Int J Clin Pharm DOI 10.1007/s11096-014-0049-0
RESEARCH ARTICLE
Respiratory drugs prescribed off-label among children in the outpatient clinics of a hospital in Malaysia Nurul Fadilah Mohamad • Adliah Mhd Ali Noraida Mohamed Shah
•
Received: 17 February 2014 / Accepted: 1 December 2014 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2014
Abstract Background Prescribing medicines in an unlicensed and off-label manner for children is a widespread practice around the world. Objectives To determine the extent and predictors of off-label respiratory drug prescriptions for children in the outpatient clinics of a hospital in Malaysia. Setting Outpatient clinics at the Universiti Kebangsaan Malaysia Medical Centre, a tertiary teaching hospital in Malaysia. Methods The pharmacy-based computer system and medical records of the patients were utilized to collect data from 220 pediatric patients who were prescribed at least one respiratory drug from July 2011 to December 2011. Main outcome measure Characteristics of the off-label respiratory drug prescriptions were measured. Results A total of 134 children (60.9 %) received at least one respiratory drug prescribed in an offlabel manner. The most common reasons for the off-label prescribing of drugs were off-label use by indication (31.5 %), followed by higher than the recommended dose (24.9 %) and lower than the recommended frequency (17.1 %). Diphenhydramine was the most common respiratory drug prescribed off-label. The number of medications prescribed was the only significant predictor of offlabel prescription of respiratory drugs. Pediatric patients receiving 4–6 medications were 7.8 times more likely to receive at least one off-label respiratory drug compared to pediatric patients that received 1–3 medications (OR 7.8, 95 % CI 1.74–37.44). Conclusion There was substantial prescribing of respiratory drugs for children in an off-label manner at the outpatient clinics at the Universiti Kebangsaan Malaysia Medical Centre. This highlights the N. F. Mohamad A. Mhd Ali N. Mohamed Shah (&) Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia e-mail: [email protected]
need for more research to be carried out on respiratory drugs in the pediatric population. Keywords Children Malaysia Off-label Outpatient Pediatrics Respiratory drugs
Impacts of findings on practice statements •
•
•
The most common off-label respiratory drugs prescribed to children at the outpatient setting in a Malaysian hospital are antiasthmatics, followed by cough and cold medications. Children who received 4–6 medications during a visit to the outpatient department are more likely to receive at least one off-label respiratory drug compared to those who receive less medications. There is an urgent need for well-designed research to be carried out on commonly prescribed off-label respiratory drugs, to ensure their safety and efficacy for use in children.
Introduction The purpose of drug licensing is to ensure that medicines are examined for safety, efficacy, and quality [1]. For a drug to be used, it must have a product license. In the UK, a Marketing Authorisation (MA) is issued by the European Medicines Agency (EMA) or the Medicines Health and Regulatory Agency (MHRA). Without a MA, the medicines are not licensed. On the other hand, the use of licensed medicines outside the terms of their MA is referred to as the off-label use of medicines [1]. In Malaysia, under the Control of Drugs and Cosmetics
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Regulations (CDCR) 1984, R7 (1) (a), no person shall manufacture, sell, supply, import, possess, or administer any product unless the product is a registered product [2]. The Drug Control Authority (DCA) was established under the CDCR 1984, to ensure the safety, quality, and efficacy of pharmaceuticals, health, and personal care products that are marketed in Malaysia. This is achieved through the registration of pharmaceutical products and cosmetics; licensing of premises for the importer, manufacturer, and wholesaler; monitoring the quality of registered products in the market; and monitoring adverse drug reactions [3]. Pharmaceutical companies then need to register their pharmaceutical products with the DCA, together with the submission of the preclinical and clinical trial results, information on the dose, dosage form, indication, route of administration, and target group for which the drug is intended [2, 3]. Most medicines administered to adults have a product license that outlines the particular indication, dose, and route of administration for a drug. However, most of the drugs used to treat children in hospitals are either not licensed for use in children or are used off-label. Therefore, the risks or benefits of using these drugs in children have not been examined by the licensing authority [1]. The main reason for the common use of unlicensed and off-label drugs in children is that children are excluded from clinical trials during the drug development process. Physicians face a dilemma when prescribing medicines for use in children due to the lack of detailed information available. Consequently, children may receive drugs in unapproved dosages that lack efficacy or have safety issues [4]. This alarming lack of research with respect to medication for children was pointed out by the regulatory bodies in the United States (US) Congress, and in 1997, this resulted in the implementation of incentives for pharmaceutical companies to develop pediatric medicines [5]. This is known as the Pediatric Exclusivity Program (Food and Drug Administration Modernization Act, 1997). Advances in the US prompted the European Union (EU) to develop the Paediatric Regulation in 2006, which was enacted on 26 January 2007 [(EC) No. 1901/2006] [6, 7]. The objective of this act was to facilitate the development and availability of medicines for children aged 0–17 years in Europe, and in so doing, ultimately improve their health [5]. It is reported that 30 % of the prescribed drugs for children are for the respiratory system. Furthermore, respiratory and allergy medicines are one of the most common types of drugs prescribed off-label for children. However, research on the safety and efficacy of these drugs with children is still lacking [8]. Baiardi et al. [9] reported that a significant percentage of the medicines used for
123
pediatric respiratory diseases in Italy were prescribed offlabel. The evidence available for the use of medicines in children with respiratory diseases has been reviewed by the European Respiratory Society task force which highlighted the gaps and research priorities in this area [10]. The present study was carried out to help understand the extent of off-label prescribing of respiratory drugs, which is one of the commonly prescribed groups of drugs in children. Identification of the respiratory drugs and the reasons for the off-label use would be useful in directing further research in this area.
