AHFS Class:

10:00 Antineoplastic Agents

Generic Name

• PACLitaxel

Paclitaxel is available as a 6-mg/mL non-aqueous concentrate for injection in 5-, 16.7-, 25-, and 50-mL multidose vials.³³³⁸; ³³³⁹; ³³⁴¹ In most formulations, each mL of the concentrate for injection also contains polyoxyl 35 castor oil (Cremophor EL; polyoxyethylated castor oil) surfactant 527 mg and dehydrated alcohol 396 mg.³³³⁸; ³³³⁹ Some formulations also incorporate citric acid anhydrous 2 mg/mL.³³³⁹ The concentrate for injection must be diluted prior to administration.³³³⁸; ³³³⁹

CAUTION: Care should be taken to ensure that the correct drug product, dose, and administration procedures are used and that no confusion with other products occurs. Although Abraxane, an albumin-bound paclitaxel suspension also exists,³²¹⁹ it is sufficiently different from conventional solvent-formulated paclitaxel that extrapolating information to or from it would be inappropriate.

pH

The pH of paclitaxel (WG Critical Care) diluted for infusion ranges from 3 to 7.³³⁴²

Trade Name(s)

Taxol

Paclitaxel is administered by intravenous infusion.³³³⁸; ³³³⁹ The concentrate must be diluted to a final paclitaxel concentration of 0.3 to 1.2 mg/mL in dextrose 5%, sodium chloride 0.9%, dextrose 5% in sodium chloride 0.9%, or dextrose 5% in Ringer's injection.³³³⁸; ³³³⁹ Manufacturers note that the Chemo Dispensing Pin device or other similar devices with spikes should not be used with paclitaxel vials because they can cause the stopper to collapse, thereby resulting in loss of solution sterility.³³³⁸; ³³³⁹

Administration of the diluted solution over 3 or 24 hours is often recommended, depending upon the indication and the specific regimen used.³³³⁸; ³³³⁹ An inline filter with a pore size not greater than 0.22 µm should be used for administration of the diluted solution.³³³⁸; ³³³⁹ Intravenous solution containers and administration sets used should be free of the plasticizer diethylhexyl phthalate (DEHP) that may be leached from polyvinyl chloride (PVC) infusion bags or sets.³³³⁸; ³³³⁹ Diluted paclitaxel solutions preferably should be stored in glass, polypropylene, or polyolefin containers and administered through polyethylene-lined administration sets.³³³⁸; ³³³⁹ The infusion site should be monitored closely for possible infiltration during administration.³³³⁸; ³³³⁹

As with other toxic drugs, caution should be exercised in the handling of paclitaxel.³³³⁸; ³³³⁹ The use of impervious gloves is always advised when handling vials of the drug.³³³⁸; ³³³⁹ If skin contact with paclitaxel occurs, the exposed area should be washed immediately and thoroughly with soap and water.³³³⁸; ³³³⁹ For mucous membrane contact, the exposed area should be flushed thoroughly with water.³³³⁸; ³³³⁹ Procedures for the proper disposal of paclitaxel should be considered.³³³⁸; ³³³⁹

Use of self-venting sets spiked into glass bottles of paclitaxel admixtures has occasionally resulted in solution dripping from the air vent. Presumably, the surfactant content wetted the hydrophobic filter, allowing the solution to drip.¹⁸⁴³ In another observation, the spikes of administration sets were made sufficiently slippery by surfactant in the paclitaxel formulation that the spike slipped out after it had been seated through the rubber bung of the glass bottle. The admixture also leaked due to a poor seal. The authors recommend use of non-PVC plastic solution containers to avoid the problem.²⁰⁵²

CAUTION: Care should be taken to ensure that the correct drug product, dose, and administration procedures are used and that no confusion with other products occurs.

Paclitaxel is a clear, colorless to slightly yellow viscous solution.³³³⁸; ³³³⁹ Intact vials should be stored at controlled room temperature in the original package to protect from light.³³³⁸; ³³³⁹ Stability is not adversely affected by refrigeration or freezing.³³³⁸; ³³³⁹ Refrigeration may result in the precipitation of formulation components; however, warming to room temperature redissolves the material and does not adversely affect the product.³³³⁸; ³³³⁹ If the solution remains cloudy or an insoluble precipitate is noted, the product should be discarded.³³³⁸; ³³³⁹ Diluted paclitaxel solutions should be visually inspected for particulate matter and discoloration prior to administration.³³³⁸; ³³³⁹

Paclitaxel 0.7 mg/mL diluted in sodium chloride 0.9% did not exhibit an antimicrobial effect on the growth of 3 of 4 organisms (Enterococcus faecium, Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans) inoculated into the solution. S. aureus remained viable for 4 hours. E. faecium and P. aeruginosa remained viable for 48 hours, and C. albicans remained viable to the end of the study at 120 hours. Diluted solutions of paclitaxel should be stored under refrigeration whenever possible, and the potential for microbiological growth should be considered when assigning expiration periods.²¹⁶⁰

