Pediatrics International (2010) 52, 290–295

Original Article

ped_2958

doi: 10.1111/j.1442-200X.2009.02958.x

290..295

Dosing information in a standard drug reference: Are pediatrics still therapeutically neglected? Jesmin Permala,1 Mohamed Azmi Hassali,2 Ahmed Awaisu1 and Asrul Akmal Shafie2 Disciplines of 1Clinical Pharmacy and 2Social and Administrative Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia Abstract

Background: In many countries, the most readily accessible drug information resources, such as the Monthly Index of Medical Specialties (MIMS), lack information concerning use in children. We reviewed the product information (PI) of medications in the most widely used drug information reference in Malaysia in an effort to determine the extent and the nature of available information related to pediatric dosing. Methods: The products listed in the 2007 Malaysian MIMS Annual were reviewed for PI on pediatric use as per inclusion and exclusion criteria. The dosing information for each PI was extracted according to age groups. Product information that claimed suitability for use in pediatrics was further evaluated for information on pediatric dosage formulations. Results: A total of 421 PI items from seven categories of therapeutic classes were reviewed. Of these, 69% gave inadequate pediatric dosing information. The proportions, for each age group of PI items that gave adequate pediatric dosing information were: neonates (13.1%), infants (23.3%), and children (32.2%). Therapeutic classes of drugs differed significantly in terms of dosing information adequacy for all pediatric age groups (P < 0.05). Most PI reviewed under all legal categories provided inadequate pediatric dosing information, but suitable pediatric formulations were commonly (70.1–85.5%) available where the dosing information existed. Overall, category B (prescription only) products did not differ significantly from category C (pharmacy only medicine) products in terms of pediatric dosing information adequacy, except for children. Conclusion: This study has managed to contribute substantial additional information regarding the extent of pediatric dosing information and dosage formulations available in the MIMS Annual, stressing that the majority of PI for the products reviewed did not provide adequate dosing information for pediatric patients, subjecting this population to a therapeutically disadvantaged status.

Key words

dosing information, formulation, MIMS, off-label use, pediatric therapies, product information.

Dosing information is of utmost importance in treating pediatric patients, who have differing pharmacokinetic and pharmacodynamic profiles.1 Many physiological differences between children and adults can lead to considerable age-related differences in pharmacokinetics and in optimal drug dosing for the pediatric population.2 Four decades ago, Shirkey recognized the serious dilemma regarding pediatric drug labeling3 and first referred to pediatric patients as “therapeutic orphans”. He also captured the concept of this problem, and described remedial measures to minimize the dilemma.4 Children have become “therapeutic orphans”3 because they are either denied the use of many new medications or exposed to medications that have bypassed rigorous clinical evaluations, including dose-ranging studies. Many Correspondence: Ahmed Awaisu, BPharm, MPharm (Clinical Pharm), PhD (Candidate), Discipline of Clinical Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia. Email: [email protected] Received 30 November 2008; revised 26 June 2009; accepted 4 August 2009.

© 2010 Japan Pediatric Society

marketed drugs that are commonly used, or could potentially be used in children, have not been studied in the relevant age groups.5 Approximately 50–75% of drugs used in pediatrics have not been studied adequately to provide appropriate labeling information.6 Hence, most of these products are not approved by regulatory authorities for use in pediatrics and where they are approved, the product information (PI) may contain grossly insufficient information concerning dosing and use among this age group. A previous report has shown that the pediatric population was therapeutically neglected, because the pharmaceutical industry and research institutions did not invest much into scientific studies in this population and perhaps regulatory authorities did not provide stringent laws on pediatric drug labeling.7 The problem with off-label use of drugs in pediatrics is international and affects pediatric patients in the USA, Europe, Asia, Africa and South America. Hence, initiatives to encourage and promote pediatric labeling for drugs to provide the needed information to use them safely and efficaciously in the pediatric population have become a prime concern for legislative and regulatory bodies.8

