Abraxane (paclitaxel protein-bound)

Paclitaxel is commercially available in 2 types of formulations: conventional paclitaxel (in a nonaqueous solution) and albumin-bound paclitaxel. The functional properties of paclitaxel may differ according to formulation, and the dosage instructions for paclitaxel are specific to formulation. Albumin-bound paclitaxel may not be substituted for or used in combination with other formulations of paclitaxel. Clinicians should consult the respective manufacturer's labeling and published protocols for formulation-specific regimens and specific dosages, methods of administration, and administration sequence of other antineoplastic agents used in combination regimens.

Dosage of albumin-bound paclitaxel is expressed in terms of paclitaxel.

Conventional or albumin-bound paclitaxel should not be administered to patients with baseline neutrophil counts less than 1500/mm3. In patients with HIV infection, conventional paclitaxel should not be administered if baseline neutrophil counts are less than 1000/mm3. To monitor the occurrence of paclitaxel-induced bone marrow suppression, mainly neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed in all patients receiving paclitaxel.

Response rates for paclitaxel therapy vary with tumor histology, volume of residual tumor, and development of resistance to previous platinum-based chemotherapy.

Current evidence suggests that increased dose intensity (amount of paclitaxel per unit time) may affect response to paclitaxel but that paclitaxel doses exceeding 175 mg/m2 are more toxic and do not improve survival in patients with advanced ovarian cancer. In addition to dose effect, the effect of duration of infusion of paclitaxel has been studied in patients with ovarian cancer. Efficacy was similar but toxicity, particularly myelosuppression, was greater when paclitaxel alone was administered by 24-hour versus 3-hour infusion for the subsequent therapy of advanced ovarian cancer. Limited evidence suggests that subsequent therapy with prolonged infusion of paclitaxel (96-hour IV infusion) does not produce response in patients with advanced ovarian cancer that was resistant to previous therapy with the drug administered by 3-hour or 24-hour IV infusion.

The effect of duration of infusion on the efficacy and toxicity of paclitaxel administered as a component of combination therapy also has not been fully established. Increased incidence and severity of neurotoxicity is associated with administration of paclitaxel by 3-hour IV infusion in combination therapy with cisplatin in patients with gynecologic cancers. In a large randomized trial, patients with advanced ovarian cancer receiving paclitaxel (175 mg/m2 administered as a 3-hour IV infusion) and cisplatin had an increased incidence of severe neurosensory toxicity compared with those receiving cyclophosphamide and cisplatin. Prolonged paclitaxel infusions do not appear to offer benefit in the treatment of ovarian cancer. In a randomized trial comparing 96-hour infusion of paclitaxel 120 mg/m2 with 24-hour infusion of paclitaxel 135 mg/m2 (each in a combination regimen of paclitaxel and cisplatin) for suboptimal stage III or IV ovarian epithelial cancer, median survival rates were similar between the groups but the relative death rate was approximately 5% greater among patients receiving the prolonged infusion of paclitaxel.

Maintenance therapy with paclitaxel for advanced ovarian cancer+ is being investigated. In a randomized trial, patients receiving 12 months of single-agent paclitaxel therapy following complete response to induction therapy with platinum/paclitaxel therapy for advanced ovarian cancer experienced longer progression-free survival but greater neurotoxicity than those receiving 3 months of such therapy. Because the trial was terminated according to study design following a planned interim analysis that detected the difference in progression-free survival, and cross-over treatment was allowed, overall survival data may be unavailable. Whether maintenance therapy with paclitaxel is superior to treatment upon progression of disease is unclear, and a confirmatory randomized trial is needed. Until further evidence is available, clinicians should discuss maintenance paclitaxel therapy and offer it as an option for patients with advanced ovarian cancer that has a complete response to induction therapy.

The effect of renal impairment on the disposition of paclitaxel has not been fully established. Reduction of paclitaxel dosage in patients with impaired renal function does not appear to be necessary.

Paclitaxel is metabolized mainly in the liver, and increased toxicity may occur in patients with hepatic impairment.

When dosage modification is necessary for patients receiving albumin-bound paclitaxel and gemcitabine for pancreatic cancer, dosage of albumin-bound paclitaxel should be reduced in decrements of 25 mg/m2 (i.e., 1 dose level) and dosage of gemcitabine should be reduced in decrements of 200 mg/m2 (i.e., 1 dose level); however, if a dose of albumin-bound paclitaxel 75 mg/m2 or gemcitabine 600 mg/m2 requires further reduction, both drugs should be discontinued.

Patients should be monitored closely since toxicity associated with paclitaxel may be exacerbated in patients with hepatic impairment. Paclitaxel should be used with caution in patients with hepatic impairment, and dosage reduction is recommended depending on the degree of hepatic impairment. No adjustment of the initial dosage is required in patients with mild hepatic impairment.

