conjunctivitis and increased lacrimation have been reported rarely in patients receiving conventional paclitaxel and may occur in patients receiving albumin-bound paclitaxel.354

Otic Effects

Ototoxicity, including hearing loss and tinnitus, has been reported in patients receiving paclitaxel.1

Other Adverse Effects

Conventional Paclitaxel

Asthenia and malaise have been reported in patients receiving paclitaxel.1 In a randomized trial for the initial treatment of advanced ovarian cancer, asthenia was reported in 17% of patients receiving paclitaxel 135 mg/m² by 24-hour IV infusion followed by cisplatin.1

Albumin-bound Paclitaxel

Asthenia was reported in 47%, and was severe in 8%, of patients receiving albumin-bound paclitaxel for metastatic breast cancer.354 Fatigue and asthenia were reported in 59 and 19%, respectively, of patients receiving albumin-bound paclitaxel combined with gemcitabine for pancreatic cancer, and were severe in 18 or 7%, respectively, of patients.354 In addition, hypokalemia was reported in 12%, and was severe in 4%, of patients receiving albumin-bound paclitaxel combined with gemcitabine for pancreatic cancer.354

Precautions and Contraindications

Paclitaxel is a toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without evidence of toxicity.1,4,7,20,22,24,25,28 The drug must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents and only when the potential benefits of paclitaxel therapy are thought to outweigh the possible risks.1 In addition, appropriate diagnostic and treatment facilities must be readily available in case the patient develops any severe hypersensitivity reactions to paclitaxel therapy (e.g., hypotension, dyspnea requiring bronchodilators, angioedema, generalized urticaria).1

Paclitaxel (conventional or albumin-bound paclitaxel) should not be used in patients with known severe hypersensitivity to the drug.1,354 In addition, paclitaxel for injection concentrate should not be used in patients with known severe hypersensitivity to the polyoxyl 35 castor oil vehicle.1 (See Cautions: Sensitivity Reactions.) To prevent severe hypersensitivity reactions, patients should be pretreated with corticosteroids (e.g., dexamethasone), diphenhydramine, and H₂-receptor antagonists (e.g., cimetidine, ranitidine) before receiving conventional paclitaxel.1,22 Premedication generally is not required in patients receiving albumin-bound paclitaxel.354 (See Dosage and Administration: Dosage.)

At least one commercially available formulation of paclitaxel injection contains metabisulfite,281 a sulfite that may cause serious allergic-type reactions in certain susceptible individuals.282,283,284,285,286,287,288,289 The overall incidence of sulfite sensitivity in the general population is probably low, but in susceptible individuals, exposure to sulfites can result in acute bronchospasm or, less frequently, life-threatening anaphylaxis.288 The paclitaxel formulation containing metabisulfite should be used with caution in atopic, nonasthmatic individuals.288

Paclitaxel therapy (with conventional or albumin-bound paclitaxel) should not be administered to patients with baseline neutrophil counts less than 1500/mm³.1,354,362 In patients with HIV infection, paclitaxel therapy should not be administered if baseline neutrophil counts are less than 1000/mm³.1 To monitor the occurrence of paclitaxel-induced bone marrow suppression, mainly neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts, including blood cell counts prior to each dose of the drug, be performed in all patients.1,354 (See Dosage and Administration: Dosage.) Because sepsis has been reported in patients receiving albumin-bound paclitaxel, administration of a broad-spectrum anti-infective should be initiated if the patient becomes febrile (regardless of neutrophil count).354

Reduction in dosage of paclitaxel and close monitoring are required in patients with hepatic impairment.1,354 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Because paclitaxel may cause adverse cardiovascular effects, including hypotension, bradycardia, and hypertension, frequent monitoring of vital signs is recommended, particularly during the first hour of the drug infusion; however, continuous cardiac monitoring is not required except in patients with preexisting serious conduction abnormalities.1

Because albumin-bound paclitaxel may cause life-threatening pneumonitis, monitoring for manifestations of pneumonitis is recommended.354

Patients should be warned that the alcohol contained in conventional paclitaxel may impair their ability to perform hazardous activities requiring mental alertness (e.g., operating machinery, driving a motor vehicle) following paclitaxel infusion, particularly when high doses of the drug are administered over short infusion periods (e.g., 3 hours), and that CNS depressants (e.g., opiates, sedatives) should be used concomitantly with caution.141

Because albumin-bound paclitaxel contains albumin, a derivative of human blood, there is a remote risk of transmission of disease, such as viral disease or Creutzfeldt-Jakob disease, associated with its use.354 To date, no cases of transmission of bloodborne illness have been associated with use of albumin.354

