“Children are not small adults” and children are “therapeutic orphans.” These two phrases, coined over 50 years ago, still ring true today in regard to the use of medications in pediatric medicine. When treating medical conditions, physicians know that infants, young children, and even adolescents may not respond the same way as an adult would to an administered medication, and often the safety and efficacy of a drug have not been tested in this population.
Years ago, doses of medicines given to infants and children were often crudely estimated (extrapolated) by comparing them to an adult medicine dose and a typical adult’s weight or body size. For some medicines, this still occurs today. For example, a 3-year-old child’s weight may be approximately 25 percent of a typical adult’s weight, and thus the child is given 25 percent of the adult dose of a medicine. Over the past 50+ years, we have learned much more about how medicines behave, or function, differently in an infant or child’s body, as compared to an adult’s, and how ineffective or dangerous medicine dose extrapolation can be. Drug functioning refers to how medicines are absorbed, distributed, metabolized, and excreted within and from the body. Drug functioning also refers to the drug’s mechanism of action, to yield its therapeutic benefits (for example, relief of symptoms or cure of an infection).
In this chapter, I discuss the underlying principles of how medicines are studied and evaluated in infants and children; common problems (and solutions) parents face when choosing and administering medicines; examples of medicines that should not be given to infants or children; and other factors that relate to safe and effective medicine use. In the rest of the book, I discuss the treatment of common pediatric medical problems, vaccines, and the “art” of medicine use in infants and children, including tips for administering medicines to infants and young children. After all, a safe and effective medicine will not be of much help if your child will not take it.
This information will help caregivers understand how medications function in children (differently from in an adult) and what medical conditions can be treated with prescription and over-the-counter (OTC) medications, as well as which medications are potentially dangerous for a child. With this understanding, parents, grandparents, and other caregivers will be better able to decide when medicine therapy can be a safe and effective choice to improve a child’s health.
One of the major challenges pediatric health care professionals, such as myself, frequently face is the lack of approval of medicines in the pediatric population. By definition, the pediatric population includes ages less than 18 years. “Approval” is not an accurate word for this topic, but it is commonly used. The United States government agency that regulates the use (that is, the manufacturing, safety, and advertising) of medicines is the Food and Drug Administration (FDA). The FDA strives to ensure that medicinal products are safe and effective when used according to the drug product’s labeling.
A medicine’s label is the official information included with the product bottle or packaging, and it describes the medicine’s dosage, adverse effects, contraindications, and interactions, among other important information. Health care professionals must review this information prior to prescribing or dispensing the medication to ensure that the medicine is used appropriately for a specific patient. This also applies to a parent or other caregiver when an OTC medicine is given to an infant or child: the parent, grandparent, daycare provider, or school nurse should read and understand the medicine product’s labeling or information prior to administering it to the child.
The product information that accompanies prescription medicines is written in medical language, not in language designed for the general public. These information sheets are included with the medicine by the manufacturer. Labeling of an OTC product includes informational wording on the product package and bottle—this is written for the public. So, the FDA does not “approve” the specific use of medicines—they approve medicines’ labeling, and it is then incumbent upon health care professionals, and consumers (parents), to ensure that medicines are used appropriately. This does not always occur, however. So it is more accurate to say that a medicine is “labeled” for specific uses or, for purposes of this discussion, a medicine is labeled for use in specific ages.
Unfortunately, most medicines—more than 50 percent of them—are not labeled for use in the pediatric population. Why? Because the medicines have not been studied or tested in this population. Studying and testing medicines in the pediatric population is considerably more difficult for a drug manufacturer; generally because it is more expensive and it is difficult to enroll study subjects (infants or small children). Unless a medicine is likely to be prescribed frequently in the pediatric population, a drug manufacturer is unlikely to test and study its drug in this population. Thus, most medicines are “labeled” for use only in adults. When a new medicine is labeled for adult use only by the FDA, we do not know the pediatric dose, nor do we know if the medicine is even safe or effective to use in the pediatric population. We know that some medicines can have different, or more severe, adverse effects or toxicities in infants and children, as compared to in adults (see the following pages for several examples). The best means to determine the safety and efficacy of medicines in infants and children is to formally test and study them in these ages.
