An I. V. admixture is said to be incompatible when the prescribed drugs cannot be combined safely and satisfactorily. The incompatibility may be between two drugs or between a drug and the I. V. solution. The incidence of incompatibilities is relatively low when compared to the number of I. V. admixtures prepared, but the possibility of an unexpected or undesirable combination always exists. If an incompatibility goes undetected, the patient may not receive the full therapeutic effect of the medication. Even worse, an incompatibility may lead to an adverse effect on the patient.

Some incompatibilities result in a physical change that is easily recognizable. This change may be a change in color, evolution of a gas, development of a haze, or formation of solid particles that settle out of solution (i.e., precipitate). These are the most obvious incompatibilities to detect because they can be seen.

Other incompatibilities cannot be visually recognized. Two drugs can react to cause the degradation of one or both. These incompatibilities are not detected visually, but they can be confirmed by analytical methods.

Although a change in color of a solution, evolution of a gas, or formation of a precipitate may signal cause for concern about potential incompatibility, these types of physical change sometimes are expected and are not a problem. For example, variations in color of imipenem-cilastatin or dobutamine do not affect potency. When ceftazidime is reconstituted, carbon dioxide gas is released and positive pressure develops. Accumulated gases should be expressed from1hesyrjnge or vented from the vial before administration. The precipitate that forms when paclitaxel is refrigerated dissolves at room temperature. This, points to the need for a pharmacist to be familiar with the literature and to exercise professional judgment in providing safe, effective drug therapy to patients.

Many factors may affect the compatibility and/or stability of drugs in I. V. admixtures. Some of the most common factors are described below.

pH The most common cause of incompatibilities is combining two drugs that require conflicting pH values of the final solution for their own stability. If the pH of an admixture is unsuitable for one of the drugs, that drug either degrades or precipitates. Care must be taken, especially when a drug with a low pH is combined with a drug having a high pH. An example is the combination of aminophylline and vitamin B complex with C. Aminophylline has a pH of 8.0 to 9.0, whereas the vitamin preparation has an acidic pH. The high pH of the resulting solution destroys vitamin activity.

Ticarcillin-clavulanate, dobutamine, ondansetron, nitroglycerin, and carmustine are each incompatible with sodium bicarbonate, which has an alkaline pH.

Complexation An example of complexation is the combination of tetracycline with a calcium- containing drug. The chemical complex formed between tetracycline and calcium reduces the antibacterial activity of the tetracycline. Thus, solutions containing calcium should be avoided with tetracycline.

Some drugs interact with aluminum, causing a problem in preparation and administration because most needles are made of aluminum. For example, cisplatin-AQ should not be used with neediest I.V. sets, or filters containing aluminum.

Light Exposure of some drugs to light may destroy or reduce the potency of the drug. Amphotericin B, cisplatin, and metronidazole must be protected from light to maintain their potency.

Dilution The concentration of a drug in solution may be a factor in its compatibility with other drugs. A common problem is the mixing of electrolytes in preparing parenteral nutrition solutions. However, the problem can be avoided by assuring that the electrolytes in question are properly diluted before they are combined. Up to 15 milliequivalents (mEq) of calcium can be added to a liter of solution containing up to 30 mEq of phosphate without precipitating. Higher concentrations of either drug, however, result in precipitation.

Time Most drugs degrade in a relatively short time when placed in an many incompatibilities are not instantaneous, but develop over time.

I.V. Solution Some drugs require specific solutions (diluents) for reconstitution and further dilution. For example, amphotericin B must be reconstituted with sterile water for injection without a bacteriostatic agent and then further diluted only with 5% dextrose injection. Amphotericin B is not compatible with normal saline. Not only is the solution designated to be 5% dextrose injection, but the pH must be above 4.2.

Some drugs are packaged with a specific diluent for use in reconstitution. For example, the diluent for immune globulin is supplied by the manufacturer with specific directions for reconstitution and dilution. Preparation time may be prolonged from 20 minutes with the diluent supplied to 75 and 135 minutes when 3% and 6% immune globulin, respectively, are reconstituted with a 5% dextrose injection. In addition, the diluent and product should be warmed to room temperature before reconstitution, and shaking should be avoided, as it causes foaming.

Temperature The degradation of a drug in solution may be regarded as a chemical reaction. Because heat increases the rate of most chemical reactions, solutions are in most cases more stable at refrigerated temperatures than at room temperature. Cefazolin, once it has been reconstituted in a vial, is stable for 24 hours at room temperature, but for 96 hours under refrigeration. Some drugs, however, should not be refrigerated. Metronidazole should not be refrigerated because it causes mannitol in the formulation to precipitate.

