Paediatric compounding and formulations in Canada: A primer for prescribers and call to action for government

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Compounding in paediatric practice

Infants and children often require different oral drug forms from adults due to their lower dose requirements, limited swallowing abilities, and taste preferences. When a medication is only marketed as a capsule or tablet for adult use, and no child-friendly formulation (e.g., oral liquid, dispersible tablet, or sprinkle) is commercially available, it may be necessary to alter the adult product to achieve the desired dose or facilitate safe administration^[1]. These adaptations can be made by pharmacy professionals (a process known as “compounding”) or at the point-of-use by caregivers (known as “manipulation”). As these adaptations fall outside of the approved Canadian product monographs, they result in “off-label” medication use.

Many paediatric prescribers are unaware of how frequently their prescriptions require compounding before dispensing and administration^[2]. Because compounding is associated with intrinsic risks, all prescribers should understand the practice and its possible impacts on individual patient outcomes. Prescribers should also be aware of the logistical issues for families associated with compounded products. For example, compounded products often have a shorter effective shelf life compared with manufactured products and procurement may require caregivers to travel to specialized pharmacies far from their home community. Moreover, compounding is a burden on the broader health system because it requires extra time, effort, and resources from highly skilled pharmacy professionals.

However, despite the significant challenges associated with compounding, Canada’s current regulatory and reimbursement structures do not encourage the commercialization of child-friendly formulations. This means that children in Canada do not have access to the safe, effective paediatric dosage forms available in comparable countries.

This statement describes the clinical issues associated with compounding that directly affect paediatric practice and the policy changes needed to improve public access to safe, effective child-friendly formulations in Canada.

COMPOUNDING

Compounding is defined as the mixing, assembling, packaging, and labelling of a medicinal product by pharmacy professionals based on a prescription order from a licensed practitioner to meet the needs of an individual patient^[3][4]. Compounding is a common practice in paediatrics, but adults may also require compounded medications to serve their individual needs. 

The prevalence of compounding to support the drug needs of infants, children, and youth in Canada is not precisely known, but a substantial proportion of paediatric off-label use relates to either pharmacy compounding or manipulation by caregivers^[1]. A 2023 Canadian study analyzing the frequency of compounding at one large paediatric hospital found that 23% of all prescriptions for enteral medications required some form of pharmacy-based manipulation, and almost one-half of children seen had at least one compounded drug for enteral administration on their file^[5]. Compounded medications include those that are commonly prescribed (i.e., dexamethasone), those that are life-saving or -sustaining (i.e., 6-mercaptopurine), and those with a narrow therapeutic index (i.e., tacrolimus)^[6]. However, in some cases, a child-friendly formulation does not exist and has not been commercialized anywhere in the world. And in many cases, paediatric formulations are available in other jurisdictions but have not been commercialized in Canada^[7]. In rare cases, paediatric formulations previously available in Canada may become unavailable if a manufacturer elects to discontinue them for commercial reasons, such as small market size or a lack of profitability (i.e., sulfamethoxazole/trimethoprim). 

RISKS ASSOCIATED WITH COMPOUNDING

Pharmacy-based compounding is an essential practice that facilitates paediatric medication dosing and administration when commercial, child-friendly formulations are not available. Compounding serves a critical unmet need, and there are robust, well-established standards, policies, and processes governing the practice to optimize patient safety^[6][8].

Despite existing safeguards, compounded medications are not equivalent to regulator-approved, commercially manufactured, age-appropriate drugs. While adult drug forms and commercial paediatric formulations are subject to the rigorous Good Manufacturing Practice (GMP) regulations governing production of all manufactured medical products (including drugs and biologics), drug products compounded in independent pharmacies or by caregivers are not^[9]. Therefore, unlike commercially manufactured drug formulations, products compounded for individuals are not clinically evaluated for safety, consistency (i.e., batch-to-batch uniformity), or durability (i.e., shelf life) before dispensing. As a result, the quality, potency, purity, stability, uniformity, sterility, and bioavailability of individual compounded products may differ from the commercial versions^[10][11]. These potential differences increase the risk for clinically significant adverse events, including concentration- and dosing-related errors that can lead to toxicity or treatment failure, contamination, and other complications^[12][13]. Compounded medications may also have an unpleasant taste or texture (or both), which may compromise adherence to treatment^[14][15], a particularly relevant issue in paediatrics. 

Furthermore, while not a result of preparation errors or product quality, the variable concentrations of routinely compounded paediatric medications pose inherent risk. The absence of standardization in compounding formulas (also known as “recipes”) can lead to dosing errors, particularly when prescribers and families reference medication volumes rather than the active ingredient’s weight. To mitigate risk, medication doses must be prescribed and communicated in gram, milligram, or microgram units rather than milliliters.

