Paclitaxel (Paclitaxel) - Indications and Dosage

INDICATIONS AND USAGE

Paclitaxel Injection, USP is indicated as first-line and subsequent therapy for the treatment of advanced carcinoma of the ovary. As first-line therapy, Paclitaxel Injection, USP is indicated in combination with cisplatin.

Paclitaxel Injection, USP is indicated for the adjuvant treatment of node-positive breast cancer administered sequentially to standard doxorubicin-containing combination chemotherapy. In the clinical trial, there was an overall favorable effect on disease-free and overall survival in the total population of patients with receptor-positive and receptor-negative tumors, but the benefit has been specifically demonstrated by available data (median follow-up 30 months) only in the patients with estrogen and progesterone receptor-negative tumors. (See CLINICAL STUDIES: Breast Carcinoma.)

Paclitaxel Injection, USP is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

Paclitaxel Injection, USP, in combination with cisplatin, is indicated for the first-line treatment of non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy.

Paclitaxel Injection, USP is indicated for the second-line treatment of AIDS-related Kaposi's sarcoma.

DOSAGE AND ADMINISTRATION

Note: Contact of the undiluted concentrate with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC infusion bags or sets, diluted Paclitaxel Injection, USP solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

All patients should be premedicated prior to Paclitaxel Injection, USP administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours before Paclitaxel Injection, USP, diphenhydramine (or its equivalent) 50 mg IV 30 to 60 minutes prior to Paclitaxel Injection, USP, and cimetidine (300 mg) or ranitidine (50 mg) IV 30 to 60 minutes before Paclitaxel Injection, USP.

For patients with carcinoma of the ovary, the following regimens are recommended (see CLINICAL STUDIES: Ovarian Carcinoma):

1. For previously untreated patients with carcinoma of the ovary, one of the following recommended regimens may be given every 3 weeks. In selecting the appropriate regimen, differences in toxicities should be considered (see TABLE 11 in ADVERSE REACTIONS: Disease-Specific Adverse Event Experiences).
   Paclitaxel administered intravenously over 3 hours at a dose of 175 mg/m² followed by cisplatin at a dose of 75 mg/m²; or
   1. Paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m² followed by cisplatin at a dose of 75 mg/m².
2. In patients previously treated with chemotherapy for carcinoma of the ovary, paclitaxel has been used at several doses and schedules; however, the optimal regimen is not yet clear. The recommended regimen is paclitaxel 135 mg/m² or 175 mg/m² administered intravenously over 3 hours every 3 weeks.

For patients with carcinoma of the breast, the following regimens are recommended (see CLINICAL STUDIES: Breast Carcinoma):

1. For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel, at a dose of 175 mg/m² intravenously over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used 4 courses of doxorubicin and cyclophosphamide (see CLINICAL STUDIES: Breast Carcinoma).
2. After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel at a dose of 175 mg/m² administered intravenously over 3 hours every 3 weeks has been shown to be effective.

For patients with non-small cell lung carcinoma, the recommended regimen, given every 3 weeks, is paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m² followed by cisplatin, 75 mg/m².

For patients with AIDS-related Kaposi's sarcoma, paclitaxel administered at a dose of 135 mg/m² given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m² given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45 to 50 mg/m²/week). In the 2 clinical trials evaluating these schedules (see CLINICAL STUDIES: AIDS-Related Kaposi's Sarcoma), the former schedule (135 mg/m² every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m² every 2 weeks).

Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients:

1. Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO);
2. Initiate or repeat treatment with Paclitaxel Injection, USP only if the neutrophil count is at least 1000 cells/mm³;
3. Reduce the dose of subsequent courses of Paclitaxel Injection, USP by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm³ for a week or longer); and
4. Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.

For the therapy of patients with solid tumors (ovary, breast, and NSCLC), courses of Paclitaxel Injection, USP should not be repeated until the neutrophil count is at least 1500 cells/mm³ and the platelet count is at least 100,000 cells/mm³. Paclitaxel Injection, USP should not be given to patients with AIDS-related Kaposi's sarcoma if the baseline or subsequent neutrophil count is less than 1000 cells/mm³. Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe peripheral neuropathy during Paclitaxel Injection, USP therapy should have dosage reduced by 20% for subsequent courses of Paclitaxel Injection, USP. The incidence of neurotoxicity and the severity of neutropenia increase with dose.

