Jonathan B. Hjelm, PharmD, BCPS, BCNSP, CGP

Clinical Pharmacist

Pharmastar PBM

Objectives1. Define IV compatibility and incompatibility.

2. Where can incompatibilities occur?

3. What can be done to prevent them?

4. How do you know if a combination of drugs are compatible?

I. What questions to ask

II. Where to look for compatibility data

III. How to interpret compatibility data

Background 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.

Definition Incompatibility = is a reaction between drugs that after

mixing are no longer safe or effective for the patient.

Characteristics of incompatibilities: Color Change

Hazy Appearance

Precipitations

NOT all incompatibilities are dangerous, some are just normal.

Color Change

Imipenem-cilastatin or dobutamine may show some color change but NOT a sign of incompatibility.

Hazy Appearance

When ceftazidime is reconstituted, carbon dioxide gas is released and can cause a hazy appearance.

Precipitation

The precipitate that forms when paclitaxel is refrigerated dissolves again at room temperature.

Contributing Factors Light

Amphotericin B, cisplatin, and metronidazole must be protected from light.

Temperature Cefazolin is stable at room temperature for 24 hours but

under refrigeration for 14 days

Dilution Up to 10 mEq of Calcium can be added to each liter of TPN

containing 20 mEq of PO4.

Concentration dependant Bactrim 5 ml/75 ml D5W stable for 2 hours, whereas 5 ml/125

ml D5W is stable for 6 hours

Buffer capacity, pH, and Time Amino acid composition and concentration in TPN

Types of Incompatibilities

1. Therapeutic Incompatibility

2. Physical Incompatibility

3. Chemical Incompatibility

4. Drug IV Container Incompatibilities

Therapeutic Incompatibility The result of pharmacological effects of several drugs

in one patient (a.k.a. drug interactions).

Mechanisms

1. Pharmacokinetic: absorption, distribution, metabolism, excretion (e.g. Ciprofloxacin and Maalox).

2. Pharmacodynamic: antagonism/ synergism (e.g. Coumadin and Vitamin K)

Example Intervention

Heparin and antibiotics Best to avoid mixing heparin with IV antibiotics since heparin can affect the stability of certain antibiotics (e.g. aminoglycosides)

Physical Incompatibility The incompatibility that is more on solubility changes

and container interactions

Type Ways to Prevent

Insolubility -Do not administer a precipitate forming drug-Avoid mixing drugs prepared in special diluents with other drugs- In administration of multiple IV medications, prepare each drug in a separate syringe

Sorption Phenomena

Gas Formation

Solution pH

Physical Incompatibility Physical precipitation of Midazolam as a result of

unfavorable pH.

Chemical Incompatibility Results from the molecular changes or rearrangement

and leads to chemical decomposition

Type Ways to Prevent

Hydrolysis Store drugs in moisture proof containers or use desiccants

Oxidation Reaction Store drugs in amber bottles

Reduction Reaction Keep away from reducingagents

Photolysis Use light proof containers

Chemical Incompatibility Chemical precipitation of Midazolam and Ketamine

Drug-IV Container Incompatibility Incompatibility that arise from the chemical reaction

of the drug and the intravenous container

Type Definition

Adsorption The property of a solid/liquid to attract and hold to its surface a gas, liquid, solute, or suspension (e.g. Propofol)

Factors Causing IV Incompatibility

Type Intervention

Difference in pH Refer to drug compatibility tables

High Concentration Determine the chemically compatible concentration of both drugs

Temperature Refrigerate the IV admixture if not used within 1 hour after mixing or leave at room temperature to avoid clouding and cracking

Order of Mixing Separate addition of ingredients or drugs (e.g. always add phosphorous after calcium to TPN)

Length of Time in Solution Refer to extended stability charts

Health Consequences Consequences for the patient:

Damage from toxic products

Particulate emboli from crystallization and separation

Tissue irritation due to major pH changes

Therapeutic failure

Little published information about frequency of drug incompatibility reactions

One PICU study showed 3.4% of drug combinations were incompatible and potentially dangerous

Clinical incompatibilities can contribute up to 25% of medication errors

Up to 80% of IV drug doses were prepared with the wrong diluent

Financial Consequences Adverse effects of drug incompatibilities extend

patients’ hospitalization and the total costs for hospitals.

Severe respiratory complications caused by toxic drug-drug interactions may lead to an additional healthcare costs of up to $76,500.

Preventive Strategies Always check for compatibility

Standardize protocol for drug preparation

Check for alternative modes of administration

Separation of drug doses by time and place

Usage of multi-lumen catheters

Use in-line filters

Checking IV Compatibility

IV Compatibility Chart

Parenteral Nutrition (PN) Three factors for incompatibilities

with parenteral nutrition

1. Precipitation of calcium and phosphate

2. Creaming/Cracking of the lipid emulsion

3. Addition/simultaneous application of drugs to/with the PN.

Incompatibility Between Drugs and PN

Four criteria for drugs commonly added to PN admixtures (e.g. insulin, heparin, and Pepcid)

1. Stable dosage regimen over 24 hours

2. Pharmacokinetic profile supporting 24-hour infusion

3. Stable PN solution infusion rate

4. Documented chemical and physical stability over 24 hours

Cracked TPN

Separation of the oil and water components of the emulsion

Coalescence Fusion of small triglyceride particles into larger

particles

Avoiding Incompatibility with PN Never use PN for electrolyte therapy

Be familiar with manufacturers’ recommendations

Add divalent cations (calcium and magnesium) and phosphate as organic bound salts (e.g. gluconate).

Do not add drugs or Iron to PN

May piggy back lipids separately from 2-in-1 PN

Avoid Y-site administration of drugs with PN

Calcium phosphate solubility curve for TPNs

Automated TPN Compounding

Where To Look For Compatibility Data

Must use professional judgment when evaluating different reference sources.

Ways to Prevent or Minimize Incompatibilities

1. Mix thoroughly when a drug is added to the preparation.

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

3. Use freshly prepared solutions for compounding.

4. Always verify correct diluent, IV fluid, drug, and final concentration before compounding.

5. Order of mixing additives affects the compatibility (e.g. add PO4 last to TPN)

6. Solutions should be administered promptly after mixing or within the stability window so that the occurrence of potential reactions can be minimized.

7. Always refer to compatibility references.

8. Visually inspect final product after compounding for integrity, leaks, solution cloudiness, particulates, color, and proper preparation.

9. Ensure proper labeling of final IV product with beyond use date and time.

Summary Main risk for incompatibility

Preparation of infusion admixtures

Simultaneous application of IV drugs

Addition of multiple electrolytes and drugs in same IV

Strategy to Prevent Incompatibility

Standardize IV drug therapy

Compatibility data from literature

Exercise professional judgment as to whether or not the reported data can be used in your situation