Conventional paclitaxel: Anaphylaxis and severe hypersensitivity reactions (dyspnea and hypotension requiring treatment, angioedema, and/or generalized urticaria) reported. Fatal reactions reported despite premedication. Administer premedication (corticosteroids, diphenhydramine, histamine H2-receptor antagonists) to all patients. Do not administer paclitaxel to patients with a history of severe hypersensitivity reactions to the drug.
Paclitaxel should not be administered to patients with solid tumors with neutrophil counts <1500/mm3 or to patients with AIDS-related Kaposi’s sarcoma with neutrophil counts <1000/mm3. Monitor blood cell counts frequently.
Albumin-bound paclitaxel differs from conventional paclitaxel; do not substitute albumin-bound paclitaxel for conventional paclitaxel or vice versa.
Administer only under the supervision of qualified clinicians experienced in the use of cytotoxic therapy. Adequate diagnostic and treatment facilities should be readily available to manage complications.
Conventional paclitaxel: Treatment of advanced carcinoma of the ovary. Used as first-line therapy with carboplatin or cisplatin; this regimen is considered the treatment of choice for primary therapy of advanced ovarian cancer. Used alone or in combination therapy as second-line (salvage) therapy or subsequent therapy in patients with advanced ovarian epithelial cancer.
Breast Cancer
Conventional paclitaxel: Adjuvant therapy in patients with evidence of axillary node tumor involvement; administered sequentially to standard doxorubicin-containing combination therapy.
Conventional paclitaxel: Treatment of breast cancer in patients who have metastatic disease refractory to combination chemotherapy or who have experienced relapse within 6 months of adjuvant chemotherapy; prior therapy should have included an anthracycline antineoplastic agent (e.g., doxorubicin) unless clinically contraindicated.
Conventional paclitaxel: Treatment of breast cancer in combination with trastuzumab for tumors that overexpress the HER2 protein.
Albumin-bound paclitaxel: Used alone for the treatment of breast cancer in patients who have metastatic disease refractory to conventional combination chemotherapy or who have experienced relapse within 6 months of adjuvant therapy; prior therapy should have included an anthracycline antineoplastic agent (e.g., doxorubicin) unless clinically contraindicated.
Non-small Cell Lung Cancer
Conventional paclitaxel: First-line treatment of non-small cell lung carcinoma in combination with carboplatin or cisplatin in patients for whom potentially curative surgery and/or radiation therapy are not possible.
Conventional paclitaxel: Adjuvant therapy† in selected patients with completely resected non-small cell lung cancer; used in conjunction with a platinum agent (e.g., carboplatin).
Small Cell Lung Cancer
Conventional paclitaxel: Active in the treatment of small cell lung carcinoma†.
AIDS-related Kaposi’s Sarcoma
Conventional paclitaxel: Second-line therapy for the palliative treatment of advanced or refractory AIDS-related Kaposi’s sarcoma (designated an orphan drug by FDA for this use).
Esophageal Cancer
Conventional paclitaxel: Has been used for the treatment of esophageal cancer† .
Bladder Cancer
Conventional paclitaxel: Active in the treatment of transitional cell bladder cancer†.
Head and Neck Cancer
Conventional paclitaxel: Active in the treatment of advanced (metastatic or locally recurrent) squamous cell carcinoma of the head and neck†.
Cervical Cancer
Conventional paclitaxel: Active in the treatment of cervical cancer.
Endometrial Cancer
Conventional paclitaxel: Has been used for the treatment of endometrial cancer†.
Dosage and Administration
General
Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.
Conventional paclitaxel: Premedicate all patients before paclitaxel administration to prevent severe hypersensitivity reactions. Oral dexamethasone 20 mg (10 mg for HIV-infected patients) administered approximately 12 and 6 hours before paclitaxel as well as IV diphenhydramine hydrochloride (or similar antihistamine) 50 mg and either IV cimetidine hydrochloride (300 mg of cimetidine) or ranitidine hydrochloride (50 mg of ranitidine) administered 30–60 minutes before paclitaxel can be given.
