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All about: Paclitaxel

Big Image Pronouncation: (pak-lih-TAX-uhl)
Class: Taxoid

Trade Names:
Onxol
- Solution for injection 6 mg/mL

Trade Names:
Taxol
- Solution for injection 6 mg/mL

Trade Names:
Abraxane
- Powder for injection, lyophilized (albumin-bound) 100 mg

Mechanism of Action

Pharmacology

Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability inhibits the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or bundles of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis, further disrupting cell function.

Pharmacokinetics

Distribution

89% to 98% protein bound.

Onxol, Taxol

Extensive extravascular distribution or tissue binding; Vd is 227 to 688 L/m 2 at steady state with 24-hr infusion.

Abraxane

Vd is 632 L/m 2 .

Metabolism

Paclitaxel is metabolized primarily to 6α-hydroxypaclitaxel by isoenzymes CYP2C8 and to 2 minor metabolites, 3-p-hydroxypactlitaxel and 6α,-p-dihyroxypaclitaxel by CYP3A4.

Elimination

Onxol, Taxol

Biphasic decline in plasma concentrations. Initial rapid decline represents distribution into the peripheral compartment and elimination of the drug; latter phase because of, in part, a relatively slow efflux from peripheral compartment. 14% excreted in urine, 71% in feces. Following 3- and 24-hr infusions, the t ½ is 13.1 to 52.7 hr and total body Cl is 12.2 to 23.8 L/hr/m 2 .

Abraxane

Biphasic decline in plasma concentrations. Initial rapid decline represents distribution into the peripheral compartment; slower second phase represents drug elimination. 4% excreted in urine, 20% in feces. Terminal t ½ is approximately 27 hr and total body Cl is 15 L/hr/m 2 .

Indications and Usage

Abraxane, Onxol, Taxol

Treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 mo of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

Onxol, Taxol

Treatment of advanced carcinoma of the ovary.

Taxol

Adjuvant treatment of node-positive breast cancer administered sequentially to standard doxorubicin-containing combination chemotherapy; in combination with cisplatin for the treatment of non-small cell lung cancer (NSCLC) in patients who are not candidates for potentially curative surgery and/or radiation therapy; second-line treatment of AIDS-related Kaposi sarcoma.

Unlabeled Uses

Squamous cell head and neck cancer, small-cell lung cancer, bladder cancer, esophageal cancer, testicular cancer, endometrial cancer, prostate cancer, gastric cancer, germ cell tumors, refractory leukemia, and recurrent Wilms tumor in children.

Contraindications

Hypersensitivity reactions to paclitaxel or other drugs formulated in Cremophor EL (polyoxyethylated castor oil) or polyoxyl 35 castor oil; patients with solid tumors who have baseline neutrophil count of fewer than 1,500 cells/mm 3 or in patients with AIDS-related Kaposi sarcoma with baseline neutrophil counts of less than 1,000 cells/mm 3 .

Dosage and Administration

Failure of Combination Chemotherapy for Metastatic Breast Cancer, Relapse within 6 mo of Adjuvant Chemotherapy
Adults

IV Abraxane : 260 mg/m 2 administered over 30 min q 3 wk. For patients experiencing severe neutropenia (neutrophil less than 500 cells/mm 3 for 1 wk or longer) or severe sensory neuropathy, reduce dosage to 220 mg/m 2 for subsequent courses. For recurrence of severe neutropenia or severe sensory neuropathy, reduce dose to 180 mg/m 2 . For grade 3 sensory neuropathy, hold treatment until resolution to grade 1 or 2, and reduce dose for all subsequent courses of treatment. Onxol , Taxol : 175 mg/m 2 administered over 3 hr q 3 wk.

Ovarian Carcinoma
Adults

IV Taxol : For previously untreated patients, give either regimen q 3 wk: 175 mg/m 2 administered over 3 hr followed by cisplatin 75 mg/m 2 ; or 135 mg/m 2 over 24 hr followed by cisplatin 75 mg/m 2 . Onxol , Taxol : For previously treated patients, 135 mg/m 2 or 175 mg/m 2 administered over 3 hr q 3 wk.