Aim of the study The present study was conducted to determine the extent of unlicensed and off-label prescription of respiratory drugs in the outpatient clinics at Universiti Kebangsaan Malaysia Medical Centre (UKMMC), and to determine the possible predictors of off-label prescriptions.
Ethical approval This study was approved by the Research Ethics Committee of the UKMMC (UKM 1.5.3.5/244/NF-024-2012).
Methods Sampling Prescription data from the pharmacy-based computer system were screened to obtain the names and registration numbers of all the pediatric outpatients in the UKMMC that were prescribed respiratory drugs from July 2011 to December 2011. Consequently, the name lists were filled into the respective request form and sent to the medical records department at the UKMMC in order to obtain the patients’ medical records. Respiratory drugs included all drugs classified under the section for the respiratory system in the UKMMC formulary [12]. These include antiasthmatics (bronchodilators, corticosteroids, cromoglycate, and other related therapy), pulmonary surfactant, antihistamines and antiallergics, and cough and cold remedies [Ammonia & Ipecacuanha Sugar Free BP (Mixt. Expectorant Stimulant), Bromhexine Hydrochloride (BisolvonG), Diphenhydramine Expectorant (Bena-G), Diphenhydramine Expectorant Pediatric (Benadryl 1:2-G), Pholcodine Linctus Sugar Free (Duro-Tuss Regular)]. Children aged B18 years who were prescribed at least one respiratory drug listed in the UKMMC formulary [12] from July 2011 to December 2011 at the outpatient clinics at the
Int J Clin Pharm
UKMMC were included in this study. Antibiotics used to treat the respiratory system were not included. Patients who were prescribed a respiratory drug for a licensed indication other than for the respiratory system were excluded.
Requirements for Registration of Pharmaceuticals for Human Use, Clinical Investigation of Medicinal Products in the Pediatric Population (E11) [14]. Statistical analysis
Data collection Patient data were collected from the patients’ medical records and transferred into the data collection form. The data that was collected included demographic data (sex, ethnicity, age, body weight, and height), diagnosis, the number of medications prescribed and the complete regimen for each of the respiratory drugs prescribed (dose, frequency, indication, route of administration, and formulation). Study methods The licensing status for each respiratory drug prescribed to each patient was evaluated using the database provided by the National Pharmaceutical Control Bureau (NPCB), Ministry of Health Malaysia (MOH). The database consists of a list of drugs registered with the licensing authority (the DCA, MOH) and is available online and known as the Quest 2 and Quest 3 product searches. Both the Quest 2 and Quest 3 product searches were used to check for the licensing status of each drug on the website [3]. The offlabel status of the drugs was checked using the Master Index of Medical Specialty (MIMS), Malaysia, which is available online [13]. If the information about the prescription of a particular product could not be obtained, the product information leaflet was referred to, which was obtained from the Drug Information Service at the UKMMC. A medicine was classified as an off-label prescription for any of the following reasons: (1) contraindicated in children of all age ranges, (2) off-label use by indication, (3) off-label use by age, (4) off-label use by route of administration, (5) lower than the licensed dose, (6) higher than the licensed dose, (7) lower than the licensed frequency, and (8) higher than the licensed frequency. These categories of off-label use were adapted from the definition of off-label use by Turner et al. [1]. If there was more than one category for the off-label drug prescription, the offlabel status was prioritized based on the above list of reasons. Parameters that were evaluated as possible predictors of off-label drug prescription included age, ethnicity, sex, and number of medications prescribed to the patients. Patients’ ages were classified into three groups: newborns and infants (\2 years), children (2–11 years), and adolescents (12–18 years). These were age groups modified from the International Conference of Harmonization of Technical
Microsoft Excel 2010 (Microsoft Corporation, USA) was used for the descriptive analysis of the data. Statistical software (SPSS Version 20.0, IBM, Armonk, NY, USA) was utilized for conducting the binary logistic regression and descriptive analyses.