Albumin-bound paclitaxel: Premedication not required.
Administration
IV Administration
Handle cautiously (by trained nonpregnant personnel); use protective equipment (e.g., gloves) and wash hands after removal of the gloves.
Immediately treat accidental contact with skin by thoroughly washing with soap and water; immediately treat accidental contact with mucous membranes by thoroughly washing with water. Dyspnea, chest pain, ocular burning, sore throat, and nausea reported upon inhalation.
Conventional Paclitaxel
For solution and drug compatibility information, see Compatibility under Stability.
Administer by IV infusion.
Contact of undiluted paclitaxel for injection concentrate with plasticized polyvinyl chloride (PVC) equipment or devices used to prepare solutions for infusion is not recommended. Diethylhexyl phthalate (DEHP) can be leached from PVC containers.
Diluted paclitaxel solutions preferably should be stored in glass or polypropylene containers or in plastic (polypropylene or polyolefin) bags and administered through polyethylene-lined administration sets.
A hydrophilic, microporous inline filter with a pore size ≤0.22 mcm is necessary during administration. Use of filter devices such as IVEX-2® filters, which incorporate short inlet and outlet PVC-coated tubing, has not resulted in significant leaching of DEHP.
Do not use a Chemo Dispensing Pen® or similar device; these devices may cause the stopper to collapse and contaminate the solution (resulting in loss of sterility).
Dilution of Conventional Paclitaxel
The concentrate for injection must be diluted prior to administration.
Dilute 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 a final paclitaxel concentration of 0.3–1.2 mg/mL.
Rate of Administration of Conventional Paclitaxel
Infuse appropriate dose IV over 3 or 24 hours, depending on the treatment regimen.
Albumin-bound Paclitaxel
Administer by IV infusion; do not use inline filters.
Reconstitution of Albumin-bound Paclitaxel
Add 20 mL of 0.9% sodium chloride injection to a vial containing 100 mg of paclitaxel lyophilized powder; slowly inject the diluent onto the inside wall of the vial. Allow the vial to sit for ≥5 minutes (to ensure wetting of cake/powder); then, gently swirl and/or invert vial for ≥2 minutes. Handle in such a manner to avoid foaming. Resulting preparation contains 5 mg/mL.
Withdraw appropriate dose from vial and transfer to an empty sterile PVC IV bag. DEHP-free containers and administration sets not needed.
Rate of Administration of Albumin-bound Paclitaxel
Infuse appropriate dose IV over 30 minutes. Limiting infusion duration to 30 minutes reduces risk of infusion-related reactions.
Dosage
Adults
Ovarian Cancer
IV (Conventional Paclitaxel)
Previously untreated patients: 175 mg/m2 given over 3 hours followed by cisplatin 75 mg/m2 in repeated 3-week cycles. Alternatively, 135 mg/m2 given over 24 hours followed by cisplatin 75 mg/m2 in repeated 3-week cycles.
Previously treated patients: 135 mg/m2 or 175 mg/m2 given over 3 hours in repeated 3-week cycles.
Reduce dose by 20% for subsequent cycles in patients who experience severe neutropenia (neutrophil count <500/mm3 for >7 days) or severe peripheral neuropathy.
Breast Cancer
IV (Conventional Paclitaxel)
Adjuvant therapy: 175 mg/m2 given over 3 hours in repeated 3-week cycles for 4 cycles administered sequentially to doxorubicin-containing chemotherapy.
Treatment after failure of initial therapy for metastatic disease or relapse within 6 months of adjuvant therapy: 175 mg/m2 given over 3 hours in repeated 3-week cycles.
Reduce dose by 20% for subsequent cycles in patients who experience severe neutropenia (neutrophil count <500/mm3 for >7 days) or severe peripheral neuropathy.