Turbidity

Paclitaxel is a clear, colorless to slightly yellow viscous solution.³³³⁸; ³³³⁹ After dilution in an infusion solution, the drug may exhibit haziness because of the surfactant content of the formulation.¹⁵²⁸; ³³³⁸; ³³³⁹

Precipitation

Although after dilution in specified infusion solutions, paclitaxel is physically and chemically stable for up to 27 hours³³³⁸; ³³³⁹ or longer,¹⁷⁴⁶; ¹⁸⁴²; ²⁷⁰⁸ precipitation has occurred irregularly and unpredictably. Such precipitation occurs within the recommended range of 0.3 to 1.2 mg/mL and at lower paclitaxel concentrations. These precipitates have been observed in the infusion tubing distal to the pump chamber.¹⁷¹⁶ Although precipitation of insoluble drugs in an aqueous medium is a foregone conclusion, the time to precipitation is irregular. It may be accelerated by the presence or formation of crystallization nuclei, agitation, and contact with incompatible drugs or materials.¹³⁷⁴; ¹⁵²¹ Since the mechanism of this irregular precipitation has not been identified,¹⁷³⁹ vigilance throughout the infusion of paclitaxel is required.

Sorption

No paclitaxel loss due to sorption to containers or sets has been observed.¹⁵²⁰; ²²³⁰; ²²³¹; ²²³²

Plasticizer Leaching

Contact of undiluted paclitaxel concentrate with plasticized PVC equipment and devices is not recommended.³³³⁸; ³³³⁹ With use of infusion bags and tubing that are free of DEHP plasticizer and the elimination of PVC precision flow regulators, a reduction in leached DEHP of up to 96% has been reported.²⁶⁷⁹

Paclitaxel vehicle equivalent to paclitaxel 1.2 mg/mL in dextrose 5% in VISIV polyolefin bags was tested at room temperature near 23°C for 24 hours. No plastic components leached within the 24-hour study period.²⁶⁶⁰; ²⁷⁹²

Paclitaxel itself does not contribute to the extraction of the plasticizer DEHP.¹⁵²⁰ However, the surfactant, Cremophor EL, in the paclitaxel formulation extracts DEHP from PVC containers and sets. The amount of DEHP extracted increases with time and drug concentration.¹⁵²⁰; ¹⁶⁸³; ²¹⁴⁶ Consequently, the use of DEHP-plasticized PVC containers and sets is not recommended for infusion of paclitaxel solutions.³³³⁸; ³³³⁹ Instead, manufacturers recommend the use of glass, polypropylene, or polyolefin containers and non-PVC containing administration sets (e.g., polyethylene-lined administration sets).³³³⁸; ³³³⁹

The use of inline filters that incorporate short PVC-coated inlet and outlet tubing (e.g., Ivex-2) has not resulted in a substantial amount of DEHP leaching.³³³⁸; ³³³⁹

A study was performed on the compatibility of paclitaxel 0.3- and 1.2-mg/mL infusions with various non-PVC infusion sets. The paclitaxel infusions were run through the study sets, and the effluent was then analyzed for leached DEHP plasticizer. The following sets had significant and unacceptable amounts of leached DEHP: Baxter vented nitroglycerin (2C7552S), Baxter vented basic solution (1C8355S), McGaw Horizon pump vented nitroglycerin (V7450), and McGaw Intelligent pump vented nitroglycerin (V7150). Although these sets were largely non-PVC, their highly plasticized pumping segments contributed the DEHP. The administration and extension sets cited in Tables 1 and 2 exhibited no more leached DEHP than the Ivex-2 filter set specified in the product labeling.¹⁸⁴³

Table 1. Administration Sets Compatible with Paclitaxel Infusions by Manufacturer¹⁸⁴³

Table 2. Extension Sets Compatible with Paclitaxel Infusions by Manufacturer¹⁸⁴³

Paclitaxel 0.3 and 1.2 mg/mL was prepared in PVC bags in dextrose 5% and in sodium chloride 0.9%. Leaching of the plasticizer was found to be time and concentration dependent; however, there was little difference between the 2 infusion solutions. After storage for 8 hours at 21°C, leached DEHP in the range from 73 to 108 mcg/mL was found for the 1.2-mg/mL concentration and from 21 to 30 mcg/mL for the 0.3-mg/mL concentration. During a simulated 1-hour infusion using DEHP plasticized administration sets, the amount of leached DEHP did not exceed 18 mcg/mL at the 0.3-mg/mL paclitaxel concentration, but resulted in a maximum of 114 mcg/mL at the 1.2-mg/mL paclitaxel concentration.¹⁸²⁵

DEHP plasticizer leaching from PVC containers and administration sets and the amount of DEHP leached was reported to depend on surfactant concentration and length of contact period. Authors also reported leaching of up to 30 mg of DEHP per dose from Flo-Gard Low Adsorption Sets (Baxter), a set with a reduced amount of PVC present in its construction.²¹⁴⁶

