INCOMPATIBILITIES OF PARENTAL DRUG ADMIXTURES

PREPARED AND PRESENTED BY :

TABARAK KHALID H

ALI SALMAN J.J

AS

OBJECTIVES :

• What is Incompatibility ?

• Why I in need to mix parental injection

• What are the guidelines for parental drug admixtures?

• When I can mix them ?

• When I can’t & why ? What happen if I give them ?

• How can I minimize risk of incompatibilities

• What are the most common admixture in Iraq todays ?

• Are they pharmaceutically compatible

WHAT IS INCOMPATIBILITY ?

• Incompatibility is defined as “ a phenomenon which occurs when one drug is mixed with others and produces an unsuitable product/s by some physicochemical means that are no longer safe or effective for the patient.

Drug stability and compatibility are critically important in the provision of safe and effective drug therapy

Multiple drugs may be administered simultaneously to a critically ill patient and determining the compatibility of those agents is of great importance.

It is estimated that over 30% of the commonly utilized drugs are incompatible or unstable when added or combined with usual fluids or agents.

TYPES OF INCOMPATIBILITIES

1. Therapeutic Incompatibility

2. Physical Incompatibility

3. Chemical Incompatibility

4. Drug IV Container Incompatibilities

• Will be discussed later in more details

WHY I IN NEED TO MIX PARENTAL DRUGS ?

• Difficulties with venous access limiting the number of intravenous lines

available for continuous administration of multiple drugs

• Multiple drugs requiring parenteral administration within a short time

frame such as in a home visit by a general practitioner

• Patients at home requiring many drugs by simultaneous continuous

infusion where multiple intravenous lines are not feasible, for example,

use of a syringe driver during palliative care.

WHAT ARE THE GUIDELINES FOR PARENTAL

DRUG ADMIXTURES?

In the UK they are the following

• Only be undertaken in the best interests of the patient;

• Be avoided where possible;

• Only be done by a person who is competent and willing to do so;

• Take place in a pharmacy (where possible).

THERAPEUTIC INCOMPATIBILITY

• The result of pharmacological effects of several drugs in one patient (a.k.a. drug interactions).

• Ex: Aminophylline administered with Cimetidine. Cimetidine inhibits degradation of Aminophylline through cytochrome P450 system thereby increasing the Aminophylline levels.

PHYSICAL INCOMPATIBILITY:

• Interaction between two or more substances which lead to change in color, odor, taste, viscosity and morphology. A visible physical change takes place

Types of physical incompatibility:

1. Insolubility and immiscibility(Alcohol or lipid solvents vs. water )

2. Change of concentration

3. The creation of gas

4. Ion reaction

5. Fat emulsion

6. Adsorption and leaching

7. precipitatation upon dilution

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Concentration change :Drugs that are compatible at lower concentrations can become incompatible at higher concentrations• Cimetidine hydrochloride compatibility.The stability of cimetidine hydrochloride mixed in intravenous solutions individually with 37 additives was investigated. Recommended doses of cimetidine hydrochloride injection and the other additives were diluted aseptically in varying concentrations in compatible intravenous solutionsThe results of this investigation suggest that incompatibility may be expected when cimetidine hydrochloride is combined with some antibiotics, and cimetidine incompatibilities may be concentration dependent.

Alcohol and lipid solvent : When the formulated product is diluted in an aqueous solution, the drug may precipitate out until

enough solution is added to enable dissolution without the need for a solvent.Diazepam lorazepam in ethanol, PG , glycerin , PEG • digoxin is formulated with propylene glycol 40% and ethanol 10%. It needs to be administered diluted at

least fourfold to prevent precipitation.

ION REACTION :

• The salts of monovalent cations, such as sodium and potassium, are generally more soluble than those of divalent cations, such as calcium and magnesium. Mixing solutions containing calcium or magnesium ions has a substantial risk of forming an insoluble calcium or magnesium salt.

• Mixing magnesium sulfate 50% and calcium chloride 10% results in precipitation of insoluble calcium sulfate.

• The mixing of drug salts of calcium, and to a lesser extent magnesium, with phosphates, carbonates, bicarbonates, tartrates or sulfates should also be avoided.

