BCCHR’s Ask an Expert Series
We asked an expert about the problems with pediatric drug dosing for kids.
More than half of all children receive at least one prescription medication a year. Despite this, few drugs have pediatric formulations. In North America and Europe, more than 75 per cent of pediatric prescriptions are considered off-label, meaning children are being prescribed medications that were never studied in their age group. Off-label use is associated with an increased risk of adverse drug reactions or treatment failure.
Dr. Bruce Carleton, an investigator, clinical pharmacologist, director of Pharmaceutical Outcomes & Policy Innovations at BC Children’s Hospital, and division head of Translational Therapeutics in the Department of Pediatrics at the University of British Columbia, focuses his research on evaluating drug effectiveness and safety.
We sat down with Dr. Carleton to learn more about the challenges and potential solutions to providing safe and effective medication to children.
What are the main problems with pediatric drug dosing in Canada?
Formulation is the first thing we need to tackle. We need to have drugs that kids will consume. If you’re under five, you need a liquid and you need something that doesn’t just say strawberry flavoured, for example. You need a liquid that actually tastes like a strawberry. When medical residents sample oral liquid medications, they quickly realize the difference between what “flavour” means when it’s written on a label and how it actually tastes.
Prednisone liquid does not taste so bad at first, but 30 seconds after tasting it, one resident remarked, “What did I just ingest? It tastes like an S.O.S pad!”
Only 20 per cent of prescription drugs have formulations suitable for pediatric patients.
The next thing we need to tackle is monitoring individual response. We all process drugs differently, so we need to assess what works and what doesn’t for each child. Monitoring individual patient outcomes is critically important so that we know what the medications are actually achieving and can adjust therapy accordingly.
For the past 30 years, my research has focused on why we have variability in drug response, what makes someone an extraordinary responder, and how we could improve effectiveness in non-responders.
What are the most common adverse drug reactions in kids?
The most common adverse drug reactions in all people are usually gastrointestinal (GI) — nausea, vomiting, diarrhea — because we take most medications by mouth. The most commonly used medications in children and adults are the same: antibiotics, pain relievers and mental health medications. Depending upon the drug you’re taking, the adverse effects are different. Antidepressants can make some people feel jittery and pain relievers make some feel sleepy. Two patients may have nausea, but in one patient it’s debilitating and in the other it’s mild. Many people develop a tolerance to a medication within a couple of weeks after starting it, so they might need to persevere. That’s why we often start at low doses, and then work up to higher doses.
Was it safe for parents to cut up pain relievers for their children when people started stockpiling this medication last year?
It’s absolutely safe. Physicians and pharmacists often split, grind up or dissolve tablets to make lower doses. But certain kinds of tablets can be split and others shouldn’t be. For example, if you cut enteric-coated tablets — commonly known as extended-release tablets — you change or destroy their function. Seizure medication, such as Divalproex, is built into a matrix so that it’s slowly absorbed and doesn’t cause GI upset. Cutting that tablet breaks the matrix and destroys this unique delivery.
It’s important to understand that tablets are formed with the active ingredient, binders and other components mixed together, and the active ingredient is not necessarily evenly distributed throughout.
If you see a score line on a tablet you can cut it and you can be confident that you’re getting about 50 per cent of the dose in each of those halves. If you cut the tablet into smaller pieces, however, the amount of active ingredients in each section will probably vary quite a bit.
What do parents need to know?
The World Medical Association’s Helsinki Declaration of ethics recognizes children and pregnant women as vulnerable groups that should not be subjects of medical experimentation. Okay, but what if they need a drug? Some children require medication, but we only have adult data to rely on in terms of benefits and harm. It’s generally not appropriate to scale an adult dose down to a child dose just by body weight. For example, for a seven-kilogram pediatric patient, common practice is to give them one-tenth of the dose for a 70-kilogram adult. That assumes children and adults are physiologically the same, but they’re not.
Children are not little adults.