In 1996, an acceptability limit of no more than 5 parts per million (5 mcg/mL) for DEHP plasticizer released from PVC-containing devices (e.g., containers, administration sets, other equipment) was proposed based on a review of metabolic and toxicologic considerations.²¹⁸⁵ FDA later evaluated the safety of DEHP exposure by comparing doses of DEHP received by patients undergoing various medical procedures with a defined tolerable intake value of DEHP, a value that was based upon the results of selected critical toxicity studies in experimental animals.³¹⁰⁰ Based on the results of the safety assessment, FDA concluded that there is little risk posed by exposure to the amount of DEHP released from PVC bags used to store and administer drugs that require an excipient for solubilization when label instructions for preparation and administration are followed.³¹⁰⁰ However, such conclusions do not take into account increased risk for adverse effects from DEHP exposure in certain patients (e.g., critically ill male neonates or infants, male infants less than 1 year of age, male offspring of pregnant or breast-feeding women undergoing certain medical treatments) or potential adverse effects related to aggregate exposure for patients exposed to multiple medical devices, procedures, or intravenous medications known to leach DEHP, for which there are varying levels of concern.³¹⁰⁰; ³¹⁰¹

Two reduced-phthalate administration sets for the Acclaim (Abbott) pump were evaluated. Administration set model 11993-48 (Abbott) is composed of polyethylene tubing but has a DEHP-plasticized pumping segment. Administration set model L-12060 (Abbott) is composed of tris(2-ethylhexyl)trimellitate (TOTM)-plasticized PVC tubing and a DEHP-plasticized pumping segment. Paclitaxel diluent at concentrations equivalent to 0.3 and 1.2 mg/mL in dextrose 5% delivered rapidly over 3 hours at 23°C did not leach detectable levels of TOTM from model L-12060 or DEHP from either set. Similarly, slow delivery over 4 days of the 0.3-mg/mL concentration yielded detectable but not quantifiable amounts of plasticizer. However, slow delivery of the equivalent of 1.2 mg/mL over 4 days yielded large but variable amounts of DEHP from both sets; DEHP concentrations ranged from 30 to 150 mcg/mL. Consequently, these 2 reduced-phthalate sets are suitable for short-term delivery up to 3 hours of paclitaxel at concentrations up to 1.2 mg/mL. However, these sets should not be used for slow delivery of paclitaxel.²¹⁹⁸

Paclitaxel vehicle equivalent to paclitaxel 0.3 and 1.2 mg/mL in dextrose 5% did not leach TOTM plasticizer from a TOTM-plasticized PVC set (SoloPak) during simulated 3-hour administration. During extremely slow delivery at 5.2 mL/hr for 4 days, no detectable TOTM was found in the 0.3-mg/mL equivalent concentration, and only a barely detectable, unquantifiable amount of TOTM was found with the 1.2-mg/mL equivalent solution.²²³²

Paclitaxel 0.3 and 1.2 mg/mL in dextrose 5% or in sodium chloride 0.9% in ethylene vinyl acetate (EVA) containers was found to leach an unknown material stored at 25 and 32°C for 24 hours.²¹⁸²

Filtration

The manufacturer recommends the use of an inline filter with a pore size not greater than 0.22 µm for administration of diluted paclitaxel.³³³⁸; ³³³⁹ No substantial loss of paclitaxel due to filtration through an inline 0.22-µm filter has occurred during simulated delivery.¹⁵²⁰; ³³³⁸; ³³³⁹

The acceptability of the 0.22-µm IV Express Filter Unit (Millipore) for the administration of paclitaxel was evaluated. Paclitaxel vehicle equivalent to paclitaxel 1.2 mg/mL (for plasticizer leaching) and paclitaxel 0.3 mg/mL (for sorption potential) in 500 mL of dextrose 5% in polyolefin containers was delivered through the filter units over a 3-hour period at a rate of 167 mL/hr at about 23°C to simulate paclitaxel administration. No leached plasticizer and no loss of paclitaxel due to sorption was found.²²³¹

Central Venous Catheter

The acceptability of the Arrow-Howes triple-lumen, 7 French, 30-cm polyurethane central catheter (Arrow International) for the administration of paclitaxel was evaluated. Paclitaxel vehicle equivalent to paclitaxel 0.3 and 1.2 mg/mL (for catheter component leaching) and paclitaxel 0.3 mg/mL (for sorption potential) were prepared in polyolefin bags of dextrose 5%. The solutions were delivered through the polyurethane central venous catheters for periods of 3 hours and of 24 hours at 23°C to simulate rapid and slow administration. No leached catheter components were found in the effluent solution and no loss of paclitaxel occurred.²²³⁰

Solution Compatibility

Additive Compatibility

Y-Site Injection Compatibility (1:1 Mixture)

For a list of references cited in the text of this monograph, search the monograph titled References.

ASHP^® Injectable Drug Information^TM. Selected Revisions March 31, 2024. © Copyright, 2024. American Society of Health-System Pharmacists^®, 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.