Paclitaxel (Page 7 of 15)

Hematology

Paclitaxel therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving paclitaxel. Patients should not be retreated with subsequent cycles of paclitaxel until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of paclitaxel therapy, a 20% reduction in dose for subsequent courses of therapy is recommended.

For patients with advanced HIV disease and poor-risk AIDS-related Kaposi’s sarcoma, paclitaxel, at the recommended dose for this disease, can be initiated and repeated if the neutrophil count is at least 1,000 cells/mm3.

Hypersensitivity Reactions

Patients with a history of severe hypersensitivity reactions to products containing Polyoxyl 35 Castor Oil, NF (e.g., cyclosporin for injection concentrate and teniposide for injection concentrate) should not be treated with paclitaxel. In order to avoid the occurrence of severe hypersensitivity reactions, all patients treated with paclitaxel should be premedicated with corticosteroids (such as dexamethasone), diphenhydramine and H2 antagonists (such as cimetidine or ranitidine). Minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia do not require interruption of therapy. However, severe reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria require immediate discontinuation of paclitaxel and aggressive symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with paclitaxel.

Cardiovascular

Hypotension, bradycardia, and hypertension have been observed during administration of Paclitaxel Injection, USP, but generally do not require treatment. Occasionally paclitaxel infusions must be interrupted or discontinued because of initial or recurrent hypertension. Frequent vital sign monitoring, particularly during the first hour of paclitaxel infusion, is recommended. Continuous cardiac monitoring is not required except for patients with serious conduction abnormalities (see WARNINGS section). When paclitaxel is used in combination with doxorubicin for treatment of metastatic breast cancer, monitoring of cardiac function is recommended (see ADVERSE REACTIONS).

Nervous System

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

Paclitaxel contains Dehydrated Alcohol USP, 396 mg/mL; consideration should be given to possible CNS and other effects of alcohol (see PRECAUTIONS, Pediatric Use section).

Hepatic

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

Injection Site Reaction

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

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

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of paclitaxel has not been studied.

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

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

Pregnancy

Pregnancy Category D

(See WARNINGS section)

Nursing Mothers

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

Pediatric Use

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

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

Geriatric Use

Of 2228 patients who received paclitaxel in 8 clinical studies evaluating its safety and effectiveness in the treatment of advanced ovarian cancer, breast carcinoma, or NSCLC, and 1570 patients who were randomized to receive paclitaxel in the adjuvant breast cancer study, 649 patients (17%) were 65 years or older and 49 patients (1%) were 75 years or older. In most studies, severe myelosuppression was more frequent in elderly patients; in some studies, severe neuropathy was more common in elderly patients. In 2 clinical studies in NSCLC, the elderly patients treated with paclitaxel had a higher incidence of cardiovascular events. Estimates of efficacy appeared similar in elderly patients and in younger patients; however, comparative efficacy cannot be determined with confidence due to the small number of elderly patients studied. In a study of first-line treatment of ovarian cancer, elderly patients had a lower median survival than younger patients, but no other efficacy parameters favored the younger group. Table 9 presents the incidences of Grade IV neutropenia and severe neuropathy in clinical studies according to age.

Table 9. Selected Adverse Events in Geriatric Patients Receiving Paclitaxel in Clinical Studies

* p<0.05

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

b Peripheral neuropathy was included within the neurotoxicity category in the Intergroup First-Line Ovarian Cancer study (see Table 11).

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

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

e Peripheral neuropathy reported as neurosensory toxicity in the Intergroup Adjuvant Breast Cancer study (see Table 13).

f Peripheral neuropathy reported as neurosensory toxicity in the ECOG NSCLC study (see Table 15).

INDICATION (Study/Regimen) Patients (n/total [%])
Neutropenia (Grade IV) Peripheral Neuropathy (Grades III/IV)
Age (y) Age (y)
≥65 <65 ≥65 <65
• OVARIAN Cancer
(Intergroup First-Line/T175/3 c75a)(GOG-111 First-Line/T135/24 c75a)(Phase 3 Second-Line/T175/3c)(Phase 3 Second-Line/T175/24c)(Phase 3 Second-Line/T135/3c)(Phase 3 Second-Line/T135/24c)(Phase 3 Second-Line Pooled) 34/83 (41)48/61 (79)5/19 (26)21/25 (84)4/16 (25)17/22 (77)47/82 (57)* 78/252 (31)106/129 (82)21/76 (28)57/79 (72)10/81 (12)53/83 (64)141/319 (44) 24/84 (29)*b 3/62 (5)1/19 (5)0/25 (0)0/17 (0)0/22 (0)1/83 (1) 46/255 (18)b 2/134 (1)0/76 (0)2/80 (3)0/81 (0)0/83 (0)2/320 (1)
• Adjuvant BREAST Cancer
(Intergroup/AC followed by Td) 56/102 (55) 734/1468 (50) 5/102 (5)e 46/1468 (3)e
• BREAST Cancer after Failure of Initial Therapy
(Phase 3/T175/3c)(Phase 3/T135/3c) 7/24 (29)7/20 (35) 56/200 (28)37/207 (18) 3/25 (12)0/20 (0) 12/204 (6)6/209 (3)
• Non-Small Cell LUNG Cancer
(ECOG/T135/24 c75a)(Phase 3/T175/3 c80a) 58/71 (82)37/89 (42)* 86/124 (69)56/267 (21) 9/71 (13)f 11/91 (12)* 16/124 (13)f 11/271 (4)

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