Lawrence A Trissel

Compatibility of Medications With 3-in-1 Parenteral Nutrition Admixtures

BACKGROUND The absence of drug compatibility information with 3-in-1 parenteral nutrition admixtures has been problematic. The purpose of this project was to evaluate the physical compatibility of 106 selected drugs during simulated Y-site injection into nine different 3-in-1 parenteral nutrition admixture formulations. METHODS Four-milliliter samples of each of the representative 3-in-1 parenteral nutrition admixture formulations were combined in a 1:1 ratio with 4-mL samples of each of 106 drugs, including supportive care drugs, anti-infectives, and antineoplastic drugs. Six replicate samples of each combination were prepared. Two samples were evaluated initially after mixing, two more after 1 hour, and the last two after 4 hours at 23 degrees C. At each test interval, the samples were subjected to centrifugation, causing the fat to rise to the top. The top fat layer and most of the aqueous phase were removed, and the remaining liquid was diluted with about 7 mL of particle-free, high-performance liquid chromatography-grade water to facilitate observation of any particulates that might have formed. Visual examinations were performed in normal diffuse fluorescent laboratory light and under high-intensity, monodirectional light. RESULTS Most of the drugs tested were physically compatible with the 3-in-1 parenteral nutrition admixtures for 4 hours at 23 degrees C. However, 23 drugs exhibited various incompatibilities with one or more of the parenteral nutrition admixtures. Six drugs resulted in the formation of precipitate with some or all of the admixtures. Seventeen drugs caused disruption of the emulsion, usually with oiling out. CONCLUSIONS Most of the test drugs were physically compatible with the nine representative 3-in-1 parenteral nutrition admixtures. However, the 23 drugs that resulted in incompatibilities should not be administered simultaneously with the incompatible parenteral nutrition admixtures via a Y injection site.

Safety of continuous intrathecal midazolam infusion in the sheep model

We investigated the safety of midazolam administered by continuous intrathecal infusion in relevant animal models. Preservative-free midazolam was delivered to sheep and pigs by using implanted infusion systems (SynchroMed® pumps plus silicone catheters). Sheep received midazolam 5 mg/d (n= 4) or 15 mg/d (n= 7) or saline (n= 2) for 43 days at 125 μL/h. One sheep received 10 mg/d. Infusion concentrations ranged from 1.7 to 2.5 mg/mL (5 mg/d) and from 2.5 to 5.0 mg/mL (15 mg/d). Pigs were evaluated for toxicity only and received 15 mg/d (n= 2) or saline (n= 1) for 43 days at 125 μL/h. Behavior, neurologic function, and vital signs were documented. Serum and cerebrospinal fluid chemistry and cytology were evaluated, and histology was performed on spinal cord tissue. Behavior and neurologic function remained normal in all subjects. Gross and microscopic evaluation of spinal tissue revealed mild inflammation surrounding the catheter tract in both the midazolam-treated and the saline-treated groups. This inflammation was likely attributable to the mechanical presence of the catheter. These data demonstrate that continuous intrathecal infusion of preservative-free midazolam at doses up to 15 mg/d were well tolerated.

The stability of diluted vincristine sulfate used as a deterrent to inadvertent intrathecal injection

The objective of this study was to evaluate the physical and chemical stability of vincristine sulfate diluted to a variety of concentrations in 0.9% sodium chloride injection and packaged in minibags and 30 mL syringes, to help deter inadvertent intrathecal injection of the drug. Test samples were prepared by diluting vincristine sulfate quantities of 0.5 mg, 1 mg, 2, mg, and 3 mg in 0.9% sodium chloride injection. These quantities were selected to span the range of doses normally expected for this cytotoxic drug. The vincristine was diluted with 0.9% sodium chloride injection in volumes of 25 mL and 50 mL packaged in polyvinyl chloride minibags and to 20 mL packaged in 30 mL polypropylene syringes. Physical and chemical stability evaluations were performed initially and after 1, 3, and 7 days of storage at 4°C followed by an evaluation at 9 days after 2 additional days of storage at a temperature of 23°C. Physical stability was assessed using visual observation in normal light and a high-intensity monodirectional light beam. In addition, turbidity and particle content were measured electronically. Chemical stability of the drug was evaluated by using a stability-indicating high performance liquid chromatographic (HPLC) analytical technique. No physical instability was noted and no unacceptable loss of vincristine sulfate concentration was found in any sample throughout the study period. The use of vincristine sulfate doses diluted in infusion volumes of 0.9% sodium chloride injection and packaged in minibags or in 30 mL syringes to help deter inadvertent intrathecal administration may be performed with no unacceptable physical or chemical instability occurring.

