A Quantitative Review of Un-licensed and Off-label Medicines Use in Children Aged 0-2 Years in the Private Sector in South Africa: Extent, Challenges, and Implications.

BACKGROUND: The global lack of suitable formulations for children leads to off-label and unlicensed medicine use, posing significant risks of adverse effects. Understanding this usage on a national level can help guide interventions for better formulations. This study aimed to measure the prevalence of off-label and unlicensed medicines among children in South Africa's private sector. METHODS: The study used a point prevalence methodology to review medicine use in children aged 0-2 years enrolled in a selected pharmaceutical benefit management company in South Africa from January to June 2022. A sample size of 1055 prescriptions was calculated using a 90% confidence interval, 50% prevalence rate, and 5% error margin. A systematic random sampling approach selected every seventh entry from 91,973 total entries, resulting in a final sample size of 13,139. Data included patient age, number and characteristics of medicines, quantity, and indications. Descriptive statistics analysed and reported the prevalence of unlicensed and off-label medicine use. RESULTS: Among the 13,139 prescribed medicines, 40% (5,246) were off-label or unlicensed, and 60% (7,893) were on-label. Of the off-label/unlicensed medicines, 16.85% (2,214) were unlicensed, and 23.08% (3,032) were off-label. Methylprednisolone was the top off-label medicine, probiotics were the top unlicensed, and the ICD10 code Z76.9 was the top diagnosis. CONCLUSION: The study found that 40% of children aged 0-2 years were prescribed unlicensed or off-label medicines in South Africa's private healthcare sector between January and June 2022. This suggests a widespread practice of off-label or unlicensed prescriptions in paediatric treatment in the South African private sector.

Access to and utilisation of antimicrobials among forcibly displaced persons in Uganda, Yemen and Colombia: a pilot cross-sectional survey.

OBJECTIVES: Identifying key barriers to accessing quality-assured and affordable antimicrobials among forcibly displaced persons in Uganda, Yemen and Colombia and investigating their (1) utilisation patterns of antibiotics, (2) knowledge about antimicrobial resistance (AMR) and (3) perception of the quality of antimicrobials received. DESIGN: Pilot cross-sectional survey. SETTING: Data were collected from five health facilities in the Kiryandongo refugee settlement (Bweyale, Uganda), three camps for internally displaced persons (IDPs) in the Dar Sad district (Aden, Yemen) and a district with a high population of Venezuelan migrants (Kennedy district, Bogotá, Colombia). Data collection took place between February and May 2021. The three countries were selected due to their high number of displaced people in their respective continents. PARTICIPANTS: South Sudanese refugees in Uganda, IDPs in Yemen and Venezuelan migrants in Colombia. OUTCOME MEASURE: The most common barriers to access to quality-assured and affordable antimicrobials. RESULTS: A total of 136 participants were enrolled in this study. Obtaining antimicrobials through informal pathways, either without a doctor's prescription or through family and friends, was common in Yemen (27/50, 54.0%) and Colombia (34/50, 68.0%). In Yemen and Uganda, respondents used antibiotics to treat (58/86, 67.4%) and prevent (39/86, 45.3%) a cold. Knowledge of AMR was generally low (24/136, 17.6%). Barriers to access included financial constraints in Colombia and Uganda, prescription requirements in Yemen and Colombia, and non-availability of drugs in Uganda and Yemen. CONCLUSION: Our multicentred research identified common barriers to accessing quality antimicrobials among refugees/IDPs/migrants and common use of informal pathways. The results suggest that knowledge gaps about AMR may lead to potential misuse of antimicrobials. Due to the study's small sample size and use of non-probability sampling, the results should be interpreted with caution, and larger-scale assessments on this topic are needed. Future interventions designed for similar humanitarian settings should consider the interlinked barriers identified.

Off-Label and Unlicenced Medicine Use among Hospitalised Children in South Africa: Practice and Policy Implications.

BACKGROUND: Information regarding off-label and unlicensed medicine use among South African children is limited. This is a concern as the prescribing of off-label and unlicensed medicines can lead to issues of effectiveness and safety as well as raise liability issues in the event of adverse events. This potentially exposes physicians to legal penalties. Consequently, we sought to determine the prevalence of off-label and unlicensed medicine use among paediatric patients in South Africa to provide future direction. METHODS: This study retrospectively examined the use of medicine in a point-prevalence survey study (PPS) involving paediatric patients aged (0-2 years) admitted to selected public hospitals in Gauteng Province, South Africa. Data were collected per hospital over two days between February 2022 and July 2022. Demographics, duration of treatment, diagnosis, and medicines prescribed were collected from patient medical records using a mobile application. Prescribed medicines were reviewed against the medicine formularies and other databases to assess their appropriateness. RESULTS: From three academic hospitals, 184 patient records were reviewed. A total of 592 medicines were dispensed, of which 379 (64.0%) were licensed and 213 (36.0%) were used off-label/unlicensed for paediatric patients 0-2 years of age. The most prevalent off-label and unlicensed medicines were multivitamins (n = 32, 15.0%) and ampicillin injections (n = 15, 7.0%). CONCLUSION: The frequency of unlicensed and off-label medicine prescribing shown in this study is consistent with the literature and can be considered high. This practice can pose a risk because it adversely affects patients if not properly regulated. Attention is needed to ensure future high-quality, safe, and effective use of medicines.