Pediatric Precautions

Safety and efficacy of conventional or albumin-bound paclitaxel in children have not been established.1,354

The manufacturer reports that CNS toxicity, rarely fatal, has been observed in pediatric patients receiving high doses of conventional paclitaxel (350-420 mg/m²) by 3-hour IV infusion in a clinical trial.1 Because paclitaxel injection contains dehydrated alcohol, toxicity may have resulted from IV administration of large amounts of alcohol over a short period of time.1 The use of concomitant antihistamine as a component of the premedication regimen may intensify the toxic effect of the alcohol.1 However, the possibility of a direct toxic effect of paclitaxel itself cannot be ruled out.1

Geriatric Precautions

When the total number of patients studied in clinical trials of conventional paclitaxel for advanced ovarian, breast, or non-small cell lung cancer and in the study for the adjuvant treatment of breast cancer is considered, 17% were 65 years of age or older, and 1% were 75 years of age or older.1 Clinical studies of conventional paclitaxel did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.1 In a study of paclitaxel for the first-line treatment of advanced ovarian cancer, median survival was lower in geriatric patients than in younger patients.1 Geriatric patients are at increased risk for certain adverse effects of paclitaxel, including severe myelosuppression and severe neuropathy.1 In 2 clinical studies of conventional paclitaxel for non-small cell lung cancer, geriatric patients had a higher incidence of cardiovascular toxicity than younger patients.1

In a randomized trial evaluating albumin-bound paclitaxel for the treatment of metastatic breast cancer, 13% of patients receiving albumin-bound paclitaxel were 65 years of age or older, and less than 2% were 75 years of age or older.354 No difference in toxicity of albumin-bound paclitaxel was observed between geriatric and younger patients.354,355

In a randomized trial evaluating albumin-bound paclitaxel combined with carboplatin for the treatment of advanced non-small cell lung cancer, 31% of patients receiving albumin-bound paclitaxel combined with carboplatin were 65 years of age or older, and less than 3.5% were 75 years of age or older.354 Although no overall differences in efficacy were observed between geriatric and younger patients, toxicity (i.e., myelosuppression, peripheral neuropathy, arthralgia) occurred more frequently in patients 65 years of age or older.354

In a clinical trial evaluating albumin-bound paclitaxel combined with gemcitabine for the treatment of metastatic pancreatic cancer, 41% of patients receiving albumin-bound paclitaxel combined with gemcitabine were 65 years of age or older, and less than 10% were 75 years of age or older.354 Although no overall differences in efficacy were observed between geriatric and younger patients, toxicity (i.e., diarrhea, decreased appetite, dehydration, epistaxis) occurred more frequently in patients 65 years of age or older.354 The clinical trial did not include sufficient numbers of patients older than 75 years of age to determine whether these patients respond differently than younger patients.354

Mutagenicity and Carcinogenicity

Paclitaxel has been shown to induce chromosome aberrations in human lymphocytes in vitro, and the drug was mutagenic in the micronucleus test in mice in vivo; however, paclitaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.1,354

Studies to determine the carcinogenic potential of paclitaxel have not been performed to date.1,354

Pregnancy, Fertility, and Lactation

Pregnancy

Paclitaxel can cause fetal toxicity when administered to pregnant women, but potential benefits may be acceptable in certain conditions despite the possible risks to the fetus.1,34,354

Reproduction studies in rabbits receiving IV conventional paclitaxel doses of 3 mg/kg daily (approximately 0.2 times the maximum recommended human dose on a mg/m² basis) during organogenesis revealed evidence of maternal toxicity, embryotoxicity, and fetotoxicity.1 The drug caused intrauterine mortality, increased resorptions, and increased fetal deaths.1 Reproduction studies in rats receiving IV paclitaxel doses of 1 mg/kg daily (approximately 0.04 times the maximum recommended human dose on a mg/m² basis) during organogenesis resulted in embryotoxicity and fetotoxicity.1 No teratogenic effects were observed in the offspring of rats receiving daily IV paclitaxel doses of 1 mg/kg; however, the teratogenic potential of higher paclitaxel doses could not be assessed because of extensive fetal mortality.1

Reproduction studies in rats receiving albumin-bound paclitaxel at IV doses of 6 mg/m² (approximately 2% of the maximum recommended human dose on a mg/m² basis) on gestation days 7 to 17 resulted in embryotoxicity and fetotoxicity.354 The drug caused intrauterine mortality, increased resorptions, reduced numbers of litters, increased fetal deaths, reduction in fetal body weight, and increased fetal anomalies including soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles.354 Fetal anomalies also occurred in the offspring of rats receiving lower doses of albumin-bound paclitaxel (IV doses of 3 mg/m² or approximately 1% of the maximum recommended human dose on a mg/m² basis).354

