Off-Label Drug Use in Pediatrics

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The Pre-brief

Off-label drug therapy refers to the use of a drug that varies from FDA approval in age, indication, and/or formulation. About half the drugs used in the pediatric intensive care unit are off-label. Up to 100% of children, in some studies, receive at least one off-label drug during their hospitalization.(1,2,3) Examples of these drugs include dexmedetomidine, ketamine, and hydromorphone.

Although off-label drug use may lack safety, efficacy, and dosing data, the practice remains common and necessary for practice. However, the risks include therapeutic failure and toxicity. Therapeutic failure is a result of drug doses that are too low to reach levels for adequate treatment. Increased toxicity is a result of doses that are too high placing patients at risk for unnecessary adverse events.

There are many reasons why off-label drug use in kids is so common. Pediatric trials are full of challenges including barriers to consent, limited blood volume, and low sample sizes. Additionally, a wide range of ages means that sampling from one age group may not be representative of the entire population.

Historically, drug development has been done by extrapolating from adult data, but throughout childhood MANY physiological parameters change.(4) Here are a few examples:

Critical illness further alters drug absorption, metabolism, distribution, and excretion.(5) Take for example the following clinical scenario:

A 2 year old child admitted in septic shock. The child is hypotensive and has received 60ml/kg of fluid resuscitation. We have all seen the puffiness that can result from significant capillary leak and aggressive fluid administration. That edema will increase volume of distribution for administered drugs.

Volume of distribution is essentially the relation between the concentration of a drug in the plasma to the total amount of drug in the body.

The child may also have shock liver or acute kidney injury both of which can reduce clearance of administered drugs from the body.

Further, alterations in GI perfusion and motility and reduction in circulating albumin effect free and bound drug concentrations.

If all that wasn’t enough therapeutic interventions including VADs, dialysis, and ECMO also affect pharmacokinetics (movement of drug through the body) and pharmacodynamic (the effect of drug in the body) including a huge increase in volume of distribution and a potential decrease in clearance related to the underlying critical illness.


What should we do about all of this!?

The Debrief

Remember these very important considerations when giving mediations to our sick pediatric patients for off-label uses.


  1. Horen B, Montastruc JL, et al. Adverse drug reactions and off-label drug use in paediatric outpatients. Br J Clin Pharmacol. 2002 Dec;54(6):665-70. doi: 10.1046/j.1365-2125.2002.t01-3-01689.x.
  2. Turner S, Nunn AJ, et al. Adverse drug reactions to unlicensed and off-label drugs on paediatric wards: a prospective study. Acta Paediatr. 1999 Sep;88(9):965-8. doi: 10.1080/08035259950168469.
  3. Kimland E, Nydert P, et al. Paediatric drug use with focus on off-label prescriptions at Swedish hospitals – a nationwide study. Acta Paediatr. 2012 Jul;101(7):772-8. doi: 10.1111/j.1651-2227.2012.02656.x.
  4. Kearns GL, Abdel-Rahman SM, et al. Developmental pharmacology–drug disposition, action, and therapy in infants and children. N Engl J Med. 2003 Sep 18;349(12):1157-67. doi: 10.1056/NEJMra035092.
  5. Smith BS, Yogaratnam D, et al. Introduction to Drug Pharmacokinetics in the Critically Ill Patient. Chest. 2012 May;141(5):1327-36. doi: 10.1378/chest.11-1396. 


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