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PubMed2005

A literature review on off-label drug use in children.

UNLABELLED: The aim was to compare results of studies performed in different settings worldwide and identify common therapeutic areas to allow for focused interventions, because off-label drug use can be a measure of the lack of knowledge concerning paediatric treatments. A secondary objective was to provide a brief review of efforts to date. A literature review of articles on off-label and unlicensed drug use in children involving general prescription samples was performed using Medline and Embase. In all, 30 studies from 1985-2004 were included. Eleven involved paediatric hospital wards, seven neonatal hospital wards, and 12 the community setting. The off-label and unlicensed classification methods varied, making results difficult to compare. In general, off-label/unlicensed prescription rates ranged from 11%-80%, and higher rates were found in younger versus older patients and in the hospital versus community settings. On the paediatric hospital wards, off-label/unlicensed prescriptions ranged from 16%-62% and most often concerned acetaminophen, cisapride, chloral hydrate, and salbutamol. In the neonatal wards, rates ranged from 55%-80% and often involved caffeine. In the community setting, rates ranged from 11%-37% and the most commonly implicated drugs were salbutamol and amoxicillin. CONCLUSION: A lack of harmonization between the evidence, the information available to doctors, and its use in clinical practice exists and this is part of the reason off-label therapies are so common. Attempts have been made to improve knowledge concerning paediatric treatments, but more focused interventions are needed, also taking into consideration this lack of harmonization.

Adolescent↗
PubMed2004

Safety related drug-labelling changes: findings from two data mining algorithms.

INTRODUCTION: With increasing volumes of postmarketing safety surveillance data, data mining algorithms (DMAs) have been developed to search large spontaneous reporting system (SRS) databases for disproportional statistical dependencies between drugs and events. A crucial question is the proper deployment of such techniques within the universe of methods historically used for signal detection. One question of interest is comparative performance of algorithms based on simple forms of disproportionality analysis versus those incorporating Bayesian modelling. A potential benefit of Bayesian methods is a reduced volume of signals, including false-positive signals. OBJECTIVE: To compare performance of two well described DMAs (proportional reporting ratios [PRRs] and an empirical Bayesian algorithm known as multi-item gamma Poisson shrinker [MGPS]) using commonly recommended thresholds on a diverse data set of adverse events that triggered drug labelling changes. METHODS: PRRs and MGPS were retrospectively applied to a diverse sample of drug-event combinations (DECs) identified on a government Internet site for a 7-month period. Metrics for this comparative analysis included the number and proportion of these DECs that generated signals of disproportionate reporting with PRRs, MGPS, both or neither method, differential timing of signal generation between the two methods, and clinical nature of events that generated signals with only one, both or neither method. RESULTS: There were 136 relevant DECs that triggered safety-related labelling changes for 39 drugs during a 7-month period. PRRs generated a signal of disproportionate reporting with almost twice as many DECs as MGPS (77 vs 40). No DECs were flagged by MGPS only. PRRs highlighted DECs in advance of MGPS (1-15 years) and a label change (1-30 years). For 59 DECs, there was no signal with either DMA. DECs generating signals of disproportionate reporting with only PRRs were both medically serious and non-serious. DISCUSSION/CONCLUSION: In most instances in which a DEC generated a signal of disproportionate reporting with both DMAs (almost twice as many with PRRs), the signal was generated using PRRs in advance of MGPS. No medically important events were signalled only by MGPS. It is likely that the incremental utility of DMAs are highly situation-dependent. It is clear, however, that the volume of signals generated by itself is an inadequate criterion for comparison and that clinical nature of signalled events and differential timing of signals needs to be considered. Accepting commonly recommended threshold criteria for DMAs examined in this study as universal benchmarks for signal detection is not justified.

Algorithms↗
PubMed2003

Iron-containing supplements and drugs; label warning statements and unit-dose packaging requirements; removal of regulations for unit-dose packaging requirements for dietary supplements and drugs. Final rule; removal of regulatory provisions in response to court order.