There are no adequate and well-controlled studies to date using paclitaxel in pregnant women.1,354 Paclitaxel should be used during pregnancy only in life-threatening situations or for severe disease for which safer drugs cannot be used or are ineffective.34 When paclitaxel is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.1,354 Women of childbearing potential should be advised to avoid becoming pregnant during therapy with paclitaxel.1,354 Men receiving albumin-bound paclitaxel should be advised to avoid fathering a child.354

Fertility

At an IV dose of 1 mg/kg daily, conventional paclitaxel reduced fertility in rats.1

Reduced fertility with decreased pregnancy rates and increased loss of embryos in mated females occurred in male rats given albumin-bound paclitaxel at a dose of 42 mg/m² weekly (approximately 16% of the daily maximum recommended human dose on a mg/m² basis) for 11 weeks prior to mating with untreated female rats.354 Fetal anomalies, including soft tissue and skeletal malformations, occurred in the offspring of male rats receiving lower doses of albumin-bound paclitaxel (IV doses of 3 and 12 mg/m² or approximately 1-5% of the maximum recommended human dose on a mg/m² basis).354 Testicular atrophy/degeneration has been observed with the administration of a single dose of albumin-bound paclitaxel in rats receiving 54 mg/m² and dogs receiving 175 mg/m².354

Lactation

It is not known whether paclitaxel is distributed into human milk.1,354 However, in lactating rats given radiolabeled paclitaxel, concentrations of radioactivity in milk were higher than those in plasma and declined in parallel with plasma concentrations of the drug.1 Because of the potential for serious adverse reactions to paclitaxel in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1,354

CNS Depressants

Concomitant administration of CNS depressants such as antihistamines or opiates with paclitaxel should be undertaken with caution as these drugs may cause potentiation of CNS depression caused by the alcohol contained in the paclitaxel formulation.1,141

Drugs Affecting Hepatic Microsomal Enzymes

Although specific studies have not been performed and the clinical importance has not been determined, concomitant administration of drugs that affect cytochrome P-450 (CYP) hepatic microsomal enzymes could alter the metabolism of paclitaxel.1,186,188,202,354 Metabolism of paclitaxel is mediated by CYP2C8 and CYP3A4, and the possibility exists that drugs that induce these isoenzymes may reduce plasma paclitaxel concentrations.1,187,202,354 Conversely, concomitant administration of paclitaxel with drugs that inhibit CYP2C8 and/or CYP3A4 may increase plasma paclitaxel concentrations.1,202,354 In addition, concomitant administration of paclitaxel with other drugs that are metabolized by CYP2C8 and/or CYP3A4 may result in decreased metabolism of the drug(s) because of competition for the enzyme.1,202,354 Caution should be exercised when paclitaxel is used concomitantly with drugs that are substrates, inhibitors, or inducers of CYP2C8 and/or CYP3A4.354,362

Lower steady-state or peak plasma concentrations of paclitaxel, increased rates of clearance, and reduced toxicity have been reported in patients receiving anticonvulsants known to induce CYP enzymes (e.g., phenobarbital, phenytoin).186,188 Histamine H₂-receptor antagonists are a component of the premedication regimen used to prevent severe hypersensitivity reactions in patients receiving conventional paclitaxel; no pharmacokinetic, toxicologic, or pharmacologic differences were observed in a prospective, crossover trial in which patients received either cimetidine or famotidine despite the variable effects of these drugs on cytochrome P-450 enzyme activity.45,186,188,243 In addition, no difference in paclitaxel steady-state concentrations was observed between cycles in a small number of patients who received standard-dose (i.e., 300 mg) versus high-dose (i.e., 2400 mg) cimetidine during subsequent cycles of paclitaxel therapy.45 The potential interaction between paclitaxel and protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, saquinavir), which are substrates and/or inhibitors of the CYP3A4 isoenzyme, has not been studied in clinical trials.1

Results of in vitro studies show that the metabolism of paclitaxel to its principal metabolite, 6α-hydroxypaclitaxel, was inhibited by ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporine, teniposide, etoposide, or vincristine; however, the concentrations of drugs used in these studies exceeded the plasma concentrations found in vivo following typical therapeutic doses.1,354 Other agents that inhibited the metabolism of paclitaxel in vitro include testosterone, 17α-ethinyl estradiol, retinoic acid, or quercetin (a specific inhibitor of CYP2C8).1,354