Dosing information for pediatrics in MIMS 291 In recent years, however, there has been an extensive interest internationally in ensuring the availability of product information for the pediatric age groups. Although there are some improvements compared to the last few decades, these improvements do not reflect the real scenario needed to improve the availability of product information in all age groups of pediatrics.9 It is of paramount importance that drug regulatory authorities regularly assess the extent of information related to pediatrics provided by manufacturers and included in the most readily accessible drug references in a country in order to observe the trend and identify areas of gross deficits in drug labeling. Several studies and reviews5–7,10–12 have highlighted the issue after the early studies by Shirkey,3,4 yet pediatric drug labeling and dosing information fail to improve to date. For instance, Wilson reviewed the 1973 Physician’s Desk Reference and found that 78% of drug product information still included a disclaimer or lacked dosing information for children.7 Similarly, Gilman and Gal noted that 81% of the drugs in the Physician’s Desk Reference contained a disclaimer or restricted use to certain pediatric age groups.10 In many countries, much PI lacks information concerning use in children.6,7,11,12 The dilemma of dosing information among this special population is therefore not a new one, but an issue of renewed interest. Drug information resources, such as the Monthly Index of Medical Specialties (MIMS), are commonly consulted for approved product information on prescription medicines in Australia, Bangladesh, China, Hong Kong, Korea, Indonesia, Malaysia, Myanmar, New Zealand, the Philippines, Singapore, Sri Lanka, Taiwan, Thailand and Vietnam.12,13 In Malaysia, unpublished studies have reported an overwhelming utilization of this resource by over 90% of general practitioners. However, the extent of pediatric dosing information available in the most readily accessible and available tertiary drug literature could vary from one nation to another. It is noteworthy that where a product has an indication in pediatrics and dosing information is available, there is corresponding need to manufacture pharmaceutical dosage formulations suitable for this age group. Has there been any change in what we know about this phenomenon over the past several decades? To our knowledge, no study has been conducted to determine the extent and nature of pediatric dosing information available in Malaysia’s most widely used drug information resource (i.e., MIMS). Information about the availability of suitable pediatric dosage forms is also scanty. In an effort to continually expand the existing literature on pediatric dosing information and availability of dosage formulations as well as to observe changes over time, we reviewed the MIMS Annual 200713 using well-defined criteria. We reviewed the approved PI for prescription medications in the MIMS to determine the extent and nature of available information on pediatric dosing and to further investigate the availability of pediatric dosage formulations.

Methods PI for prescription medications contained in the MIMS Annual 200713 was reviewed for pediatric use. Pediatric patients were

Table 1 Type of dosing information 1 = No dosing information for at least one indication 2 = Specific / complete dosing information present for at least one indication 3 = Non-specific / incomplete dosing information present for one or more indication 4 = Safety and effectiveness of product not established 5 = No suggestion that product can be used in age group 6 = Product not approved for use in age group 7 = Product is contraindicated for use in age group

defined as children younger than 12 years of age. Dosing information for each PI was collected based on physiological age groupings as follows: neonate, <1 month old; infant, 1 month–<2 years old; child, 2 years–<12 years old; adolescent, 12 years–<18 years old; and adult >18 years old.12 A standardized and validated data collection form was used. Extent of the dosing information contained in the PI was assigned to one of seven categories12 (Table 1) for each age group. Dosing information that was categorized as “specific or complete”, were considered as “adequate” dosing information for the specific age group, whereas all other categories were labeled as “inadequate”. PI that mentioned use in pediatrics was further reviewed for the availability of pediatric dosage formulations. Dosage forms that were considered suitable for pediatrics were liquid preparations (e.g. suspension, elixir, syrups, and drops), dispersible tablets, injection solutions/powders, creams/ ointments/lotions, nasal solutions and drops, inhalation devices and solution, eardrops and ointments, eye drops and ointments, scalp applications, rectal preparations (e.g. suppositories), and powders (e.g. powder for reconstitution). Each product was allocated to one of three legal categories of drugs used in Malaysia: Poison Group A, B or C. Poison Group A are drugs categorized as dangerous drugs and psychotropics. Whereas, Poison Group B are drugs that can be dispensed only per the prescription of a registered medical practitioner, dentist, or veterinary surgeon. Poison Group C are drugs that can be sold only in a pharmacy as dispensed medications with an entry in the prescription book.14 Products were included in the study if they satisfied the following fundamental eligibility criteria: categorized as poison Group A, B, or C; the product is registered in Malaysia; the product belonged to any of the seven major therapeutic categories (central nervous/neuromuscular system, antibiotics/ chemotherapeutic agents, metabolic/endocrine system, gastrointestinal tract (GIT)/ genitourinary tract (GUT)/hepatic system, respiratory, cardiovascular/hematopoietic system, and eye/ear/throat/skin). Products were excluded if they were: over-the-counter drugs; oral contraceptive agents; vitamins; nutritional products/supplements; diagnostic agents; intravenous and other sterile solutions; antidotes used for substance dependence; and therapeutic categories other than those listed above. The results were analyzed using spss, version 15.0 (spss Inc., Chicago, IL) and Microsoft Excel. Descriptive statistics including frequencies and percentages were mainly used for the data analysis. In addition, inferential statistical tests, including the © 2010 Japan Pediatric Society