IV (Albumin-bound Paclitaxel)
Treatment after failure of initial therapy for metastatic disease or relapse within 6 months of adjuvant therapy: 260 mg/m2 every 3 weeks.
Reduce dose to 220 mg/m2 for subsequent cycles in patients who experience severe neutropenia (neutrophil count <500/mm3 for >7 days) or severe sensory neuropathy. Reduce dose to 180 mg/m2 if severe neutropenia or severe sensory neuropathy recur. For grade 3 sensory neuropathy, withhold therapy until resolution to grade 1 or 2; when therapy is resumed, reduce dose.
Non-small Cell Lung Cancer
IV (Conventional Paclitaxel)
135 mg/m2 given over 24 hours followed by cisplatin 75 mg/m2 in repeated 3-week cycles. Alternatively, 175 mg/m2 given over 3 hours followed by cisplatin 80 mg/m2 in repeated 3-week cycles has been used.
Reduce dose by 20% for subsequent cycles in patients who experience severe neutropenia (neutrophil count <500/mm3 for >7 days) or severe peripheral neuropathy.
AIDS-related Kaposi’s Sarcoma
IV (Conventional Paclitaxel)
135 mg/m2 given over 3 hours in repeated 3-week cycles. Alternatively, 100 mg/m2 over 3 hours in repeated 2-weeks cycles. The regimen given every 3 weeks is more toxic than the regimen given every 2 weeks; patients with poor performance status have been treated with paclitaxel 100 mg/m2.
Reduce dose by 20% for subsequent cycles in patients who experience severe neutropenia (neutrophil count <500/mm3 for >7 days); initiate granulocyte colony stimulating factor (G-CSF) as indicated.
Special Populations
Hepatic Impairment
Conventional paclitaxel: Increased risk of toxicity, particularly grade III-IV myelosuppression. Adjust dosage as follows.
Table 1. Solid Tumors (ovary, breast, non-small cell lung carcinoma): Recommendations for dosing in patients with hepatic impairment based on clinical trial data
Known hypersensitivity to paclitaxel, polyoxyl 35 castor oil (Cremophor® EL, polyethoxylated castor oil), or any other ingredient in the formulation.
Baseline neutrophil counts <1500/mm3 in patients with solid tumors.
Baseline neutrophil counts <1000/mm3 in patients with AIDS-related Kaposi’s sarcoma.
Albumin-bound Paclitaxel
Baseline neutrophil counts <1500/mm3.
Warnings/Precautions
Warnings
Adequate Patient Evaluation and Monitoring
Administer only under the supervision of qualified clinicians experienced in the use of cytotoxic therapy.
Patients must have recovered from acute toxicities (e.g., neutrophils >1500/mm3 [>1000/mm3 for patients with Kaposi’s sarcoma], platelets >100,000/mm3) of previous cytotoxic therapy before each cycle.
Prior to and during therapy with conventional paclitaxel, assess blood cell counts, serum bilirubin, and AST and/or ALT.
Prior to and during therapy with albumin-bound paclitaxel, assess blood cell counts.
Conventional paclitaxel: Neutrophil nadir at day 10–12, return to baseline by day 15–21. Platelet nadir at day 8–9 occurs.
Cardiovascular Effects
Severe conduction abnormalities documented with conventional paclitaxel; pacemaker placement needed in some patients. Institute appropriate therapy if clinically important conduction abnormalities occur; perform continuous cardiac monitoring during subsequent cycles.
Hypotension, bradycardia, and hypertension reported during infusion of conventional paclitaxel; interruption of therapy not needed for mild symptoms. Interruption or discontinuance may be needed because of initial or recurrent hypertension.
Monitor vital signs frequently during conventional paclitaxel administration, especially during the first hour of the infusion. Continuous cardiac monitoring not required except in patients with serious conduction abnormalities.
Hypotension or bradycardia reported during infusion of albumin-bound paclitaxel: specific therapy or interruption of paclitaxel not needed. ECG abnormalities reported.
