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Potential Problems in Compounding for Pediatric Patients
The uniqueness of pharmacy compounding is the ability to prepare individualized medications for special populations, such as pediatric patients.
Pediatric Patients
Children's medications can be a challenge for physicians and pharmacists. Because most marketed drugs do not have U.S. Food and Drug Administration (FDA)-approved indications for pediatric use, physicians must prescribe them "off label." When drugs do not have labeled indications for children, drug manufacturers do not produce strengths and dosage forms appropriate for this patient population. Technological limitations are rarely the reason for the lack of pediatric formulations; rather, market conditions often dictate the types of drugs for which formulations suitable for children are made available. So, how can a child receive proper medical care when pharmaceutical resources are limited?
Oral liquids, including solutions, suspensions, and emulsions, are the most commonly used dosage forms for pediatric patients, along with injections and suppositories. Other common dosage forms include lozenges, flavored ices, gummy gels, chewing gums, lollipops, puddings, flavored gelatins, and topical formulations.
When commercial liquid formulations are not available, extemporaneously prepared formulations are an option. The development and compounding of pediatric formulations, particularly those suitable for infants and young children, can be vexing for the dispensing pharmacist. A major problem in treating sick newborns is the lack of appropriate concentrations of various drugs for parenteral administration. Preparation of oral medicines for children is subject to much variation in U.S. hospitals, and there is little harmonization of formulations or information on the stability of preparations.
Tablets and capsules are usually unsuitable for children under the age of 4 years, and available tablets may not be of appropriate strength for older children. Splitting or breaking tablets is common practice but does not result in accurate or uniform dosing. Choking by aspiration of tablets is associated with significant morbidity.
Much emphasis has been placed on the availability of liquid preparations for use in infants and small children. Liquid preparations are clearly needed for small infants, but for limited-resource pharmacies, they are not the dosage form of choice because of their weight and volume and the instability of formulations.
Bulk powders and sometimes tablets can be used in formulations when commercial products are not available. For example, lorazepam 2-mg/mL suspension can be compounded using lorazepam bulk powder. The commercial injection should not be used as a drug source in compounding for young children because of its high propylene glycol content; it can be toxic to newborns in high doses. If tablets are used, the concentration may need to be reduced to about 1 mg/mL because the excipients in the tablets thicken the suspension.
Taste is probably the primary factor influencing patient compliance. Children may not like the taste of "masked" formulations or may object to the bitter or metallic taste of nonmasked formulations. It can sometimes be advantageous to prepare placebo taste samples and ask the child to select one, giving the child a role in decision-making about the therapy. The taste of a formulation involves factors such as flavor, sweetener, pH, color, and mouth feel. Children's and parents' preferences concerning flavor, palatability, and dosage forms are influenced by culture.
Variables that must be considered in preparing pediatric formulations include dose (concentration and quantity to be administered), stability (chemical, physical, microbiological), taste, color, packaging, storage, and the necessary administration devices or techniques.
Commercial Products as Source of Active Drugs
Is it wise to use commercial products in compounding? When doing so, can the pharmacist be assured of a quality preparation? Is it possible to meet the standards of USP Chapters <795> and <797> using commercial products as the source of drugs? The answer to these questions is "sometimes, but not always."
Historically, pharmacists have used commercially available medications to prepare different dosage forms. The most common examples are the use of oral tablets and capsules to prepare oral liquids (solutions and suspensions) for pediatric patients and the use of injectable drugs to prepare intravenous admixtures. Even though FDA-approved commercial products are used, the final compounded preparation does not have FDA approval.
Considerations concerning commercial product use include the following:
- Using commercial products as a source of active drugs usually will result in a higher prescription cost to the patient than would using bulk drug substances. This is especially true when injectables are used as the drug source.
- All the excipients present in the commercial dosage form must be considered for their effects on the efficacy, safety, stability, and assay potency of the final compounded preparation.
- When using solutions as the source of drugs, the pharmacist must be aware of the pH of the solution and the pH of the compounded preparation. If there is a significant difference in pH (i.e., 2 to 3 pH units), the solubility and stability of the drug and formulation may change. If the pH of the final solution is insufficient to keep the drug in solution, the preparation may be a suspension rather than a solution.
- The presence of buffers in the commercial drug product can affect the pH of the final compounded preparation.
- Before using a commercial product to compound large batches, it may be advisable to assay the product for potency. An assay is especially important if the USP allowable range for the commercial product exceeds the 90% to 110% potency range acceptable for compounded preparations. For most commercial drugs, the potency range is 95% to 105% or 90% to 110% of the labeled quantity; for some, the range is 80% to 120%. Some USP monographs for commercial products go as high as 165% of the labeled quantity; although this is unusual, it is a variable the pharmacist must consider. Even if the compounding pharmacist performed every step correctly, the final preparation could fail to meet specifications because wide variability was allowed in the commercial product.
- Some dosage forms should not be used in compounding. Modified-release dosage forms (e.g., extended release, delayed release, repeat action, targeted release) should not be used unless their suitability for use in compounding has been documented.
- When commercial products are used in compounding, it is important to list their manufacturer and lot number. This is especially important in the case of multisource generic drugs, as different excipients may be used by different manufacturers.
- A limiting factor can be the quantity of commercial product that must be used to provide the required amount of active drug. Often, the required quantity makes use of the commercial product impractical.
In addition to these factors, some commercial dosage forms are inappropriate for use in compounding particular dosage forms. We will discuss this in more detail in a future issue of this newsletter.
Loyd V. Allen, Jr., Ph.D., R.Ph.
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