Paclitaxel (Page 4 of 7)

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

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 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 1,570 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

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

* 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).

Information for Patients (See Patient Information Leaflet).

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