Adjuvant Treatment of Node-Positive Breast Carcinoma
Adults

IV Taxol : 175 mg/m 2 over 3 hr q 3 wk for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy.

NSCLC
Adults

IV Taxol : 135 mg/m 2 given q 3 wk administered over 24 hr followed by cisplatin 75 mg/m 2 .

AIDS-Related Kaposi Sarcoma
Adults

IV Taxol : 135 mg/m 2 administered over 3 hr q 3 wk; or 100 mg/m 2 administered over 3 hr q 2 wk.

Pretreatment Regimen
Adults

Onxol , Taxol only: Reduce incidence of hypersensitivity reactions. Premedicate with each of the following:

Dexamethasone

20 mg PO 12 and 6 hr before paclitaxel administration. Reduce each dexamethasone dose to 10 mg in AIDS patients.

Diphenhydramine

50 mg IV 30 to 60 min before paclitaxel.

Cimetidine

300 mg, ranitidine 50 mg IV 30 to 60 min before paclitaxel administration.

Severe Neuropathy or Severe Neutropenia (less than 500 cells/mm 3 for more than 7 days)
Adults

IV Onxol , Taxol : Reduce dose 20% for all subsequent courses.

Hepatic Impairment
Adults

IV Onxol , Taxol : For 135 mg/m 2 over 24 hr regimen only: reduce dose of first course of therapy as follows: transaminase levels less than 2 × upper limits of normal (ULN) and bilirubin 1.5 mg/dL or less, give 135 mg/m 2 ; transaminase levels 2 to less than 10 × ULN and bilirubin 1.5 mg/dL or less, give 100 mg/m 2 ; transaminase levels less than 10 × ULN and bilirubin 1.6 to 7.5 mg/dL, give 50 mg/m 2 ; transaminase levels more than 10 × ULN or bilirubin more than 7.5 mg/dL, not recommended. For 175 mg/m 2 over 24 hr regimen only: reduce dose of first course of therapy as follows: transaminase levels less than 10× ULN and bilirubin 1.25 × ULN or less, give 175 mg/m 2 ; transaminase levels less than 10 × ULN and bilirubin 1.26 to 2 × ULN, give 135 mg/m 2 ; transaminase levels less than 10 × ULN and bilirubin 2.01 to 5 × ULN, give 90 mg/m 2 ; transaminase levels 10 × ULN or more or bilirubin more than 5 × ULN, not recommended. Dose reduction for subsequent courses is based on individual tolerance.