The Food and Drug Administration (FDA) is removing, in part, a final rule that required unit-dose packaging for iron-containing dietary supplement and drug products that contain 30 milligrams (mg) or more of iron per dosage unit. FDA is taking this action in response to the Court's ruling in Nutritional Health Alliance v. FDA, in which the Court concluded that the Federal Food, Drug, and Cosmetic Act (the act) does not provide FDA with authority to require manufacturers of iron-containing dietary supplement and drug products to use unit-dose packaging for poison prevention purposes. Today's action takes the ministerial step of removing the unit-dose packaging provisions from title 21 of the Code of Federal Regulations.

Dietary Supplements↗
PubMed2004

The impact of unlicensed and off-label drug use on adverse drug reactions in paediatric patients.

BACKGROUND AND OBJECTIVE: Many drugs that are used to treat children are either not licensed for use in paediatric patients (unlicensed) or prescribed outside the terms of the product licence (off label). The incidence of adverse drug reactions (ADRs) associated with the use of such drugs is yet to be established. This study investigates, for the first time in a German patient population, the impact of unlicensed and off-label drug use on ADRs in paediatric patients. PATIENTS AND METHODS: An 8-month prospective pharmacoepidemiological cohort-based survey was conducted on a ten-bed paediatric isolation ward at the University Hospital Erlangen-Nuremberg, Germany. All patients were intensively monitored for ADRs by a pharmacoepidemiological team. ADRs were characterised according to international classification methods. All drug prescriptions were evaluated retrospectively as to unlicensed or off-label use on the basis of the product information. RESULTS: A total of 178 patients were included in the study and 740 drug prescriptions were given to 156 patients (median three prescriptions per patient). In 198 cases (27.7% of all prescriptions) drugs were used in either an unlicensed (n = 3) or off-label (n = 195) manner. A total of 46 ADRs were observed in 31 patients (17.4%). Patients receiving at least one unlicensed or off-label drug prescription during hospitalisation (n = 92) experienced an ADR significantly more frequently (n = 26 patients) than patients receiving only licensed drugs (n = 64 vs 5 patients). ADRs were associated with 29 (5.6%) of the 517 licensed drug prescriptions and with 12 (6.1%) of the 198 unlicensed or off-label drug prescriptions. The majority of ADRs caused by unlicensed and off-label drug use were recognised by the attending physician. However, statistical analysis revealed no significant difference in the number of licensed and unlicensed/off-label drug prescriptions causing ADRs. CONCLUSION: This study demonstrated that at a paediatric isolation ward the incidence of ADRs caused by unlicensed or off-label drug use was not significantly more than that caused by the licensed drug use. However, patients treated with unlicensed or off-label drugs were shown to possess a significantly increased risk for developing ADRs.

Adolescent↗
PubMed2003

Pediatric drug labeling: improving the safety and efficacy of pediatric therapies.

CONTEXT: Approximately 50% to 75% of drugs used in pediatric medicine have not been studied adequately to provide appropriate labeling information. In 1997, Congress passed the Food and Drug Administration Modernization Act (FDAMA), which encouraged pediatric drug development by providing an incentive in the form of additional marketing exclusivity. OBJECTIVE: To identify new drug labeling information from pediatric studies submitted to the FDA in response to written requests. DESIGN AND SETTING: Between July 1998 and April 1, 2002, the FDA requested studies on 242 drugs, and 53 drugs were granted exclusivity. As of January 2003, 49 drugs have new labels. Data from the studies of the first 33 drugs with new pediatric information on the label as of April 2002 are included. Significant labeling information was analyzed along with baseline data and types of studies requested. MAIN OUTCOME MEASURES: Safety data and pediatric information for labeled drugs. RESULTS: There were 53 studies for 33 drug products, 12 (23%) were evaluated for safety only; 23 (43%), safety and efficacy; and 18 (34%), pharmacokinetics and/or pharmacodynamics. Significant new dosing and/or safety information was identified for 12 (36%) drugs. New dosing information was determined for 7 of these drugs. Safety information was defined for gabapentin, propofol, sevoflurane, the combination of ribavirin and interferon alfa-2b, and various betamethasone-containing dermatologic preparations. There was a higher percentage of deaths reported with patients who received propofol compared with controls in the pediatric intensive care unit. Seizures were seen in patients administered sevoflurane. Patients receiving a combination of ribavirin and interferon alfa-2b experienced an increased incidence of suicidal ideation when compared with adults. An unexpectedly high percentage of those receiving betamethasone-containing dermatologic preparations had documented hypopituitary-adrenal axis suppression. CONCLUSION: The FDAMA has stimulated pediatric clinical studies resulting in improved understanding of the pharmacokinetics of drugs prescribed in pediatric medicine, important dose changes, and improved safety for children taking certain drugs.

