Recognizing adverse drug events related to paediatric medication compounding

A 30-month old female with Dravet syndrome, an epileptic encephalopathy associated with refractory seizures, presented to hospital following a prolonged generalized tonic-clonic seizure. This was her first prolonged seizure in 6 months. After her first seizure at 5 months of age, she was initiated on clobazam with adequate seizure control. Five days prior to presentation, during a routine follow-up visit, her clobazam dose was adjusted for weight. Her new prescription was compounded and dispensed at a community pharmacy in a 1 mg/mL suspension. One day prior to presentation, she was noted to have a increased upper and lower body tone. She was afebrile with no infectious symptoms. There was no history of trauma, no changes to her feeding schedule and no recent immunizations. At the hospital, her seizures aborted after receiving two doses of lorazepam. She was admitted for observation and was restarted on clobazam, prepared in the hospital pharmacy, at her recently updated out-patient dose. On the second day of hospitalization, their community pharmacist called to inform the family that a compounding error (10-fold under-dosing by concentration) was suspected after a routine stock review revealed an excess of medication on hand. A new bottle of clobazam was compounded at the appropriate concentration, and she was discharged in stable condition. The differential diagnosis for increased seizure activity in children with epilepsy is broad and includes conditions that lower seizure threshold (e.g., intercurrent illness), disease progression and non-adherence. When patients are receiving medications that require compounding, physicians should also consider the possibility of a compounding error. This is especially true if a patient presents with an unexpected deterioration in the days following a new or refilled prescription of a compounded medication. Extemporaneous compounding is defined as the preparation, mixing and assembling of a medicinal product by a pharmacy or caregivers based on a prescription order for an individual patient (1). When a commercially available child-friendly formulation (e.g., premixed oral liquid or low-dose minitab) is unavailable, adult medications are often manipulated to achieve the necessary dose or to make administration to children, who may be unable to swallow a pill, possible (2). While compounding is considered ‘off-label use’, it is also recognized as an essential practice and is regulated by provincial/territorial pharmacy standards (3). At present, clobazam is only available in Canada as 10 mg tablets, therefore clobazam must be compounded to achieve an appropriate dose in a form suitable for paediatric patients. Compounding is associated with intrinsic risks, including concentration errors (4), with under-dosing concentration errors presenting as treatment failure or disease progression and over-dosing concentration errors presenting as toxicity. In rare instances, liquid suspensions can be prepared using the wrong medication, which may present as treatment failure, disease progression or toxicity associated with the unintended active ingredient. In very rare instances, compounding errors have caused death in paediatric patients (5). In addition to concentration and preparation errors, individual pharmacy-compounded products are not evaluated for stability, potency, uniformity, purity, sterility and/or bioavailability, making many compounded products, even those prepared correctly, subject to lower quality standards than commercially available medications (6). The exact prevalence of compounding for children in Canada is unknown. However, it is estimated that 80% of all paediatric prescriptions fall outside of Health Canada approved indications, and that a substantial proportion represent pharmacy compounding or manipulation by caregivers (7). A 2023 Canadian study analyzing the frequency of compounding at a large paediatric hospital found that 23% of all prescriptions for enteral medications required some form of pharmacy-based manipulation, and almost half (49%) of all children had at least one compounded drug for enteral administration on their file (8). This includes commonly prescribed paediatric medications, life-sustaining medications and medications with a narrow therapeutic index (9). In some cases, child-friendly formulations simply do not exist. In other cases, paediatric formulations that are available in other jurisdictions have not yet been approved for sale in Canada (10). Occasionally, manufacturers will discontinue a paediatric formulation for commercial reasons, leaving compounding as the only option for administration. In Canada, many commonly prescribed paediatric medications require compounding. Specific to this case, commonly prescribed anti-epileptic medications that require compounding include clobazam, topiramate, gabapentin and lamotrigine. A liquid formulation of levetiracetam was recently approved in Canada (https://pdf.hres.ca/dpd_pm/00052139.PDF). Given that compounded medications are administered off-label, adverse event reporting is not technically required. However, reporting adverse events associated with compounding to Health Canada, or the Canadian Paediatric Surveillance Program Adverse Drug Reaction Study (11), is important to understand the risks associated with compounding in Canada. Reporting suspected or confirmed compounding errors to pharmacy colleagues is also essential to maintain and improve quality assurance practices. The authors would like to thank Jas Otal PharmD, ACPR and Derek McCreath BScPharm, ACPR, EPPh for their thoughtful review of this manuscript. No funding to report. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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