Doxorubicin hydrochloride is available as a lyophilized powder or cake in single-dose vials containing doxorubicin hydrochloride 10, 20, or 50 mg with 50 mg of lactose for each 10 mg of doxorubicin hydrochloride.3985; 3986 The powder should be reconstituted by adding 5, 10, or 25 mL of sodium chloride 0.9% to the 10-, 20-, or 50-mg vial, respectively, to yield a solution containing doxorubicin hydrochloride 2 mg/mL.3985; 3986 After the diluent is added, the vial should be shaken until the contents have dissolved.3985; 3986 The reconstituted solution should be further diluted prior to intravenous administration.3986
Doxorubicin hydrochloride is also available as a 2-mg/mL solution in 5-, 10-, or 25-mL single-dose vials and 75- or 100-mL multiple-dose vials3984 Each mL contains doxorubicin hydrochloride 2 mg in sodium chloride 0.9% with hydrochloric acid to adjust the pH.3984
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.
Equivalency
Doxorubicin hydrochloride 2 mg is equivalent to 1.87 mg of doxorubicin.3984
pH
The solution has a pH adjusted to 3.3984
Osmolality
Doxorubicin hydrochloride solution is isotonic.3984
Trade Name(s)
Adriamycin
Doxorubicin hydrochloride is administered by intravenous injection or continuous intravenous infusion.3984; 3985; 3986 Intravenous injection should be administered over 3 to 10 minutes through a central intravenous line or a secure and free-flowing peripheral venous line containing sodium chloride 0.9%, sodium chloride 0.45%, or dextrose 5%.3984; 3985; 3986 Continuous intravenous infusions should be administered only through a central intravenous line.3984; 3985; 3986 Extravasation should be avoided because severe tissue injury and necrosis may occur.3984; 3985; 3986
In the event of spills or leaks, a doxorubicin hydrochloride manufacturer has recommended the use of sodium hypochlorite 5% (household bleach) for inactivation.1200
Doxorubicin hydrochloride solution is a clear, red solution.3984 Intact vials of the solution should be stored under refrigeration at 2 to 8°C and protected from light.3984 Vials should be kept in their cartons until use; multiple-dose vials should be stored in the carton until contents are used.3984
Doxorubicin hydrochloride lyophilized powder is a red to orange red powder.3985; 3986 Intact vials of the powder should be stored at controlled room temperature in the original carton and protected from light.3985; 3986 The reconstituted solution should be protected from light but is stated to be stable for 7 days at room temperature and normal room light or 15 days at 2 to 8°C.3985
Refrigeration of the solution or reconstituted solution can result in the formation of a gelled product.3984; 3985 Solutions that have gelled may be allowed to stand at room temperature (15 to 30°C) for 2 to 4 hours to return the solution to a slightly viscous, mobile solution.3985; 3984
The manufacturers state diluted solutions for infusion (prepared from the solution or reconstituted solution) should be used within 1 hour of preparation and should be protected from light until completion of infusion.3984; 3986
For 50-mcg/mL and 0.5-mg/mL doxorubicin hydrochloride solutions, Janssen et al. reported that a greater rate of decomposition occurred in the more concentrated solution.1206 However, most other studies found no concentration dependence for the degradation rate.489; 526; 1208; 1255
A darkening of doxorubicin hydrochloride color has been noted when solutions of the drug contact aluminum metal. This change was initially noticed in the first small amount of drug to be injected through a needle with an aluminum hub. When solutions of doxorubicin hydrochloride containing aluminum are allowed to stand, the color becomes much darker than the control. Precipitation may also occur. As a precautionary measure, the author recommended not using any aluminum-containing apparatus for preparing or administering doxorubicin hydrochloride.653
