Submitted: 23 February 2012; Revised manuscript received: 16 May 2012; Accepted: 23 May 2012
The latest version of the guidelines was prompted by a renewed interest in generics substitution. The first edition of the guidelines was published following the introduction, in 1988, of a financial rule for pharmacists that offered them a fee of one-third of the price difference between a generic and a brand-name drug per substitution. This rule changed many times thereafter, but in year 2000 the interest in substitution rose again, partly for financial reasons and partly because ‘prescribing on generics name’ had been introduced. An updated version of the guidelines was deemed important for pharmacists as an instrument to weigh out the risks and benefits of substitution based on patient safety.
Generics substitution is defined as the mutual substitution of medicinal products having the same active ingredient, the same strength, and the same dosage form. Substitution of medicinal products with different dosage forms and therapeutic substitution is excluded from the scope of the Dutch guidelines.
Every drug given marketing approval has been rigorously evaluated by licensing authorities and can be safely dispensed by any pharmacist. Legally, however, the pharmacist has to dispense only the prescribed product, and substitution requires the physician’s consent. This is especially relevant to branded products. In practice, in a local healthcare setting, this usually means that physicians and pharmacists reach agreements about substitution. When a drug is prescribed using a generic name, the pharmacist will dispense the most cost-effective formulation.
The decision on whether to substitute or not is determined by the degree of similarity of the products in question. For the market approval of generic drugs, pharmacokinetic bioequivalence studies are required. The European Medicines Agency (EMA) regards products as bioequivalent if the AUC ratio and Cmax results of comparative bioavailability studies produce a 90% confidence interval within 80.00–125.00% of the reference product. For narrow therapeutic index drugs the AUC limits are 90.00–111.11%, and similar Cmax is only required in specific situations .
However, for drug substitution, other factors may be involved besides pharmacokinetic bioequivalence, as explained in the guidelines.
Guidelines for generic medicine substitution in community pharmacies
When dispensing a licensed generic drug alternative for the first time, it is assumed to be as safe and efficacious for the patient as the innovator product.
However, when repeat dispensing is required for chronic use there may be situations–described in detail below–when caution is indicated before substitution:
When substitution is unavoidable, for example, when the innovator product is out of stock, the pharmacist should inform the patient properly, indicating the differences and similarities between the drugs in question. The patient should be warned not to take both drugs simultaneously and asked to monitor their drug responses in terms of efficacy and adverse reactions.
Generic products are tested for bioequivalence with the brand product as a reference. This means that the difference between two generic products can exceed the limit that is accepted for bioequivalence between a generic product and the reference product. If product A is bioequivalent with the reference product in the upper boundary of the AUC and product B in the lower boundary, these two generics versions are considerably different. Proper product information is mandatory in such a situation. The difference between two generics can be greater than the difference between a generic and a single reference product.
Although there may appear to be bioequivalence in a given small volunteer population, in practice, some patients experience problems following generics substitution. In most cases there is no satisfactory scientific explanation, but the patient’s responses to substitution should always be taken seriously.
Marketed medicines that have been tested for bioequivalence should in general be substitutable. However, caution in substitution is warranted in certain situations. To provide support to the pharmacy community, KNMP has issued a set of guidelines to promote a responsible substitution process in community pharmacies. This should help to maintain professional standards which in turn should help protect patients against harm caused by the effects of product substitution.
The English version of the published Guideline for generic substitution is available for download on the KNMP website as well as GaBI Online.
A brief article detailing the process followed when drafting the guidelines is published on GaBI Online, available from: www.gabionline.net/Guidelines/Guidelines-for-substitution-of-generics-in-The-Netherlands
Competing interests: None. Dr Leonora Grandia declared that there is no competing interest in substitution besides being the author of the Guideline for generic substitution of KNMP. Professor Arnold G Vulto was involved in commenting on the draft guidelines.
Provenance and peer review: Commissioned; externally peer reviewed.
Professor Arnold G Vulto, PharmD, PhD
Deputy Head Hospital Pharmacy, Professor of Hospital Pharmacy and Practical Therapeutics, Erasmus University Medical Center, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands
1. Guideline for generic substitution. KNMP The Hague, February 2012.
2. Guideline on the investigation of bioequivalence, CPMP/EWP/QWP/1401/98 Rev. 1/Corr**.
3. Guideline on similar biological medicinal products, CHMP/437/04, 2005.
Author for correspondence: Leonora Grandia, PharmD, Coordinator G-Standaard, Royal Dutch Pharmacists Association, PO Box 30460, NL-2500 GL The Hague, The Netherlands
Disclosure of Conflict of Interest Statement is available upon request.
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