Every single day, medicines are prescribed to infants and children that are not labeled for use at their age. This is referred to as “off-label” use and, fortunately, most of the time, significant adverse effects do not occur. However, the potential for significant adverse effects or lack of efficacy is greater when a medicine is used off-label in pediatrics, and thus medical professionals would prefer that all medicines prescribed for infants and children be labeled for their ages.
Although improvements are still needed, pediatric drug labeling—formally testing and studying medicines in the pediatric population—has advanced during the past 25 years. Two major legislative acts have contributed to this—the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA). In 2012, the BPCA and the PREA were reauthorized under the FDA Safety and Innovation Act. These legislations have used both a carrot and a stick approach (incentives and requirements) to entice pharmaceutical manufacturers to formally test and label more drug products for use in the pediatric population. If a medicine is determined to have significant beneficial use for infants and children, then the manufacturer is required to formally study and test it in infants and children. For other medicines in specified circumstances, a manufacturer may voluntarily study their medicine in the pediatric population in return for certain financial incentives, such as extended marketing exclusivities.
One recently published study found that between 1998 and 2012 the FDA granted new pediatric labeling information for more than 170 medicines. Collectively, implementation of BPCA and PREA has resulted in more than 500 pediatric drug labeling changes, a significant step toward a greater availability of drug information for health care professionals. Significantly, some medicines studied in the pediatric population turned out to not be effective for treatment of specific medical problems in infants or children—even when those medications had been shown to be effective for the same condition in adults.
The differences in how medicines function in, and how diseases affect, the pediatric versus the adult population explains why we say that “children are not small adults.” The physiologic and medical differences between children and adults underlie certain specific disease states, such as some types of cancer. Also, medicines behave or function differently in an infant or child’s body as compared to an adult’s body. Although the pediatric population includes ages younger than 18 years, some medicines are labeled for use in specific pediatric subgroups. For example, it is not uncommon for some medicines to be labeled for use at 12 years of age and older, and in adults. While a 12-year-old boy or girl is considered a pediatric patient, the dose and adverse effects of many medicines at this age may not differ significantly from that of an adult. In general, the younger the pediatric patient, the more likely a medicine’s dose, adverse effects, contraindications, and so on will differ from that of an adult, and thus the more we need information from pediatric testing. How a medicine behaves or functions in a 1-year-old infant male can significantly differ from how it behaves or functions in a 15-year-old adolescent male, although both of these males are classified as belonging within the pediatric population. Neonates—infants younger than 1 month of age—demonstrate even greater differences in how medicines function, and for most medicines, we have very little information on how to best use medicines safely and effectively in newborn infants.
It is also important to note that although most medicines are not formally FDA age labeled for use in infants and children, we have accumulated many years of pediatric clinical experience for some of them. This experience is often described and published in medical journals. Your child’s physician, prescriber, or pharmacist likely subscribes to some of these medical journals. For example, albuterol is a commonly used medicine to treat breathing problems, such as asthma, in infants and children. Albuterol is given as a metered dose inhaler or as a solution in a nebulizer. Albuterol inhalers such as Ventolin HFA or Proair HFA are labeled for use in children 4 years of age and older, and albuterol nebulizer solutions are labeled for use at 2 years of age and older. However, because breathing difficulties occur so often in infants and young children, albuterol is commonly given to infants less than 2 years of age, and when used appropriately (the correct dose and frequency) for these young patients, it is safe and effective. Why is a medicine such as albuterol not labeled for use in these young ages if it is commonly used? Obtaining FDA age labeling would require the pharmaceutical manufacturer to submit thousands of pages of data from formal drug testing and studies in these ages, and because this is expensive and difficult, it is not done.
When we have the practical experience of many years of safe and effective clinical use of the medicine in these age groups, we are not quite as concerned with FDA age labeling, although it would certainly be welcomed. We are most concerned when giving new medicines, or medicines with which we have very little pediatric clinical experience, to infants and children that are not age labeled by the FDA. It is also important to note that some medicines include warnings or contraindications that are more likely to have significant adverse effects or toxicities when given to infants or children. These medicines should rarely, or never, be given to infants and children. This distinction—prescribing a medicine that does not have pediatric FDA labeling versus giving a medicine that is contraindicated or more likely to cause harm to an infant or child—is important to understand.