Results Demographic data of pediatric patients in outpatient clinics at the UKMMC Data from a total of 220 pediatric patients were collected in this study. The demographic data of the study subjects are presented in Table 1. From the participants, 125 (56.8 %) children were males. The majority of the patients were Malay (75.9 %). The age range was from 1 month to 17 years with a mean (SD) age of 6.81 (3.92) years. The most commonly prescribed respiratory drug was salbutamol (29.3 %). Unlicensed and off-label prescription of respiratory drugs for children at outpatient clinics at the UKMMC A total of 508 prescription items for respiratory drugs were issued to 220 patients. Approximately 181 (35.6 %) of the Table 1 Demographic data of the study subjects Characteristics
n (%)
Gender Male
125 (56.8 %)
Female
95 (43.2 %)
Ethnicity Malay
167 (75.9 %)
Chinese
30 (13.6 %)
Indian
15 (6.8 %)
Others
8 (3.6 %)
Age (years; mean ± SD)
6.81 ± 3.92
ICH age category (modified) Newborns and infants (\2 years)
14 (6.4 %)
Children (2–11 years)
177 (80.5 %)
Adolescents (12–18 years)
29 (13.2 %)
Number of prescribed medicines 1–3 4–6
199 (90.5 %) 21 (9.5 %)
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Percentage of drugs prescribed (%)
50 40 31.5 30
24.9
20
17.1
14.9 8.3
10
0
0
0
22.1
20 16.0
15 10
12.2 7.7
7.2
7.2
5 0
Top six respiratory drugs prescribed off-label
Fig. 2 Top six respiratory drugs prescribed off-label by percentage
standard error associated with the coefficient (SE) 0.77]. There were no other significant predictors of off-label respiratory drug prescription.
Discussion Extent of unlicensed or off-label prescriptions In this study, the percentage of prescription items (n = 508) prescribed in an off-label manner was 35.6 %, which was comparable to previous studies that reported rates of prescribing off-label medicines for children ranging from 11 to 60 % [15, 16]. There was no unlicensed medicine prescription recorded in this study. This could be because most of the respiratory drugs are available in different formulations, including liquid form, and do not require modifications from the original licensed product (e.g. crushed tablets formulated into a suspension). Previous studies also found that medicines for children prescribed in an off-label manner were higher than unlicensed medicine prescriptions [11, 15, 16]. Study settings, therapeutic area, and age ranges may result in the different percentages of unlicensed and off-label drugs used for pediatric patients from different studies. These factors may affect the percentage or extent of unlicensed and off-label prescriptions and need to be taken into account when making comparisons.
3.3
Categories of off-label respiratory drug prescription items
Fig. 1 Percentages of respiratory drugs prescribed by off-label categories
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25
Percentage prescribed off-label (%)
total prescription items were used in an off-label manner. A total of 134 patients (60.9 %) received at least one respiratory drug prescribed in an off-label manner. According to the pre-determined age groups, children (2–11 years; 76.1 %) received the most off-label drug prescriptions, followed by adolescents (12–18 years; 13.4 %) and newborns and infants (\2 years; 10.5 %). None of the subjects recruited in this study were prescribed an unlicensed respiratory drug. The main reasons for the off-label prescriptions of respiratory drugs were off-label use by indication (31.5 %), followed by higher than the recommended dose (24.9 %) and lower than the licensed frequency (17.1 %). None of the respiratory drugs were prescribed off-label due to contraindicated use in children or off-label use by route of administration (Fig. 1). Antiasthmatics were the most frequent respiratory drugs prescribed in an off-label manner (45.3 %), followed by cough and cold medications (29.3 %) and antihistamines/ antiallergics (25.4 %). Diphenhydramine (22.1 %) was the most common respiratory drug prescribed off-label, followed by budesonide (16.0 %) and loratadine (12.2 %; Fig. 2). Diphenhydramine was prescribed off-label due to higher than the licensed dose whereas budesonide had been prescribed at lower than the licensed frequency. Off-label use by indication was the main reason for off-label prescribing of loratadine. The number of medications prescribed was the only significant predictor of off-label respiratory drug prescription to children (p = 0.007). Those receiving 4–6 medications during the outpatient visits were 7.8 times more likely to receive an off-label respiratory drug prescription compared to children that received 1–3 medications [OR 7.8, 95 % CI 1.74–37.44; regression coefficient (B) 2.06;
Off-label categories of prescriptions The most common category of off-label prescriptions in the present study was off-label use by indication, followed by higher than the recommended licensed dose, and lower than the licensed frequency. A study by ‘t Jong et al. [11] on the unlicensed and off-label prescriptions of respiratory drugs to children at an outpatient setting in the Netherlands reported that prescribing medicines outside
Int J Clin Pharm
the licensed dose was the main reason for off-label prescriptions (7.8 %), followed by outside the licensed age, and indication (7.3 and 4.5 %, respectively). Another study conducted in a general ward in Brazil found that the most frequent reason for off-label prescription of medicines to children was the inconsistency with dose/frequency (17.7 %), followed by reasons related to age/ weight (7.9 %) [17]. In the present study, 14.9 % of the drugs were prescribed to children because of off-label use by age. For example, the metered dose inhaler (MDI) fluticasone plus salmeterol (25/125) 1 puff daily has been prescribed to one-year-old children, even though there is no information or data available on the use of this product in children under 4 years of age. Such prescribing practices may put these children at a high risk of experiencing the adverse effects of the drug, since there is no established study to support the use of the drug in children younger than 4 years of age. Many studies have shown that there is an increased risk of adverse drug reactions related to the use of off-label medicines in