General Advice

  • For IV infusion only. Not for intradermal, subcutaneous, IM, IV bolus, or intra-arterial administration.
  • Paclitaxel injectable suspension (albumin-bound paclitaxel) cannot be substituted for or with other paclitaxel formulations.
  • Follow institutional and National Institutes of Health guidelines for preparing and administering paclitaxel and disposing of used supplies and unused paclitaxel.
  • Avoid exposure by inhalation or direct contact with the skin, mucous membranes, and eyes. Wear appropriate protective equipment when preparing and administering paclitaxel.
  • If accidental skin contact occurs, wash immediately and thoroughly with soap and water. If accidental eye or mucus membrane contact occurs, immediately institute copious irrigation with plain water.
  • Injection
  • Ensure patient is premedicated with a corticosteroid, diphenhydramine, and H 2 antagonist to prevent severe hypersensitivity reactions.
  • Paclitaxel injection must be diluted prior to infusion. Dilute prescribed dose in 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, or 5% dextrose in Ringer's injection to provide final concentration of 0.3 to 1.2 mg paclitaxel/mL.
  • Paclitaxel injection is clear and colorless to slightly yellow. Do not administer if particulate matter, cloudiness, or discoloration is noted. A slight haziness may be noted.
  • Avoid contact of undiluted paclitaxel solution with PVC equipment or devices. Store diluted paclitaxel solutions in bottles (eg, glass, polypropylene) or plastic bags (eg, polypropylene, polyolefin), and administer through polyethylene-lined administration sets.
  • Administer paclitaxel through an in-line filter with a microporous membrane no greater than 0.22 microns.
  • Injectable suspension (albumin-bound paclitaxel)
  • Powder for injection must be reconstituted with 0.9% sodium chloride injection only. Slowly add, over a minimum of 1 min, 20 mL of 0.9% sodium chloride injection by directing solution flow onto the inside wall of the vial. Do not inject the sodium chloride injection directly onto the lyophilized cake as this will result in foaming. Allow vial to sit for a minimum of 5 min then gently swirl and/or invert vial slowly for at least 2 min until complete dissolution of the cake/powder occurs. If foaming or clumping occurs, let solution stand for at least 15 min until foam subsides. Each mL of reconstituted solution provides 5 mg paclitaxel/mL.
  • Reconstituted injectable suspension should be milky and homogeneous without visible particles. If particles or settling are visible, gently invert vial until complete resuspension has occurred.
  • Transfer prescribed amount of reconstituted injectable suspension from vial into an empty, sterile, PVC-type IV bag. Discard any unused paclitaxel suspension. Do not save for future use.
  • Do not administer through an in-line filter.

Storage/Stability

Store unopened vials of Onxol and Taxol at controlled room temperature (68° to 77°F) in original package. Refrigeration or freezing do not adversely affect the stability of paclitaxel. Upon refrigeration, components in the vial may precipitate but will redissolve upon reaching room temperature with little or no agitation. Use diluted solution for infusion immediately. If not used immediately, the diluted solution is stable at ambient temperature (approximately 77°F) and lighting conditions for up to 27 hr.

Store unopened vials of Abraxane at controlled room temperature in original package. Use reconstituted suspension immediately. If not used immediately, vials can be replaced in original carton to protect suspension from bright light and stored in refrigerator (36° to 46°F) for a max of 8 hr. Some settling of the suspension may occur during storage. Ensure complete resuspension by mild agitation before use. Discard reconstituted suspension if precipitates are observed. Reconstituted suspension for injection in infusion bag is stable at ambient temperature and lighting conditions for up to 8 hr.

Drug Interactions

Alcohol

Onxol contains dehydrated alcohol; consider possible CNS and other effects of alcohol.

Cisplatin

Paclitaxel Cl may decrease when given after cisplatin, resulting in increased hematologic toxicity.

CYP450 2C8 and 3A4 inducers

May induce the metabolism of paclitaxel.

CYP450 2C8 and 3A4 inhibitors

May decrease the metabolism of paclitaxel.

Doxorubicin

Paclitaxel may increase plasma concentrations of doxorubicin and its active metabolite, doxorubicinol.

Laboratory Test Interactions

None well documented.

Adverse Reactions

The following adverse reactions data are based on the experience of 812 patients with ovarian cancer or breast cancer who were enrolled in 10 studies and received single-agent paclitaxel injection.

Cardiovascular

Abnormal ECG (23%); hypotension (12%); bradycardia (3%).

CNS

Peripheral neuropathy (60% [severe symptoms 3%]).

Dermatologic

Alopecia (87%).

GI

Nausea, vomiting (52%); diarrhea (38%); mucositis (31%).

Hematologic-Lymphatic

Leukopenia, neutropenia (90%); anemia (78%); thrombocytopenia (20%); bleeding (14%).

Hepatic

Elevated alkaline phosphatase (22%); elevated AST (19%); elevated bilirubin (7%).

Hypersensitivity

Hypersensitivity (41% [severe 2%]).

Local

Injection site reaction (13%).

Musculoskeletal

Myalgia, arthralgia (60% [severe symptoms 8%]).

Miscellaneous

Bone marrow infections (30%).