How should you, as a parent or other caregiver, evaluate information about labeling? First off, you should ask your child’s physician or nurse practitioner if the prescribed medicine is labeled for use at your child’s age. If the medicine is not labeled at this age, ask how much clinical experience the medical community has had using this medicine in infants or children. If the medicine is not age labeled, ask your pediatrician if it is likely to be effective and safe for treating your child’s illness.
As discussed in the previous section, all medicines behave, or function, differently in infants and children as compared to in adults. The younger the infant or child, the more important these differences become. As parents know, the bodies and behavior of infants and children change quite rapidly during childhood. For example, a healthy infant’s weight will double at about age 6 months, triple at 12 months, and quadruple at 24 months. I am certainly glad that my weight does not double in 6 months!
When a medicine’s pharmacology is reviewed, four major areas are discussed:
• Absorption
• Distribution
• Metabolism
• Excretion
Collectively they are known by the acronym ADME.
Most medicines function inside the body and must be absorbed into the blood and then distributed throughout the body to their site of action. Some medicines function topically—they are applied to the skin to treat conditions such as acne or to protect the skin from damage, for example, from the sun. Even when a medicine is applied to the skin, some of the medicine is absorbed and enters the bloodstream. Differences in skin characteristics (for example, thickness, hydration status) between an infant, older child, and adult can be very important and can increase a medicine’s adverse effects. For example, topical corticosteroid (anti-inflammatory) creams or ointments are commonly used to treat inflammatory diaper rash in infants. Numerous different corticosteroid medicines are available, and they differ primarily in their potency, or strength. Hydrocortisone is one of the least potent topical corticosteroids, and beclomethasone is a more potent topical corticosteroid.
Since infants characteristically have thinner, more hydrated skin, caution should be used in applying more potent corticosteroids like beclomethasone. If too much of a potent corticosteroid is absorbed through the skin, severe adverse effects may occur. Case reports describing this scenario have been published in medical journals. If a physician diagnoses an infant with inflammatory diaper rash, a low potency topical corticosteroid cream or ointment, such as hydrocortisone, may be indicated. The parent should apply only a thin layer of the corticosteroid to the affected skin, and when used appropriately, it is likely to be safe and effective.
Most medicines are given to infants and children orally, and physiologic differences among infants, children, and adults can affect oral medicine absorption. These differences include the pH (acidity) of the stomach and how quickly swallowed medicines move through the stomach and intestines (medicines are absorbed into the blood from the intestinal tract), among others. These differences, affecting the amount and rate at which medicines are absorbed into the blood to reach their site of action, can result in important clinical alterations in how we use medicines in the pediatric population. Once a medicine is absorbed into the blood, it distributes throughout the body. A medicine’s chemical characteristics and physiologic factors affect how widely it distributes, and to what areas of the body. The main physiologic factors include body water content and proteins in the blood. A healthy infant born at term gestation (≥ 37 weeks) is composed of approximately 75 percent water; in comparison, an adult is 55 to 60 percent water. As the amount of body water decreases in infancy, body fat increases. Medicines can display important chemical differences in their attraction for water (hydrophilic) or fat (lipophilic), and these characteristics affect how widely the medicine distributes throughout the body (known as the drug’s volume of distribution). Some medicines are transported in the blood by attaching to blood proteins, namely albumin. Differences in the quantity and quality of albumin and other blood proteins in infants, children, and adults can affect how safe and effective a medicine is. Some medicines that extensively bind to albumin, such as the commonly used antibiotic Rocephin, can cause levels of bilirubin (a breakdown product of red blood cells) to dangerously increase in newborn infants, resulting in jaundice. This adverse effect is less likely to occur in older infants, children, and adults.
Medicines are removed from our bodies primarily by the liver and kidneys. The liver additionally functions to metabolize many chemicals that our bodies naturally produce, and chemicals and medicines that are introduced into our bodies. Some medicines are not active in the body until they are metabolized by the liver to an active form. Within the liver are numerous types of specific enzymes that metabolize medicines and these natural chemicals. At birth, many of these metabolizing enzymes are not fully mature, and are much less active. They mature, or become active, at different rates, with some drug-metabolizing systems not fully maturing until 3 to 5 years of age, or even until the adolescent years for others.
