Abraxane

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

The metabolism of TAXOL is catalyzed by cytochrome P450 isoen-zymes CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering TAXOL concomitantly with known substrates or inhibitors of the cytochrome P450 isoenzymes CYP2C8 and CYP3A4.

Potential interactions between TAXOL, 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: TAXOL 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 TAXOL. Patients should not be re-treated with subsequent cycles of TAXOL 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 seven days or more) during a course of TAXOL 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, TAXOL, 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 TAXOL. In order to avoid the occurrence of severe hypersensitivity reactions, all patients treated with TAXOL should be premedicated with corticosteroids (such as dexamethasone), diphen-hydramine 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 TAXOL and aggressive symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with TAXOL.

Cardiovascular: Hypotension, bradycardia, and hypertension have been observed during administration of TAXOL, but generally do not require treatment. Occasionally TAXOL infusions must be interrupted or discontinued because of initial or recurrent hypertension. Frequent vital sign monitoring, particularly during the first hour of TAXOL infusion, is recommended. Continuous cardiac monitoring is not required except for patients with serious conduction abnormalities.

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 subsequentcourses of TAXOL.

TAXOL contains dehydrated alcohol USP, 396 mg/mL; consideration should be given to possible CNS and other effects of alcohol.

Hepatic: There is limited evidence that the myelotoxicity of TAXOL may be exacerbated in patients with serum total bilirubin >2 times ULN. Extreme caution should be exercised when administering TAXOL to such patients, with dose reduction as recommended in DOSAGE AND ADMINISTRATION, Table 17.

InjectionSite 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 TAXOL at a different site, ie, "recall", has been reported rarely.

Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been received as part of the continuing surveillance of TAXOL safety. 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.