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Paclitaxel (Paclitaxel) - Warnings and Precautions

 
 



WARNING

Paclitaxel Injection, USP should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2 to 4% of patients receiving paclitaxel in clinical trials. Fatal reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H2 antagonists. (See DOSAGE AND ADMINISTRATION.) Patients who experience severe hypersensitivity reactions to paclitaxel should not be rechallenged with the drug.

Paclitaxel Injection, USP therapy should not be given to patients with solid tumors who have baseline neutrophil counts of less than 1500 cells/mm3 and should not be given to patients with AIDS-related Kaposi's sarcoma if the baseline neutrophil count is less than 1000 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving Paclitaxel Injection, USP.

 

WARNINGS

Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2 to 4% of patients receiving paclitaxel in clinical trials. Fatal reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H2 antagonists. (See DOSAGE AND ADMINISTRATION.) Patients who experience severe hypersensitivity reactions to paclitaxel should not be rechallenged with the drug.

Bone marrow suppression (primarily neutropenia) is dose-dependent and is the dose-limiting toxicity. Neutrophil nadirs occurred at a median of 11 days. Paclitaxel Injection, USP should not be administered to patients with baseline neutrophil counts of less than 1500 cells/mm3 (<1000 cells/mm3 for patients with KS). Frequent monitoring of blood counts should be instituted during Paclitaxel Injection, USP treatment. Patients should not be re-treated with subsequent cycles of Paclitaxel Injection, USP until neutrophils recover to a level >1500 cells/mm3 (>1000 cells/mm3 for patients with KS) and platelets recover to a level >100,000 cells/mm3.

Severe conduction abnormalities have been documented in <1% of patients during paclitaxel therapy and in some cases requiring pacemaker placement. If patients develop significant conduction abnormalities during paclitaxel infusion, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with paclitaxel.

Pregnancy

Paclitaxel can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel during the period of organogenesis to rabbits at doses of 3.0 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 Paclitaxel Injection, USP 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.

PRECAUTIONS

Contact of the undiluted concentrate with plasticized polyvinyl chloride (PVC) equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC infusion bags or sets, diluted Paclitaxel Injection, USP solutions should preferably be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

Paclitaxel Injection, USP 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.

Drug Interactions: In a Phase 1 trial using escalating doses of paclitaxel (110 to 200 mg/m2) and cisplatin (50 or 75 mg/m2) given as sequential infusions, myelosuppression was more profound when paclitaxel was given after cisplatin than with the alternate sequence (ie, paclitaxel before cisplatin). Pharmacokinetic data from these patients demonstrated a decrease in paclitaxel clearance of approximately 33% when paclitaxel was administered following cisplatin.

The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Caution should be exercised when paclitaxel is concomitantly administered with known substrates (eg, midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (eg, rifampin and carbamazepine) of CYP3A4. (See CLINICAL PHARMACOLOGY.)

Caution should also be exercised when paclitaxel is concomitantly administered with known substrates (eg, repaglinide and rosiglitazone), inhibitors (eg, gemfibrozil), and inducers (eg, rifampin) of CYP2C8. (See CLINICAL PHARMACOLOGY.)

Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors (ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of CYP3A4, have not been evaluated in clinical trials.

Reports in the literature suggest that plasma levels of doxorubicin (and its active metabolite doxorubicinol) may be increased when paclitaxel and doxorubicin are used in combination.

Hematology: Paclitaxel therapy should not be administered to patients with baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving paclitaxel. Patients should not be re-treated with subsequent cycles of paclitaxel until neutrophils recover to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of paclitaxel therapy, a 20% reduction in dose for subsequent courses of therapy is recommended.

For patients with advanced HIV disease and poor-risk AIDS-related Kaposi's sarcoma, paclitaxel, at the recommended dose for this disease, can be initiated and repeated if the neutrophil count is at least 1000 cells/mm3.

Hypersensitivity Reactions: Patients with a history of severe hypersensitivity reactions to products containing Cremophor® EL (eg, cyclosporin for injection concentrate and teniposide for injection concentrate) should not be treated with Paclitaxel Injection, USP. 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, 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.) 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 Injection, USP.

Paclitaxel Injection, USP contains dehydrated alcohol USP, 385 mg/mL; consideration should be given to possible CNS and other effects of alcohol. (See PRECAUTIONS: Pediatric Use.)

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, ie, “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 10 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 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: Pregnancy Category D. (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 eight clinical studies evaluating its safety and effectiveness in the treatment of advanced ovarian cancer, breast carcinoma, or NSCLC, and 1570 patients who were randomized to receive paclitaxel in the adjuvant breast cancer study, 649 patients (17%) were 65 years or older and 49 patients (1%) were 75 years or older. In most studies, severe myelosuppression was more frequent in elderly patients; in some studies, severe neuropathy was more common in elderly patients. In two clinical studies in NSCLC, the elderly patients treated with paclitaxel had a higher incidence of cardiovascular events. Estimates of efficacy appeared similar in elderly patients and in younger patients; however, comparative efficacy cannot be determined with confidence due to the small number of elderly patients studied. In a study of first-line treatment of ovarian cancer, elderly patients had a lower median survival than younger patients, but no other efficacy parameters favored the younger group. TABLE 9 presents the incidences of Grade IV neutropenia and severe neuropathy in clinical studies according to age.

TABLE 9

* 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).

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) ≥65 <65 ≥65 <65
 OVARIAN 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)
 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) 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)

Information for Patients: (See Patient Information Leaflet.)

Page last updated: 2011-11-23

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