Physical and Chemical Stability of Gemcitabine Hydrochloride Solutions

OBJECTIVE To evaluate the physical and chemical stability of gemcitabine hydrochloride (Gemzar-Eli Lilly and Company) solutions in a variety of solution concentrations, packaging, and storage conditions. DESIGN Controlled experimental trial. SETTING Laboratory. INTERVENTIONS Test conditions included (1) reconstituted gemcitabine at a concentration of 38 mg/mL as the hydrochloride salt in 0.9% sodium chloride or sterile water for injection in the original 200 mg and 1 gram vials; (2) reconstituted gemcitabine 38 mg/mL as the hydrochloride salt in 0.9% sodium chloride injection packaged in plastic syringes; (3) diluted gemcitabine at concentrations of 0.1 and 10 mg/mL as the hydrochloride salt in polyvinyl chloride (PVC) minibags of 0.9% sodium chloride injection and 5% dextrose injection; and (4) gemcitabine 0.1, 10, and 38 mg/mL as the hydrochloride salt in 5% dextrose in water and 0.9% sodium chloride injection as simulated ambulatory infusions at 32 degrees C. Test samples of gemcitabine hydrochloride were prepared in the concentrations, solutions, and packaging required. MAIN OUTCOME MEASURES Physical and chemical stability based on drug concentrations initially and after 1, 3, and 7 days of storage at 32 degrees C and after 1, 7, 14, 21, and 35 days of storage at 4 degrees C and 23 degrees C. RESULTS The reconstituted solutions at a gemcitabine concentration of 38 mg/mL as the hydrochloride salt in the original vials occasionally exhibited large crystal formation when stored at 4 degrees C for 14 days or more. These crystals did not redissolve upon warming to room temperature. All other samples were physically stable throughout the study. Little or no change in particulate burden or the presence of haze were found. Gemcitabine as the hydrochloride salt in the solutions tested was found to be chemically stable at all concentrations and temperatures tested that did not exhibit crystallization. Little or no loss of gemcitabine occurred in any of the samples throughout the entire study period. However, refrigerated vials that developed crystals also exhibited losses of 20% to 35% in gemcitabine content. Exposure to or protection from light did not alter the stability of gemcitabine as the hydrochloride salt in the solutions tested. CONCLUSION Reconstituted gemcitabine as the hydrochloride salt in the original vials is chemically stable at room temperature for 35 days but may develop crystals when stored at 4 degrees C. The crystals do not redissolve upon warming. Gemcitabine prepared as intravenous admixtures of 0.1 and 10 mg/mL as the hydrochloride salt in 5% dextrose injection and 0.9% sodium chloride injection in PVC bags and as a solution of 38 mg/mL in 0.9% sodium chloride injection packaged in plastic syringes is physically and chemically stable for at least 35 days at 4 degrees C and 23 degrees C. Gemcitabine as the hydrochloride salt is stable for at least 7 days at concentrations of 0.1, 10, and 38 mg/mL in 5% dextrose injection and 0.9% sodium chloride injection stored at 32 degrees C during simulated ambulatory infusion.

Physical and Chemical Stability of Pemetrexed in Infusion Solutions

Background: Pemetrexed is a multitargeted, antifolate, antineoplastic agent that is indicated for single-agent use in locally advanced or metastatic non-small-cell lung cancer after prior chemotherapy and in combination with cisplatin for the treatment of malignant pleural mesothelioma not treatable by surgery. Currently, there is no information on the long-term stability of pemetrexed beyond 24 hours. Objective: To evaluate the longer-term physical and chemical stability of pemetrexed 2, 10, and 20 mg/mL in polyvinyl chloride (PVC) bags of dextrose 5% injection and NaCI 0.9% injection. Methods: Triplicate samples of pemetrexed were prepared in the concentrations and infusion solutions required. Evaluations for physical and chemical stability were performed initially and over 2 days at 23 °C protected from light and exposed to fluorescent light, and over 31 days of storage at 4 °C protected from light. Physical stability was assessed using turbidimetric and particulate measurement as well as visual observation. Chemical stability was evaluated by HPLC. Results: All pemetrexed solutions remained chemically stable, with little or no loss of pemetrexed over 2 days at 23 °C, protected from light and exposed to fluorescent light, and over 31 days of storage at 4°C, protected from light. The room temperature samples were physically stable throughout the 48 hour test period. However, pemetrexed admixtures developed large numbers of microparticulates during refrigerated storage exceeding 24 hours. Conclusions: Pemetrexed is chemically stable for 2 days at room temperature and 31 days refrigerated in dextrose 5% injection and NaCI 0.9% injection. However, substantial numbers of microparticulates may form in pemetrexed diluted in the infusion solutions in PVC bags, especially during longer periods of refrigerated storage. Limiting the refrigerated storage period to the manufacturer-recommended 24 hours will limit particulate formation.