children [18–20]. The current study showed that the most commonly prescribed off-label respiratory drugs were antiasthmatics followed by cough and cold medications. According to ‘t Jong et al. (2004), off-label drug use was especially high for antiasthmatic drugs (39 %) and cough and cold medications (30 %). Antiasthmatic drugs were frequently prescribed off-label due to dose (14 %), and/or indication (10 %), or age/weight (15 %), and cough and cold medications were mostly prescribed off-label due to dose (19 %) [11]. A study by Conroy et al. [16] found that the majority of antiasthmatics prescribed off-label were due to prescribing at higher than the licensed doses for inhaled steroid preparations and lower than the licensed doses for inhaled sodium cromoglycate. In contrast, the present study identified antiasthmatics such as budesonide, which were commonly prescribed off-label due to lower than the recommended frequency. For example, the dose of 200 lg should be given in two to four divided doses (twice or four times daily) [13]. However, this drug was prescribed only once a day. Loratadine and chlorpheniramine are antihistamines used to relieve symptoms associated with allergic rhinitis [13]. In the present study, the most common reason for offlabel use of both drugs was the off-label use by indication, in which they were prescribed to the patients despite patients not experiencing any signs or symptoms of allergic rhinitis. Predictors of off-label respiratory drug prescriptions In the present study, the number of medications that patients received was the only predictor significantly
associated with off-label respiratory drug prescriptions. This result was similar to that of a previous study conducted in an outpatient setting in the US, which found that children who received more than one drug were significantly more likely to receive off-label prescriptions (26–39 % increased probability depending on the number of medications received; p \ 0.001) [21]. This study also did not find any significant differences with respect to predictors such as ethnicity, sex, and age group. This may be because respiratory drug prescriptions are not made based on considerations of ethnicity and sex, as the dose will depend only on the age and weight/body surface area of the pediatric patient. This finding was also similar to the findings of a previous study, where no significant difference was found in the incidence of unlicensed or off-label prescriptions between different age groups [16]. However, another published study found that the visits by children aged\1, 1 to\2, 2 to\6, and 6–12 years had an adjusted probability of 74, 67, 65, and 59 % respectively, of receiving at least one prescription that was not FDA-approved for their age or diagnosis at outpatient visits [21]. According to Giacoia et al. [22], younger children, mostly those below 2 years of age, were more likely to receive medicines prescribed off-label because few medications are tested or approved for this age group, giving physicians very limited choices of medications that were approved for young children. Study limitations The sample size in the present study was relatively small, which may have resulted in the reduced number of predictors that may potentially influence the off-label drug prescriptions for children at the UKMMC. Another limitation is that this study focused only on respiratory drugs and not all medicines. Therefore, it was difficult to compare the results of this study with those of other studies, in which different types of drug classes were also investigated for their off-label status. The present study does not reflect the practice of prescribing off-label medicines to children at other clinics or hospitals in Malaysia as it was conducted specifically at the UKMMC. Therefore, the results of this study need to be generalized to the population with caution.
Conclusion In conclusion, this study highlighted the need to conduct further research on the use of medicines in the pediatric population. Such studies may lead to an increase in information that is crucial for safe and effective drug prescriptions for children, and consequently, a decrease in our reliance on adult clinical data.
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Int J Clin Pharm Acknowledgments Special thanks to the pharmacy staff at the UKMMC for access to the pharmacy’s computerized dispensing database. The authors would also like to thank the hospital medical records staff for their help in retrieving the medical records. Funding
No funding was received for this research study.
Conflicts of interest
There are no conflicts of interest to declare.
References 1. Turner S, Nunn A, Choonara I. Unlicensed drug use in children in the UK. Paediatr Perinat Drug Ther. 1997;1:52–5. 2. Drug Control Authority. Terms of Reference. National Pharmaceutical Control Bureau: Ministry of Health Malaysia. 1984. 3. National Pharmaceutical Control Bureau, (NPCB) Ministry of Health Malaysia. [cited 1 Nov 2012]; Available from http://por tal.bpfk.gov.my/index.cfm?&menuid=47. 4. Mason J, Pirmohamed M, Nunn T. Off-label and unlicensed medicine use and adverse drug reactions in children: a narrative review of the literature. Eur J Clin Pharmacol. 2012;68:21–8. 5. Rocchi F, Paolucci P, Ceci A, Rossi P. The European paediatric legislation: benefits and perspectives. Ital J Pediatr. 2010;36:56. 6. European Commission. EU pharmaceutical legislation 2006. [cited 20 Oct 2014]; Available from http://ec.europa.eu/health/ files/eudralex/vol-1/reg_2006_1901/reg_2006_1901_en.pdf. 7. Kemper EM, Merkus M, Wierenga PC, Van Rijn PC, Van der Werff D, Lie-A-Huen L, Offringa M. Towards evidence-based pharmacotherapy in children. Paediatr Anaesth. 2011;21:183–9. 8. Silva D, Ansotegui I, Morais-Almeida M. Off-label prescribing for allergic diseases in children. World Allergy Organ J. 2014;7:4. 9. Baiardi P, Ceci A, Felisi M, Cantarutti L, Girotto S, Sturkenboom M, Baraldi E. In-label and off-label use of respiratory drugs in the Italian paediatric population. Acta Paediatr. 2010;99:544–9. 10. Smyth AR, Barbato A, Beydon N, Bisgaard H, de Boeck K, Brand P, et al. Respiratory medicines for children: current evidence, unlicensed use and research priorities. Eur Respir J. 2010;35:247–65.