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c2-test and Fisher’s exact tests, were used wherever appropriate. The level of significance was set at P < 0.05.

Results The MIMS Annual 2007 comprised of 1755 PI items. A total of 421 PI items from seven categories of therapeutic classes that satisfied our eligibility criteria were reviewed. Of the 421 PI items reviewed, the majority of the products (295/421; 70.1%) were from legal category B, while the rest (126/421; 29.9%) belonged to legal category C. About 69.4% of all the products reviewed provided inadequate pediatric dosing information. The proportion of PI providing pediatric dosing information and availability of dosage forms suitable for pediatrics was determined. Figure 1 shows the extent of dosing information available for various age groups. About 13.1% of the PI contained specific dosing information for neonates. The proportion of PI giving specific dosing information increased consistently with age group. The adult age category had the highest proportion (54.4%) of PI providing specific dosing information. This study found that 4.1%, 2.6%, 2.1%, 0.2% and 2.1% of PI contraindicated the use of medicines among neonates, infants, children, adolescents and adults, respectively. The therapeutic classes with the highest proportion of inadequate dosing information for neonates were “central

nervous/neuromuscular” category followed by the “antibiotic/ chemotherapy” category with 22.09% and 19.95% of the PI having inadequate dosing information, respectively. There were significant differences in terms of dosing information adequacy between the therapeutic categories for all of the age groups, except for the adults (Table 2). The present study found that the adult age group had the highest proportion of PI with specific dosing information in both legal categories. Furthermore, there were no significant differences between category B and C products in the adequacy of dosing information for the neonatal and infant age groups. In contrast, there were significantly higher proportions of legal category C products that had adequate dosing information compared to category B, for children and adolescent age groups (P < 0.05). Detail is provided in Table 3. Among all the PI items under legal category B, the therapeutic category of “antibiotics/chemotherapy” had the highest proportion of adequate dosing information. This therapeutic category had the highest proportion of adequate dosing information for all of the age groups of children: 60%, 54% and 51% for neonates, infants, and children, respectively (Fig. 2). Although there was generally a low proportion of PI that gave specific dosing information for pediatric patients, this PI mostly reported the availability of pediatric dosage formulations. For instance, the available PI with specific dosing information for

Fig. 1 Extent of product dosing information available in the Monthly Index of Medical Specialties (MIMS) for 421 prescription medications according to age category. , nil dosing information present for one or more indications; , specific/complete dosing information present for one or more indications; , non-specific/incomplete dosing information present for one or more indications; , safety and effectiveness of product not established; , no suggestion that product can be used in age group; , product not approved for use in age group; , product is contraindicated for use in age group. © 2010 Japan Pediatric Society

0.001 <0.001 <0.001 <0.001 0.057

neonates was only 13.1%, yet 85.5% of these had available pediatric dosage forms (Fig. 3). This finding was consistent for all children’s age categories.

Cardiovascular & hematopoietic, n (%) 47 (11.16) 46 (10.92) 46 (10.92) 47 (11.16) 37 (8.79)

P*

Dosing information for pediatrics in MIMS 293

Neonates Infants Children Adolescents Adults a. b. c. d. e.

*c2-test. CNS, central nervous system; GIT, gastrointestinal tract; GUT, genitourinary tract.

