DRUG INCOMPATIBILITIES : definition, risks and management

1 DRUG INCOMPATIBILITIES : definition, risks and management Dre Caroline Fonzo-ChristePharmacie des HUGA dvanced Studies, Universit t BaselAugust 26st20112 MAIN POINTSWhat are drug INCOMPATIBILITIES ?How frequent in the hospital?How can we prevent them?How can we treat them?What should you know?3 MAIN POINTSWhat are drug INCOMPATIBILITIES ?How frequent in the hospital?How can we prevent them?How can we treat them?What should you know?CASE STUDYICU patient with GVH (graft-versus-host disease) central IV catheter, 3 lumenIV drugs infusedover 24h: Nutriflex Lipid special, Nexium ( ), Sandimmun (1mg/ml) et Trandate(5mg/ml).Other drugs as bolus ou short infusion :Bactrim, Cancidas, Cellcept, Cymevene, Lasix, Solumedrol, TazobacReserve drugs: morphine, Perfalgan et DroperidolNew drug: blood4 Drug incompatibility5 WHICH PARTNERS?Drug incompatibilityDrug ADrug BSolvent + excipientsSolvent + excipientsEnvironment Temperature LightMaterial PVC (DEHP) Silicone ..Factors Concentration Time of contactWHERE?

2 Drug incompatibilityFrom: KIK , BBraun, 200267 WHAT KIND OF REACTIONS?Physico- chemical reactions: Acid-base reactions (pH) Solubility changes Emulsion cracking Oxido-reduction ..Consequences precipitates(visible) coloration (visible) gas formation (visible) pH change (invisible) drug concentration (invisible)Drug incompatibility Catheter occlusion Particles emboli (renal, pulmonary) therapeutic effect Toxic effect (ex. peroxide)patient8 INCIDENTS IN PATIENTS?Drug incompatibilityMcNearney T et al. Dig Dis Sci 2003;48:1352-4 Knowles JB et al. JPEN 1989;13:209-13 Hill SE et al. JPEN 1996;20:81-879 CEFTRIAXONE- CALCIUMDrug incompatibilityPrescrire 1997;17:506 Bradley JS et al. Pediatrics 2009;123:609-13 PEROXIDES10 Helbock H et al. Pediatrics 1993;91;83-711pH AND DRUGSA cidic drugs Basic drugslow pH < 7high pH > 7 Amiodarone (Cordarone )pH = 4 Aciclovir (Zovirax ) pH = 11 Adrenaline pH = 3 Cotrimoxazole (Bactrim ) pH = 10 Dobutamine (Dobutrex )pH = 3 Furosemide (Lasix ) pH = 9 Midazolam (Dormicum ) pH = 4 Ganciclovir (Cymevene ) pH = 9 Morphine HUG pH = (Antra ) pH = 9 Vancomycine (Vancocin ) pH = 3 Phenytoin (Phenhydan ) pH = 12 Drug incompatibilityDrug incompatibilityACIDIC AND BASIC DRUGSTo be put in solution, saltsof active substances are used An acid is soluble in a basic solution drug solution is basic A base is soluble in an acidic solution drug solution is acidicDrug incompatibilityfurosemide sodique (pH 9) + vancomycine HCl (pH 3) From.

3 KIK , BBraun, 2002 Don t mix or infuse on Y-site acidic with basic drug solutions!furosemide sodique (pH 9) + midazolam HCl (pH 4) 1213 SOLVENT (DILUENT)Glucose 5%-20% pH = - , amphotericine BNaCl 0,9% pH = - , phenytoin, furosemideTheoryDrug incompatibilityBe careful with solvent pH !SolventpHAppropriate forFrom: KIK , BBraun, 200214 HEPARIN FLUSHINGT heoryDrug incompatibilityAsk careful what has been added to the solution !Solvent: NaCl 0,9% + heparine 20 UI/ml ! heparine + caspofungine precipitationSOLUBILITY Pastis effect drugexcipientamiodarone Cordarone polysorbate (tween)paracetamol Perfalgan mannitol, phosphate, NaOHesomeprazole Nexium NaOH, EDTA phenytoin Phenhydan glycofurol-75, EDTA clonazepamRivotril propyleneglycol, acetic acidCo-solvent and/or adjusting pH can increase the solubility of drugs in solutionDilution of drugs dilution of co-solvents pH change Risk of precipitation !Drug incompatibility15 COMPLEXATION16 Formation of insoluble calcium-ceftriaxone complexDrug administration of calcium and ceftriaxoneby thesame IV line !