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11. ‘t Jong GW, Eland IA, Sturkenboom MC, van den Anker JN, Strickerf BH. Unlicensed and off-label prescription of respiratory drugs to children. Eur Respir J. 2004;23:310–3. 12. Drug Formulary, 5th ed. Pharmacy Department, Pusat Perubatan Universiti Kebangsaan Malaysia; 2010. 13. Master Index of Medical Specialties (MIMS) Malaysia. [cited 12 Nov 2012]; Available from http://www.mims.com. 14. ICH Expert Working Group. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use: ICH Harmonized Tripartite Guidelines, Clinical Investigation of Medicinal Products in the Pediatric Population (E11). 2000. [cited 20 Oct 2014]; Available from http://www.ich.org. 15. Chalumeau M, Tre´luyer JM, Salanave B, Assathiany R, Che´ron G, Crocheton N, et al. Off label and unlicensed drug use among French office based paediatricians. Arch Dis Child. 2000;83:502–5. 16. Conroy S, Choonara I, Impicciatore P, Mohn A, Arnell H, Rane A, et al. Survey of unlicensed and off-label drug use in paediatric wards in European countries. BMJ. 2000;320:79–82. 17. Santos DB, Clavenna A, Bonati M, Coelho HLL. Off-label and unlicensed drug utilization in hospitalized children in Fortazela, Brazil. Eur J Clin Pharmacol. 2008;64:1111–8. 18. Horen B, Montastruc JL, Lapeyre-Mestre M. Adverse drug reactions and off-label drug use in paediatric outpatients. Br J Clin Pharmacol. 2002;54:665–70. 19. Impicciatore P, Mohn A, Chiarelli F, Pandolfini C, Bonati M. Adverse drug reactions to off-label drugs on a paediatric ward: an Italian prospective pilot study. Paediatr Perinat Drug Ther. 2002;5:19–24. 20. Turner S, Nunn AJ, Fielding K, Choonara I. Adverse drug reactions to unlicensed and off-label drugs on paediatric wards: a prospective study. Acta Paediatr. 1999;88:965–8. 21. Bazzano AT, Mangione-Smith R, Schonlau M, Suttorp MJ, Brook RH. Off-label prescribing to children in the United States outpatient setting. Acad Pediatr. 2009;9:81–8. 22. Giacoia G, Birenbaum D, Sachs H, Mattison D. The newborn drug development initiative. Pediatrics. 2006;117:S1–8.
RESEARCH ARTICLE
Respiratory drugs prescribed off-label among children in the outpatient clinics of a hospital in Malaysia Nurul Fadilah Mohamad • Adliah Mhd Ali Noraida Mohamed Shah
•
Received: 17 February 2014 / Accepted: 1 December 2014 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2014
Abstract Background Prescribing medicines in an unlicensed and off-label manner for children is a widespread practice around the world. Objectives To determine the extent and predictors of off-label respiratory drug prescriptions for children in the outpatient clinics of a hospital in Malaysia. Setting Outpatient clinics at the Universiti Kebangsaan Malaysia Medical Centre, a tertiary teaching hospital in Malaysia. Methods The pharmacy-based computer system and medical records of the patients were utilized to collect data from 220 pediatric patients who were prescribed at least one respiratory drug from July 2011 to December 2011. Main outcome measure Characteristics of the off-label respiratory drug prescriptions were measured. Results A total of 134 children (60.9 %) received at least one respiratory drug prescribed in an offlabel manner. The most common reasons for the off-label prescribing of drugs were off-label use by indication (31.5 %), followed by higher than the recommended dose (24.9 %) and lower than the recommended frequency (17.1 %). Diphenhydramine was the most common respiratory drug prescribed off-label. The number of medications prescribed was the only significant predictor of offlabel prescription of respiratory drugs. Pediatric patients receiving 4–6 medications were 7.8 times more likely to receive at least one off-label respiratory drug compared to pediatric patients that received 1–3 medications (OR 7.8, 95 % CI 1.74–37.44). Conclusion There was substantial prescribing of respiratory drugs for children in an off-label manner at the outpatient clinics at the Universiti Kebangsaan Malaysia Medical Centre. This highlights the N. F. Mohamad A. Mhd Ali N. Mohamed Shah (&) Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia e-mail: [email protected]
need for more research to be carried out on respiratory drugs in the pediatric population. Keywords Children Malaysia Off-label Outpatient Pediatrics Respiratory drugs
Impacts of findings on practice statements •
•
•
The most common off-label respiratory drugs prescribed to children at the outpatient setting in a Malaysian hospital are antiasthmatics, followed by cough and cold medications. Children who received 4–6 medications during a visit to the outpatient department are more likely to receive at least one off-label respiratory drug compared to those who receive less medications. There is an urgent need for well-designed research to be carried out on commonly prescribed off-label respiratory drugs, to ensure their safety and efficacy for use in children.