Some drugs can be frozen after reconstitution and stored for prolonged periods. For example, cefazolin is stable for at least 12 weeks when frozen at -20° C. Ampicillin is an unusual drug with respect to temperature. It is more stable at refrigerated temperatures than at room temperature, but less stable at frozen temperatures than at refrigerated temperatures. For this reason, ampicillin should not be frozen for purposes of prolonging the stability of reconstituted solutions. It is recommended that many drugs not be frozen, either because freezing has not been investigated or it results in a problem. For example, ganciclovir, trimethoprim/sulfamethoxazole, and impipenem-cilastatin should not be frozen .

Buffer Capacity The buffer capacity of a solution is the ability of that solution to resist a change in pH when either an acidic or alkaline substance is added to it. Many drugs contain buffers to increase their stability. In general, I.V. solutions do not have high buffer capacities. Thus, when a drug with a high buffer capacity is added to a common I. V. solution such as 5% dextrose injection, the pH of the resulting solution is close to that of the drug additive. Important exceptions are I. V. solutions that contain lactates and acetates, both of which have a relatively high buffer capacity. Thus, the pH of these solutions does not change as easily, making them more prone to compatibility problems.

Penicillin G may be added to 5% dextrose injection even though the pH of the dextrose solution may be 4.0 and penicillin G is not stable at that pH. However, penicillin G contains a citrate buffer that provides a final pH of 6.0 to 6.5 when added to 5% dextrose injection. The 5% dextrose injection has a very low buffer capacity; that is, it is unable to resist the change in pH when the buffer in penicillin G is added.

Order of Mixing The order in which drugs are added to the solution may be a factor in compatibility. Drugs that are in concentrated solutions may react to form a precipitate, whereas both drugs in diluted solutions may be combined satisfactorily. In preparation of parenteral nutrition solutions, electrolytes such as calcium and magnesium are commonly prescribed with phosphates, creating a compounding problem if not done correctly. By adding the diluted electrolytes last and mixing well after each addition, the electrolytes are well diluted when they come into contact with each other, and the chance of precipitation is minimized.

When compounding all-in-one parenteral nutrition solutions, the order of mixing is also critical. These complex admixtures consist of a fat emulsion, a dextrose solution, and an amino acid solution. Mixing should start with the fat; then the amino acid is added; and finally the dextrose. The important concept is to avoid adding the dextrose directly to the fat, because it will break the emulsion, causing it to separate.

Plastic In addition to drug-drug and drug-solution incompatibi1ities, some drugs are incompatible with plastic I. V. bags and administration sets. This is especially true of polyvinyl chloride (PVC) plastic; The drug may leach plasticizers out of the bag or set, or the drug may adhere to the bag or set, making it unavailable for its intended therapeutic effect. It is recommended that carmustine be used in glass containers only. Cyclosporin and paclitaxel should always be mixed in non-PVC bags and administered in non-PVC tubing. Interferons are not stable in polypropylene syringes designed for use in ambulatory infusion pumps.

Small amounts of albumin can sometimes be added to the admixture if the drug adheres to the I. V. bag because it is preferentially adsorbed to the surface of the plastic. However, this is an expensive practice and the advantages of doing so should be carefully considered. Albumin (1 mL/50 mL 0.9% sodium chloride injection) can be added to solutions of sargramostim to prevent adsorption to the plastic of the I. V. delivery system.

Filters Final filters represent a possible problem in effective delivery of the drug to the patient, even though technically the problem may not be a compatibility or stability issue. The addition of an in-line filter causes an 86% to 94% reduction in the delivered concentration of nitroglycerin. Cisplatin-AQ should not be used with filters containing aluminum (common paper filters do not contain aluminum). On the other hand, it is recommended that some drugs be administered with an in-line filter; e.g., ganciclovir must be infused using a 5 or 0.22-micron filter. Again, knowledge about the safe and effective preparation and administration of each drug is a professional responsibility of the pharmacist.

The most frequently used sources of information on incompatibilities are manufacturers' drug package inserts, incompatibility charts, published articles, and reference books.

Package Inserts A package insert generally contains little incompatibility information, especially for new drugs. The package insert is developed by the manufacturer and approved by the FDA when the drug is marketed. At that point, few studies have been done to determine with which agents the new drug can be safely combined. It is also an expensive and time-consuming process to add such information to the package insert voluntarily at a later time.

