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Drug-drug interactions (hereafter, drug interactions) occur when concurrent administration of two drugs renders the effect of one or both drugs more potent — so that a recommended dose becomes an overdose — or makes the drug less powerful or ineffective altogether.[1] Some of these interactions are considered major because they can cause serious adverse effects, sometimes resulting in life-threatening outcomes.
Although many studies have examined drug interactions in adults, older adults...
Drug-drug interactions (hereafter, drug interactions) occur when concurrent administration of two drugs renders the effect of one or both drugs more potent — so that a recommended dose becomes an overdose — or makes the drug less powerful or ineffective altogether.[1] Some of these interactions are considered major because they can cause serious adverse effects, sometimes resulting in life-threatening outcomes.
Although many studies have examined drug interactions in adults, older adults or hospitalized patients, there is little information about these interactions in children, particularly outside of hospitals.
A new large, multistate study, funded by the National Institutes of Health, demonstrated that major drug interactions are common among outpatient children with Medicaid insurance and that these interactions involve drugs that are routinely prescribed for children with common chronic health conditions. The study was published in the January 2024 issue of Pediatrics.
Details of the new study[2]
Using commercial Medicaid claims data from 11 geographically diverse states in 2019, the researchers obtained information pertaining to 781,019 children aged zero to 18 years who had at least one health care encounter that did not include hospitalization. These children also had at least two dispensed pharmacy prescriptions for drugs that are most likely to have systemic effects. Of those children, 167,339 (21%) were exposed to at least one major drug interaction for at least one day during the study year. The researchers focused on major drug interactions because those have the most serious effects on children’s health.
The highest percentage of exposure to major drug interactions occurred in adolescents (51%), followed by children aged six to 11 years (37%), those age two to five years (10%) and infants (2%). Of all children who were exposed to major drug interactions, 46% were exposed to more than one such interaction.
The researchers found that as the number of chronic diseases and mental health conditions increased, the proportion of children exposed to drug interactions increased. Notably, the high blood pressure drug clonidine (CATAPRES-TTS, NEXICLON XR and generics) — which Public Citizen’s Health Research Group has designated as Do Not Use — was the most frequently implicated drug in exposure to major drug interactions, as it had more than 18 million exposure days affecting 82,639 children. Additionally, the allergy drug cetirizine (CHILDREN’S ZYRTEC ALLERGY, ZYRTEC ALLERGY, other brands and generics) was implicated in exposure to major drug interactions in more than 217,000 children over 1.3 million days.
As shown in the Table below, other frequently implicated drugs in exposure to major drug interactions include certain allergy and asthma drugs, attention deficit hyperactivity disorder drugs and antipsychotics.
The adverse effects caused by exposure to major drug interactions that had the highest rates per 100 children were increased drug levels in the blood, central nervous system depression, prolongation of the QT interval (a change in the electrical activity of the heart that can cause a fatal heart rhythm disturbance) and suppression of the immune system. In contrast, the adverse events with the lowest exposure rates were bleeding, blood clots and toxicity of the kidneys and gastrointestinal system.
The main limitations of the study are that it excluded uninsured children and those with commercial insurance and did not include drug interactions caused by nonprescription drugs.
Nonetheless, the study findings underscore the importance of protecting children from exposure to drug interactions in outpatient settings.
This is because prescribers often do not monitor drug levels or work with clinical pharmacists to monitor drug levels in outpatient settings.
Table: Top 10 Drugs Frequently Implicated in Major Drug Interactions in the Pediatrics Study
| Generic Name | Brand Name(s) | Drug Class |
|---|---|---|
| amphetamine* | ADDERALL,† ADZENYS XR-ODT, EVEKEO, MYDAYIS,† other brands and generics | Attention deficit hyperactivity disorder drug |
| aripiprazole* | ABILIFY, ABILIFY MYCITE KIT and generics | Antipsychotic |
| cetirizine* | CHILDREN’S ZYRTEC ALLERGY, CHILDREN’S ZYRTEC HIVES RELIEF, ZYRTEC ALLERGY, ZYRTEC-D 12 HOUR† and generics | Allergy drug |
| clonidine** | CATAPRES-TTS, NEXICLON XR and generics | Hypertension drug |
| fluticasone propionate | ADVAIR HFA,† AIRDUO RESPICLICK,† ARMONAIR DIGIHALER, DYMISTA,† FLONASE ALLERGY RELIEF, FLOVENT DISKUS, FLOVENT HFA, WIXELA INHUB†, XHANCE, other brands and generics | Asthma/allergy drug |
| hydroxyzine | VISTARIL and generics | Allergy drug |
| lisdexamfetamine** | VYVANSE and generics | Attention deficit hyperactivity disorder drug |
| montelukast** | SINGULAIR and generics | Asthma/allergy drug |
| risperidone* | RISPERDAL, UZEDY and generics | Antipsychotic |
| trazodone** | generic only | Antidepressant |
†Brand-name combination products that contain other active ingredients
*Designated as Limited Use by Worst Pills, Best Pills News
**Designated as Do Not Use by Worst Pills, Best Pills News
What You Can Do
It is important to be proactive in safeguarding your children’s health. Therefore, if you have a child who is taking several medications at the same time or has multiple health conditions, review all their medications (including prescription drugs, over-the-counter medicines, vitamins and herbal supplements) with their clinician to determine the risk of significant drug interactions. If any of your child’s medications can interact with each other, the clinician may recommend stopping or adjusting the dosage of the drugs or advise that different drugs be taken. Ask the clinician about the signs and symptoms that may suggest interactions between your child’s medications, and monitor your child for those.
Follow instructions regarding how to give your children their medications, including whether to take them with food or on an empty stomach. It also is helpful to read the prescribing information and ask questions at the pharmacy. The pharmacist can clarify the instructions of your child’s clinician and may offer additional information about avoiding dangerous drug interactions. Report all serious adverse events related to drugs, including interactions with other drugs, to the FDA’s MedWatch adverse event reporting program by visiting www.fda.gov/MedWatch or by calling 800-FDA-1088.
References
[1] Gonzalez D, Sinha J. Pediatric drug-drug interaction evaluation: Drug, patient population, and methodological considerations. J Clin Pharmacol. 2021;61(Suppl 1):S175-S187.
[2] Kyler KE, Hall M, Antoon JW, et al. Major drug-drug interaction exposure among Medicaid-insured children in the outpatient setting. Pediatrics. 2024;153(2):e2023063506.
