Child-resistant packaging and the F value report
A medicine that needs child-resistant packaging also needs an F value, the number of its dose units that can seriously harm a small child. Few methods for setting it are laid down, so a manufacturer weighs the evidence available, often without data from children, and justifies the value in a report.
Child-resistant packaging
Acute poisoning is the third leading cause of unintentional death in children up to the age of 14, according to the World Health Organization. The World Health Organization estimates that acute poisoning is fatal in approximately 3,000 children each year, and that 90% of those poisonings take place in the home.
In the 2016 annual report of the American Association of Poison Control Centers' National Poison Data System, the five substance classes most frequently involved in all human exposures were analgesics (11.2%), household cleaning substances (7.54%), cosmetics and personal care products (7.20%), sedatives, hypnotics and antipsychotics (5.84%) and antidepressants (4.74%). In children aged five or younger, the five most common exposures were cosmetics and personal care products (13.3%), household cleaning substances (11.1%), analgesics (9.21%), foreign bodies, toys and miscellaneous items (6.48%) and topical preparations (5.07%). The overall rate of poison exposures was 660 per 100,000 population, and the rate was highest in children aged one (8,083 per 100,000) and two (7,675 per 100,000).
Various regulatory requirements exist to prevent unintentional drug poisoning in children. The Consumer Product Safety Commission's special packaging standards, also known as child-resistant packaging standards, apply to most oral prescription drugs, many nonprescription drugs and various household products. Under the Poison Prevention Packaging Act, any package containing a substance the act regulates, blisters and pouches included, must meet the child-resistant packaging standards. Otherwise the product can be misbranded or recalled, and the marketing authorisation holder penalised. The FDA also recommends a labelling statement declaring that the product complies with the standards. The act is one of the best-documented successes in preventing unintentional poisoning in children, and reported deaths of children from ingesting toxic household products, medicines included, have declined remarkably since it took effect.
The International Organization for Standardization has published an internationally agreed standard test procedure for reclosable child-resistant packaging. In Europe, several regulatory requirements have been introduced that complement it.
The F value
For a product that requires child-resistant packaging, there is also a regulatory requirement to calculate its F value, or failure value. For unit-dose packages, the F value is the number of individual dose units of a drug that can cause serious illness or injury in a child weighing 25 lb (11.4 kg). Failure occurs when such a child can gain access to that number of tablets or capsules in 10 minutes. For example, a substance that breaches this toxicity threshold after exposure to three units is assigned an F value of 3.
For highly toxic or harmful products, the F value is usually set at 1, meaning that a child's access to even a single unit counts as failure. For less toxic or harmful products, the F value may be higher. A default limit of "greater than 8" is usually adopted in the United States. Unless a lower failure limit is declared, failure then occurs when a child gains access to a ninth unit.
The F value guides the design of the packaging and the tests that evaluate its safety. A product with a lower F value requires reinforced child-resistant packaging, such as a strip pack, a blister pack or a container with a child-resistant closure system, designed or constructed to be significantly difficult for most children younger than five to open.
Determining the F value
Guidance is available on the conduct and reporting of packaging tests, but it is scarce on specific methods for determining the F value. For oral medicines, guidelines on determining it are unavailable, despite the regulations and standards for child-resistant packaging. Each manufacturer needs to conduct risk assessments and decide what constitutes serious personal injury or serious illness for its products. Acute and chronic animal toxicology data, adult clinical dose–response data scaled to children and postmarketing surveillance reports of acute overdose in children are generally evaluated for this purpose. No single method for determining the F value can be applied to all drugs. Further scientific discussion is needed to evaluate the approaches in use critically, and the use of data and the documentation processes should be standardised to fulfil the obligation effectively.
A weight-of-evidence approach is usually applied to calculate the F value, and the evidence is given an order of priority. Data on overdose in children, if available, are given the highest priority, followed by data on overdose and adverse events in adults. Because the F value is defined for a child weighing no more than 25 lb, a body-weight scaling method is usually used in the calculation. When paediatric or adult overdose data are scarce or unavailable, the maximum tolerated dose in adults, the largest dose a patient can take without unacceptable adverse events, or even preclinical data can be used. When none of this evidence is available, overdose data on a similar compound can be used. For a combination product, the F value of each drug is calculated, and the lower value is assigned to the combination.
Many oral drugs are not approved for use in children, so direct clinical dose–response or pharmacokinetic data for a 25-lb child may not be available. The maximum tolerated dose in adults is then usually the basis for calculating the F value. In the absence of paediatric data, a provisional F value can be assigned, on the assumption that the nature of toxicity is similar in adults and children, until paediatric data are available.
Worked calculations
Bupropion XL
The safety and efficacy of bupropion XL, an extended-release antidepressant, have not been established in children. No maximum tolerated dose has been established in adults either, but overdose with neurological, cardiovascular and gastrointestinal signs has been reported in adults who ingested up to 30 g.
