PEER REVIEWED IJPC Compatibility of Caspofungin Acetate Injection with Other Drugs During Simulated Y-Site Coadministration Pak Chan Abstract Kathy Heatherly, MS The physical compatibility of caspofungin acetate injection with selected other drugs Thomas C. Kupiec, PhD during simulated Y-site coadministration was evaluated by visual observation and tur- Analytical Research Laboratories bidity measurement. Five-milliliter samples of caspofungin acetate 0.7 mg/mL in 0.9% Oklahoma City, Oklahoma sodium chloride injection were combined with 5 mL of 67 other drugs including anti- neoplastics, analgesics, anti-infectives, and supportive care drugs, undiluted or diluted Lawrence A. Trissel, BS, RPh, FASHP in 0.9% sodium chloride injection or 5% dextrose injection, and with a parenteral nu- TriPharma Research trition admixture. Visual examinations were performed with the unaided eye in normal Ponte Vedra Beach, Florida laboratory fluorescent light and with a Tyndall beam (high-intensity monodirectional light beam) to enhance visualization of small particles and low-level turbidity. The tur- Acknowledgment bidity of each sample was measured as well. The sample mixtures were evaluated im- This study was supported by a grant from mediately and at 1 and 4 hours after preparation. Nineteen of the drugs tested and the Merck & Co., Inc., Whitehouse Station, parenteral nutrition admixture were incompatible with caspofungin acetate 0.7 mg/mL New Jersey. during the 4-hour observation period. The remaining drugs were compatible for at least 4 hours. Gross precipitation or turbidity changes visible in normal diffuse room light with the unaided eye occurred with 18 drugs and with the parenteral nutrition INTRODUCTION admixture. Microprecipitation of particulates not visible with the unaided eye occurred Caspofungin acetate (CANCIDAS; with cytarabine. The measured turbidity of the caspofungin acetate control solutions Merck & Co., Inc., Whitehouse Station, and the compatible test samples remained essentially unchanged throughout the ob- New Jersey) is a semisynthetic lipopeptide servation period. In combination with caspofungin acetate, 48 drugs and a parenteral antifungal agent. The drug acts by inhibit- nutrition admixture were considered to be physically compatible. In contrast, 19 drugs ing the synthesis of β(1,3)-D-glucan, an with the parenteral nutrition admixture exhibited frank precipitation or microparticu- integral component of the fungal cell wall. late formation within 4 hours and should not be simultaneously administered via Y-site Caspofungin acetate is active in vitro against several species of Aspergillis and Candida. with caspofungin acetate. The drug is indicated in the treatment of presumed fungal infections in febrile, METHODS AND were selected to represent the higher end of neutropenic patients. It is indicated in Can- concentrations typically administered. dida infections, including intra-abdominal Materials Allen et al reported that the mixing of an abscess, peritonitis, infection of the pleural Materials intravenous fluid in an administration set space, and esophageal candidiasis. Caspo- Caspofungin acetate injection (Lots with a secondary additive from a Y-injection fungin acetate is also used to treat invasive 0199U, 0421U, and 1567F; Merck & Co., site occurs in a 1:1 ratio.2 Therefore, a 5-mL aspergillosis in cases refractory to other Inc.) was supplied in 70-mg lyophilized sample of the caspofungin acetate treatments or in patients who cannot toler- single-use vials. The vial contents were 0.7 mg/mL solution was combined with ate other medications. Caspofungin acetate reconstituted with 10 mL of 0.9% sodium a 5-mL sample of each of the other study is administered by slow intravenous infusion chloride injection (Lot 34-012-JT; Hospira, drug solutions individually in colorless over 1 hour.1 Lake Forest, Illinois; or Lot J6S909; B. 15-mL borosilicate glass screw-cap culture Patients receiving caspofungin acetate Braun, Bethlehem, Pennsylvania) removed tubes (Kimble, Division of Owens-Illinois, infusion may be receiving many other from a 100-mL bag of the infusion solution. Toledo, Ohio) with polypropylene caps parenteral drugs via Y-site coadministration, The reconstituted caspofungin acetate was including anti-infectives, antiemetics, anti- (Kimble, Division of Owens-Illinois) as added back to the 100-mL bags of 0.9% 3 neoplastics, steroids, analgesics, and other described elsewhere. Each of the sample supportive care drugs. The potential exists sodium chloride solution, yielding a solutions was passed through an appropri- during coadministration for development 0.7-mg/mL caspofungin acetate solution ate 0.22-mcm filter (Millex-GV; Millipore of physical incompatibilities of caspofungin used for this testing. The 