Antineoplastic Agents

Sequence-dependent drug interactions have been reported to occur when paclitaxel is administered with other antineoplastic agents, including cisplatin, doxorubicin, and cyclophosphamide.124,167,186,188,203 In a phase I trial using escalating doses of IV conventional paclitaxel 110-200 mg/m² sequentially administered with IV cisplatin 50 or 75 mg/m², increased severity of myelosuppression was observed when paclitaxel was administered following cisplatin compared with the alternative sequence (paclitaxel administered preceding cisplatin).1,186,188 Pharmacokinetic studies show that administration of cisplatin followed by conventional paclitaxel decreases paclitaxel clearance by approximately 25-33%.1,186,188,203 When cisplatin and paclitaxel must be administered sequentially, the sequence of paclitaxel followed by cisplatin is recommended.25 Increased severity of neutropenia and thrombocytopenia have been reported when paclitaxel is administered (by 24-hour IV infusion) followed by cyclophosphamide.186,188

Use of paclitaxel in combination therapy with doxorubicin may result in increased plasma concentrations of doxorubicin and its active metabolite doxorubicinol; this interaction may contribute to the antitumor efficacy as well as the increased incidence of cardiac toxicity when paclitaxel is used in conjunction with doxorubicin.1,167,184,186,188,203 Synergistic cytotoxicity with paclitaxel followed by doxorubicin has been observed in in vitro studies and may result from a paclitaxel-induced increase in activity of DNA topoisomerase II, one of the intracellular targets involved in doxorubicin cytotoxicity.188,203

Administration of conventional paclitaxel followed by carboplatin was associated with similar rates of neutropenia but less severe thrombocytopenia compared with carboplatin alone;186,188,204 a pharmacodynamic mechanism for the interaction between the drugs has been postulated since the pharmacokinetics of the agents were unchanged.188,204 When administration of albumin-bound paclitaxel was followed immediately by carboplatin, no clinically important changes in paclitaxel exposure occurred; although mean exposure to free carboplatin was about 23% higher than the targeted exposure (6 mg/mL per minute), mean half-life and clearance of carboplatin were consistent with values reported for carboplatin alone.354

The potential for pharmacokinetic interactions between paclitaxel and gemcitabine has not been elucidated.354

Protein-bound Drugs

In vitro data indicate that paclitaxel is highly bound (89-98%) to plasma proteins; however, the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not displace paclitaxel from plasma proteins.354,362

Acute Toxicity

Manifestations

Limited information is available on acute overdosage of paclitaxel.1 Overdosage with paclitaxel would be expected to produce effects such as myelosuppression, peripheral or sensory neurotoxicity, and mucositis.1,354

Overdosage of conventional paclitaxel in pediatric patients may be associated with acute ethanol toxicity because of the presence of dehydrated alcohol in the formulation.1 (See Cautions: Pediatric Precautions.)

Treatment

There is no known specific antidote for paclitaxel overdosage.1,354 Management of paclitaxel overdosage consists of discontinuance of the drug and initiation of supportive measures appropriate for the type of toxicity observed. Paclitaxel appears to be minimally removed by hemodialysis.183

Pharmacology

Paclitaxel is an antimicrotubule antineoplastic agent.1,3,6,7,20,22,187,206 Unlike some other common antimicrotubule agents (e.g., vinca alkaloids, colchicine, podophyllotoxin), which inhibit microtubule assembly, paclitaxel and docetaxel (a semisynthetic taxoid) promote microtubule assembly.1,3,6,7,20,124,183,184,186,187,201,206

Microtubules are organelles that exist in a state of dynamic equilibrium with their components, tubulin dimers.2,3,20,45,183 They are an essential part of the mitotic spindle and also are involved in maintenance of cell shape and motility, and transport between organelles within the cell.2,3,20,45,124,183

By binding in a reversible, concentration-dependent manner to the β-subunit of tubulin at the N -terminal domain, paclitaxel enhances the polymerization of tubulin, the protein subunit of the spindle microtubules, even in the absence of factors that are normally required for microtubule assembly (e.g., guanosine triphosphate [GTP]), and induces the formation of stable, nonfunctional microtubules.1,2,3,20,45,183,186,187 Paclitaxel promotes microtubule stability even under conditions that typically cause depolymerization in vitro (e.g., cold temperature, the addition of calcium, the presence of antimitotic drugs).183,186 While the precise mechanism of action of the drug is not understood fully, paclitaxel disrupts the dynamic equilibrium within the microtubule system and blocks cells in the late G₂ phase and M phase of the cell cycle, inhibiting cell replication.2,3,20,22,45,183,184,186,187

