Archive \ Volume.11 2020 Issue 3

DISCUSSION

Unlicensed and off-label utilization

The accessibility of oral pediatric formulations is generally absent in low and middle-income countries, for instance, because of illness burden and financial limitations, as well as disconnected supply chains and uneven healthcare systems. The nonexistence of authorized pediatric medicines repeatedly leads to the administration and manipulation of products intended for adults, with an enhanced risk of mis-dosing and difficulty to administration ^[19]. Based on our knowledge, this is the first investigation which aimed to define characteristics of unlicensed and off-label utilization in children in Vietnam, its correlated factors, and its influences.

The prevalence of unlicensed and off-label utilization of drugs in the investigated population was 17.8% and 28.1%, respectively. A systematic review of Gore et al. in 2017 revealed that many investigations noted high rates of unlicensed (0.3% to 35%) and off-label (9% to 78.7%) drug utilization in different pediatric patient settings in fourteen research from different countries ^[8]. Nevertheless, the off-label and unlicensed classification techniques varied, making the findings difficult to compare but providing an overall picture of the problem ^[20].

Concerning unlicensed drug utilization, the only reason was the inaccessibility of pediatric oral formulations (17.8%). In our investigation, at least 57 drug products were considered unlicensed because nurses or parents had to compound a formulation suitable for children. This rate is comparable one in a study of the 17.668 prescriptions of medicines intended for oral utilization in children under six years old found that 15.1% were unsuitable pharmaceutical forms ^[11]. Prescribing practices also vary between countries. Many preparations in Netherlands hospitals are prepared from commercial presentations. This finding in a greater number of unlicensed medicine prescriptions, range from 28% to 42% ^{[7, 21]}. However, only a limited number of pharmacy preparations were issued in Vietnamese hospitals. Many capsules were opened and mixed with patients’ food. Some were not capable to swallow tablets and needed conversion of pharmaceutical products into proper forms for children by crushing, dissolving, and dividing. These raised issues of bioavailability, the accuracy of the dose administered, and stability. Unpackaging and repackaging these medicines also enhances the risk of medication errors ^[22].

Unlike other studies in other countries, there was no case which required using an unmarketed drug in our study. Vietnamese hospitals don’t have a clear policy to resolve a drug shortage or unlicensed drug use, which make physicians not to be confident to prescribe the unlicensed drug in the patient’s medical records. In some situations, physicians prescribed in a separate prescription form and asked patients to buy by themselves and did not document in the patient records.

The assessment of off-label drug administration rates is more complex than that of unlicensed drug administration rates. First, it necessitates a medical chart review to recognize indications for drug prescription. Second, the classification of a drug prescription as on- or off-label will be dependent on the gold standards designated for comparison (e.g., scientific databases, drug monographs, books) ^[15]. Our investigation indicated that 28.1% of all drug prescriptions inspected were off-label and were unapproved for the age group (15.9%) and dosage (12.2%). Unlike these earlier investigations, our findings demonstrate that there were no off-label prescriptions correlated with unproved indication and route of administration. Corny et al. in Canada reported that there were unapproved drugs for the age group (53.2%), dosage (27.6%), frequency (25.2%), administration route (5.6%), and indication (5.5%) ^[15]. The research of Santos et al. in Brazil reported that dose/frequency was the most frequent method of off-label drug administration ^[9].

Paracetamol was the most frequently prescribed unlicensed/off-label drug. In the research of Corny et al., the most frequent off-label drug prescriptions were paracetamol, dimenhydrinate, and morphine sulfate ^[15]. Delmas et al. revealed that the proportion of off-label prescriptions by ATC class was maximum in the cardiovascular system (77.2%).

Predictors for receiving at least one unlicensed and off-label utilization

Numerous investigations determined predictors for receiving off-label and unlicensed administration. Research in the Netherlands indicated that the percentage of patients utilized one or more unlicensed or off-label prescriptions was meaningfully greater in children below six months of age than in older children ^[21]. Another investigation in Malaysia noted that children aged 28 days to 23 months, preterm infants, patients with hospital stays of more than 2 weeks, and those prescribed increasing numbers of medicines were more probable to get medicines for unlicensed administration. Term neonates and patients prescribed increasing numbers of medicines had improved the risk of receiving medicines for off-label utilization ^[23].

Our study determined that predictors were age (<2 years), number of oral drugs per patient (> 3 drugs), and oral dosage forms (liquid) for off-label regimen; and was oral dosage forms (solid) for the unlicensed prescription (p < 0.05).

The oral route of administration is the favored route for patients of all ages owing to ease and stability. Drugs given orally include liquid dosage methods (such as suspensions, syrups, solutions, and emulsions) as well as solid dosage methods (such as tablets and capsules). Oral liquid drops can deliver small and flexible volumes or low doses of a drug to children with the utilization of suitable measuring devices (such as oral syringes, graduated pipettes, or measuring spoons). Conventional tablets are restricted by their rigid dose content and the capability of the child to swallow a tablet ^[24]. Our study found that 53 (51.0%) drug prescriptions had difficulty in the accurate dose preparation and 109 (34.1%) drug prescriptions had difficulty in completely taking drugs orally. Boztepe et al. indicated that the most regularly reported issues in the preparation of drugs were the incomplete dissolution of tablets or non-homogeneous distribution in fluids (54.6%) and difficulty in breaking tablets in proper doses (45.3%), and the most regularly reported issue during the administration of drugs was the rejection of drugs which tasted bad by babies/children or spitting out the drug (75.9%) ^[13]. Results from our study found that off-label use was prone to having difficulty in dosing and unlicensed use was highly likely to have difficulty taking the drug orally. Other investigations also indicated that unlicensed/off-label drug utilization was significantly correlated with medication errors ^[22] and adverse drug reactions ^[9].

A study limitation that needs to be considered when interpreting findings is the study conducted in one pediatric department with a modest sample size (104 patients and 320 drug prescriptions).

CONCLUSIONS

A high rate of unlicensed/off-label drug utilization was revealed and was also correlated with an increased risk of having difficulty in dose preparations and administrations. More efforts should be required to enhance rational drug utilization in children.

Key Messages: A high rate of unlicensed/off-label drug utilization was revealed and was also correlated with an enhanced risk of having difficulty in dose preparations and administrations

Declarations

ACKNOWLEDGMENTS

The authors wish to thank physicians and nurses in a pediatric department and parents of pediatric patients for cooperation in this study.

Conflicts of Interest

All authors declared that there were no conflicts of interest concerning this work.

Funding

There is no funding for this project.

Ethics approval and consent to participate:

The research protocol was approved by a university academic committee (H2018/064).

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