4 Neonates: no calcium infusion if ceftriaxone has beenadministered (48h wash out period) !17 LIPID EMULSION Increased risk of coalescence: pH conc. AA electrolytes with high valence (Ca2+, Mg2+, PO43-)reversibleirreversibleTheoryDrug incompatibilityLipid emulsion is not water !18 LIPID EMULSIONL ipofundin or Disoprivan+ Garamycine Phase separation over 24hOil phase + fat soluble-dye (Sudan red III)Drug incompatibilityPHOTODEGRADATIOND egradation of drug under light exposition (sun, phototherapy) Store in the darkEx. furosemide, adrenaline, vecuronium Protection during administration nifedipine, isoprenaline, nitroprussiatelipides (neonatology) Drug incompatibility19 CORDARONE AND LIGHT 2003, mg/ml 5 mg/ml Drug incompatibility20 CORDARONE AND LIGHTNICU and PICU: 15 mg*BW ad 50 mlStability if conc. > 5 mg/ml (patients >15kg)But: No 10 or 20 ml amber syringe on the market Pediatric references: stable over 24h without light protectionHUG: No protection, even if conc.

5 < 5 mg/mlDrug incompatibility21 SORPTIONP hysical interaction between molecule and material (adsorption onto surface)Sorption loss of drugadsorption to PVC Ex: amiodarone, nitroglycerine, tacrolimus HUG: Flexs Bioren and syringues BD in PP Standard iv-lines in PVCC onnecting lines for syrines in PEadsorption to in-line filter Ex. phenobarbitalDrug incompatibility22 LEACHING (DESORPTION)Leaching of DEHP from PVC by cosolventDEHP: diethylhexylphtalate (plasticizer): hepatotoxic, carcinogen, toxic for reproduction friability of material, particules in solution Cosolvent: castor oil, PEG-35 castor oil, Cremophor, polysorbate 80 Ex: Taxol, Sandimmun, PrografDEHP-free material (NoDEHP) !Drug incompatibility23 LEACHING24 Increase with: Temperature Lipid content Contact time (storage) Amount of fluidHigh risk:Preterm neonates and critically ill patient IV therapy Parenteral and enteral feedings Ventilation Blood transfusion Long hospital stay , prolonged therapiesSchettler T.

6 2002 incompatibility25 MAIN POINTSWhat are drug INCOMPATIBILITIES ?How frequent in the ICU?How can we prevent them?How can we treat them?What should you know?26 MEDICATION ERRORSA dult ward 3%1incompatible drug combinationsAdult ICU - drug combinations, life-threatening, 29% no information4 Pediatric ICU combinationsNeonatal ICU combinations, no information1 Westbrook JI. BMJ Qual Saf 2011; 2 Bertsche T et al. Am J Health Syst Pharm 2008;65:1834-403 Tissot E et al. Intensive Care Med 1999;25:353-94 Vogel Kahmann I et al. Anaesthesist 2003;52:409-12 5 Gikic M et al. Pharm World Sci 2002;22:88-916 Kalikstad B et al. Arch Dis Child 2010;95:745-8 Frequence PRIORITY FOR QUALITY IMPROVEMENT 27 Bertsche T et al. PWS 2008;30:907-1528 MAIN POINTSWhat are drug INCOMPATIBILITIES ?How frequent in the ICU?How can we prevent them? in the wardHow can we treat them?What should you know?29 TOOLSP revention: ward30R ef er enc e an d it s ab re vi a ti on Trissel handbook 14th ed.

7 Ref Tools and their abreviations CHUV cross-table CHUV K IK database KIK King 2008 cross-table King Neofax 2007 handbook NeoF Perfysi 2 database Perf pH 2007 cross-table pH Stabilis 3 database Stab Th riaque 2007 database Th TOOLSP revention: wardDe Giorgi I et al. PWS 2010;32520-9 Evaluation by 2 pharmacists 40 drug pairs usually used in NICU and PICU Trissel s as gold referenceTOOLS Assessment interpretation adapted cross-tables (charts) pH- color code (Schaffhausen Model)Main problems: - exhaustiveness- assessment of drug pairs31 Prevention: wardCROSS-TABLESP revention: COLOR CODEA dult ICU in Schaffhausen (Switzerland) since 10 yearsVogel Kahmann I. et al. Anaesthesist 2003;52:409-12 Prevention: ward34pH COLOR CODEV ogel Kahmann I. et al. Anaesthesist 2003;52:409-12On IV-linesPharmacy wardPrevention: ward35pH COLOR CODEA bout 78 drug combinations (636 different drugs)Vogel Kahmann I. et al. Anaesthesist 2003;52:409-12 Prevention: ward Y-site infusion of potentially incompatible drugsHUG NURSE EVALUATION36 Prevention: wardGschwind L et al.