Evidence suggests that paclitaxel also may induce cell death by triggering apoptosis.183,184,186,187,201 In addition, paclitaxel and docetaxel enhance the effects of ionizing radiation, possibly by blocking cells in the G₂ phase, the phase of the cell cycle in which cells are most radiosensitive.186,223 Preclinical evidence suggests that cross-resistance between paclitaxel and docetaxel is incomplete.206

Pharmacokinetics

Conventional paclitaxel exhibits nonlinear, dose-dependent pharmacokinetics,167,184,185,186,196,198,200 particularly when the drug is administered over shorter periods of infusion (e.g., 3 hours).167,185,186,196,198 Both saturable distribution and elimination contribute to the nonlinear disposition of conventional paclitaxel.45,167,185,186,198,246 Although the relevance of these findings in humans is unknown, a study in mice comparing the pharmacokinetic profiles of differing formulations of paclitaxel suggests that the nonlinear distribution of conventional paclitaxel may be related to the formulation vehicle, polyoxyl 35 castor oil (Cremophor^® EL, polyoxyethylated castor oil).185 Because of the nonlinearity of pharmacokinetics for conventional paclitaxel, relatively small changes in dose may lead to large changes in peak plasma concentrations and total drug exposure.45,124,185,186,196,200 The pharmacokinetics of conventional paclitaxel in patients with AIDS-related Kaposi's sarcoma have not been evaluated.1 In addition, the disposition of conventional paclitaxel and its metabolites has not been evaluated in geriatric patients.184

Absorption

Conventional Paclitaxel

Peak plasma concentrations and areas under the plasma concentration-time curve (AUCs) following IV administration of paclitaxel exhibit marked interindividual variation.184 Plasma concentrations of paclitaxel increase during continuous IV administration of the drug and decline immediately following completion of the infusion.183,184 Following 24-hour IV infusion of paclitaxel at doses of 135 or 175 mg/m² in patients with advanced ovarian cancer, peak plasma concentrations averaged 195 or 365 ng/mL, respectively; the increase in dose (30%) was associated with a disproportionately greater increase in peak plasma concentration (87%), but the increase in AUC was proportional.1 When paclitaxel was administered by continuous IV infusion over 3 hours at doses of 135 or 175 mg/m² in patients with advanced ovarian cancer, peak plasma concentrations averaged 2.17 or 3.65 mcg/mL, respectively; the increase in dose (30%) was associated with disproportionately greater increases in peak plasma concentration (68%) and AUC (89%).1

Albumin-bound Paclitaxel

For the dose range 80-375 mg/m², increase in dose of albumin-bound paclitaxel was associated with a proportional increase in AUC.354 The duration of infusion did not affect the pharmacokinetic disposition of albumin-bound paclitaxel.354 Following 30-minute or 3-hour IV infusion of albumin-bound paclitaxel 260 mg/m² in patients with metastatic breast cancer, the peak plasma concentration averaged 18,741 ng/mL.354

Distribution

At plasma concentrations ranging from 0.1-50 mcg/mL, 88-98% of paclitaxel is bound to plasma proteins.1,20,45,124,183,184,246,354

Conventional Paclitaxel

Following IV administration, paclitaxel is widely distributed into body fluids and tissues.1,45,183,184 Paclitaxel has a large volume of distribution that appears to be affected by dose and duration of infusion.183 Following administration of paclitaxel doses of 135 or 175 mg/m² by IV infusion over 24 hours in patients with advanced ovarian cancer, the mean apparent volume of distribution at steady state ranged from 227-688 L/m².1 The steady-state volume of distribution ranged from 18.9-260 L/m² in children with solid tumors or refractory leukemia receiving paclitaxel 200-500 mg/m²by 24-hour IV infusion.183,200

Paclitaxel does not appear to readily penetrate the CNS,20,45,183,184,186,199 but paclitaxel has been detected in ascitic fluid following IV infusion of the drug.20,45 It is not known whether paclitaxel is distributed into human milk, but in lactating rats given radiolabeled paclitaxel, concentrations of radioactivity in milk were higher than those in plasma and declined in parallel with plasma concentrations of the drug.1

Albumin-bound Paclitaxel

Paclitaxel bound to nanoparticles of the serum protein albumin is delivered via endothelial transport mediated by albumin receptors, and the resulting concentration of paclitaxel in tumor cells is increased compared with that achieved using an equivalent dose of conventional paclitaxel.357

Like conventional paclitaxel, albumin-bound paclitaxel has a large volume of distribution.354 Following 30-minute or 3-hour IV infusion of 80-375 mg/m² albumin-bound paclitaxel, the volume of distribution averaged 632 L/m².354 The volume of distribution of albumin-bound paclitaxel 260 mg/m² by 30-minute IV infusion was 53% larger than the volume of distribution of conventional paclitaxel 175 mg/m² by 3-hour IV infusion.354