• A recent warning has been issued about mixing calcium-containing solutions, including ringer 's solution, with ceftriaxone causing the formation of the insoluble ceftriaxone calcium salt.

• The ceftriaxone-calcium compound may form a precipitate in blood, which may damage kidneys, lungs, or gallbladder.

• Cisplatin (Platinol-AQ) ,Interacts with aluminum to cause a blackish colored precipitate that results in loss of potency. Cisplatin molecule is being forced out of solution. Use stainless steel needles to avoid this.

Creation of gas :

the creation of extensive amounts of gas can be hazardous.• Metoclopramide formulated as its hydrochloride salt is incompatible with sodium bicarbonate for this reason .• Control solutions were cloxacillin in NS for injection, vancomycin in NS, and NS alone. Incompatibility was defined

as any visible particulate matter, substantial haze or change in turbidity relative to the controls, change in colour, or evolution of gas.

Fat emulsion : • such as Intralipid, TPN and some drug formulations (e.g.

Diazemuls), can easily be destabilised, cracked or separated when they are mixed with solutions containing highly positively charged ions.

• electrolytes should only ever be added to TPN in a specialist pharmacy aseptic unit where the stability of the final product can be checked before use.

TOTAL PARENTERAL NUTRITION (TPN) AND DRUG COMPATIBILITY

• The co-infusion of drugs and PN should be avoided

• . PN solutions are diverse in their composition and compatibilities with drugs can never be guaranteed.

• Drugs administered to patients receiving PN should be given through a separate IV site or catheter lumen. If a separate site is not available, the drug may be given through a separate line that has a Y-connection to the PN line as close to the patient as possible. The PN

should not be running and the common tubing must be adequately flushed before and after drug administration

• The following drugs are INCOMPATIBLE with PN and MUST NOT be run concurrently with PN solutions under any circumstances. These drugs may be administered through a Y-connection provided the PN solution is stopped, the line clamped immediately above

the Y and the line adequately flushed.

• acetazolamide calcium doxorubicin phenytoin acyclovir cefazolin etoposide phosphate amphotericin ceftriaxone furosemide sodium bicarbonate ampicillin cisplatin mannitol ATG( Anti-thymocyte globulin) deferoxamine paraldehyde

• PARENTERAL NUTRITION (PN) AND BLOOD PRODUCT COMPATIBILITY

• No blood products are to be co-infused with PN.

• Furosemide injection is permitted with Albumin for Renal Dialysis patients only.

accumulation

of triglyceride

particles at

the top of the

emulsion.

ADSORPTION

• Non-polar, sparingly soluble drugs stored in plastic containers tend to partition into the plastic container wall. A classical example is nitroglycerin.

• Nitroglycerin has low water solubility, approximately 0.1%, which suggests that it has high non-polar solubility.

• Indeed, if nitroglycerin in aqueous solution is placed in a polyvinylchloride IV bag (non-polar medium) or is delivered through a polyvinylchloride IV set, the drug will be lost by adsorption to the plastic. Since the dosing of nitroglycerin is critical, it should be dispensed in glass IV bottles and infused with a special, non-adsorbing infusion set , Polyolefin (semi-rigid) and Polyethylene plastics are acceptable.

• Large polymeric drugs (e.g. paclitaxel), proteins (e.g. insulin) and highly lipid-soluble drugs, the flow rate, concentration of drug and pH can all affect the extent to which adsorption occurs.

LEACHING

• Leaching is the release of DEHP from PVC containers into the IV bag medication. DEHP has been shown to produce a wide range of toxic effects, particularly in male neonates where the infant’s reproductive system can be compromised.

• Products that exacerbate leaching: Chlordiazepoxide HCl, Cyclosporine, Dosetaxel, Etoposide Lipid Emulsions, Paclitaxel, Teniposide

• susceptible populations: critically ill male neonates, pregnant and lactating women, pediatric patients, adolescent boys, and chemotherapy patients. Animal toxicity studies indicate that PVC and DEHP target the testes, liver and kidneys.

DRUGS THAT PRECIPITATE UPON DILUTIONPrecipitation of a drug from its concentrated injection solution when it is diluted with water or saline is counter-intuitive.

• Diazepam is very poorly water soluble so it is formulated as an injection solution in a vehicle comprising 50% propylene glycol and 10% ethanol.