Precautions

Warnings

Taxol/Onxol

Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2% to 4% of patients. Fatal reactions have occurred despite premedication. Pretreat patients receiving paclitaxel with corticosteroids, diphenhydramine, and H 2 antagonists to prevent these reactions. Do not rechallenge patients who experience severe hypersensitivity reactions to paclitaxel with the drug. Contraindicated in patients with solid tumors who have baseline neutrophil counts of less than 1,500 cells/mm 3 and in AIDS-related Kaposi sarcoma patients with baseline neutrophil counts less than 1,000 cells/m 3 .

Abraxane

Contraindicated in patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm 3 . An albumin form of paclitaxel may substantially affect a drugs functional properties relative to those of drug in solution. Do not substitute for or with other paclitaxel formulations.


Monitor

Frequently monitor CBC, differential, and platelet counts. Closely monitor infusion site for possible infiltration during administration. Monitor vital signs frequently during infusion of Onxol and Taxol , especially during first hour. Perform continuous cardiac monitoring during subsequent therapy in patient who has developed a conduction abnormality during a previous paclitaxel infusion.


Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Severe myelosuppression, neuropathy, and CV events may occur more frequently in elderly patients receiving Taxol or Onxol .

Hypersensitivity

Taxol, Onxol

Do not use in patients with a history of severe hypersensitivity reactions to products containing Cremophor EL (polyoxyethylated castor oil) or polyoryl 35 castor oil. Pretreat patients with corticosteroids, diphenhydramine, and H 2 antagonists.

Hepatic Function

May require dosage reduction. Exercise caution when administering to patients with moderate to severe hepatic impairment bilirubin more than 1.5 mg/dL or more than 1.26 × ULN) and consider dose adjustments.

Albumin

Because Abraxane contains human albumin, it carries an extremely remote risk for transmission of viral diseases or Creutzfeldt-Jakob disease.

Cardiac effects

Severe conduction abnormalities have been documented in fewer than 1% of patients during therapy, sometimes requiring a pacemaker. Hypotension, hypertension, and bradycardia also have been observed.

CNS

Peripheral neuropathy (glove-and-stocking distribution) occurs frequently.

Extravasation

Can cause local irritation or phlebitis.

Use in men

Advise men to avoid procreation while receiving paclitaxel treatment.

Overdosage

Symptoms

Bone marrow suppression, peripheral neurotoxicity, mucositis.

Patient Information

  • Explain name, action, and potential side effects of drug. Review the treatment regimen including dosing schedule, duration of treatment, and monitoring that will be required.
  • Advise patient or caregiver that medication will be prepared and administered by health care professionals in a health care setting.
  • Advise patient or caregiver to read the Patient Information leaflet before starting therapy.
  • Advise patient or caregiver that medication may be used in combination with other agents to achieve max benefit.
  • Advise patient or caregiver that additional medications may be given before paclitaxel administration to reduce side effects of paclitaxel.
  • Advise patient or caregiver to immediately report any of the following to health care provider: rash; hives; unexplained shortness of breath; difficulty breathing; fever, chills, or other signs of infection; numbness, tingling, or burning in hands and/or feet; mouth or lip sores; bleeding or unusual bruising; paleness; pain, redness, or swelling at injection site.
  • Advise patient or caregiver to report any of the following to health care provider: persistent nausea, vomiting, diarrhea, or appetite loss; persistent muscle or joint pain; any unusual or unexplained symptom or feeling.
  • Advise patient or caregiver that medication may cause hair loss, which is reversible when therapy is stopped.
  • Instruct patient not to take any prescription or OTC medications, dietary supplements, or herbal products unless advised by health care provider.
  • Caution women of childbearing potential to avoid becoming pregnant while being treated with paclitaxel.
  • Caution men to avoid procreating during treatment with paclitaxel.
  • Advise women to notify health care provider if pregnant, planning to become pregnant, or breastfeeding.
  • Advise patient that follow-up visits and laboratory tests will be required to monitor therapy and to keep appointments.

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