In one case report, an 11-month-old boy weighing 12 kg ingested 30 tablets of 300 mg bupropion SR, a dose of 750 mg/kg. He developed generalised tonic-clonic seizures, dilated pupils, tachycardia and severe hypotension with metabolic acidosis, and became comatose with a Glasgow Coma Scale score of 7. He received mechanical ventilation, inotropic support and extracorporeal membrane oxygenation along with other overdose management, was extubated on day 8 and was discharged two weeks after extubation, with no neurological sequelae at the 12-month follow-up.
In another case, a 7-year-old boy weighing 21.8 kg ingested seven tablets of 150 mg bupropion XL, 1,050 mg, which is equivalent to 48.17 mg/kg. He had vomiting, hallucinations, tachycardia and a tonic-clonic seizure, and recovered and was discharged after 48 hours without sequelae.
Scaled by body weight, the dose that could cause adverse events in an 11.4-kg child is approximately 549.08 mg. On these data, the F value assigned to bupropion XL 150 mg tablets is 3, and to 300 mg tablets 1.
Pyrimethamine
Pyrimethamine is an antiparasitic with a good safety and tolerability profile. Its adverse events, including anorexia, vomiting, atrophic glossitis, haematuria, megaloblastic anaemia, leukopenia, agranulocytosis, thrombocytopenia and cardiac rhythm disorders, are primarily due to central nervous system toxicity in acute overdose and to folate depletion in chronic overdose. The lowest reported fatal dose is 375 mg, but children have been reported to recover after an overdose of up to 625 mg.
Several case reports have been published on pyrimethamine overdose in children. In one, a 23-month-old girl ingested eight 25 mg tablets, 200 mg, and had vomiting, irritability, jerky movements of the limbs, opisthotonus and ataxia for two hours, but recovered spontaneously without any intervention.
The average weight of a 23-month-old child is 11.27 kg according to the 2006 WHO child growth standards, so 200 mg is equivalent to 17.74 mg/kg. Scaled by body weight, the corresponding dose in an 11.4-kg child is approximately 202.3 mg, and the recommended F value for pyrimethamine 25 mg tablets is therefore 8.
The F value report
Any package of a drug regulated under the Poison Prevention Packaging Act must state the F value of the packaged substance. The evidence-based justification and calculation of the F value are described in a report, which must be submitted to the Consumer Product Safety Commission. Authoring the report fulfils the regulatory requirement for calculating the F value.
The report, titled "F Value Calculation and Justification", is intended to give a critical analysis of the available clinical and preclinical information on the drug, with the conclusions and implications of that information. It should also be a useful reference for regulatory authorities on the drug's clinical safety information, especially paediatric overdose case reports.
Preparing the report
Preclinical and clinical literature is identified through a targeted search of databases such as PubMed and Embase. Additional relevant data are included from sources such as Poisindex, the peer-reviewed literature and overdose case reports. The rationale for calculating the F value from the weight of evidence is then developed and added to the report. If paediatric data are not available, a temporary F value is calculated from adult data and assigned to the molecule until paediatric data become available. The process of authoring the report also includes the F value calculation and disclaimers.
Length and sections
The report is a succinct account of the drug's pharmacology, prescribing information, adverse events and overdose information, and of the implications of these data for child safety. For a single product it is typically 30 pages long, and for a combination product it can be longer. When exhaustive information on the molecule is available, tables may be used for brevity. The report includes the following sections.
- Introduction and background: the drug's physicochemical properties and pharmacological class; its mechanism of action, such as receptor binding, and its onset or offset of action; its clinical indications; and its approved dosage, formulation and administration.
- Animal toxicology: an overview of the pharmacological, pharmacokinetic and toxicological evaluation of the product in animals such as rats, mice, rabbits, guinea pigs, hamsters, dogs and monkeys; the onset, severity and duration of the toxic effects, their dose dependency and degree of reversibility, and differences between species or genders; the effect of the drug in nonclinical studies in relation to that expected or observed in humans; and the maximum tolerated dose and no-observed-adverse-effect level, whenever available.
- Effects in humans: a brief overview of the pharmacokinetic data, covering comparative pharmacokinetics in healthy individuals, patients and special populations, the extent of absorption, distribution including binding to plasma proteins, excretion and time-dependent changes, and of the pharmacodynamic data, covering the mechanism of action and the relationship of favourable and unfavourable effects to dose or plasma concentration; the nature, absolute number and frequency of common, nonserious and serious adverse events in clinical trials and postmarketing studies, including deaths and other events leading to discontinuation or dose modification, generally taken from the prescribing information and substantiated by published literature; and case reports of overdose in adults and children, discussing each patient's age, weight and health status, the dose ingested and the nature, severity and frequency of the adverse events, mentioning any conclusion on a causal relationship to the product and the laboratory findings, discussing the potential for dependence, rebound phenomena and abuse, and including the management and outcome of each case.
- Rationale for the F value calculation: the interpretation of the data and evidence, the case report or the maximum tolerated dose, used as the basis for the calculation, and a justification for using the chosen case report followed by the calculation of an appropriate F value.
- Conclusion: the F values assigned to the various strengths of the drug.