Metabolic & endocrine, n (%) 45 (10.69) 42 (9.98) 39 (9.26) 39 (9.26) 26 (6.17) Therapeutic classes CNS/neuromuscular, n (%) 93 (22.09) 82 (19.48) 74 (17.58) 80 (19.00) 48 (11.40) Antibiotic & chemotherapy, n (%) 84 (19.95) 72 (17.10) 65 (15.44) 71 (16.86) 36 (8.55) Respiratory, n (%) 33 (7.84) 21 (4.99) 7 (1.66) 7 (1.66) 3 (0.71) GIT/GUT/hepatic, n (%) 27 (6.41) 25 (5.94) 23 (5.46) 22 (5.23) 15 (3.56) Age category

Table 2 Proportion of product information with inadequate dosing information in relation to the reviewed therapeutic classes

Eye, ear, mouth & skin, n (%) 37 (8.79) 34 (8.08) 30 (7.13) 32 (7.60) 26 (6.18)

Discussion The finding that 69% of all PI reviewed in the MIMS Annual 2007 provided inadequate pediatric dosing information is comparable to that reported in other studies around the world (78%– 81%),6,7,12,15–17 suggesting that there has not been tremendous changes in this phenomenon over the last three decades in developing nations like Malaysia. With the advent of new legislations related to licensing requirements in the USA and Europe, pharmaceutical manufacturers would likely be mandated to provide necessary prescribing information for pediatrics.16–18 In these, recommendations have been made to improve the licensing of medicines for children, i.e., detailed data for prescribing for children whenever the drug is likely to be used for them. This could possibly account for the tremendous improvements in pediatric prescribing information observed in some of the developed nations. On the wider international scope, however, there is no evidence of change in this trend. For instance a study from Australia concluded that there has been no change in the proportion of medicines licensed for children, that the majority of newly introduced medicines were for the treatment of infections and that dosing information was predominantly for children over o the age of 2 years.9 Moreover, there is paucity of data from this part of the world. This reaffirms the importance of wider studies from developing nations to assess the availability and extent of prescribing information for pediatrics. Medicines used for the central nervous system and neuromuscular disorders had the highest proportion of inadequate dosing information compared to other therapeutic categories for all age groups except infants. Of the seven therapeutic classes evaluated, antibiotics and chemotherapeutic agents had the highest proportion of PI with specific pediatric dosing information. Perhaps this was not an unexpected finding, given that vaccines and antibiotics are frequently prescribed for children.12 In terms of legal category, our study found that most of the medicines reviewed in the MIMS Annual 2007 were under legal category B (70% of PI) and the rest were under legal category C. In both legal category B and C, the highest proportion of specific and adequate dosing information was found among the adult age group. Even though there was a high proportion of PI with inadequate pediatric dosing information, a substantial proportion of products with specific dosing information for pediatric patients had suitable dosage forms for all pediatric age groups. This finding did not significantly differ from the study by Tan et al.12 A medicine with dosing information for pediatric patients should be available in suitable pediatric formulation.15 Absence of pediatric dosage forms may lead to problems such as higher rates of medication errors resulting from dilution of adult dosage forms and lack of stability associated with liquid formulations that are prepared by the pharmacist from solid-dosage forms.6 Dosing information is of utmost importance in treating the pediatric patient, so a strong strategic partnership is needed between the © 2010 Japan Pediatric Society

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Table 3 Proportion of product information with specific dosing information according to products’ legal category Age category

a. b. c. d. e.

Neonates Infants Children Adolescents Adults

Legal category Category B, n (%) (n = 295) 42 (14.2) 68 (23.1) 85 (28.8) 73 (24.7) 162 (54.9)

P* Category C, n (%) (n = 126) 13 (10.3) 31 (24.6) 52 (41.3) 50 (39.7) 68 (54.0)

0.344 0.802 0.017 0.002 0.915

*Fisher’s exact test.

pharmaceutical industry, the regulatory authority, academic institutions and practitioners in order to bring about the necessary changes.12

Conclusion Overall, this study has managed to contribute substantial additional information regarding the extent of pediatric dosing

information and dosage formulations available in the Malaysian MIMS Annual, highlighting the fact that the majority of PI for the products reviewed did not provide specific or adequate dosing information for pediatric patients, subjecting this population to a therapeutically disadvantaged status. Nevertheless, the study has revealed that dosage formulations suitable for various pediatric age groups were available in more than 70% of cases where the