Potential errors and intrinsic risks associated with compounding are described in Table 1^{[12]-[14][16]-[18]}.

Table 1. Potential errors and intrinsic risks associated with compounding
Type of error/risk	Description	Case example
Concentration error – Overdosing	10-, 100-, or 1000-fold overdosing concentration error	Clonidine suspension dispensed at a concentration 1000 times greater than prescribed, leading to clonidine toxicity[12]
Concentration error – Underdosing	10-, 100-, or 1000-fold underdosing concentration error	Tacrolimus suspension dispensed at a concentration 10 times less than prescribed, leading to organ rejection[16]
Product error	Administering an unintended medication as a primary or secondary agent	Accidental substitution of tryptophan with baclofen, leading to a fatal baclofen overdose[13]
Lack of formulation standards	Variable pharmacy formulations (or “recipes”) when compounding the same medication	A family reported clobazam use in milliliters of prescribed suspension rather than milligrams of active drug, leading to widely discrepant inpatient versus outpatient dosing A family switched to a compounding pharmacy where a different concentration of clobazam was prepared, leading to a significant dosing error when the drug was administered in the previously prescribed volume at home[17]
Contamination	Microbiological or substance-related contamination of a compounded product	Improper autoclaving leading to fungal contamination of injected methylprednisolone[18]
Administration error	Limited drug stability or bioavailability data for compounded drugs	Inadequate shaking of a compounded medication before administration (with active drug settled at the bottom of its container) leading to under-dosing and treatment failure
Palatability	Inability to tolerate a medication due to taste, texture, or volume	Poorly tolerated antiretrovirals, leading to increased viral load and treatment failure[14]
Cytotoxic exposure	Exposing family members to cytotoxic substances during medication manipulation (i.e., tablet splitting) at home	Incorrect handling of 6-mercaptopurine to treat paediatric acute lymphoblastic leukemia, leading to cytotoxic exposure of parents and siblings

RECOGNIZING COMPOUNDING-RELATED ADVERSE DRUG EVENTS (ADEs)

Despite evidence suggesting that the incidence of ADEs in hospitalized children is approximately 9%^[19], and that a significant proportion of ADEs in paediatric patients are associated with harm^[20], ADEs in children are rarely considered as a cause of unexplained clinical outcomes. Moreover, despite the frequency of compounding in paediatric practice, compounding-related errors are almost never considered as contributing causes of ADEs. Prescribers should consider the possibility of a compounding-related error when managing patient outcomes that are unexpected, when treatment failure is unexplained, and in cases of medication toxicity^[11]. These presentations can be easily mistaken for disease progression, adherence issues, or as purposeful or accidental overdoses. 

The federal Protecting Canadians from Unsafe Drugs Act^[21], known as “Vanessa’s Law”, requires all hospitals to report serious ADEs to Health Canada within 30 days of the event being documented. To ensure compliance with and optimize the positive impacts of this patient safety legislation, it is essential to both identify and report all ADEs, including those related to compounding. 

When a compounding error is suspected, the drug should be discontinued and the dispensing pharmacy contacted. Comprehensive guidance documents issued by the National Association of Pharmacy Regulatory Authorities (NAPRA)^[22] describe product, preparation, and documentation requirements for pharmacy professionals compounding non-sterile preparations, including oral paediatric formulations. When the integrity of a compounded product is in doubt, pharmacy professionals can conduct a root cause analysis, including an audit and review of pharmacy calculations, to help confirm or disprove that a compounding error occurred. In some cases, testing a suspected product may be possible. In all cases, when the index of suspicion for a compounding error is high, a new product should be dispensed and the patient’s clinical response monitored closely as part of the review process.

FREQUENTLY COMPOUNDED PAEDIATRIC MEDICATIONS

Specific questions regarding the need to compound individual medications should be directed to a hospital pharmacy or a specialized compounding pharmacy. Table 2 highlights commonly compounded medications for children in Canada in alphabetical order.

Table 2. Commonly prescribed oral medications that require compounding in Canada
Baclofen	Metronidazole
Caffeine base	Nifedipine
Clobazam	Prednisone
Clonidine	Rifampin
Dexamethasone	Sildenafil
Domperidone	Spironolactone
Enalapril	Spironolactone/Hydrochlorothiazide
Famotidine	Sulfamethoxazole/Trimethoprim
Gabapentin	Tacrolimus
Hydrochlorothiazide	Topiramate
Hydrocortisone	Ursodiol

Many medications, including frequently prescribed oral medications, are not readily available in sugar-free formulations. When caring for patients requiring the ketogenic diet, direct communication with a pharmacy professional is required to ensure the best drug therapy solution is prescribed and dispensed.