Elimination

Paclitaxel is extensively metabolized in the liver.183,184,186,197,205,246 Metabolism of paclitaxel to its major metabolite, 6α-hydroxypaclitaxel, is mediated by cytochrome P-450 isoenzyme CYP2C8,1,185,187,202,354 while metabolism to 2 of its minor metabolites, 3'- p -hydroxypaclitaxel and 6α,3'- p -dihydroxypaclitaxel, is catalyzed by CYP3A4.1,202,354

Conventional Paclitaxel

Following IV infusion of paclitaxel over periods ranging from 6-24 hours in adults with malignancy, plasma concentrations of paclitaxel appeared to decline in a biphasic manner in some studies,1,183,186,265 with an average distribution half-life (t_½α) of 0.34 hours and an average elimination half-life (t_½β) of 5.8 hours.186 However, additional studies, particularly those in which paclitaxel is administered over shorter periods of infusion, show that the drug exhibits nonlinear pharmacokinetic behavior.183,186,196 In patients receiving paclitaxel 175 mg/m²administered by 3-hour IV infusion, the distribution half-life (t_½α) averages 0.27 hours and the elimination half-life (t_½β) averages 2.33 hours.246

The plasma clearance of paclitaxel was studied in patients with ovarian cancer; the total body clearance averaged 12.2 L/hour per m² in those receiving paclitaxel 175 mg/m² by 3-hour IV infusion, 17.7 L/hour per m² in those receiving paclitaxel 135 mg/m² by 3-hour IV infusion, and 21.7 L/hour per m² in those receiving paclitaxel 135 mg/m² by 24-hour IV infusion.1

Paclitaxel and its metabolites are excreted principally in the feces via biliary elimination.184,196,197,205,246 Urinary excretion of paclitaxel is minimal,183,184,196,197,198,205 with unchanged drug in urine typically accounting for less than 10% of an administered dose.196,197,205,246 Following IV administration of paclitaxel over 1, 6, or 24 hours, 1.3-12.6% of the dose was excreted as unchanged drug in the urine.1 In patients receiving 3-hour IV infusions of radiolabeled paclitaxel, a mean of 71% of the radioactivity (about 5% of which was unchanged drug) was excreted in the feces in 120 hours and 14% was recovered in urine.1

Administration of cisplatin followed by paclitaxel decreases paclitaxel clearance by approximately 25-33%.1,186,188,203 When cisplatin and paclitaxel must be administered sequentially, the sequence of paclitaxel followed by cisplatin is recommended.25 (See Drug Interaction: Antineoplastic Agents.)

The effect of renal impairment on the elimination of conventional paclitaxel has not been fully established.1,20,23,183 Paclitaxel is metabolized mainly in the liver,183,184,186,197,205 and limited data indicate that clearance of conventional paclitaxel is reduced in patients with hepatic impairment.1,183,184 The frequency and severity of myelotoxicity associated with paclitaxel may be increased in patients with elevated serum total bilirubin concentrations, and dosage reduction is advised.1 (See Dosage in Renal and Hepatic Impairment.)

Paclitaxel appears to be minimally removed by hemodialysis.183 In a patient undergoing hemodialysis approximately 24 hours following administration of paclitaxel 135 mg/m² by 3-hour IV infusion, paclitaxel was not detected in the dialysate; AUC and clearance of paclitaxel were within the range of values reported for patients not undergoing dialysis.183

Albumin-bound Paclitaxel

Following 30-minute or 3-hour IV infusion of 80-375 mg/m² albumin-bound paclitaxel, plasma concentrations of paclitaxel declined in a biphasic manner with initial rapid distribution to the peripheral compartment and then a slower phase of elimination; the terminal half-life of albumin-bound paclitaxel was about 27 hours.354 The total body clearance of albumin-bound paclitaxel averaged 15 L/hour per m².354 The plasma clearance of albumin-bound paclitaxel 260 mg/m² by 30-minute IV infusion was 43% higher than the plasma clearance of conventional paclitaxel 175 mg/m² by 3-hour IV infusion.354

Urinary excretion of albumin-bound paclitaxel is minimal.354 Following 30-minute IV infusion of albumin-bound paclitaxel 260 mg/m², about 4% of the dose was excreted in the urine as unchanged drug and less than 1% was excreted as metabolites.354 Approximately 20% of the dose was excreted in feces.354

