Off label prescribing to children in primary care in Germany: retrospective cohort studyBMJ 2002; 324 doi: https://doi.org/10.1136/bmj.324.7349.1311 (Published 01 June 2002) Cite this as: BMJ 2002;324:1311
- Reinhild Bücheler, specialist in internal medicine and social medicinea,
- Matthias Schwab, senior registrar in clinical pharmacology and paediatricianb,
- Klaus Mörike, lecturer in clinical pharmacologya,
- Bernhard Kalchthaler, IT engineerc,
- Hartmut Mohr, pharmacistc,
- Helmut Schröder, head of the German drug indexd,
- Peter Schwoerer, headc,
- Christoph H Gleiter, professor in clinical pharmacology ()a
- a Division of Clinical Pharmacology, University Hospital Tübingen, D-72076 Tübingen, Germany
- b Dr Margarete Fischer-Bosch Institut für Klinische Pharmakologie, D-70376 Stuttgart, Germany
- c Medizinischer Dienst der Krankenversicherung Baden-Württemberg, D-77933 Lahr, Germany
- d Wissenschaftliches Institut der AOK (Allgemeine Ortskrankenkasse), D-53177 Bonn, Germany
- Correspondence to: C H Gleiter
- Accepted 2 January 2002
Between 35% and 90% of the drugs prescribed to hospitalised children are either not licensed for children's use or are prescribed outside the terms of their product licence (off label prescribing). 1 2 Subsequent adverse reactions are more likely than with licensed products (6.0% v 3.9%).3 We analysed the extent of prescribing off labelled products in a representative cohort of children in primary care.
Patients, methods, and results
We used the electronic database of prescriptions of Allgemeine Ortskrankenkasse, Baden-Württemberg. This health insurer covers more than four million people, 42% of the total population of the state. We retrospectively reviewed 1.74 million anonymous prescriptions written by 6886 office based doctors—specialists in paediatric, general, or internal medicine—between 1 January and 31 March 1999 for 455 661 patients aged 0-16 years.
Each prescription was represented by a numerical code, describing the drug's brand name, generic name, formulation, and content per dose unit. Our database did not contain diagnoses, dosage recommendations, or individually prepared drug formulations.
To assess the licence status of prescriptions we used the summary of product characteristics (Fach information) or drug lists provided by German pharmaceutical manufacturers' associations (Gelbe Liste or Rote Liste).
We categorised prescriptions by age group and the World Health Organization's anatomical, therapeutic, and chemical classification. A prescription was considered off label if the drug itself, its dose unit, or its formulation was not explicitly covered by documentation for the specific age group to which it was prescribed. Unlicensed drugs are not specified in the database because they are not automatically reimbursed by insurance.
Of 1740 238 prescriptions, 115 366 (6.6%) prescriptions for medical accessories, diets, and cosmetics and 32 866 with unidentifiable codes were excluded; the prescriptions with unidentifiable codes might have included an unknown number of unlicensed prescriptions but accounted for only 1.9% of the database.
Among the remaining 1 592 006 prescriptions for 10 452 different active ingredients, we found 210 528 (13.2%, 95% confidence interval 13.2% to 13.3%) off label prescriptions. The table shows the most common examples and some of the associated risks.
Three quarters of off label prescriptions (157 951) resulted from lack of information about use of the drugs among children or in particular age ranges. Of the off label prescriptions, 35 234 (16.7%) ignored recommendations on active ingredient, dose units, or formulations for a specific age group—for example, quinolones in children and xylometazoline 1% formulations for babies.
The proportion of off label prescriptions was highest for 1-2 year olds (68 791 (17.9%, 17.8% to 18.1%) prescriptions) and lowest for 7-11 year olds (40 539 (10.5%, 10.4% to 10.6%) prescriptions).
Of the 181 914 (8.8%) prescriptions for topical treatments of the skin, eye, or ear, 116 060 (63.8%, 63.6% to 64.0%) were off label. The active ingredients of the most commonly prescribed systemic off label drugs are shown in the table.
Off label prescribing was common for cardiovascular drugs (3646; 55.2%, 53.9% to 56.4%), drugs for genitourinary disorders (1869; 48.5%, 46.9% to 50.1%), anti-inflammatory agents (7194; 45.0%, 45.2% to 46.0%), antidepressants (246; 36.6%, 33.0% to 40.4%), and antidementia (11; 34.4%, 18.6% to 53.2%), antiepileptic (932; 14.2%, 13.3% to 15.0%), and antipsychotic drugs (54; 10.2%, 7.8% to 13.2%).
We found that 13.2% of prescriptions for a representative group of children in primary care in Germany were off label. Although we could not detect off label use due to dosage or indication with this database, the proportion of prescriptions that were off label was similar to that in much smaller studies that analysed dosage and diagnoses. 4 5 Our data show that efforts to improve the quality of pharmacotherapy in children should not exclude widely marketed and firmly established drugs.
We thank Christoph Meisner, Institute for Medical Information, University of Tübingen, for statistical analysis and Doris Merz, Allgemeine Ortskrankenkasse, Baden-Württemberg, for help with the database.
Contributors: MS, KM, and CG designed the study. PS provided access to Allgemeine Ortskrankenkasse, Baden-Württemberg, and gave information concerning drug prescription patterns in outpatients. HS matched the file with prescription data to another database including the anatomical, therapeutic, and chemical classification of the World Health Organization. BK and HM provided computer based analyses. RB designed the study, coordinated study procedures, determined licence status of prescriptions, analysed the results, and wrote the paper. CG is guarantor.
Funding KM and CG are supported by the German Bundesministerium für Bildung und Forschung, grant 01EC 0001, and the Ministerium für Wissenschaft und Kunst, Baden-Württemberg, Germany. MS is supported by the Robert Bosch Foundation, Stuttgart.