"Sabahaddin Akman, owner of the Istanbul, Turkey, firm Ozay Pharmaceuticals, has pleaded guilty to charges of smuggling misbranded and adulterated cancer treatment drugs into the United States.
Akman pleaded guilty in the U.S. District Court"...
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2 to 4% of patients receiving TAXOL in clinical trials. Fatal reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H2 antagonists. (See DOSAGE AND ADMINISTRATION.) Patients who experience severe hypersensitivity reactions to TAXOL should not be rechallenged with the drug.
Bone marrow suppression (primarily neutropenia) is dose-dependent and is the dose-limiting toxicity. Neutrophil nadirs occurred at a median of 11 days. TAXOL should not be administered to patients with baseline neutrophil counts of less than 1500 cells/mm3 ( < 1000 cells/mm3 for patients with KS). Frequent monitoring of blood counts should be instituted during TAXOL treatment. Patients should not be re-treated with subsequent cycles of TAXOL until neutrophils recover to a level > 1500 cells/mm3 ( > 1000 cells/mm3 for patients with KS) and platelets recover to a level > 100,000 cells/mm3.
Severe conduction abnormalities have been documented in < 1% of patients during TAXOL therapy and in some cases requiring pacemaker placement. If patients develop significant conduction abnormalities during TAXOL infusion, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with TAXOL.
TAXOL can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel during the period of organogenesis to rabbits at doses of 3.0 mg/kg/day (about 0.2 the daily maximum recommended human dose on a mg/m2 basis) caused embryo- and fetotoxicity, as indicated by intrauterine mortality, increased resorptions, and increased fetal deaths. Maternal toxicity was also observed at this dose. No teratogenic effects were observed at 1.0 mg/kg/day (about 1/15 the daily maximum recommended human dose on a mg/m2 basis); teratogenic potential could not be assessed at higher doses due to extensive fetal mortality.
There are no adequate and well-controlled studies in pregnant women. If TAXOL is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Contact of the undiluted concentrate with plasticized polyvinyl chloride (PVC) equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC infusion bags or sets, diluted TAXOL solutions should preferably be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.
TAXOL should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns. Use of filter devices such as IVEX-2® filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.
Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of TAXOL (paclitaxel) has not been studied.
Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). Paclitaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.
Administration of paclitaxel prior to and during mating produced impairment of fertility in male and female rats at doses equal to or greater than 1 mg/kg/day (about 0.04 the daily maximum recommended human dose on a mg/m2 basis). At this dose, paclitaxel caused reduced fertility and reproductive indices, and increased embryo- and fetotoxicity. (See WARNINGS.)
Pregnancy Category D. (See WARNINGS.)
It is not known whether the drug is excreted in human milk. Following intravenous administration of carbon 14-labeled TAXOL to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving TAXOL therapy.
The safety and effectiveness of TAXOL (paclitaxel) in pediatric patients have not been established.
There have been reports of central nervous system (CNS) toxicity (rarely associated with death) in a clinical trial in pediatric patients in which TAXOL was infused intravenously over 3 hours at doses ranging from 350 mg/m2 to 420 mg/m2. The toxicity is most likely attributable to the high dose of the ethanol component of the TAXOL vehicle given over a short infusion time. The use of concomitant antihistamines may intensify this effect. Although a direct effect of the paclitaxel itself cannot be discounted, the high doses used in this study (over twice the recommended adult dosage) must be considered in assessing the safety of TAXOL for use in this population.
Of 2228 patients who received TAXOL in 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 TAXOL in the adjuvant breast cancer study, 649 patients (17%) were 65 years or older and 49 patients (1%) were 75 years or older. In most studies, severe myelosuppression was more frequent in elderly patients; in some studies, severe neuropathy was more common in elderly patients. In 2 clinical studies in NSCLC, the elderly patients treated with TAXOL had a higher incidence of cardiovascular events. Estimates of efficacy appeared similar in elderly patients and in younger patients; however, comparative efficacy cannot be determined with confidence due to the small number of elderly patients studied. In a study of first-line treatment of ovarian cancer, elderly patients had a lower median survival than younger patients, but no other efficacy parameters favored the younger group. TABLE 9 presents the incidences of Grade IV neutropenia and severe neuropathy in clinical studies according to age.
TABLE 9: SELECTED ADVERSE EVENTS IN GERIATRIC PATIENTS RECEIVING
TAXOL IN CLINICAL STUDIES
|Patients (n/total [%])|
| Peripheral Neuropathy
|Age (y)||Age (y)|
|INDICATION (Study/Regimen)||> 65||< 65||≥ 65||< 65|
|(Intergroup First-Line/T 175/3 c75a)||34/83 (41)||78/252 (31)||24/84 (29)*b||46/255 (18)b|
|(GOG-1 1 1 First-Line/T135/24 c75a)||48/61 (79)||106/129 (82)||3/62 (5)||2/134 (1)|
|(Phase 3 Second-Line/T 175/3c)||5/19 (26)||21/76 (28)||1/19 (5)||0/76 (0)|
|(Phase 3 Second-Line/T 175/24c)||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/T 13 5/24c)||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)|
|•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/T 175/3c)||7/24 (29)||56/200 (28)||3/25 (12)||12/204 (6)|
|(Phase 3/T 135/3c)||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 TAXOL 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 TAXOL dose in mg/m2/infusion duration in hours.
d TAXOL (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.)
Last reviewed on RxList: 6/13/2011
This monograph has been modified to include the generic and brand name in many instances.
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