Introduction The purpose of drug licensing is to ensure that medicines are examined for safety, efficacy, and quality [1]. For a drug to be used, it must have a product license. In the UK, a Marketing Authorisation (MA) is issued by the European Medicines Agency (EMA) or the Medicines Health and Regulatory Agency (MHRA). Without a MA, the medicines are not licensed. On the other hand, the use of licensed medicines outside the terms of their MA is referred to as the off-label use of medicines [1]. In Malaysia, under the Control of Drugs and Cosmetics
123
Int J Clin Pharm
Regulations (CDCR) 1984, R7 (1) (a), no person shall manufacture, sell, supply, import, possess, or administer any product unless the product is a registered product [2]. The Drug Control Authority (DCA) was established under the CDCR 1984, to ensure the safety, quality, and efficacy of pharmaceuticals, health, and personal care products that are marketed in Malaysia. This is achieved through the registration of pharmaceutical products and cosmetics; licensing of premises for the importer, manufacturer, and wholesaler; monitoring the quality of registered products in the market; and monitoring adverse drug reactions [3]. Pharmaceutical companies then need to register their pharmaceutical products with the DCA, together with the submission of the preclinical and clinical trial results, information on the dose, dosage form, indication, route of administration, and target group for which the drug is intended [2, 3]. Most medicines administered to adults have a product license that outlines the particular indication, dose, and route of administration for a drug. However, most of the drugs used to treat children in hospitals are either not licensed for use in children or are used off-label. Therefore, the risks or benefits of using these drugs in children have not been examined by the licensing authority [1]. The main reason for the common use of unlicensed and off-label drugs in children is that children are excluded from clinical trials during the drug development process. Physicians face a dilemma when prescribing medicines for use in children due to the lack of detailed information available. Consequently, children may receive drugs in unapproved dosages that lack efficacy or have safety issues [4]. This alarming lack of research with respect to medication for children was pointed out by the regulatory bodies in the United States (US) Congress, and in 1997, this resulted in the implementation of incentives for pharmaceutical companies to develop pediatric medicines [5]. This is known as the Pediatric Exclusivity Program (Food and Drug Administration Modernization Act, 1997). Advances in the US prompted the European Union (EU) to develop the Paediatric Regulation in 2006, which was enacted on 26 January 2007 [(EC) No. 1901/2006] [6, 7]. The objective of this act was to facilitate the development and availability of medicines for children aged 0–17 years in Europe, and in so doing, ultimately improve their health [5]. It is reported that 30 % of the prescribed drugs for children are for the respiratory system. Furthermore, respiratory and allergy medicines are one of the most common types of drugs prescribed off-label for children. However, research on the safety and efficacy of these drugs with children is still lacking [8]. Baiardi et al. [9] reported that a significant percentage of the medicines used for
123
pediatric respiratory diseases in Italy were prescribed offlabel. The evidence available for the use of medicines in children with respiratory diseases has been reviewed by the European Respiratory Society task force which highlighted the gaps and research priorities in this area [10]. The present study was carried out to help understand the extent of off-label prescribing of respiratory drugs, which is one of the commonly prescribed groups of drugs in children. Identification of the respiratory drugs and the reasons for the off-label use would be useful in directing further research in this area.
Aim of the study The present study was conducted to determine the extent of unlicensed and off-label prescription of respiratory drugs in the outpatient clinics at Universiti Kebangsaan Malaysia Medical Centre (UKMMC), and to determine the possible predictors of off-label prescriptions.
Ethical approval This study was approved by the Research Ethics Committee of the UKMMC (UKM 1.5.3.5/244/NF-024-2012).
Methods Sampling Prescription data from the pharmacy-based computer system were screened to obtain the names and registration numbers of all the pediatric outpatients in the UKMMC that were prescribed respiratory drugs from July 2011 to December 2011. Consequently, the name lists were filled into the respective request form and sent to the medical records department at the UKMMC in order to obtain the patients’ medical records. Respiratory drugs included all drugs classified under the section for the respiratory system in the UKMMC formulary [12]. These include antiasthmatics (bronchodilators, corticosteroids, cromoglycate, and other related therapy), pulmonary surfactant, antihistamines and antiallergics, and cough and cold remedies [Ammonia & Ipecacuanha Sugar Free BP (Mixt. Expectorant Stimulant), Bromhexine Hydrochloride (BisolvonG), Diphenhydramine Expectorant (Bena-G), Diphenhydramine Expectorant Pediatric (Benadryl 1:2-G), Pholcodine Linctus Sugar Free (Duro-Tuss Regular)]. Children aged B18 years who were prescribed at least one respiratory drug listed in the UKMMC formulary [12] from July 2011 to December 2011 at the outpatient clinics at the
Int J Clin Pharm
UKMMC were included in this study. Antibiotics used to treat the respiratory system were not included. Patients who were prescribed a respiratory drug for a licensed indication other than for the respiratory system were excluded.