In another evaluation, stainless steel needles with steel or plastic hubs and pieces of aluminum were immersed in doxorubicin hydrochloride 2 mg/mL in sterile water for injection or sodium chloride 0.9%. After 24 hours, the solutions containing the needles were unchanged in appearance and pH. The solution containing the aluminum was darker in color, and the pH had changed from 4.8 to 5.2. The concentrations of all solutions remained the same after 6 hours, but after 3 days, the solution containing aluminum was down to 91.9% while the others were only down to 94.4%. The authors concluded that doxorubicin hydrochloride does react with aluminum but at a slow rate and without major loss. They recommended not storing the drug in syringes capped with aluminum-hubbed needles but thought that doxorubicin could be injected safely through aluminum-hubbed needles.887
Immersion of a needle with an aluminum component in doxorubicin hydrochloride (Adria) 2 mg/mL resulted in a darkening of the solution, with black patches forming on the aluminum in 12 to 24 hours at 24°C with protection from light.988
Doxorubicin hydrochloride 0.5 mg/mL in sodium chloride 0.9% supported the growth of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Candida albicans, which are implicated in nosocomial infections. The arbitrary extension of expiration dates to doxorubicin hydrochloride solutions is highly questionable.827
Doxorubicin hydrochloride, etoposide phosphate, and vincristine sulfate admixtures at a variety of concentrations were unable to pass the USP test for antimicrobial effectiveness. Mixtures of these drugs are not “self-preserving” and permit microbial growth.2343 The potential for microbiological growth should be considered when assigning expiration periods.
pH Effects
Doxorubicin hydrochloride appears to have pH-dependent stability in solution.526; 1007; 1037 It becomes progressively more stable as the pH of drug-infusion solution admixtures becomes more acidic at 7.4 to 4.5.526 The pH range of maximum stability has been variously stated to be about 4 to 5,1007; 1460 3 to 4,1037 and about 4.1208 At a concentration of 0.1 mg/mL in buffer solutions stored at 4°C, no significant doxorubicin loss occurred in 60 days at pH 4, but substantial decomposition occurred at pH 7.4.1206 Doxorubicin hydrochloride is unstable at pH values less than 3 or greater than 7.4 In acidic media, splitting of the glycosidic bond results in a red-colored, water-insoluble aglycone and a water-soluble amino sugar.4 In alkaline media, a color change to deep purple is indicative of decomposition. This color change also occurs with other anthracyclines.394 It is thought to reflect cleavage of the amino sugar, resulting in an ineffective moiety.524
Freezing Solutions
Hoffman et al. found that doxorubicin hydrochloride, reconstituted to 2 mg/mL with sterile water for injection and kept at 4°C, exhibited a 1.5% loss in 1 month and a 10.5% loss in 6 months. Freezing the solutions at -20°C resulted in no loss over 30 days. It was indicated that filtration of stored solutions through a 0.22-µm filter was appropriate to ensure sterility.652
Doxorubicin hydrochloride (Farmitalia) 70 mg/50 mL in polyvinyl chloride (PVC) bags of sodium chloride 0.9% (Travenol) could be frozen at -20°C for at least 30 days and thawed by exposure to microwave radiation for 2 minutes with no significant change in concentration. However, the doxorubicin hydrochloride concentration apparently began declining after the fourth repetition of the freeze-thaw treatment with a loss of about 5%.818
The stability of doxorubicin hydrochloride 1 mg/mL in sodium chloride 0.9% in PVC containers at -20°C was evaluated. No drug loss occurred after 2 weeks of storage and thawing for 150 minutes at room temperature or 180 seconds in a microwave oven. Refreezing the solutions and rethawing at room temperature or in a microwave oven 3 weeks later (total of 5 weeks of frozen storage) resulted in 3% drug loss.1256
Although the thawing of frozen doxorubicin hydrochloride solutions in microwave ovens has been suggested,818; 1256 Williamson recommended only room temperature thawing because of the risks of drug decomposition from overheating and exposure if the bags burst.1257
Light Effects