• At first, dilution produces a slight turbidity which clears upon mixing, but dilution beyond fourfold produces an opaque white precipitate which does not clear until substantial further dilution.

• Other drugs which demonstrate solubility problems and which are formulated in injection vehicles other than simple aqueous solutions include digoxin, clonazepam, phenytoin, amiodarone and phytomenadione

CHEMICAL INCOMPATIBILITYReaction between two or more substances which lead to change in chemical properties of pharmaceutical dosage form.

• Types of chemical changes:

1. Oxidation-reduction and hydrolysis

2. PH change

• Acid and base drug

3. Denaturation

4. Formation of insoluble complexes

• Chemical incompatibility is two types:

• Tolerated

• Adjusted

AS

CHANGE PH :Can cause drugs to precipitate out of solution.

Most medicines are small chemical organic molecules that are often formulated as weak acid or weak base salts.

EXAMPLE// Furosemide & Phenytoin & daptomycin can precipitate if mixed with a solution that lowers its ph like glucose 5% morphine sulphate precipitate out of solution in an alkaline environment.

Physical precipitation of Midazolam as a result of an unfavorable pH medium5

OXIDATION, REDUCTION AND HYDROLYSIS

• Can cause the chemical degradation of a drug, resulting in a loss of

potency or the formation of toxic by-products.

• Erythromycin is reconstituted, it is degraded by hydrolysis and will lose potency after eight hours. This reaction is accelerated by a change in pH and therefore erythromycin should not be diluted with glucose or combined with acidic drugs, such as linezolid. Most stable in pH= 6-8. Buffer each 100 mL of D5W with 1 mL of sterile 4% NaHCO3 solution (24 hour stability under refrigeration).

• Ampicillin Sodium , Dextrose solution exhibits a catalytic effect on the hydrolysis of Ampicillin.

MECHANISM OF CHEMICAL INCOMPATIBLITY OF AMINOGLYCOSIDES WITH BETA-LACTAMS

N-Acylation of aminocyclitol portion by the beta-lactam(nucleophilic addition of the NH2 to the carbonyl group of b-lactam ring-- N-acylation) leading to inactive complex

Denaturation

Denaturation can occur when biological compounds — large, complex

molecules that are extremely sensitive to being denatured — are mixed with

other drugs, particularly if they are exposed to extremes of pH, or if they are

agitated for a prolonged period.

• Biologics, such as blood products and monoclonal antibodies, should never

be mixed with other drug compounds and should always be administered

through separate lines.

• Many proteins are stable only at specific pH values and ionic strengths

(filgrastim, for instance, is unstable in normal saline).

WHAT HAPPENS IF WE ADMINISTERED INCOMPATIBLE INJECTION :

• Damage from toxic products

• Particulate emboli from crystallization and separation

• Tissue irritation due to major pH changes

• Therapeutic failure

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PREVENTIVE STRATEGIES :

• Plausibility check strict indications for each drug preparation

• Separation of drug doses by time and place This can include the rinsing of the infusion system with a neutral IV solution prior to the application of another drug

• Consistent check of alternative modes of administration

• Usage of multi-lumen catheters Protection of particle

• Infusion use appropriate in-line filters.

• Mix thoroughly when a drug is added to the preparation

• Minimize the number of drugs mixed together in an IV solution.

• Solutions should be administered promptly after mixing so that occurrence potential reactions can be minimized.

• Always refer to compatibility references.

WHERE TO LOOK FOR COMPATIBILITY DATA

• Must use professional judgment when evaluating different reference sources.

APPLICATIONS TO CHECK FOR INCOMPATIBILITIES

REFRENCE• http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3806420/

• http://www.australianprescriber.com/magazine/31/4/98/101

• http://www.bbraun.lv/documents/drug_incompatibility.pdf

• https://quizlet.com/15437721/parenteral-compatibility-incompatibility-and-stability-flash-cards/

• http://www.ncbi.nlm.nih.gov/pubmed/6343964

• http://www.bbraunusa.com/8090.html

• http://www.ncbi.nlm.nih.gov/pubmed/7325173

• http://www.ncbi.nlm.nih.gov/pubmed/2305952