Requirements for Registration of Pharmaceuticals for Human Use, Clinical Investigation of Medicinal Products in the Pediatric Population (E11) [14]. Statistical analysis
Data collection Patient data were collected from the patients’ medical records and transferred into the data collection form. The data that was collected included demographic data (sex, ethnicity, age, body weight, and height), diagnosis, the number of medications prescribed and the complete regimen for each of the respiratory drugs prescribed (dose, frequency, indication, route of administration, and formulation). Study methods The licensing status for each respiratory drug prescribed to each patient was evaluated using the database provided by the National Pharmaceutical Control Bureau (NPCB), Ministry of Health Malaysia (MOH). The database consists of a list of drugs registered with the licensing authority (the DCA, MOH) and is available online and known as the Quest 2 and Quest 3 product searches. Both the Quest 2 and Quest 3 product searches were used to check for the licensing status of each drug on the website [3]. The offlabel status of the drugs was checked using the Master Index of Medical Specialty (MIMS), Malaysia, which is available online [13]. If the information about the prescription of a particular product could not be obtained, the product information leaflet was referred to, which was obtained from the Drug Information Service at the UKMMC. A medicine was classified as an off-label prescription for any of the following reasons: (1) contraindicated in children of all age ranges, (2) off-label use by indication, (3) off-label use by age, (4) off-label use by route of administration, (5) lower than the licensed dose, (6) higher than the licensed dose, (7) lower than the licensed frequency, and (8) higher than the licensed frequency. These categories of off-label use were adapted from the definition of off-label use by Turner et al. [1]. If there was more than one category for the off-label drug prescription, the offlabel status was prioritized based on the above list of reasons. Parameters that were evaluated as possible predictors of off-label drug prescription included age, ethnicity, sex, and number of medications prescribed to the patients. Patients’ ages were classified into three groups: newborns and infants (\2 years), children (2–11 years), and adolescents (12–18 years). These were age groups modified from the International Conference of Harmonization of Technical
Microsoft Excel 2010 (Microsoft Corporation, USA) was used for the descriptive analysis of the data. Statistical software (SPSS Version 20.0, IBM, Armonk, NY, USA) was utilized for conducting the binary logistic regression and descriptive analyses.
Results Demographic data of pediatric patients in outpatient clinics at the UKMMC Data from a total of 220 pediatric patients were collected in this study. The demographic data of the study subjects are presented in Table 1. From the participants, 125 (56.8 %) children were males. The majority of the patients were Malay (75.9 %). The age range was from 1 month to 17 years with a mean (SD) age of 6.81 (3.92) years. The most commonly prescribed respiratory drug was salbutamol (29.3 %). Unlicensed and off-label prescription of respiratory drugs for children at outpatient clinics at the UKMMC A total of 508 prescription items for respiratory drugs were issued to 220 patients. Approximately 181 (35.6 %) of the Table 1 Demographic data of the study subjects Characteristics
n (%)
Gender Male
125 (56.8 %)
Female
95 (43.2 %)
Ethnicity Malay
167 (75.9 %)
Chinese
30 (13.6 %)
Indian
15 (6.8 %)
Others
8 (3.6 %)
Age (years; mean ± SD)
6.81 ± 3.92
ICH age category (modified) Newborns and infants (\2 years)
14 (6.4 %)
Children (2–11 years)
177 (80.5 %)
Adolescents (12–18 years)
29 (13.2 %)
Number of prescribed medicines 1–3 4–6
199 (90.5 %) 21 (9.5 %)
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Percentage of drugs prescribed (%)
50 40 31.5 30
24.9
20
17.1
14.9 8.3
10
0
0
0
22.1
20 16.0
15 10
12.2 7.7
7.2
7.2
5 0
Top six respiratory drugs prescribed off-label
Fig. 2 Top six respiratory drugs prescribed off-label by percentage
standard error associated with the coefficient (SE) 0.77]. There were no other significant predictors of off-label respiratory drug prescription.
Discussion Extent of unlicensed or off-label prescriptions In this study, the percentage of prescription items (n = 508) prescribed in an off-label manner was 35.6 %, which was comparable to previous studies that reported rates of prescribing off-label medicines for children ranging from 11 to 60 % [15, 16]. There was no unlicensed medicine prescription recorded in this study. This could be because most of the respiratory drugs are available in different formulations, including liquid form, and do not require modifications from the original licensed product (e.g. crushed tablets formulated into a suspension). Previous studies also found that medicines for children prescribed in an off-label manner were higher than unlicensed medicine prescriptions [11, 15, 16]. Study settings, therapeutic area, and age ranges may result in the different percentages of unlicensed and off-label drugs used for pediatric patients from different studies. These factors may affect the percentage or extent of unlicensed and off-label prescriptions and need to be taken into account when making comparisons.