Adolescent↗
PubMed2006

The major role of clinicians in the discovery of off-label drug therapies.

OBJECTIVE: To determine the role of clinicians in the discovery of off-label use of prescription drugs approved by the United States Food and Drug Administration (FDA). Data Sources. Micromedex Healthcare Series was used to identify new uses of new molecular entities approved by the FDA in 1998, literature from January 1999-December 2003 was accessed through MEDLINE, and relevant patents were identified through the U.S. Patent and Trademark Office. DATA SYNTHESIS AND MAIN FINDING: A survey of new therapeutic uses for new molecular entity drugs approved in 1998 was conducted for the subsequent 5 years of commercial availability. During that period, 143 new applications were identified in a computerized search of the literature for the 29 new drugs considered and approved in 1998. Literature and patent searches were conducted to identify the first report of each new application. Authors of the seminal articles were contacted through an electronic survey to determine whether they were in fact the originators of the new applications. If they were, examination of article content and author surveys were used to explore if each new application was discovered through clinical practice that was independent of pharmaceutical company or university research (field discovery) or if the discovery was made by or with the involvement of pharmaceutical company or university researchers (central discovery). Eighty-two (57%) of the 143 drug therapy innovations in our sample were discovered by practicing clinicians through field discovery. CONCLUSION: To our knowledge, the major role of clinicians in the discovery of new, off-label drug therapies has not been previously documented or explored. We propose that this finding has important regulatory and health policy implications.

Botulinum Toxins, Type A↗
PubMed2004

Simultaneous expression of guinea pig UDP-glucuronosyltransferase 2B21 (UGT2B21) and 2B22 in COS-7 cells enhances UGT2B21-catalyzed chloramphenicol glucuronidation.

Our previous study suggested that hetero-oligomer formation of guinea pig liver UDP-glucuronosyltransferases (UGTs) 2B21 and 2B22 enhances UGT2B21-catalyzed morphine-6-glucuronidation. In this work, further evidence for a functional hetero-oligomer between UGT2B21 and UGT2B22 was provided by studies of the glucuronidation of chloramphenicol with dual expression in COS-7 cells. UGT2B21 expressed in COS cells was capable of glucuronidating the 3-hydroxyl group of morphine, 4-hydroxybiphenyl, borneol, testosterone, androsterone, and estriol, whereas it had some effect on chloramphenicol. On the contrary, UGT2B22 does not exhibit any significant activity toward these typical substrates tested in this study. When UGT2B21 and UGT2B22 were expressed simultaneously, the chloramphenicol glucuronidation was enhanced to 4.5-fold, whereas the activities toward other substrates were little affected except that for the 6-hydroxyl group of morphine. The protein expression level of UGT2B21 was comparable when UGT2B21 was expressed with or without UGT2B22. These results suggest that simultaneous expression of UGT2B21 and UGT2B22 enhances UGT2B21-catalyzed chloramphenicol glucuronidation. Hetero-oligomer formation of UGT2B21 and UGT2B22 may act by fine-tuning the catalytic glucuronidation of chloramphenicol.

Animals↗