Fig. 2 Proportion of product information with adequate dosing information under legal category B in relation to therapeutic groups for pediatric age groups. , gastrointestinal tract/genitourinary tract/hepatic; 䊐, respiratory; , antibiotics and chemotherapy; , central nervous/ neuromuscular system; , metabolic and endocrine; , cardiovascular and hematopoietic. © 2010 Japan Pediatric Society

Dosing information for pediatrics in MIMS 295 Fig. 3 Proportion of available pediatric dosage formulations compared to adequate dosing information in relation to pediatric age groups. , available; , adequate.

PI had adequate pediatric dosing information. This study has important implications on policy and clearly suggests a closer collaboration between various stakeholders to liberate a therapeutically neglected population. Drug regulatory authorities in Malaysia and other countries need to introduce an obligatory requirement for all the medicines with indications or potential use in children to have pediatric dosing information and to be available in appropriate dosage formulations.

References 1 Shirkey H. Therapeutic orphans [editorial]. J. Pediatr. 1968; 72: 119–20. 2 Anderson GD, Lynn AM. Optimizing pediatric dosing: A developmental pharmacologic approach. Pharmacotherapy 2009; 29: 680– 90. 3 Stephenson T. Medicines for children—the last century and the next. Arch. Dis. Child. 2001; 85: 177–9. 4 Shirkey HC. Therapeutic orphans: Who speaks for children? South. Med. J. 1970; 63: 1361–3. 5 Wilson JT. Pragmatic assessment of medicines available for young children and pregnant or breast-feeding women. In: Morselli PL, Garattini S, Sereni F (eds). Basic and Therapeutic Aspects of Perinatal Pharmacology. Raven Press, New York, 1975; 411–21. 6 Benjamin DK Jr, Smith PB, Murphy MD et al. Peer-reviewed publication of clinical trials completed for pediatric exclusivity. JAMA 2006; 296: 1266–73. 7 Wilson JT. An update on the therapeutic orphan. Pediatrics 1999; 104: 585–90.

8 Roberts R, Rodriguez W, Murphy D, Crescenzi T. Pediatric drug labeling: Improving the safety and efficacy of pediatric therapies. JAMA 2003; 290: 905–11. 9 Chui J, Tordoff J, Reith D. Changes in availability of paediatric medicines in Australia between 1998 and 2002. Br. J. Clin. Pharmacol. 2005; 59: 736–42. 10 Gilman JT, Gal P. Pharmacokinetic and pharmacodynamic data collection in children and neonates. Clin. Pharmacokinet. 1992; 23: 1–9. 11 Cote CJ, Kauffman RE, Troendle GJ, Lambert GH. Is the “therapeutic orphan” about to be adopted? [Commentary] Pediatrics 1996; 98: 118–23. 12 Tan E, Cranswick NE, Rayner CR, Chapman CB. Dosing information for paediatric patients: Are they really “therapeutic orphans”? Med. J. A. 2003; 179: 195–8. 13 Malaysian MIMS Annual 2007, 18th edn. Media Medica, Selangor, 2007. 14 Law of Malaysia, Act 366. Poison Act 1952. 15 Nordeberg T. Paediatric drug studies. Protecting pint-sized patients. FDA Consum. 1999; 33: 23–8. 16 Collier J. Pediatric prescribing: Using unlicensed drugs and medicines outside their licensed indication. Br. J. Clin. Pharmacol. 1999; 48: 5–8. 17 Ward RM. Children, drugs, and the food and drug administration: Studies of pediatric drugs are beginning to catch up. Pediatr. Ann. 2001; 30: 189–94. 18 Center for Drug Evaluation and Research. Pediatric Drug Development. [Accessed 15 May 2009.] Available from URL: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ DevelopmentResources/ucm049867.htm

© 2010 Japan Pediatric Society

Dosing information in a standard drug reference - Wiley Online Library

dosing information were: neonates (13.1%), infants (23.3%), and children (32.2%). Therapeutic classes of drugs differed significantly in terms of dosing information adequacy for all pediatric age groups (P < 0.05). Most PI reviewed under all legal categories provided inadequate pediatric dosing information, but suitable ...

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