Paclitaxel

Actions Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules. 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 esters of microtubules during mitosis, further disrupting cell function. The mean steady-state volume of distribution with the 24-hr infusion ranges from 227 to 688 L/m2. The drug is 89% to 98% protein bound. Major plasma proteins involved are alpha1-acid glycoprotein, albumin, and lipoproteins. Paclitaxel is metabolized by the cytochrome P450 isoenzyme CYP2C8 and by CYP3A4. The drug exhibits a biphasic decline in plasma concentrations. Following 3- and 24-hr infusions at dosing levels of 135 and 175 mg/m2, mean terminal half-life ranges from 13.1 to 52.7 hours, respectively, and mean values for total body clearance range from 12.2 to 23.8 L/hr/m2, respectively.

 Indications Advanced ovarian carcinoma, breast cancer, AIDS-related Kaposi's sarcoma, non-small lung cancer.

Squamous cell head and neck cancer, small-cell lung cancer, bladder cancer.

 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 1500 cells/mm3 or in patients with AIDS-related Kaposi's sarcoma with baseline neutrophil counts of less than 1000 cells/mm3.

 Route/Dosage

Usual Dose

ADULTS: IV Usual dose ranges from 135 mg/m2 to 250 mg/m2 per course of therapy.

Repeat Doses

ADULTS: IV After the initial course, hold further courses of therapy until neutrophil count is at least 1500/mm3 and platelet count is no less than 100,000/mm3. Reduce dose 20% for subsequent courses in patients who develop severe neutropenia or severe neuropathy. Hold therapy until neutrophil count is at least 1000/mm3 in AIDS patients.

Ovarian Carcinoma

ADULTS: IV infusion Single-agent: 135 to 175 mg/m2 over 3 hr q 3 wk. Combined with other agents: 135 mg/m2 by IV infusion over 24 hr q 3 wk.

Breast Cancer

ADULTS: IV infusion 175 mg/m2 over 3 hr q 3 wk.

Non-Small Cell Lung Cancer

ADULT: IV infusion Combined with other agents: 135 mg/m2 over 24 hr q 3 wk.

Kaposi's Sarcoma

ADULTS: IV infusion 135 mg/m2 over 3 hr q 3 wk. Alternate regimen: 100 mg/m2 by IV infusion over 3 hr q 2 wk.

Pretreatment Regimen

ADULTS: PO or IV Reduce incidence of hypersensitivity reactions. Premedicate with each of the following:

• Corticosteroid: Dexamethasone 20 mg PO or IV 12 and 6 hr before paclitaxel administration. Reduce each dexamethasone dose to 10 mg in AIDS patients. Some clinicians give a third dexamethasone dose immediately prior to paclitaxel.
• Diphenhydramine 50 mg IV 30 to 60 min before paclitaxel.
• Histamine H2 antagonist: Cimetidine 300 mg, ranitidine 50 mg, or famotidine 20 mg IV 30 to 60 min before paclitaxel administration.

Interactions

Cisplatin

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

CYP450 inducers

May induce the metabolism of paclitaxel.

CYP450 inhibitors

May decrease the metabolism of paclitaxel.

Doxorubicin

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

Ketoconazole

Ketoconazole may inhibit paclitaxel metabolism.

Lab Test Interferences None well documented.

 Adverse Reactions

CARDIOVASCULAR: Hypotension, bradycardia. CNS: Peripheral neuropathy. DERMATOLOGIC: Alopecia, radiation recall. GI: Nausea, vomiting, diarrhea, mucositis, elevated LFTs. HEMATOLOGIC: Bone marrow suppression, neutrophil nadir at 11 days, platelet nadir at 8 to 9 days. HYPERSENSITIVITY: Acute anaphylactic reactions with symptoms of dyspnea, hypotension, angioedema, and generalized urticaria. MUSCULOSKELETAL: Arthralgias and myalgias.

 Precautions

Pregnancy: Category D. Lactation: Undetermined. Children: Safety and efficacy have not been established. Adjustment in hepatic insufficiency: May require dosage reduction. Extravasation: Can cause local irritation or phlebitis. Bone marrow suppression: Bone marrow suppression (primarily neutropenia) is dose-dependent and is the major dose-limiting toxicity. Do not administer to patients with baseline neutrophil counts of less than 1500 cells/mm3. Cardiac effects: Severe conduction abnormalities have been documented in fewer than 1% of patients during therapy, sometimes requiring a pacemaker. Hypotension, hypertension, and bradycardia have also been observed. Hypersensitivity reactions: Do not use is patients with a history of severe hypersensitivity reactions to products containing Cremophor EL (polyoxyethylated castor oil). Pretreat patients with corticosteroids, diphenhydramine, and H2 antagonists. Patients with a history of allergic reactions to bee stings may have an increased risk for a hypersensitivity reaction with paclitaxel. Hepatic function impairment: Exercise caution when administering to patients with moderate to severe hepatic impairment and consider dose adjustments. CNS: Peripheral neuropathy (glove-and-stocking distribution) occurs frequently.

 Administration/Storage

• Store at room temperature and protect from light. Diluted 0.3 to 1.2 mg/mL solutions are stable for no more than 27 hr at room temperature under normal room lighting.
• Dilute to a final concentration of 0.3 to 1.2 mg/mL with any of the following solutions: 0.9% Sodium Chloride, 5% Dextrose, or 0.9% Sodium Chloride with 5% Dextrose.
• Solution may appear hazy.
• May leach DEHP from PVC infusion sets or bags. Use glass, polypropylene, or polyolefin containers.
• IV infusion over 1 to 24 hr via non-PVC-containing administration sets.
• Administer through an in-line 0.22 micron filter.

 Assessment/Interventions

• Monitor WBC and platelet counts at baseline and throughout therapy. For WBC < 1500/mm3 or platelet count less than 100,000/mm3, withhold therapy.
• Avoid use in patients with previous hypersensitivity reactions to Cremophor EL (eg, cyclosporine injection, teniposide injection).
• Frequently monitor vital signs, particularly during the first hour of infusion.

 Patient/Family Education

• Explain name, action, and potential side effects of drug.
• Advise patient, family, or caregiver that medication will be prepared and administered by health care provider in a health care setting.
• Advise patient, family, or caregiver that medication may be used in combination with other agents to achieve maximum benefit possible.
• Review dosing schedule with patient, family, or caregiver.
• Advise patient, family or caregiver that additional medications will be given before paclitaxel administration to reduce side effects of paclitaxel.
• Advise patient, family, or caregiver to immediately report any of the following to health care provider: rash; hives; shortness of breath or difficulty breathing; fever, chills or other signs of infection; sores in mouth; unusual bleeding or bruising; pain, redness or swelling at injection site.
• Advise patient, family, or caregiver to report any of the following to health care provider: persistent nausea, vomiting, diarrhea or appetite loss; numbness, tingling or burning in arms or legs; persistent muscle or joint pain.
• Advise patient, family, or caregiver that medication may cause hair loss but that this is reversible when therapy is stopped.
• Instruct patient to not take any prescription or otc medications or dietary supplements unless advised by health care provider.
• Caution women of childbearing potential to avoid becoming pregnant while being treated.
• Instruct women of childbearing potential to notify health care provider if they become pregnant, plan on becoming pregnant, or are breastfeeding.
• Advise patient that after discharge follow-up visits and laboratory tests will be required to monitor therapy and to be sure to keep appointments.