Veterinary consumption of highest priority critically important antimicrobials and various growth promoters based on import data in Pakistan.

BACKGROUND: Antimicrobial resistance (AMR) is a global public health emergency driven by the indiscriminate use of antimicrobial agents in humans and animals. Antimicrobial consumption surveillance guides its containment efforts. In this study, we estimated, for the first time, veterinary consumption of Critically Important Antimicrobials with Highest Priority (CIA-HtP) for Pakistan. METHODS: The study used an export/import database which provided imports data collected from the Pakistan Customs Authority. We investigated imports of 7 CIA-HtP and various poultry feed additives/growth promoters (FAs/GPs) identified from a survey of 10 poultry and dairy farms in Punjab province in Pakistan and a previously published study, over a three-year period of 2017-2019. Antimicrobial consumption was estimated in mg/kg of country's animal biomass. FINDINGS: Imports, in tonnes, for these 7 CIA-HtP were for the years 2017-19: tylosin 240.84, enrofloxacin 235.14, colistin 219.73, tilmicosin 97.32, spiramycin 5.79, norfloxacin 5.55, ceftiofur 1.02 for a total 805.39 tonnes. The corresponding antimicrobial consumption was 10.05 mg/kg of animal biomass. The poultry FAs/GPs contained: zinc bacitracin, enramycin, bacitracin methylene disalicylate, tylosin, tiamulin, colistin, lincomycin, streptomycin, flavophospholipol, tilmicosin, and penicillin with a total antimicrobial chemical compound (ACC) import volume of 577.18 tonnes for the years 2017-2019; and an estimated consumption of 96.53 mg/kg of poultry biomass. INTERPRETATION: These antimicrobials were a mix of macrolides, quinolones, polymyxins and cephalosporins, among which are some also on the Watch or Reserve list by the WHO, indicating the need for stewardship and to conserve essential antimicrobials to contain AMR. The finding that a yearly average of 192.39 tonnes of the ACC imported were FAs/GPs further highlight the need for stronger regulation and enforcement.

The Current States, Challenges, Ongoing Efforts, and Future Perspectives of Pharmaceutical Excipients in Pediatric Patients in Each Country and Region.

A major hurdle in pediatric formulation development is the lack of safety and toxicity data on some of the commonly used excipients. While the maximum oral safe dose for several kinds of excipients is known in the adult population, the doses in pediatric patients, including preterm neonates, are not established yet due to the lack of evidence-based data. This paper consists of four parts: (1) country-specific perspectives in different parts of the world (current state, challenges in excipients, and ongoing efforts) for ensuring the use of safe excipients, (2) comparing and contrasting the country-specific perspectives, (3) past and ongoing collaborative efforts, and (4) future perspectives on excipients for pediatric formulation. The regulatory process for pharmaceutical excipients has been developed. However, there are gaps between each region where a lack of information and an insufficient regulation process was found. Ongoing efforts include raising issues on excipient exposure, building a region-specific database, and improving excipient regulation; however, there is a lack of evidence-based information on safety for the pediatric population. More progress on clear safety limits, quantitative information on excipients of concern in the pediatric population, and international harmonization of excipients' regulatory processes for the pediatric population are required.

Evaluating the Taste Masking Ability of Two Novel Dispersible Tablet Platforms Containing Zinc Sulfate and Paracetamol Reconstituted in a Breast Milk Substitute.

Milk is often used as a dispersion medium for medicines administration in young children but its taste-masking ability is unknown. A human taste panel was conducted to assess the potential of infant formula milk (Aptamil® 1) to mask the taste of two model WHO priority medicines, zinc sulfate and paracetamol, manufactured as dispersible tablets. Simultaneously, the palatability of powder blends of the tablet platforms was assessed. Twenty healthy adult volunteers performed a swirl-and-spit assessment of placebos and API-containing blends in either a lactose-based or a mannitol-based dispersible tablet platform, reconstituted in 10 mL of either water or Aptamil® 1. Eighteen samples were rated for aversion using a 100-mm Visual Analogue Scale, grittiness using a 5-point Likert scale, and "acceptability-as-a-medicine" evaluated as: "Would you find this sample acceptable to swallow as a medicine?" with binary answers of Yes/No. The API-containing formulations were more aversive than the placebos; the paracetamol-containing samples being more aversive than zinc sulfate samples. The platforms themselves were not aversive. Non-gritty samples had four-fold greater odds of being acceptable as a medicine. Aptamil® 1 masked the taste of zinc sulfate in the mannitol-based formulation but did not mask the taste of paracetamol in either platform, suggesting a limited taste-masking ability, which may be API and formulation dependent.