3.3
Categories of off-label respiratory drug prescription items
Fig. 1 Percentages of respiratory drugs prescribed by off-label categories
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25
Percentage prescribed off-label (%)
total prescription items were used in an off-label manner. A total of 134 patients (60.9 %) received at least one respiratory drug prescribed in an off-label manner. According to the pre-determined age groups, children (2–11 years; 76.1 %) received the most off-label drug prescriptions, followed by adolescents (12–18 years; 13.4 %) and newborns and infants (\2 years; 10.5 %). None of the subjects recruited in this study were prescribed an unlicensed respiratory drug. The main reasons for the off-label prescriptions of respiratory drugs were off-label use by indication (31.5 %), followed by higher than the recommended dose (24.9 %) and lower than the licensed frequency (17.1 %). None of the respiratory drugs were prescribed off-label due to contraindicated use in children or off-label use by route of administration (Fig. 1). Antiasthmatics were the most frequent respiratory drugs prescribed in an off-label manner (45.3 %), followed by cough and cold medications (29.3 %) and antihistamines/ antiallergics (25.4 %). Diphenhydramine (22.1 %) was the most common respiratory drug prescribed off-label, followed by budesonide (16.0 %) and loratadine (12.2 %; Fig. 2). Diphenhydramine was prescribed off-label due to higher than the licensed dose whereas budesonide had been prescribed at lower than the licensed frequency. Off-label use by indication was the main reason for off-label prescribing of loratadine. The number of medications prescribed was the only significant predictor of off-label respiratory drug prescription to children (p = 0.007). Those receiving 4–6 medications during the outpatient visits were 7.8 times more likely to receive an off-label respiratory drug prescription compared to children that received 1–3 medications [OR 7.8, 95 % CI 1.74–37.44; regression coefficient (B) 2.06;
Off-label categories of prescriptions The most common category of off-label prescriptions in the present study was off-label use by indication, followed by higher than the recommended licensed dose, and lower than the licensed frequency. A study by ‘t Jong et al. [11] on the unlicensed and off-label prescriptions of respiratory drugs to children at an outpatient setting in the Netherlands reported that prescribing medicines outside
Int J Clin Pharm
the licensed dose was the main reason for off-label prescriptions (7.8 %), followed by outside the licensed age, and indication (7.3 and 4.5 %, respectively). Another study conducted in a general ward in Brazil found that the most frequent reason for off-label prescription of medicines to children was the inconsistency with dose/frequency (17.7 %), followed by reasons related to age/ weight (7.9 %) [17]. In the present study, 14.9 % of the drugs were prescribed to children because of off-label use by age. For example, the metered dose inhaler (MDI) fluticasone plus salmeterol (25/125) 1 puff daily has been prescribed to one-year-old children, even though there is no information or data available on the use of this product in children under 4 years of age. Such prescribing practices may put these children at a high risk of experiencing the adverse effects of the drug, since there is no established study to support the use of the drug in children younger than 4 years of age. Many studies have shown that there is an increased risk of adverse drug reactions related to the use of off-label medicines in children [18–20]. The current study showed that the most commonly prescribed off-label respiratory drugs were antiasthmatics followed by cough and cold medications. According to ‘t Jong et al. (2004), off-label drug use was especially high for antiasthmatic drugs (39 %) and cough and cold medications (30 %). Antiasthmatic drugs were frequently prescribed off-label due to dose (14 %), and/or indication (10 %), or age/weight (15 %), and cough and cold medications were mostly prescribed off-label due to dose (19 %) [11]. A study by Conroy et al. [16] found that the majority of antiasthmatics prescribed off-label were due to prescribing at higher than the licensed doses for inhaled steroid preparations and lower than the licensed doses for inhaled sodium cromoglycate. In contrast, the present study identified antiasthmatics such as budesonide, which were commonly prescribed off-label due to lower than the recommended frequency. For example, the dose of 200 lg should be given in two to four divided doses (twice or four times daily) [13]. However, this drug was prescribed only once a day. Loratadine and chlorpheniramine are antihistamines used to relieve symptoms associated with allergic rhinitis [13]. In the present study, the most common reason for offlabel use of both drugs was the off-label use by indication, in which they were prescribed to the patients despite patients not experiencing any signs or symptoms of allergic rhinitis. Predictors of off-label respiratory drug prescriptions In the present study, the number of medications that patients received was the only predictor significantly
associated with off-label respiratory drug prescriptions. This result was similar to that of a previous study conducted in an outpatient setting in the US, which found that children who received more than one drug were significantly more likely to receive off-label prescriptions (26–39 % increased probability depending on the number of medications received; p \ 0.001) [21]. This study also did not find any significant differences with respect to predictors such as ethnicity, sex, and age group. This may be because respiratory drug prescriptions are not made based on considerations of ethnicity and sex, as the dose will depend only on the age and weight/body surface area of the pediatric patient. This finding was also similar to the findings of a previous study, where no significant difference was found in the incidence of unlicensed or off-label prescriptions between different age groups [16]. However, another published study found that the visits by children aged\1, 1 to\2, 2 to\6, and 6–12 years had an adjusted probability of 74, 67, 65, and 59 % respectively, of receiving at least one prescription that was not FDA-approved for their age or diagnosis at outpatient visits [21]. According to Giacoia et al. [22], younger children, mostly those below 2 years of age, were more likely to receive medicines prescribed off-label because few medications are tested or approved for this age group, giving physicians very limited choices of medications that were approved for young children. Study limitations The sample size in the present study was relatively small, which may have resulted in the reduced number of predictors that may potentially influence the off-label drug prescriptions for children at the UKMMC. Another limitation is that this study focused only on respiratory drugs and not all medicines. Therefore, it was difficult to compare the results of this study with those of other studies, in which different types of drug classes were also investigated for their off-label status. The present study does not reflect the practice of prescribing off-label medicines to children at other clinics or hospitals in Malaysia as it was conducted specifically at the UKMMC. Therefore, the results of this study need to be generalized to the population with caution.
Conclusion In conclusion, this study highlighted the need to conduct further research on the use of medicines in the pediatric population. Such studies may lead to an increase in information that is crucial for safe and effective drug prescriptions for children, and consequently, a decrease in our reliance on adult clinical data.
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Int J Clin Pharm Acknowledgments Special thanks to the pharmacy staff at the UKMMC for access to the pharmacy’s computerized dispensing database. The authors would also like to thank the hospital medical records staff for their help in retrieving the medical records. Funding
No funding was received for this research study.
Conflicts of interest
There are no conflicts of interest to declare.
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