67 drugs and Products, Bedford, Massachusetts) as it was acetate and other agents or components of parenteral nutrition admixture that served as introduced into the tube. Each caspofungin their formulations. secondary additives in this study are listed in acetate/test drug combination was prepared The purpose of this study was to evaluate Table 1. The secondary additives were tested in duplicate, the second trial reversing the the physical compatibility of caspofungin undiluted, prepared in 0.9% sodium chlo- order in which the drugs were added in the acetate during simulated Y-site injection ride injection, or prepared in 5% dextrose first trial. with 67 other drugs and a parenteral nutri- injection (Lot P198622; Baxter Healthcare, Caspofungin acetate 0.7 mg/mL in 0.9% tion admixture by visual observation and Deerfield, Illinois) for testing (see Table 1). sodium chloride injection and the other test turbidity measurement. Drug concentrations used for this testing drug solutions each were diluted with an International Journal of Pharmaceutical Compounding www.IJPC.com 276 Vol. 12 No. 3 | May/June 2008 PEER REVIEWEDFEATURE IJPC equal volume of 0.9% sodium chloride injection to a concentration drug combinations was defined as any visible particulate matter, sub- of 0.35 mg/mL to simulate test sample preparation. These dilutions stantial haze or turbidity change from that in the controls, a color served as controls. Incompatibility in the caspofungin acetate/test change, or gas evolution. Table 1. Drugs Tested for Compatibility with Caspofungin Acetate 0.7 mg/mL in 0.9% Sodium Chloride Injection. Drug Manufacturer Lot Number Concentrationa Drug Manufacturer Lot Number Concentrationa Acyclovir sodium Ben Venue 733396 7 mg/mL Hydromorphone Baxter 037067 1 mg/mL Amikacin sulfate Hospira 45-325-DK 5 mg/mL hydrochloride Amiodarone Sicor 06N216 4 mg/mL Ifosfamide Baxter 5L163L 20 mg/mL hydrochloride Imipenem- Merck 3967R 5 mg/mL Amphotericin B X-Gen 5L6AB 0.6 mg/mLb cilastatin (colloidal) Insulin human Novo Nordisk SZF0177 1 unit/mL Amphotericin B Enzon 6569A 1 mg/mLb regular lipid complex Pharmaceuticals Lansoprazole TAP 48004RX 0.55 mg/mL Amphotericin B Astellas Pharma 042640AA 1 mg/mLb Levofloxacin Janssen 6KB5500 5 mg/mL liposomal Linezolid Pharmacia & 06105Z04 2 mg/mLc Ampicillin sodium American 6F12AY 20 mg/mL Upjohn Pharmaceutical Lorazepam Hospira 39220DD 0.5 mg/mL Partners Magnesium sulfate American Regent 5447 100 mg/mL Aztreonam Bristol-Myers 6B12498 40 mg/mL Melphalan Cardinal Health A502 1 mg/mL Squibb hydrochloride Bumetanide Bedford 957786 0.04 mg/mL Meperidine Hospira 45625LL 10 mg/mL Carboplatin Mayne Pharma S041709 5 mg/mL hydrochloride Cefazolin sodium Cura C026083 20 mg/mL Meropenem AstraZeneca MM0108 2.5 mg/mL Pharmaceuticals Methylprednisolone Pharmacia & 56PYD 5 mg/mL Cefepime Bristol-Myers 6C19179 20 mg/mL sodium succinate Upjohn hydrochloride Squibb Metronidazole Baxter P200337 5 mg/mLc Ceftazidime GlaxoSmith A176 40 mg/mL Midazolam American 402072 2 mg/mL Kline hydrochloride Pharmaceutical Ceftriaxone sodium Orchid C086014 20 mg/mL Partners Ciprofloxacin Hospira 51-279-DK 2 mg/mL Milrinone lactate Baxter 116097 0.2 mg/mL Cisplatin American 201720 0.5 mg/mL Mitomycin Bedford 1106707 0.5 mg/mL Pharmaceutical Morphine sulfate Baxter 116078 15 mg/mLc Partners Mycophenolate Roche H3057 6 mg/mL Clindamycin Bedford 974322 10 mg/mL mofetil hydrochloride phosphate Nafcillin sodium Sandoz 140345 20 mg/mL Cyclosporine Bedford 710699 5 mg/mL Norepinephrine Bedford 922401 0.128 mg/mL Cytarabine Mayne Pharma S021982AA 50 mg/mLc bitartrate Daptomycin Cubist 451653 10 mg/mL Pantoprazole sodium Wyeth 17283A 0.4 mg/mL Daunorubicin Bedford 957972 1 mg/mL Parenteral nutrition Mercy Health None hydrochloride admixtured Center Diltiazem Hospira 50470DD 5 mg/mLc Phenylephrine Baxter 163504 1 mg/mL hydrochloride hydrochloride Dobutamine Hospira 44-287-DK 4 mg/mL Piperacillin sodium/ Wyeth B45832 40/5 mg/mL hydrochloride tazobactam sodium Dopamine American 5123 3.2 mg/mL Potassium chloride American 402446 0.1 mEq/mL hydrochloride Regent Pharmaceutical Doxorubicin Bedford 954153 1 mg/mL Partners hydrochloride Potassium American 141489 0.5 mmol/mL Epinephrine Amphastar-IMS DT029C7 0.05 mg/mL phosphates Pharmaceutical hydrochloride Partners Ertapenem Merck 3918R 20 mg/mL Quinupristin/ Monarch A18640 5 mg/mL Etoposide Sicor 06N614 5 mg/mL dalfopristin phosphate Sulfamethoxazole/ Sicor 06N102 4 + 0.8 mg/mL Fentanyl citrate Hospira 47-346-DK 0.05 mg/mL trimethoprim Furosemide American Regent 5475 3 mg/mL Tacrolimus Astellas Pharma 5A3118A 0.02 mg/mL Ganciclovir sodium Roche U2186 20 mg/mL Tobramycin sulfate Sicor 06E127 5 mg/mL Gentamicin sulfate Hospira 41-468-DK 5 mg/mL Vancomycin Hospira 45-730Z7 10 mg/mL Heparin sodium