8 ESCP 2010. NURSE EVALUATION37 Gschwind L et al. ESCP 2010. : wardCHOICE OF NURSE TOOLS hould be adapted to the hospital Type of patients Type of medications Clinical pharmacist presence Language Computerization of prescription, electronicmedical record Individualized tool for each hospital38 Prevention: ward39IN-LINE FILTERSP revention: wardPotential difficulties for implementation at least two types of filters ( and m) technical aspects (priming, flushing) aseptic risks no filtration for some products blocked filters Teaching, operating procedures and follow-up are essentialBLOCKED FILTERSDrug incompatibility :40 Nexium + Dormicum + Morphine Esomeprazole discoloration precipitation in acidic solutionsPrevention: wardMAIN POINTSWhat are drug INCOMPATIBILITIES ?How frequent in the ICU?How can we prevent them? in the hospital pharmacyHow can we treat them?What should you know?4142IN VITRO STUDYP revention: pharmacyHumbert Delaloye V et al. ESCP 2009. IN VITRO STUDYC ompatibility lipid emulsions and drugsPrevention: pharmacyGranulometry mean size < 500 nm % globule > 5 m < potential measurementpH measureVisual inspection (microscope)43 NUTRIFLEX LIPID SPECIALDCI Concentration testedY-site Compatibility with NPT / 1hY-site Compatibility with NPT / 4hHeparin417 UI/mlCCFurosemide10 mg/mlIIOctreotide25 mg/mlCCCefepime100 mg/mlCIMeropeneme50 mg/mlCCCo-Amoxicilline50 mg/ml (amox.)

9 CIMetronidazole5 mg/mlCCParacetamol10 mg/mlCCVancomycine10 mg/mlCCOndansetron2 mg/mlCCBouchoud L et al. SFNEP 2009. ventionPrevention: pharmacy 44 DISOPRIVANS tucki C et al. ESCP 2009 ventionPrevention: pharmacy 4546PN: reduced risk of precipitationPhosphate mmol/L (Na2 HPO4)Calcium mmol/L (CaCl2) mmol/L (Na2 HPO4)Calcium mmol/L (CaCl2) mmol/L (G1P)Calcium mmol/L (CaCl2or Ca-Glu)Stability Zone504030201050403020105040302010504030 2010 Phosphate mmol/L (G1P)Calcium mmol/L (CaCl2or Ca-Glu)Stability ZoneUse of organic calcium and phosphates saltsPrevention: pharmacy BouchoudL et al. JPEN J Parenter Enteral Nutr. 2010;4:542-547 MAIN POINTSWhat are drug INCOMPATIBILITIES ?How frequent in the ICU?How can we prevent them?How can we treat them?What should you know?CATHETER RESCUENon thrombotic catheter occlusions in pediatric patients:Drug precipitates Lipid Residue48 TreatmentKerner J et al. JPEN 2006;30: S73-S81 Acidic drugs Basic ml/kg 70% ethanol , max 3 to 1 ml N HCl 1 ml N NaOH or Na -bicarbonate49 MAIN POINTSWhat are drug INCOMPATIBILITIES ?

10 How frequent in the ICU?How can we prevent them?How can we treat them?What should you know?TO REMEMBERDrug ADrug BSolvent + excipientsSolvent + excipientsAcidic drugs Basic drugs50 WHICH DRUGS?51 Always ALONE: Blood and derivates : agglutination and hemolysis risksBe careful WITH: Low and high pH: precipitation risks crystal deposit in kidney, lung, liver Drugs with co-solvent: precipitation risks crystal deposit in kidney, lung, liver Lipidemulsions: cracking risks fat embolismReduce contact time to a minimum ! Connexion near to the patientCASE STUDY: resolutionLumen 1(nutrition) Nutriflex Sandimmun Bactrim Cancidas (stop Nutriflex)Lumen 2 (basic pH) Nexium Cymevene Lasix In-line m Blood (stop Nexium for 1h, no filter)Lumen 3(acidic pH) Trandate Cellcept Solumedrol Tazobac In-line m Reserve drugscontinuousintermittentmaterial52 TAKE HOME MESSAGE53 Hospital and clinical pharmacists can help!