Following 30-minute IV infusion of albumin-bound paclitaxel 260 or 200 mg/m² in patients with mild or moderate hepatic impairment, respectively, systemic exposure to the drug was similar to values previously reported for patients with normal hepatic function.354,364 In patients with severe hepatic impairment, systemic exposure following 30-minute IV infusion of albumin-bound paclitaxel 130 mg/m² was lower than reported exposure levels for patients with normal hepatic function.354 In addition, mean nadir neutrophil counts in cycle 1 were higher in patients with severe hepatic impairment compared with patients with mild or moderate hepatic impairment.354 Doses of 200 mg/m² have not been evaluated in patients with severe hepatic impairment but are predicted to result in systemic exposure levels similar to those reported for patients with normal hepatic function.354 Pharmacokinetics of albumin-bound paclitaxel have not been elucidated in patients with AST concentrations exceeding 10 times the upper limit of normal or bilirubin concentrations of 5 or more times the upper limit of normal.354

The effect of renal impairment on the elimination of albumin-bound paclitaxel has not been established.354

Chemistry and Stability

Chemistry

Paclitaxel, a natural product extracted from the bark of the Western (Pacific) yew ( Taxus brevifolia ) or produced from the needles and twigs of a more prevalent yew ( Taxus baccata ) using a semisynthetic process, is an antineoplastic agent.1,2,3,4,6,7,20,22,71,183 Paclitaxel also is obtained from Taxus media .354 The taxanes (paclitaxel and docetaxel) differ structurally from other currently available antineoplastic agents.2,3,6,7,20,206,246 Because of paclitaxel's complex, unusual chemistry, supplies initially were limited to drug extracted from the slow-growing Western (Pacific) yew.2,3,4,5,6 An alternative method allowing preparation of the drug in larger yields (i.e., a semisynthetic method using a precursor extracted from needles and twigs of a more prevalent yew) has been developed; semisynthetic paclitaxel is bioequivalent to the natural drug.71,184 Additional sources of the drug (e.g., production of paclitaxel by Taxomyces andreanae , an endophytic fungus associated with Pacific yew) continue to be explored.2,3,4,5,6,8,9,22,71

Paclitaxel is a complex diterpene with a taxane ring system and a four-membered oxetane ring.2,3,4,5,6,20,45,185 An ester side chain at position 13 of the taxane ring is essential for the drug's cytotoxic activity.2,3,6,20,45,185,187 In addition, presence of an accessible hydroxyl group at position 2' of this ester side chain enhances the drug's activity.3,6 Paclitaxel differs structurally from docetaxel by the presence of an acetyl group rather than a hydroxyl group on position 10 of the baccatin III ring and by a benzamide phenyl group instead of a trimethylmethoxy moiety on the 3' position of the side chain at position 13 of the taxane ring.206

Paclitaxel occurs as a white to off-white crystalline powder.1,45,354 Paclitaxel is highly lipophilic and insoluble in water.1,263,354

Conventional Paclitaxel

Because paclitaxel is extremely hydrophobic,1,2,20 the commercially available injection concentrate is a sterile, nonaqueous solution of the drug in polyoxyl 35 castor oil (Cremophor^® EL, polyoxyethylated castor oil) and dehydrated alcohol.1,7,20,189 Commercially available paclitaxel for injection concentrate is a clear, colorless to slightly yellow, viscous solution.1,45 Following dilution of paclitaxel for injection concentrate with 5% dextrose and 0.9% sodium chloride injection or 5% dextrose and Ringer's injection, solutions containing 0.6 or 1.2 mg of paclitaxel per mL maintain a pH of 4.4-5.6 for up to 27 hours.23,263

Albumin-bound Paclitaxel

Paclitaxel is commercially available as protein-bound particles consisting of paclitaxel bound to albumin; the mean particle size of albumin-bound paclitaxel is about 130 nm.354 Albumin-bound paclitaxel is a sterile, white to yellow lyophilized powder that must be reconstituted for use as an injectable suspension; there are no solvents.354 Each single-use vial contains 100 mg of paclitaxel and approximately 900 mg of human albumin.354

Stability

Conventional Paclitaxel

Commercially available paclitaxel for injection concentrate should be stored in unopened vials at 20-25°C and retained in the original package for protection from light.1,214 Neither freezing nor refrigeration adversely affects paclitaxel for injection concentrate.1,20 Refrigeration may result in precipitation of the drug or formulation vehicle;1 however, the precipitate typically will dissolve at room temperature without loss of potency.23,1 If freezing occurs, paclitaxel for injection concentrate may be thawed at room temperature until precipitate dissolves; the manufacturer states that the chemical or physical stability of the injection is not affected.1,23 If the solution remains cloudy or if an insoluble precipitate remains at room temperature, the vial should be discarded.1 When stored under recommended conditions, unopened vials of commercially available paclitaxel for injection concentrate are stable until the date indicated on the package.1