They metabolize drugs differently than adults, so understanding those physiologic pathways helps us better understand how to dose drugs safely. Dosing by body weight alone, which is what we currently do, is simply not adequate now that we know how much a person's physiology, their biological processing of drugs, and even their genetics can influence the impact of a drug.
What factors, besides body weight, should be considered in pediatric drug dosing?
It turns out that genetics can explain a lot of the variability in drug outcomes, so understanding both body weight and genetics is critically important to avoiding toxicity and ensuring effectiveness.
Talking about pediatric patients or children as one group is also problematic because a premature baby is very different physiologically than a 17-year-old adolescent.
It’s an incredibly complex area with lots of changes occurring in how the body transforms drug during childhood. We ought to be studying premature babies, full-term babies, toddlers and adolescents as distinct groups with distinct physiology.
What are the challenges to making the necessary changes to pediatric drug labelling and formulations?
In the 1990s, the FDA created the Food and Drug Modernization Act and what’s known as the Pediatric Rule, which gives manufacturers six months of additional marketing exclusivity and patent protection when studies are performed in children as requested by the FDA. That has helped, but we’re still pretty far from having a lot of drugs labelled with proper pediatric data. That means we have to be extra careful when we use medications, the most frequent medical intervention in Western society, because each time we use a drug, there is limited data on safety and effectiveness in children.
The lack of labelling is in part also due to ethical concerns about studying children. But we need the data, so we use expert committees to help us do so ethically and responsibly.
It’s also a market issue. If you can get a drug on the world market, which is composed of 75 per cent adults, and drug regulators do not regulate whether clinicians prescribe drugs according to the label, then why do you really need pediatric studies? Physicians are going to prescribe to children anyway. One in five prescriptions written today are for off-label use.
What are some of the potential solutions to these problems?
Potential solutions include creating formulations that are palatable to children, improving our understanding of pediatric drug bioavailability, and building knowledge about how characteristics of a drug change when the form is changed — tablet, liquid, or even lollipop!
In terms of individualizing therapy, we need more drug outcome monitoring. Right now, the prescriber provides a prescription, the pharmacist dispenses the medication (sometimes with a list of potential adverse effects to watch for), and both generally say to the parent, “Let me know how it goes.” The entire responsibility of monitoring drug outcomes is therefore placed on the parent or the child. What if you’ve got a two-year-old who can’t tell you whether their joints hurt more before or after starting a medication? Babies and small children can grow up to an inch in a 24-hour period. Trying to differentiate growing pains from adverse effects of a drug can be very difficult.
We need a feedback loop. We need physicians and pharmacists to say: “Here is when you should expect improvement, here are the adverse effects to look for, here’s how to look for them in your child at their age, and I’m going to check in with you in a few days to see how things are going.” There needs to be a system that encourages and rewards that feedback.
What questions should parents be asking doctors or pharmacists when getting prescription medication for their children?
Parents should be asking:
- What are the potential adverse effects?
- What should I look for as an indication of these adverse effects?
- How should I look for those effects?
- How often should I look?
- When would I likely see any adverse effects?
- When are the benefits of the prescription medication likely to be seen?
For example, when we talk about hair loss from a drug, when would it typically occur? How much hair are we talking about? Are we talking about clumps of hair falling out or just a few more strands in the brush over time? We need to be very specific. Otherwise, parents don’t know what they should be looking for.
Why is addressing pediatric drug dosing problems so important?
Addressing problems with pediatric drug dosing is important because children are only 25 per cent of our population, but they’re 100 per cent of our future.
We know we have a problem with a lack of drug labelling that’s specific to pediatric patients. We know we lack important data. We need to bring people together to solve these problems. We need an interdisciplinary approach with drug formulation experts, geneticists, clinical pharmacologists, drug regulators and others working together toward shared goals. This can’t just be delegated to Health Canada or the manufacturers. We, as clinicians and researchers, have a responsibility to solve these problems for future generations.