Simple thin layer chromatography-ultraviolet spectrophotometric method for quality assessment of binary fixed-dose-combinations of lamivudine/tenofovir disoproxil fumarate and lamivudine/zidovudine in tablet formulations.

Antiretroviral fixed-dose-combination drugs are best assayed with high-performance liquid chromatography, or liquid chromatography-tandem mass spectrometry. However, most scientists in developing nations have no access to these expensive instruments. A more affordable quantitative technique is the use of ultraviolet-visible spectroscopy-where often the absorption spectra of these antiretrovirals are overlapping; thus complex derivative methodologies are required for quantification. A simple, rapid, and accurate thin layer chromatography-ultraviolet spectrophotometric method for the quantification of binary mixtures of lamivudine, zidovudine, and tenofovir-disoproxil-fumarate in tablet formulations was developed. Lamivudine/tenofovir-disoproxil-fumarate and lamivudine/zidovudine were extracted and separated on glass thin-layer chromatography plates. Drugs were identified in ultraviolet light at 254 nm and quantified in acidic medium using ultraviolet spectrophotometry. The retardation factors were 0.43, 0.79, and 0.81 for lamivudine, tenofovir-disoproxil-fumarate, and zidovudine, respectively, with corresponding absorption maxima at 270, 260, and 265 nm. Linearity ranged from 1 to 40 µg/mL for all drugs (R = 0.9998-0.9999), while recovery studies were 95.10-102.11% and amount in formulations ranged from 97.99 ± 0.63 to 101.47 ± 2.39%. The paired t-test (n = 5) indicated no significant difference between the proposed and high-performance liquid chromatography methods, hence comparable and can be used as an alternative method in routine quality determination of antiretroviral medicines.

Access to medicines through health systems in low- and middle-income countries.

Nearly 2 billion people globally have no access to essential medicines. This means essential medicines are unavailable, unaffordable, inaccessible, unacceptable or of low quality for more than a quarter of the population worldwide. This supplement demonstrates the implications of poor medicine access and highlights recent innovations to improve access to essential medicines by presenting new research findings from low- and middle-income countries (LMICs). These studies answer key questions such as: Can performance-based financing improve availability of essential medicines? How affordable are cardiovascular treatments for children? Which countries' legal frameworks promote universal access to medicines? How appropriately are people using medicines? Do poor-quality medicines impact equity? Answers to these questions are important as essential medicines are vital to the Sustainable Development Goals and are central to the goal of achieving Universal Health Coverage. Access to affordable, quality-assured essential medicines is crucial to reducing the financial burden of care, preventing greater pain and suffering, shortening the duration of illness, and averting needless disabilities and deaths worldwide. This supplement was organized by the Medicines in Health Systems Thematic Working Group of Health Systems Global, a membership organization dedicated to promoting health systems research and knowledge translation. The five studies in the supplement further our understanding by showcasing recent successes and challenges of improving access to quality-assured medicines through health systems in LMICs.

Drug and therapeutics committees in Nigeria: evaluation of scope and functionality.

Introduction: Inappropriate use of medicines remains a problem, with consequences including increasing adverse drug reactions (ADRs) and prolonged hospitalizations. The Essential Medicines List and Drug and Therapeutics Committees (DTCs) are accepted initiatives to promote the rational use of medicines. However, little is known about DTC activities in Nigeria, the most populous African country. Areas covered: A cross-sectional questionnaire-based study was conducted among senior pharmacists, consultant physicians, and clinical pharmacologists in 12 leading tertiary health-care facilities across Nigeria. Expert commentary: Six (50%, 6/12) health-care facilities had existing DTCs with three (50%) having a subcommittee on antimicrobials. Seventy-five percent had infection control committees, with presence even in centers without DTCs. Chairpersons and secretaries of the DTCs were predominantly physicians (83.3%) and pharmacists (100%), respectively. Hospital formularies were available in five facilities with DTCs, while one facility without a DTC had an Essential Medicines Committee responsible for developing and updating the hospital formulary. The evaluation of ADRs was undertaken by pharmacovigilance units in nine facilities. Overall, DTCs were present in only half of the surveyed facilities and most were performing their statutory functions sub-optimally. The functioning of DTCs can be improved through government directives and mechanisms for continuous evaluation of activities.

A survey of caregivers of Nigerian children less than 6 years of age to determine the experience and perception of acceptability of oral solid dosage forms.

