Nearly three-fourths of the commercially available drugs in the United States have not been labeled for use in infants and children. When a drug has not been approved by the US Food and Drug Administration (FDA) for the pediatric population, it is most likely not commercially available in an appropriate formulation. Many of these unapproved drugs, however, are useful for the treatment of pediatric patients. Thus, these drugs must be reformulated or compounded in an appropriate dosage form extemporaneously by pharmacists, often for one patient at a time.

When gabapentin, lamotrigine, tiagabine, and topiramate were approved by the FDA for adults with seizure disorders, many pediatricians found one or more of these important for use in pediatric patients whose seizures could not be adequately controlled by the previously available anticonvulsants. None of these four drugs were available in liquid dose forms for several years, and three of the four are still not available in a liquid formulation. These are compounded for individual patients by the pharmacists. Table 10.1 provides a partial list of drugs that are not available commercially in a liquid formulation and must be compounded by the pharmacists.

Infants younger than the age of 6 months are not capable of ingesting solid or pureed food from a spoon. Thus, the contents of a capsule or triturated tablet mixed in applesauce or ice cream cannot be successfully given to young infants. Similarly, children below the age of 6 to 8 years have difficulty swallowing a tablet or a capsule. Liquid formulations of all oral drugs are needed for such infants and children. Furthermore, the doses of drugs in infants and young children are not fixed, but are given in milligrams per kilogram of body weight. For example, captopril is commercially available only as 12.5-, 25-, 50-, and 100-mg tablets. These meet the need of adult patients requiring fixed doses. The dose in infants, however, may be 0.1 to 0.3 mg per kg, and thus the required dose in a patient weighing 3 kg would be different from that for a patient weighing 5 kg. Furthermore, it will be impossible to use a 12.5-mg tablet to provide 0.3 mg or 1.5 mg of captopril to these patients. This emphasizes the need to develop liquid formulations, as was done for captopril at a concentration of 1 mg per mL. Table 10.2 provides examples of drugs, commercially available dose forms, normal pediatric doses, and the liquid formulations developed at appropriate concentrations for use in infants and children (3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18).

Intravenous drugs marketed for adult patients (but not labeled for pediatric patients) are often too concentrated for accurate measurement of small doses for newborn infants. For example, injectable morphine is available at 2 to 50 mg per mL and phenobarbital at 30 to 130 mg per mL. Measurement of small volumes to provide the needed doses in premature infants can be associated with inaccurate administration of these drugs. In fact, intoxication has been reported in infants with the use of concentrated digoxin and morphine (19,20). Thus, the intravenous drugs marketed for adults should be diluted prior to the measurement of the needed dose. Table 10.2 provides examples of some intravenous dose formulations for use in infants and young children. Morphine injection was diluted from 10 to 1 mg per mL in bacteriostatic 0.9% sodium chloride injection and found to be stable for 60 days (14). Phenobarbital sodium injection was diluted from 65 to 10 mg per mL in bacteriostatic water for injection and found to be stable for 90 days (15).

It is important to realize that when a commercially available formulation is altered or modified in any form, the modified formulation must be tested for potency of the active ingredient (drug). Stability studies must be done under the normal conditions of storage and use for all modified formulations. For intravenous drugs, the modified formulations must also be tested for sterility and pyrogens. Finally, the efficacy and safety of the modified formulations must be assured by close monitoring of patients’ response to therapy.

The cost of drug development (more than $800 million) is enormous. The overall size of the pediatric market is much smaller than for adults for many common diseases such as hypertension. It may take 7 to 8 years to develop and market a drug for only the adult population. Thus, unless a condition occurs frequently in the pediatric population (e.g., fever or acute otitis media), the industry may not seek labeling for infants and children. A manufacturer cannot market a formulation unless it has been adequately studied for efficacy and safety in pediatric patients. Therefore, additional costs, limited financial returns, potential delay in marketing for adults, and perceived greater legal liability and regulatory requirements are impediments to developing and marketing a pediatric drug formulation.

When an appropriate formulation is not available, the options include the following:

An acceptable option in most cases is to prepare an extemporaneous oral formulation with documented stability and palatability. Ideally, the formulation should have been studied for bioavailability, efficacy, and safety. Such data, however, are often missing.