The manufacturer states that, when diluted as directed, paclitaxel solutions are stable for up to 27 hours when stored at approximately 25°C under ambient lighting conditions.1,20,45,263

Contact of undiluted paclitaxel for injection concentrate with plasticized polyvinyl chloride (PVC) equipment or devices used to prepare solutions for infusion is not recommended.1,11,12,189,195 Polyoxyl 35 castor oil can cause leaching of diethylhexylphthalate (DEHP) from PVC containers11,12 and, following dilution of paclitaxel for injection concentrate in PVC containers, substantial leaching of DEHP occurs in a time- and concentration-dependent manner.1,11,191 To minimize exposure of the patient to leached DEHP, diluted paclitaxel solutions preferably should be stored in glass or polypropylene bottles or in plastic (polypropylene or polyolefin) bags and administered through polyethylene-lined administration sets.1,11,12,20,45 Leaching of unacceptable amounts of DEHP has been reported with some administration sets labeled as not containing PVC (probably because of pumping segments made of heavily plasticized PVC);195 therefore, compatibility of administration sets with paclitaxel solutions should be verified prior to their use.189

Solutions of paclitaxel prepared with 5% dextrose injection or 0.9% sodium chloride injection at concentrations of 0.3-1.2 mg/mL reportedly were chemically and physically stable for up to 48 hours when prepared and stored in polyolefin containers at ambient temperature (20-23°C) under normal fluorescent light;190 however, in this study, physical stability was determined only by the absence of gross precipitation.189,190 In another study, paclitaxel solutions of 0.1 and 1 mg/mL in 5% dextrose injection or 0.9% sodium chloride injection were stable for up to 3 days when prepared and stored in polyolefin bags at 4, 22, or 32°C.193 Extemporaneously compounded admixtures of paclitaxel 1 mg/mL in 5% dextrose solution with addition of dehydrated alcohol injection to achieve a final ethanol concentration of 20 or 25% were chemically and physically stable for up to 7 days when prepared and stored in polyolefin containers at 4, 22, or 32°C.194

Solutions of paclitaxel have been reported to be physically incompatible with various drugs, including amphotericin B, chlorpromazine hydrochloride, hydroxyzine hydrochloride, methylprednisolone sodium succinate, and mitoxantrone hydrochloride.189,192 The physical and/or chemical compatibility of paclitaxel with other drugs depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature); studies evaluating the stability of paclitaxel with other drugs, particularly other antineoplastic agents, are ongoing.189,264 Specialized references should be consulted for specific information.264

Because a small number of fibers (within acceptable USP limits) have been detected in paclitaxel solutions prepared from the commercially available for injection concentrate,7,20,45 a hydrophilic, microporous inline filter with a pore size not exceeding 0.22 µm is necessary during administration of paclitaxel solutions.1,7,20,45 The manufacturer reports that 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

Diluted solutions of paclitaxel may appear hazy.1,11,20,45,189 When such solutions are passed through a 0.22-µm filter, no clinically important loss of potency is observed, suggesting that the haze is caused by the formulation vehicle rather than precipitation of the drug.1,11,20

Albumin-bound Paclitaxel

Commercially available albumin-bound paclitaxel for injectable suspension should be stored in unopened vials at 20-25°C and retained in the original package for protection from bright light.354 Neither freezing nor refrigeration adversely affects albumin-bound paclitaxel for injectable suspension.354 When stored under recommended conditions, unopened vials of commercially available albumin-bound paclitaxel for injectable suspension are stable until the date indicated on the package.354

Reconstituted suspensions of albumin-bound paclitaxel should be used immediately; if immediate use is not possible, vials of reconstituted albumin-bound paclitaxel suspension may be placed in the original carton to protect them from bright light and refrigerated at 2-8°C for up to 8 hours.354 After 8 hours, any unused portion of the reconstituted albumin-bound paclitaxel suspension should be discarded.354

Before the dosing volume is withdrawn from the vial, the suspension should be inspected.354 Settling of the reconstituted albumin-bound paclitaxel suspension may occur.354 Mild agitation of the vial should ensure complete resuspension of the albumin-bound paclitaxel.354 If particulates are visible after mild agitation of the vial, the suspension should be discarded and another reconstituted albumin-bound paclitaxel suspension should be prepared.354 When reconstituted as directed, albumin-bound paclitaxel suspension is stable in the IV infusion bag for up to 4 hours when stored at approximately 25°C under ambient lighting conditions.354

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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