Fetal/Neonatal Morbidity and Mortality
Embryotoxic and fetotoxic. (See Pregnancy under Cautions.)
Therapy with albumin-bound paclitaxel not advised in men wishing to father a child.
Sensitivity Reactions
Hypersensitivity Reactions to Conventional Paclitaxel
Anaphylaxis and severe reactions, characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria, reported. Fatal reactions reported in patients who received premedication.
Premedicate patients with corticosteroids, diphenhydramine, and histamine H2-receptor antagonists to reduce the severity of hypersensitivity reactions. (See General under Dosage and Administration.)
Interruption of therapy generally is not needed for mild reactions (e.g., flushing, localized skin reactions, hypotension, tachycardia).
Discontinue immediately and treat if severe reaction occurs (hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, generalized urticaria).
Do not administer to any patient who experienced a severe hypersensitivity reaction during a previous course.
Sulfite Sensitivity
Some formulations of conventional paclitaxel contain sulfites, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.
Major Toxicities
Nervous System Effects
Neuropathy (sensory, peripheral) occurs frequently with conventional or albumin-bound paclitaxel; severe symptoms are unusual. Reduce dose for subsequent cycles for severe symptoms.
Injection Site Reaction
Injection site reactions to conventional paclitaxel, including reactions secondary to extravasation, are mild and characterized by erythema, tenderness, skin discoloration, or swelling at the injection site. Reactions more frequent with the 24-hour infusion than the 3-hour infusion. Recurrence of skin reactions at a previous site of extravasation (i.e., “recall” reactions) following administration at a different injection site reported rarely.
Severe events (phlebitis, cellulitis, induration, skin exfoliation, necrosis, fibrosis) reported rarely with conventional paclitaxel.
Injection site reaction to conventional paclitaxel usually occurs during prolonged infusion; delayed onset of reaction, 3–13 days after infusion, also reported.
Specific treatment for extravasation reactions to conventional paclitaxel unknown. Monitor the infusion site for possible infiltration during administration.
Mild injection site reactions to albumin-bound paclitaxel reported infrequently. Monitor the infusion site for possible infiltration during administration.
General Precautions
Prescribing and Dispensing Precautions
Ensure accuracy of prescription; similarity of spelling of Taxol® (paclitaxel) and Taxotere® (docetaxel) may result in errors.
Risk of Transmissible Agents in Plasma-derived Preparations
Albumin-bound paclitaxel: Potential vehicle for transmission of viruses or other infectious agents. Despite screening for certain viruses, remote risk for transmission of viral infections. Theoretical risk for transmission of Creutzfeldt-Jacob disease.
Specific Populations
Pregnancy
Category D.
Lactation
Distributed into milk in rats; not known whether distributed into human milk. Discontinue nursing because of the potential risk to nursing infant.
Pediatric Use
Safety and efficacy not established.
CNS toxicity, rarely fatal, reported in pediatric patients receiving high doses of conventional paclitaxel (350–420 mg/m2) by 3-hour IV infusion. Paclitaxel injection contains dehydrated alcohol; toxicity may have resulted from administration of large amounts of alcohol over a short period of time. The use of concomitant antihistamine may intensify the toxic effect of the alcohol. The possibility of a direct toxic effect of paclitaxel itself cannot be ruled out.
Geriatric Use
Conventional paclitaxel: No substantial differences in efficacy relative to younger adults. Severe myelosuppression and severe neuropathy reported more frequently in geriatric individuals than in younger adults. Increased incidence of cardiovascular events noted in geriatric patients receiving conventional paclitaxel for non-small cell lung carcinoma.
Albumin-bound paclitaxel: No difference in toxicity relative to younger adults observed in clinical studies.
Hepatic Impairment
Conventional paclitaxel: Myelotoxicity may be exacerbated in patients with total bilirubin >2 times ULN. Use with extreme caution in these patients; dosage adjustment recommended. (See Hepatic Impairment under Dosage and Administration.)