Hepatic Impairment: Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III–IV myelosuppression (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Hepatic). Recommendations for dosage adjustment for the first course of therapy are shown in TABLE 17 for both 3- and 24-hour infusions. Further dose reduction in subsequent courses should be based on individual tolerance. Patients should be monitored closely for the development of profound myelosuppression.

TABLE 17

a These recommendations are based on dosages for patients without hepatic impairment of 135 mg/m2 over 24 hours or 175 mg/m2 over 3 hours; data are not available to make dose adjustment recommendations for other regimens (eg, for AIDS-related Kaposi's sarcoma).
b Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to differences in clinical trial design.
c Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance.
RECOMMENDATIONS FOR DOSING IN PATIENTS WITH HEPATIC IMPAIRMENT BASED ON CLINICAL TRIAL DATAa
Degree of Hepatic Impairment
Transaminase Levels		Bilirubin Levelsb	Recommended PACLITAXEL Dosec
24-hour infusion
<2 x ULN	and	≤1.5 mg/dL	135 mg/m2
2 to <10 x ULN	and	≤1.5 mg/dL	100 mg/m2
<10 x ULN	and	1.6 to 7.5 mg/dL	50 mg/m2
≥10 x ULN	or	>7.5 mg/dL	Not recommended
3-hour infusion
<10 x ULN	and	≤1.25 x ULN	175 mg/m2
<10 x ULN	and	1.26 to 2.0 x ULN	135 mg/m2
<10 x ULN	and	2.01 to 5.0 x ULN	90 mg/m2
≥10 x ULN	or	>5.0 x ULN	Not recommended

Preparation and Administration Precautions

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.^1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing Paclitaxel Injection, USP. If Paclitaxel Injection, USP solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. If Paclitaxel Injection, USP contacts mucous membranes, the membranes should be flushed thoroughly with water. Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration (see PRECAUTIONS: Injection Site Reaction).

Preparation for Intravenous Administration

Paclitaxel Injection, USP must be diluted prior to infusion. Paclitaxel Injection, USP should be diluted in 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, 5% Dextrose and 0.9% Sodium Chloride Injection, USP, or 5% Dextrose in Ringer's Injection to a final concentration of 0.3 to 1.2 mg/mL. The solutions are physically and chemically stable for up to 27 hours at ambient temperature (approximately 25° C) and room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. No significant losses in potency have been noted following simulated delivery of the solution through IV tubing containing an in-line (0.22 micron) filter.

Data collected for the presence of the extractable plasticizer DEHP [di-(2-ethylhexyl)phthalate] show that levels increase with time and concentration when dilutions are prepared in PVC containers. Consequently, the use of plasticized PVC containers and administration sets is not recommended. Paclitaxel Injection, USP solutions should be prepared and stored in glass, polypropylene, or polyolefin containers. Non-PVC containing administration sets, such as those which are polyethylene-lined, should be used.

Paclitaxel Injection, USP should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns. 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.

The Chemo Dispensing Pin™ device or similar devices with spikes should not be used with vials of Paclitaxel Injection, USP since they can cause the stopper to collapse resulting in loss of sterile integrity of the Paclitaxel Injection, USP solution.

Parenteral products should be visually inspected for particulate matter.

Stability

Unopened vials of Paclitaxel Injection, USP are stable until the date indicated on the package when stored between 20°–25° C (68°–77° F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration, components in the Paclitaxel Injection, USP vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation. There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25° C) and lighting conditions for up to 27 hours.

HOW SUPPLIED

Paclitaxel Injection, USP is supplied as follows:

NDC	Paclitaxel Injection, USP (6 mg per mL)	Package Factor
25021-213-05	30 mg per 5 mL Multi-Dose Vial	1 vial per carton
25021-213-17	100 mg per 16.7 mL Multi-Dose Vial	1 vial per carton
25021-213-50	300 mg per 50 mL Multi-Dose Vial	1 vial per carton

Storage Conditions

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Protect from light. Retain in carton until time of use.

Handling and Disposal

See DOSAGE AND ADMINISTRATION: Preparation and Administration Precautions.

Sterile, Nonpyrogenic, Preservative-free.

The container closure is not made with natural rubber latex.