Effect of two work practice changes on the microbial contamination rates of pharmacy-compounded sterile preparations

PURPOSE Using a multiple-step testing medium-risk-level compounding test procedure, the evaluation of two work-practice changes to determine if the changes could effectively reduce the potential for contamination occurrence was conducted. SUMMARY Along with training and evaluation of aseptic sterile compounding techniques, each individual pharmacist and pharmacy technician at M. D. Anderson Cancer Center must successfully demonstrate aseptic preparation competency annually by performing the complicated multistep aseptic transfers of growth medium with no resulting growth of microorganisms. The multistep aseptic transfers are designed to simulate manual compounding of the most complicated medium-risk-level preparations anticipated as specified in the United States Pharmacopeias chapter 797. An evaluation of two modest and simple work-practice changes was conducted: The use of bare hands and nonsterile gloves with only initial disinfection with 70% isopropyl alcohol (IPA) during years 1 and 2 (group A) was compared with the use of nonsterile chemotherapy gloves with initial and repeated disinfection with IPA for year 3 (group B) and the use of sterile gloves with initial and repeated disinfection with IPA for year 4 (group C). The process involved multiple discrete manipulations, including reconstitution of dry-growth medium; transfers of growth medium from vials and ampules using syringes, needles, a dispensing pin, and a filter straw; and transfers to an empty plastic i.v. bag. For groups B and C, significant reductions in contaminated samples were found compared with group A. CONCLUSION The use of protective chemotherapy gloves that were repeatedly disinfected with IPA decreased the contamination rate of pharmacy-compounded sterile preparations.

Combined administration of opioids with selected drugs to manage pain and other cancer symptoms initial safety screening for compatibility

Cancer patients suffer multiple symptoms and require numerous drug therapies. Parenteral administration of multiple medications from a single container can simplify drug regimens for patient self-administration. This simplification reduces drug preparation costs and risk of infection. Therapeutic options are limited by the lack of published information on the compatibility of opioids and adjuvant drugs. We report the results of a study evaluating the physical compatibility of injectable opioids with selected drugs for pain and symptom management. Fentanyl citrate, hydromorphone hydrochloride, methadone hydrochloride, and morphine sulfate solutions were physically compatible with 14 of 15 supportive care drugs tested through visual examination using a high intensity light beam and through measured examination using a turbidimeter over a range of times up to 48 hr. Phenytoin sodium was the only drug found to be incompatible with all opioid solutions tested. This compatibility information will assist clinicians in selecting the most efficient, safe, and cost-effective supportive care drug regimen.

Compatibility of ceftobiprole medocaril with selected drugs during simulated Y-site administration.

PURPOSE The physical compatibility of the new cephalosporin ceftobiprole medocaril with 70 other drugs during simulated Y-site injection was studied. METHODS Ceftobiprole was reconstituted with sterile water for injection. Dilutions of ceftobiprole 2 mg/mL (as ceftobiprole medocaril 2.67 mg/mL) were prepared in 5% dextrose injection, 0.9% sodium chloride injection, and lactated Ringers injection. For testing compatibility with the other drugs, a 5-mL sample of the ceftobiprole 2-mg/mL admixtures was combined with a 5-mL sample of the other drug either undiluted or diluted with one of the three vehicles. Each combination was prepared in duplicate, switching the order of drug addition, and kept at room temperature. At intervals up to four hours after preparation, samples were examined visually and with the aid of a Tyndall beam and measured with a turbidimeter and a particle sizer and counter. Compatibility with propofol was evaluated by checking for emulsion separation and particles after centrifugation. RESULTS In all three vehicles, ceftobiprole was compatible with 31 other drugs and incompatible with 32. With 7 drugs, compatibility was dependent on the vehicle used. Signs of incompatibility included the presence of visible and subvisible particles, haze, and turbidity. No incompatibilities were related to the order of mixing. CONCLUSION Of the 70 drugs evaluated for compatibility with ceftobiprole 2 mg/ mL (as medocaril) in 5% dextrose injection, 0.9% sodium chloride injection, and lactated Ringers injection, 31 were found to be compatible and 32 were found to be incompatible in all three of the infusion solutions. For 7 of the drugs, compatibility was dependent on which infusion solution was used. Ceftobiprole medocaril should not be simultaneously administered via a Y site with drugs with which it was shown to be incompatible.