PAEDIATRIC FORMULATIONS: A CALL TO ACTION

Over the last two decades, leading jurisdictions, including the United States and the European Union, have passed legislation, implemented powerful incentives, and supported platforms that bring together scientists, researchers, and pharmaceutical industry representatives to facilitate and accelerate development of child-friendly formulations. While this work remains challenging and costly, the Best Pharmaceuticals for Children Act (U.S.), the European Paediatric Formulation Initiative (EuPFI)^[23], and the Global Accelerator for Paediatric Formulations Network (GAP-F, World Health Organization) have achieved tangible outcomes, including the commercialization of several important new child-friendly products.

Unfortunately, Canada’s children and youth have not benefited from many global advances made in paediatric formulations. Child-friendly formulations approved and on market elsewhere are often inaccessible in Canada. One Canadian study from 2020 found that of the 56 medications commonly compounded in a large, free-standing children’s hospital, 27 (or 48%) had a GMP-certified child-friendly formulation available in a comparable jurisdiction outside Canada^[24]. Canadian health care professionals, patients, and families remain dependent on compounding or manipulation of adult dosage forms to treat children, despite superior products being available in other countries. 

Paediatric formulations that are commercially available in the US or EU may not be brought to market in Canada for multiple reasons, including:

• Limitations inherent to a small market, including limited revenue potential associated with commercializing paediatric-friendly formulations for Canada’s small paediatric population,
• Canada’s complex and cumbersome regulatory and reimbursement environment, specifically the time and costs associated with leading reimbursement conversations with multiple provincial/territorial public formulary managers, and
• Paediatric-specific regulatory deficiencies and practice norms (e.g., the absence of a mandate to provide paediatric data or paediatric formulations to Health Canada as part of new drug submissions and supplements to new drug submissions together with a longstanding overreliance on off-label prescribing).

The need for a more robust paediatric regulatory framework is well recognized^[7][25], and while Canada’s small market size cannot be readily modified, effective advocacy can improve the structures and systems governing paediatric drug approvals and public listings in the near term. 

To address critical access issues associated with paediatric formulations in Canada, the following actions are required:

1. Prioritize the review, approval, and commercialization of child-friendly formulations that are available in trusted foreign jurisdictions. The National Priority List of Pediatric Drugs (NPLPD)^[26], an initiative within Health Canada’s Pediatric Drug Action Plan (PDAP), identifies medications and formulations that require urgent re-labelling or commercialization (or both) to increase timely access to safe, effective, on-label paediatric medications and formulations in Canada. The NPLPD was informed by physicians caring for children across the country and adjudicated by a committee of paediatricians, pharmacists, and health policy experts. The list highlights essential child-friendly formulations that are on market in either the US or the EU. Taking action on the NPLPD requires proactive engagement by Health Canada with industry to solicit new and supplemental drug submissions for child-friendly formulations identified on the NPLPD list. Health Canada must also provide tangible incentives to manufacturers to encourage and streamline the commercialization of formulations on the NPLPD and commit to regularly revising the NPLPD as new unmet product needs are identified.

2. Leverage the “Precision Regulation” initiative to lower barriers to entry for manufacturers. “Precision Regulating” refers to a set of reforms proposed by Health Canada as part of their Forward Regulatory Plan^[27]. The changes are designed to address market gaps by expanding Health Canada’s reliance on decisions made by trusted foreign regulatory authorities. Increased reliance on foreign data and regulatory decisions could expedite Health Canada’s approval of medicines already authorized by comparable regulators, such as the Food and Drug Administration (FDA-US) and European Medicines Agency (EMA-EU), when supported by sufficient post-market experience.
   
   At time of writing, no specific paediatric provisions had yet been articulated as part of the “Precision Regulation” plan. However, successful implementation of this initiative would require prioritizing select populations with significant unmet drug needs and ensuring appropriate flexibilities are in place for those populations. More specifically, special conditions should be established for child-friendly formulations of products now available in Canada in non-child friendly forms, with safety profiles established through off-label use. Importantly, standards defining “adequate post-market experience” must account for disease-specific epidemiological data, the risk profiles of drugs in review, and the urgency of unmet needs.
3. Mandate the submission of paediatric data and child-friendly drug forms for new drug submissions whenever use in children is expected or anticipated. Regulatory requirements that mandate the submission of paediatric data and child-friendly dosage forms when seeking new or supplemental drug approvals are necessary to secure equitable regulatory protections for paediatric patients and improve access to the safest possible paediatric drug products^[1][7].
4. Ensure that the incremental benefits associated with child-friendly formulations are appropriately reflected in cost-effectiveness analyses, that products are fairly priced, and that they are listed on public formularies. There are, at present, no standards to ensure that the added value of a commercially prepared child-friendly formulation (as compared with a compounded product) is considered as part of its Health Technology Assessment (HTA) or subsequent reimbursement decisions. Formally recognizing the safety and other benefits of commercial formulations is essential to attract new products to Canada, ensure appropriate pricing, and optimize listing decisions. 