Albumin-bound paclitaxel: Not systematically evaluated in patients with hepatic impairment. Patients with baseline serum bilirubin >1.5 times ULN excluded from clinical trials.
Renal Impairment
Albumin-bound paclitaxel: Not systematically evaluated in patients with renal impairment. Patients with baseline Scr >2 mg/dL excluded from clinical trials.
No formal drug interaction studies conducted to date with albumin-bound paclitaxel.
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Pharmacokinetic interactions possible with drugs that are inhibitors, inducers, or substrates of CYP2C8 or CYP3A4 with possible alteration in metabolism of paclitaxel and/or other drug.
Sequence-dependent interaction; increased severity of myelosuppression when conventional paclitaxel administered following cisplatin compared with the alternative sequence
Paclitaxel clearance reduced by 25–33% when conventional paclitaxel administered following cisplatin
CNS depressants
Potentiation of CNS depression due to alcohol in the conventional paclitaxel formulation
Sequence-dependent interaction; increased severity of neutropenia and thrombocytopenia when conventional paclitaxel (24-hour infusion) administered before cyclophosphamide
Paclitaxel metabolism inhibited in vitro at concentrations greater than usual therapeutic concentrations
Pharmacokinetics
Absorption
Conventional paclitaxel: Exhibits nonlinear pharmacokinetic behavior when administered over short periods (i.e., 3 hours).
Albumin-bound paclitaxel: Increase in AUC proportional to increase in dose for doses of 80–375 mg/m2. Duration of infusion does not affect pharmacokinetics.
Special Populations
Conventional paclitaxel: Plasma paclitaxel exposure increased with abnormal serum bilirubin concentrations ≤2 times ULN.
Distribution
Extent
Widely distributed.
Conventional paclitaxel is detected in ascitic fluid; does not penetrate the CNS.
Not known whether paclitaxel is distributed into human milk.
Following administration of albumin-bound paclitaxel, concentration of drug in tumor cells is increased compared with concentration achieved following an equivalent dose of conventional paclitaxel.
Plasma Protein Binding
88–98%.
Elimination
Metabolism
Metabolized by CYP2C8 and, to a lesser extent, by CYP3A4.
Elimination Route
Excreted principally in feces as metabolites and unchanged drug.
Minimal urinary excretion.
Half-life
Conventional paclitaxel: Average elimination half-life: 5.8 hours for 6- to 24-hour infusions, 2.33 hours for 3-hour infusions.
Albumin-bound paclitaxel: 27 hours.
Stability
Storage
Parenteral
For Injection Concentrate (Conventional Paclitaxel)
20–25°C in the original package to protect from light.
No adverse effect on drug from freezing or refrigeration. Drug or vehicle that precipitates during refrigeration or freezing will redissolve at room temperature without potency loss.
Solutions for infusion are stable at ambient temperature (approximately 25°C) and lighting conditions for up to 27 hours.
Suspension for Injection (Albumin-bound Paclitaxel)
20–25°C in the original package to protect from bright light.
Use reconstituted suspension immediately; alternatively, store vial in the original package for up to 8 hours at 2–8°C. No adverse effect on drug from freezing or refrigeration.
Discard reconstituted suspension if precipitation occurs.
Reconstituted suspension for infusion is stable in the IV infusion bag at ambient temperature (approximately 25°C) and lighting conditions for up to 8 hours.
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
A natural or semisynthetic diterpene extracted from the bark of the Western (Pacific) yew (Taxus brevifolia) or produced from the needles and twigs of a more prevalent yew (Taxus baccata). Structurally and pharmacologically similar to docetaxel.
Disrupts the microtubular network in cells that is essential for mitotic and interphase cellular function.
Advice to Patients
Importance of recognizing and reporting adverse effects including myelosuppressive effects and infectious complications.
Importance of reading the patient information leaflet.
Potential for alcohol in conventional paclitaxel to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual known.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illness.
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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