OBJECTIVES: The World Health Organization (WHO) recommends flexible solid oral dosage forms such as dispersible tablet as the preferred formulation for (young) children, especially in developing/low- and middle-income countries, LMIC. The aim of this study was to assess experience, perceptions of acceptability, and formulation preferences, among 10 oral dosage forms for young children in a sample of end-users in Nigeria as an exemplar LMIC. METHODS: Using a semi-structured and validated questionnaire, 148 caregivers were surveyed. Acceptability was assessed by level of liking using a 3-point Likert scale and ease of administration. Preference was assessed from participants' dosage form of choice. Oral dosage forms assessed were those mentioned in the British National Formulary for children, 2013. RESULTS: The formulation perceived as the most acceptable was the chewable/suckable tablet. However, preference was for liquids. Specifically with the dispersible tablet, whilst 89% (n=111) of caregivers of young children found it easy-to-administer, only 50% of children liked it. CONCLUSION: There is a gap between the proposal of dispersible tablet as the preferred dosage form for young children and caregivers' perceptions of acceptability and preference. Educational strategies to increase acceptability of dispersible tablets as the preferred formulation for young children would be required.

Off-label prescribing for children with chronic diseases in Nigeria; findings and implications.

BACKGROUND: Prescribing medicines in an off-label manner for children with chronic conditions is sparsely documented, even more so among developing countries. This needs addressing. The objective of this research was to investigate the extent of off-label prescribing among children with epilepsy, asthma, and sickle cell anaemia in Nigeria. METHODS: Prescriptions for children ≤16 years documented in their case files that attended paediatric clinics in Lagos, Nigeria, for these three conditions between January and October 2015, were reviewed retrospectively to extract data on the medicines prescribed. British National Formulary for children and American Hospital Formulary Service Drug information were used as references. RESULTS: 477 patients received 1746 prescriptions. Off-label prescriptions were seen in 7.7% of prescriptions, related to dose (93; 68.9%), indication (22; 16.3%), and age (20; 14.8%). Nervous system (525; 30.1%) and anti-infective (441; 25.2%) medicines were the most prescribed but only 9.5% and 8.2% of the respective prescriptions were off-label. Children with epilepsy received the most number (94; 69.6%) of off-label prescriptions. The three chronic conditions did not associate significantly with the category of off-label medicine prescribed (p = 0.925). CONCLUSION: Off-label prescribing for children with epilepsy, asthma and sickle cell anaemia occurs. Encouragingly, the overall rate appears low in Nigeria.

The Milky Way: paediatric milk-based dispersible tablets prepared by direct compression - a proof-of-concept study.

OBJECTIVES: Dispersible tablets are proposed by the World Health Organization as the preferred paediatric formulation. It was hypothesised that tablets made from a powdered milk-base that disperse in water to form suspensions resembling milk might be a useful platform to improve acceptability in children. METHODS: Milk-based dispersible tablets containing various types of powdered milk and infant formulae were formulated. The influence of milk type and content on placebo tablet properties was investigated using a design-of-experiments approach. Responses measured included friability, crushing strength and disintegration time. Additionally, the influence of compression force on the tablet properties of a model formulation was studied by compaction simulation. KEY FINDINGS: Disintegration times increased as milk content increased. Compaction simulation studies showed that compression force influenced disintegration time. These results suggest that the milk content, rather than type, and compression force were the most important determinants of disintegration. CONCLUSION: Up to 30% milk could be incorporated to produce 200 mg 10-mm flat-faced placebo tablets by direct compression disintegrating within 3 min in 5-10 ml of water, which is a realistic administration volume in children. The platform could accommodate 30% of a model active pharmaceutical ingredient (caffeine citrate).

Potential drug-drug interactions in paediatric outpatient prescriptions in Nigeria and implications for the future.

BACKGROUND: Information regarding the incidence of drug-drug interactions (DDIs) and adverse drug events (ADEs) among paediatric patients in Nigeria is limited. METHODS: Prospective clinical audit among paediatric outpatients in four general hospitals in Nigeria over a 3-month period. Details of ADEs documented in case files was extracted. RESULTS: Among 1233 eligible patients, 208 (16.9%) received prescriptions with at least one potential DDI. Seven drug classes were implicated with antimalarial combination therapies predominating. Exposure mostly to a single potential DDI, commonly involved promethazine, artemether/lumefantrine, ciprofloxacin and artemether/lumefantrine. Exposure mostly to major and serious, and moderate and clinically significant, potential DDIs. Overall exposure similar across all age groups and across genders. A significant association was seen between severity of potential DDIs and age. Only 48 (23.1%) of these patients presented at follow-up clinics with only 15 reporting ADEs. CONCLUSION: There was exposure to potential DDIs in this population. However, potential DDIs were associated with only a few reported ADEs.