Public formulary managers must work together with HTA agencies and pricing entities to produce clear, transparent guidance on appropriate pricing for paediatric formulations. At the same time, manufacturers should avoid pricing formulations exorbitantly and making access problems worse^[28][29]. Excessively priced paediatric formulations can compromise the goal of improving access to safe, effective, on-label drugs suitable for children in Canada.

Recommendations

Prescribers should:

• Recognize the widespread use of compounding in paediatric practice, be knowledgeable about medications they routinely prescribe in practice that require compounding, and be aware of intrinsic safety and other risks associated with manipulating medications.
• Counsel families on the risks for medication error associated with compounded medications, specifically those associated with filling prescriptions at different pharmacies and when communicating about home medications in different medical environments.
• Express medication doses in units of metric weight (i.e., mg, mcg, mEq), not volume, to optimize safety. Include the patient’s weight and date of birth on prescriptions, with weight-based dosing (i.e., mg/kg/dose) calculations when appropriate.
• Communicate with a pharmacist to evaluate the possibility of a compounding error in the event of unexpected toxicity or treatment failure following use of a compounded product.
• Communicate with the dispensing pharmacist when concerns about the integrity of a compounded product are raised. If the index of suspicion for a compounding error is high, prescribers should discontinue use of the product.  

Hospitals, community-based practices and other medical practice settings should:

• Enhance existing formularies and computerized order entry systems to highlight which medications require pharmacy compounding or manipulation.
• Collaborate with partners across health regions to standardize drug concentrations of compounded products.

Health Canada should:

• Increase access to on-label paediatric formulations by engaging with industry to solicit new or supplemental drug submissions for products identified on the National Priority List of Pediatric Drugs (NPLPD) and provide meaningful incentives to manufacturers able to commercialize formulations identified on the NPLPD. 
• Implement paediatric-specific “Precision Regulation” provisions to allow market entry for safe, effective paediatric-friendly formulations that are approved by trusted foreign regulators and available in comparable jurisdictions.
• Implement regulations that mandate the submission of paediatric data when a medication’s use for children can be expected or anticipated and require the submission of paediatric-friendly dosage forms to ensure safe and effective administration.

Provincial/territorial public formulary managers, together with government, public sector, and institutional health partners should:

• Establish standards to ensure that the incremental safety and other benefits of paediatric formulations, over their compounded counterparts, are formally evaluated as part of health technology assessments (HTAs).
• Ensure timely public coverage of appropriately priced child-friendly formulations when they are brought to market in Canada.

Acknowledgements

The authors gratefully acknowledge the thoughtful review and feedback provided by the Goodman Pediatric Formulations Centre, the Canadian Pharmacists Association, the Institute for Safe Medication Practices, and the Canadian Society of Pharmacology and Therapeutics. This statement was reviewed by the Acute Care and Community Paediatrics Committees of the Canadian Paediatric Society.

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CANADIAN PAEDIATRIC SOCIETY DRUG THERAPY COMMITTEE (2023-2024)

Members: Geert 't Jong MD PhD (Chair), Marc-André Dugas MD (Board Representative), Yaron Finkelstein MD, Tom McLaughlin MD, Derek McCreath BScPharm, Charlotte Moore Hepburn MD, Eva Slight-Simcoe BScH MD (Resident Member)
Liaisons: Michael Rieder MD (Canadian Society of Pharmacology and Therapeutics)
Authors: Charlotte Moore Hepburn MD, Catherine Litalien MD, Derek McCreath BScPharm, Geert 't Jong MD PhD

Funding
There is no funding to declare.

Potential Conflict of Interest
Dr. Moore Hepburn reported having a financial and fiduciary relationship with a private life sciences company, ZYUS Life Sciences Inc. The company is focused on medical cannabinoids, including both exempt market and regulated medical products. The company does not research, sell, or distribute products (either in Canada or overseas) that are designed to meet the therapeutic needs of children. Dr. Litalien reported receiving financial support for traveling expenses from the Goodman Pediatric Formulations Centre of the CHU Sainte-Justine. No other disclosures were reported.

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References

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Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.