Stability of Three Cephalosporin Antibiotics in AutoDose Infusion System Bags

OBJECTIVE To evaluate the physical and chemical stability of three commonly used cephalosporin antibiotic solutions packaged in AutoDose Infusion System bags stored and evaluated at appropriate intervals for up to 7 days at 23 degrees C and up to 30 days at 4 degrees C. SETTING Laboratory. INTERVENTIONS The test samples were prepared by adding the required amount of the cephalosporin antibiotic to the AutoDose Infusion System bags and diluting to the target concentration with 0.9% sodium chloride injection. MAIN OUTCOME MEASURES Physical stability and chemical stability based on drug concentrations initially and at appropriate intervals over periods of up to 7 days at 23 degrees C and up to 30 days at 4 degrees C. RESULTS All of the cephalosporin admixtures were clear when viewed in normal fluorescent room light and with a Tyndall beam. Measured turbidity and particulate content were low and exhibited little change. The cefazolin sodium-containing samples were colorless throughout the study. The admixtures with ceftazidime and ceftriaxone sodium had a slight yellow tinge initially, and the room temperature samples turned a frank yellow color after 5 days. The refrigerated samples did not change color. High-performance liquid chromatography analysis showed that cefazolin sodium and ceftriaxone sodium remained stable for 30 days and ceftazidime remained stable for 7 days at 4 degrees C. At room temperature, losses were much more rapid. Cefazolin sodium and ceftriaxone sodium retained at least 90% of their initial concentrations through 7 days and 5 days, respectively, when stored at 23 degrees C. Ceftazidime remained stable for only 1 day at 23 degrees C. CONCLUSION Cefazolin sodium, ceftazidime, and ceftriaxone sodium exhibited physical and chemical stabilities consistent with those found in previous studies of these drugs. The AutoDose Infusion System bags did not adversely affect the physical and chemical stabilities of these three cephalosporin antibiotics.

PHYSICAL AND CHEMICAL STABILITY OF ETOPOSIDE PHOSPHATE SOLUTIONS

OBJECTIVE To evaluate the physical and chemical stability of etoposide phosphate solutions over 7 days at 32 degrees C and 31 days at 4 degrees C and 23 degrees C: (1) at etoposide concentrations of 0.1 and 10 mg/mL as phosphate in 0.9% sodium chloride injection and 5% dextrose injection and (2) at etoposide concentrations of 10 and 20 mg/mL as phosphate in bacteriostatic water for injection packaged in plastic syringes. DESIGN Test samples of etoposide phosphate were prepared in polyvinyl chloride (PVC) bags of the two infusion solutions at etoposide concentrations of 0.1 and 10 mg/mL as phosphate. Additional test samples were prepared in bacteriostatic water for injection containing benzyl alcohol 0.9% at etoposide concentrations of 10 and 20 mg/mL as phosphate and were packaged in 5 mL plastic syringes. Evaluations for physical and chemical stability were performed initially; after 1 and 7 days of storage at 32 degrees C; and after 1, 7, 14, and 31 days of storage at 4 degrees C and 23 degrees C. Physical stability was assessed using visual observation in normal light and using a high-intensity monodirectional light beam. Turbidity and particle content were measured electronically. Chemical stability of the drug was evaluated by using a stability-indicating high-performance liquid chromatographic (HPLC) analytic technique. RESULTS All samples were physically stable throughout the study. Little or no change in particulate burden and haze level were found. In the intravenous infusion solutions, little or no loss of etoposide phosphate occurred in any of the samples throughout the study period. The 10 and 20 mg/mL samples in bacteriostatic water for injection repackaged in syringes were also stable throughout the study, exhibiting a maximum of 6% or 7% loss after 31 days of storage at 23 degrees C and less than 4% in 31 days at 4 degrees C. CONCLUSION Etoposide phosphate prepared as intravenous admixtures of etoposide 0.1 and 10 mg/mL as phosphate in 5% dextrose injection and 0.9% sodium chloride injection in PVC bags and as etoposide 10 and 20 mg/mL as phosphate in bacteriostatic water for injection packaged in plastic syringes is physically and chemically stable for at least 7 days at 32 degrees C and 31 days at 4 degrees C and 23 degrees C. This new water-soluble phosphate-ester of etoposide formulation solves the precipitation problems associated with the old organic solvent and surfactant-based formulation.