Well-known examples of the severe consequences of administering medicines that have not been tested or studied in infants and children to that population include the antibiotic chloramphenicol and the drug product preservative benzyl alcohol. When given to young infants, chloramphenicol and benzyl alcohol can result in severe adverse effects, including death, known as “gray baby syndrome” for chloramphenicol and the “gasping syndrome” for benzyl alcohol. Conversely, the efficiency of other drug metabolizing systems in the liver, once fully matured, are significantly greater in young children as opposed to adults. This results in the need for larger weight-based doses of some medicines as compared to adults.
The kidneys are also responsible for eliminating many medicines from the body. At birth, a healthy infant’s kidneys function well enough to eliminate waste products in urine. However, this functioning efficiency is decreased as compared to older children and adults, and it matures at approximately 1 year of age. This difference becomes important for medicines that are eliminated from the body primarily through the kidneys. If the frequency of dosing is not adjusted for the infant’s age, it can lead to increased drug adverse effects or toxicity. Similar to drug elimination by the liver, as drug elimination by the kidneys matures in young children, it may become even more efficient than in adults, requiring some medicines to be given more frequently than to an adult.
Thus, as infants and children grow, their bodies undergo significant changes, and these changes affect how we use medicines, including dosing, adverse effects, and the potential for severe toxicity. Testing and studying medicines in the pediatric population is the best means to improve their safe and effective use.
Further descriptions and explanations of how medicines differ in the pediatric population relate to the unique adverse effects some medicines produce in infants and children. Most parents are aware that children should not receive aspirin (a contraindication) when treating fever in infants and children, as aspirin use can result in severe liver and brain injury, and death, known as Reye’s syndrome. Reye’s syndrome is more likely to occur when aspirin is given to a child with a viral infection, such as influenza. In 1986 the FDA recommended that aspirin and chemically similar medicines (salicylates) not be given to children 18 years of age and younger when treating illnesses with fever. Aspirin can be cautiously used in some children when treating other medical conditions, such as Kawasaki disease, and should only be given when recommended by a physician.
Tetracycline is an older antibiotic that still has many uses to treat bacterial infections. Tetracycline should not be given to children less than 8 years of age, however, as it can bind with calcium in teeth and bones, resulting in an ugly gray staining of teeth and decreased bone growth. Antihistamines are commonly given to children and adults to treat a variety of symptoms, most notably allergic conditions. Older antihistamines, such as diphenhydramine (for example, Benadryl), can commonly cause sedation or drowsiness. Young children given these older antihistamines can also develop paradoxical adverse reactions, resulting in excitability, tremors, convulsions, or hallucinations. These adverse reactions are significantly less likely to occur in children given newer antihistamines, such as cetirizine (for example, Zyrtec) or loratadine (for example, Claritin).
Conversely, adverse effects from some medicines are less likely to occur in children as compared to adults. Ibuprofen (sold under the common trade names Motrin and Advil) and other nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly given to children and adults to treat fever, pain, and various inflammatory conditions. A feared and relatively common adverse effect of ibuprofen and other NSAID use in adults is bleeding from the intestinal tract, such as from an ulcer. Fortunately, this adverse effect rarely occurs in children. Isoniazid is an antibiotic used to treat tuberculosis and other infections and may cause severe inflammation of the liver in adults. This is another example where the medicine’s adverse effect is significantly less likely to occur in children.
From an understanding of how medicines are absorbed, distributed, metabolized, and eliminated from the body, and their potential for unique adverse effects, comes a major principle: in many ways, medicines behave and function differently in infants and children as compared to in adults. Keep this principle in mind when speaking with your child’s physician, pharmacist, and other health care providers and when choosing medicine therapies for your child. Recently enacted regulations requiring more medicines to be tested in children have improved our knowledge of how to use medicines safely and effectively in the pediatric population. Many medicines, however, remain inadequately studied in infants and children, and so the parent and the health care providers need to work together to be informed and choose wisely when it comes to a child’s medications.
• Many medicines are not tested and studied in the pediatric population, although new laws and regulations now require more medicines to be tested and studied in infants and children prior to their being marketed and made available to the public.
• Many differences exist between how medicines function and distribute in infants, children, and adults. These differences affect medicine effectiveness and safety.
• Some medicines can result in more adverse effects in children than in adults.
• Knowledge of these differences, as well as appreciation for how medicines are tested in children, can aid parents when choosing and discussing medicine therapies with their child’s physician, pharmacist, and other health care professionals.