Many generic and brand medicines frequently used in infants and children are not available in suitable formulations (Table 10.1). This poses important clinical dilemmas. Captopril is used for the treatment of hypertension
or congestive heart failure in infants. It is available, however, only as a tablet. When we received a prescription for an infant, we got in touch with the manufacturer. The manufacturer had no data on its stability in any liquid vehicles except that “it underwent oxidation in aqueous medium.” Two actions were taken:

Powder packets are extremely time-consuming to prepare and the caretaker must take responsibility to accurately administer the entire dose. A liquid formulation in water and ascorbic acid provided consistency and stability for at least 6 weeks at 4°C and 25°C, and thus has become a standard formulation for the treatment of pediatric patients (7).

The excipients used to prepare drug formulations are generally considered as inert substances; however, some of these may be associated with adverse effects. Propylene glycol is used as a vehicle in many formulations, and excessive use of this agent has led to hyperosmolality in patients. Benzyl alcohol has been used as a preservative and has been associated with severe toxicity in infants. Finally, increased use of sorbitol as an excipient can lead to diarrhea and pneumatosis intestinalis (21).

Because of limited resources, the bioavailability, efficacy, and safety of extemporaneous formulations are rarely studied. Sustained- or extended-release formulations should not be used to prepare extemporaneous formulations because they may lose the delayed-release characteristics of the drugs. Patients receiving an extemporaneous formulation should be closely monitored to assure expected therapeutic outcomes.

A survey of 57 hospitals, with 36 to 350 licensed pediatric beds (mean ± SD = 146 ± 83), conducted during 1998 to 1999 identified the needs for drug formulations for pediatric patients. Table 10.3 provides a list of drugs for which greater than 5% of hospitals indicated that no compounding and/or stability data were available or more data were needed. Table 10.4 identifies additional drugs for which a liquid formulation was needed (2).

The physicochemical properties of the drug and the characteristics of the available dose form (e.g., tablet or capsule) should be considered in preparing the extemporaneous dose form. Most drugs are not completely water soluble. Thus, a suspension is generally prepared to yield a uniformly dispersed oral formulation. Carboxymethylcellulose and methylcellulose are commonly used suspending agents. We have used commercially available carboxymethylcellulose in a ready-to-use suspension (Ora-Plus, Paddock Laboratories, Minneapolis, MN) and extemporaneously prepared 1% methylcellulose suspension (6) at our hospital. The pH of Ora-Plus is about 4.4, whereas that of methylcellulose is nearly 6.8. We routinely mix the suspending agent with an equal volume of commercially available simple syrup or Ora Sweet (sugared or sugar free). Sweetners containing sucrose and fructose can increase blood sugar and those containing sorbitol and xylitol may cause osmotic diarrhea. Lactrose should be avoided in patients with lactrose intolerance. Flavors and preservatives may be added, as necessary. The commercially available parenteral drugs are normally diluted in sterile or bacteriostatic water for injection or 0.9% sodium chloride injection.

The physical and chemical stability of the extemporaneous formulations is determined at clinically simulated conditions. For example, about 1 oz of the prepared formulation is stored in each of 10 plastic prescription bottles. Five bottles are stored at 4°C in a refrigerator and five at 25°C to simulate a room temperature condition. Small aliquots are collected and normally studied on day 0 (soon after preparation) and on days 3, 7, 14, 28, 42, 56, 70, and 91 during storage. Physical stability is determined by visual appearance against a white and black background to rule out any changes in color and appearance; odor is also assessed. The chemical stability is determined by measuring the concentration of the drug using an accurate, specific, reproducible, and stability-indicating analytical method (e.g., high-performance liquid chromatography). The stability-indicating nature of the method is confirmed by subjecting samples of the extemporaneous formulation to extremes of temperature by heating and to different pH by mixing with an acid and a base. The degradation products should not interfere with the measurement of the drug for a method to be stability-indicating (22). The pH is also measured on each study day. The drug is considered stable if its physical characteristics have not changed and its concentration has remained above 90% of the initial concentration.

The child’s acceptance of a liquid dose form is primarily dependent on its palatability. A better-tasting drug is easier to administer to infants and young children, and thus loss of drug from spillage during dose administration is minimized. In general, ease of administration and adherence may be enhanced with improved taste.

The taste of drug formulations should be evaluated in children by using a 5-point hedonic (facial expression) scale (23). The overall taste perception should reflect initial taste, aftertaste, flavor, and texture of the formulations. Interestingly, taste is rarely studied in children, even for commercially available formulations. These studies
generally are performed in adult volunteers. It is difficult to predict whether the Human Subjects Research Committee would approve such comparative studies in children.