Doxorubicin hydrochloride is sensitive to light, especially in very dilute solutions.489; 1073; 1094 However, the photolability of dilute solutions is not observed with more concentrated solutions. A 10-fold difference in photolability half-life was found between concentrations of 0.01 and 0.1 mg/mL.1594 The manufacturers recommend protecting the lyophilized powder and solutions from light from preparation until completion of infusion.3984; 3985; 3986
An evaluation of etoposide phosphate (Bristol-Myers Squibb) 2 mg/mL, doxorubicin hydrochloride 0.4 mg/mL, and vincristine sulfate 0.016 mg/mL (16 mcg/mL) in sodium chloride 0.9% in polyolefin plastic bags (McGaw) found little or no effect of constant exposure to normal fluorescent room light for 124 hours. The admixtures were physically compatible, and all 3 drugs in the admixture remained stable throughout the time period stored at an elevated temperature of 35 to 40°C.2343
Syringes
Doxorubicin hydrochloride (Farmitalia) 2 mg/mL repackaged in polypropylene syringes exhibited little loss after storage for 43 days at 4°C.1460
Doxorubicin hydrochloride (Adria) 2 mg/mL in sodium chloride 0.9% in glass vials and plastic syringes (Monoject and Terumo) and also 1 mg/mL in sodium chloride 0.9% in plastic syringes (Monoject) exhibited no visual changes and little or no loss when stored at 4 and 23°C while exposed to light for 124 days. Potential extractable materials from the syringes were not detected during the study period.1594
Implantable Pumps
Vogelzang et al. reported the stability of 3- and 5-mg/mL concentrations in sodium chloride 0.9% in the reservoir of a Medtronic DAD implantable pump at 37°C. Losses of about 5 to 6% in 1 week and 9 to 11% in 2 weeks occurred. Analyses after longer periods continued to show about a 5 to 6% loss per week at 37°C.1255
Sorption
Doxorubicin hydrochloride 16 mcg/mL in dextrose 5% and sodium chloride 0.9% in PVC containers was infused through PVC infusion sets at 21 mL/hr over 24 hours at 22°C while exposed to light. No evidence of sorption was found.1700
Doxorubicin hydrochloride (Farmitalia) 1 mg/mL in sodium chloride 0.9% exhibited no loss due to sorption to PVC and polyethylene administration lines during simulated infusions at 0.875 mL/hr for 2.5 hours via a syringe pump.1795
Filtration
Although doxorubicin hydrochloride was reported to undergo considerable binding to cellulose ester and polytetrafluoroethylene filters,1249; 1415; 1416 other studies did not confirm unacceptable losses at clinical concentrations. Doxorubicin hydrochloride 2 mg/mL in sterile water for injection showed no loss due to filtration when filtered through a 0.22-µm Millex filter.652
In another study, doxorubicin hydrochloride (Adria) 30 mg/15 mL was injected as a bolus through a 0.2-µm nylon, air-eliminating filter (Ultipor, Pall) to evaluate the effect of filtration on simulated intravenous push delivery. About 92% of the drug was delivered through the filter after flushing with 10 mL of sodium chloride 0.9%.809
Doxorubicin hydrochloride 1 mg/mL in sodium chloride 0.9% exhibited little loss due to sorption to cellulose acetate (Minisart 45, Sartorius), polysulfone (Acrodisc 45, Gelman), and nylon (Nylaflo, Gelman) filters. However, a 20 to 25% loss due to sorption occurred during the first 60 minutes of infusion through nylon filters (Utipore, Pall). A 35% loss was found during the first 15 min using a nylon filter (Posidyne ELD96, Pall). Return to the full concentrations occurred gradually within 1.5 to 2.5 hours.1795
Central Venous Catheter
Doxorubicin hydrochloride (Pharmacia) 0.25 mg/mL in dextrose 5% was found to be compatible with the ARROWg+ard Blue Plus (Arrow International) chlorhexidine-bearing triple-lumen central catheter. Essentially complete delivery of the drug was found with little or no drug loss occurring. Furthermore, chlorhexidine delivered from the catheter remained at trace amounts with no substantial increase due to the delivery of the drug through the catheter.2335
For a list of references cited in the text of this monograph, search the monograph titled References.