The package insert, however, often provides important information that enables a pharmacist to make an informed judgment as to the compatibility of a drug combination. For example, a package insert may specify the pH range over which the drug is most stable or the stability of the drug once it has been added to an I. V. solution. Some package inserts do provide valuable information by actually listing specific drugs that have been tested and shown to be compatible or incompatible with that drug.

Incompatibilitv Charts Incompatibility charts are available that list drugs that can and cannot be mixed in par1icular solutions. Some charts list drugs horizontally across the top and vertically down one side. One drug is found in the top list and the other drug in the side list; then the two constituents of the admixture are followed along the lines from the top and the side until they intersect. A notation in the space where the lines intersect denotes whether or not the mixture is compatible. The major limitation of some char1s is that they do not state why a particular mixture is incompatible, providing little, if any, information on the relative conditions (e.g., pH, concentration) under which the tests were conducted.

The Guide to Parenteral Admixtures is one example of a chart that provides information beyond whether or not two drugs are compatible. The Guide, may specify the concentration of the constituents and reasons that a drug combination is not compatible. An important advantage to this reference is that the data are continually updated by supplements. To use the guide:

1. Select the chart for one of the drug constituents under its generic name.
2. Find the other drug on the list down the side and follow that line horizontally across to the space under the solution prescribed.
3. At this intersection, a notation is made as to the compatibility of the admixture solution- whether the mixture is compatible (C), incompatible (X), conflicting data exist (O) or no data exist (blank).

Literature and Books Information on incompatibilities can often be found in articles in professional journals and in reference books dealing specifically with the subject. The American Journal of Health- System Pharmacy (formerly the American Journal of Hospital Pharmacy) frequently has detailed research articles on intravenous incompatibilities. Two reference books that are very useful are the Handbook on Injectable Drugs and the American Hospital Formulary Service, Drug Information. All three are published by the American Society of Health-System Pharmacists, Bethesda, MD.

Many pharmacy departments maintain a file of published articles to provide detailed information from the primary literature that would not otherwise be readily available. This practice has been carried one step further In some pharmacies that have established index card files with information on each drug condensed from journal articles and other sources. This filing system permits ready access to information when needed. Alternatively, some articles republished periodically provide similar compatibility and stability information, e.g., Injectable Medications 1994. Some pharmacy computer systems screen for I.V. admixture incompatibilities as well as drug interactions, alerting the pharmacist or pharmacy technician at the time the order is entered into the computer.

Electronic Databases Pharmacies commonly use electronic databases on CD-ROM to access information quickly. These databases, such as Micromedex (Denver, Colorado), contain information on incompatibilities and stability within each drug monograph described. These types of databases have several advantages over printed references: (1) they are updated frequently; (2) they are accessible by any person able to access the computer network regardless of their location; and (3) they take up less space.

Incompatibilities can be minimized by following a few general guidelines whenever possible:

1. Use solutions promptly after preparation in order to assure administration of the most stable product, since the degradation of many drugs is time related. If freshly prepared admixtures cannot be used immediately, they should be refrigerated.
2. Minimize the number of drugs added to one solution. As the number of drug additives increases, the possibility of incompatibilities increases geometrically. When more than two drugs are combined in a solution, it is difficult to find adequate information about potential compatibility of the resultant admixture.
3. Check incompatibility references closely if one of the drugs has a very high or very low pH. Because most drugs are acidic, their combination with a drug having a very high pH, such as sodium bicarbonate or aminophylline, is more likely to result in an incompatibility.
4. Check incompatibility references closely when one additive is a drug containing calcium, magnesium, or phosphate, because these substances cause precipitation of many drugs and each other.
5. Check incompatibility references closely if one of the drugs or the I. V. solution contains an acetate or lactate (these substances have a buffering capacity).

Although physicians and pharmacists have a shared responsibility for selecting the most appropriate medication for each patient, pharmacists are best qualified to assure the compatibility of an admixture. Frequently, the I. V. solution is not specified when intermittent (piggyback) drugs are prescribed, leaving it to the pharmacist to select the one most appropriate.

If an incompatible drug combination is prescribed, the pharmacist has a professionl and legal responsibility to correct the situation: by clarifying questions with the physician or nurse as appropriate. The pharmacist should be prepared to provide an explanation of why the admixture is incompatible, a recommendation of alternative drug therapy, alternative methods of administering the drugs to avoid their mixing, or other possible solutions to the problem. A practical solution to the problem often is changing the I. V. infusion setup to keep the two incompatible drugs separated.