Toxicity associated with paclitaxel, particularly grade 3 or 4 myelosuppression, may be exacerbated in patients with serum total bilirubin concentrations greater than 2 times the upper limit of normal. Paclitaxel should be used with extreme caution in patients with hepatic impairment, and dosage reduction is recommended depending on the degree of hepatic impairment. Such patients should be monitored closely for the development of profound myelosuppression.

For patients receiving conventional paclitaxel as a 24-hour IV infusion for ovarian or non-small cell lung cancer, the usual dose of 135 mg/m2 may be administered for the first course of therapy in those who have serum transaminase concentrations less than 2 times the upper limit of normal and serum bilirubin concentrations up to 1.5 mg/dL; for patients with elevated serum transaminase concentrations less than 10 times the upper limit of normal and serum bilirubin concentrations up to 1.5 mg/dL, a reduced dose of paclitaxel 100 mg/m2 is recommended; for patients with elevated serum transaminase concentrations less than 10 times the upper limit of normal and serum bilirubin concentrations of 1.6-7.5 mg/dL, a reduced dose of paclitaxel 50 mg/m2 is recommended. For patients with elevated serum transaminase concentrations at least 10 times the upper limit of normal or serum bilirubin concentrations exceeding 7.5 mg/dL, paclitaxel therapy is not recommended.

For patients receiving conventional paclitaxel as a 3-hour IV infusion for ovarian or breast cancer, the usual dose of 175 mg/m2 may be administered for the first course of therapy in those who have serum transaminase concentrations less than 10 times the upper limit of normal and serum bilirubin concentrations up to 1.25 times the upper limit of normal; for patients with serum transaminase concentrations less than 10 times the upper limit of normal and serum bilirubin concentrations of 1.26-2 times the upper limit of normal, a reduced dose of paclitaxel 135 mg/m2 is recommended; for patients with serum transaminase concentrations less than 10 times the upper limit of normal and serum bilirubin concentrations of 2.01-5 times the upper limit of normal, a reduced dose of paclitaxel 90 mg/m2 is recommended. For patients with elevated serum transaminase concentrations at least 10 times the upper limit of normal or serum bilirubin concentrations exceeding 5 times the upper limit of normal, paclitaxel therapy is not recommended.

Further reduction of paclitaxel dosage for subsequent courses of therapy should be based on patient tolerance.

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There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

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There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

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Paclitaxel can cause fetal toxicity when administered to pregnant women, but potential benefits may be acceptable in certain conditions despite the possible risks to the fetus.

Reproduction studies in rabbits receiving IV conventional paclitaxel doses of 3 mg/kg daily (approximately 0.2 times the maximum recommended human dose on a mg/m2 basis) during organogenesis revealed evidence of maternal toxicity, embryotoxicity, and fetotoxicity. The drug caused intrauterine mortality, increased resorptions, and increased fetal deaths. Reproduction studies in rats receiving IV paclitaxel doses of 1 mg/kg daily (approximately 0.04 times the maximum recommended human dose on a mg/m2 basis) during organogenesis resulted in embryotoxicity and fetotoxicity. No teratogenic effects were observed in the offspring of rats receiving daily IV paclitaxel doses of 1 mg/kg; however, the teratogenic potential of higher paclitaxel doses could not be assessed because of extensive fetal mortality.

Reproduction studies in rats receiving albumin-bound paclitaxel at IV doses of 6 mg/m2 (approximately 2% of the maximum recommended human dose on a mg/m2 basis) on gestation days 7 to 17 resulted in embryotoxicity and fetotoxicity. The drug caused intrauterine mortality, increased resorptions, reduced numbers of litters, increased fetal deaths, reduction in fetal body weight, and increased fetal anomalies including soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. Fetal anomalies also occurred in the offspring of rats receiving lower doses of albumin-bound paclitaxel (IV doses of 3 mg/m2 or approximately 1% of the maximum recommended human dose on a mg/m2 basis).

There are no adequate and well-controlled studies to date using paclitaxel in pregnant women. Paclitaxel should be used during pregnancy only in life-threatening situations or for severe disease for which safer drugs cannot be used or are ineffective. When paclitaxel is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with paclitaxel. Men receiving albumin-bound paclitaxel should be advised to avoid fathering a child.

It is not known whether paclitaxel is distributed into human milk. However, in lactating rats given radiolabeled paclitaxel, concentrations of radioactivity in milk were higher than those in plasma and declined in parallel with plasma concentrations of the drug. Because of the potential for serious adverse reactions to paclitaxel in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

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