Oncology: Paclitaxel Protein-Bound Particles for Injectable Suspension (Abraxane)
Manufacturer: American Pharmaceutical Partners, Inc./American Bioscience, Inc.
Description: Abraxane™ combines the active drug pacli-taxel (Taxol®, Bristol-Myers Squibb) with a natural protein (albumin) into a nanoparticle that is one-hundredth the size of a red blood cell. As a result, no solvent is needed. This product is the first approved solvent-free, nanoparticle albumin-bound chemotherapeutic agent. It has the potential to exploit an inherent pathway for albumin receptor-mediated transport of drugs across the endothelial cell walls of the tumor neo-vasculature.
Indication: Abraxane™ is indicated for the treatment of metastatic breast cancer after failure of combination chemotherapy or relapse within six months of adjuvant chemotherapy. Unless it has been clinically contraindicated, prior therapy should have included an anthracycline.
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Pharmacology: The FDA’s approval was based on the results of clinical trials comparing the effect of albumin-bound paclitaxel particles (260 mg/m2) infused over 30 minutes with that of paclitaxel (175 mg/m2) plus standard premedication, infused over three hours.
Treatment with the higher-dose, albumin-bound paclitaxel was associated with a significant increase in target lesion response rates compared with paclitaxel. In a pivotal clinical trial involving 460 women, tumors shrank in 21.5% of patients who received paclitaxel protein-bound particles for injectable suspension, compared with 11.1% of those who received paclitaxel. The manufacturer has not yet provided data on whether the suspension extended the lives of those women, which is a more important measurement.
Black-Box Warning: Abraxane™ 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.
This agent should not be given to patients with metastatic breast cancer who have baseline ANC counts below 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, frequent peripheral blood cell counts should be performed for all patients receiving the suspension. kamagra uk
Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of the drug in solution. No other paclitaxel formulation should be substituted.
Precautions Drug Interactions
- The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of clinical drug interaction studies, caution should be exercised when the product is given concomitantly with known substrates of CYP2C8 and CYP3A4.
- The potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors have not been evaluated in clinical trials.
- When administered as sequential infusions, taxane derivatives should be given before platinum derivatives to limit myelosuppression and to enhance efficacy.
- CYP2C8/9 inducers may decrease the levels or effects of paclitaxel. Examples include carbamazepine, phenobarbi-tal, rifampin, rifapentine, and secobarbital.
- CYP2C8 and CYP2C9 inhibitors may increase the levels or effects of paclitaxel. Examples include delavirdine, flu-conazole, nicardipine, non-steroidal anti-inflammatory drugs (NSAIDs), and sulfonamides.
- CYP3A4 inducers may decrease the levels or effects of paclitaxel. Examples include aminoglutethimide, carba-mazepine, nafcillin, nevirapine, phenobarbital, canadian phenytoin, and the rifamycins (e.g., rifabutin, rifampin, rifampacin, rifapentine).
- CYP3A4 inhibitors may increase the levels or effects of paclitaxel. Examples include azole antifungal agents, imatinib, isoniazid, nefazodone, nicardi-pine, propofol, protease inhibitors, quinidine, and vera-pamil.
- Doxorubicin: Paclitaxel may increase doxorubicin concentrations and toxicity.
Food Interactions: The following herbs and nutraceuticals should be avoided with protein-bound paclitaxel: black co-hosh, dong quai in patients with estrogen-dependent tumors; valerian, St. John’s wort, kava kava, and gotu kola, which may increase central nervous system depression.
Hematology: Protein-bound paclitaxel should not be administered to patients with baseline ANC counts of less than 1,200 cells/mm3. Frequent peripheral blood cell counts should be performed for all patients receiving this agent.
For myelotoxicity to be monitored, patients should not be re-treated with subsequent cycles of this agent until the ANC count recovers to a concentration of more than 1,500 cells/mm3 and patients have more than 100,000 cells/mm3. In the case of severe neutropenia (below 500 cells/mm3) for seven days or more during a course of Abraxane™ therapy, a dose reduction for subsequent courses of therapy is recommended.
Nervous System: Sensory neuropathy occurs frequently with Abraxane™. The occurrence of grade 1 or 2 sensory neuropathy does not generally warrant a dose modification. If grade 3 sensory neuropathy develops, treatment should be withheld until there is resolution to grade 1 or 2, followed by a dose reduction for all subsequent courses of this agent.
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Conclusion: Abraxane™ is a second-generation taxane formulation in which paclitaxel is albumin-bound and therefore water-soluble. Conversely, because paclitaxel is not miscible with water, the agent must be administered in a cremo-phor/alcohol-based solution, which is where most of its toxicities and dose limitation arise.
Protein-bound paclitaxel is associated with significantly less toxicity so that its formulation allows a greater dose of pacli-taxel to be delivered. Patients who receive paclitaxel need premedication with steroids and antihistamines to avoid severe hypersensitivity reactions; this requirement is eliminated with the protein-bound paclitaxel. The protein-bound form can be given over 30 minutes instead of three hours.