Dermatological extemporaneous preparations - guidelines for dermatological prescription
Established by a consensus conference at Eschborn on 18 November 1998 and authorized by the department "extemporaneous preparations" of the Society of Dermopharmacy.
Preamble - Dermatological prescription stands for prescription, manufacturing and marketing of topica, which are prepared under the responsibility of a pharmacist - in general for each individual case - in a public pharmacy or hospital pharmacy. The prescription is oriented by special circumstances for single patients. In a narrower sense prescription designates as well the prescription formula and the prescription drug. Dermatological extemporaneous preparations is often spoken of if prescriptions have proved a success from experience or if rationally justified recommendations in relevant publications, especially collections of corresponding suggestions are made use of. Particular importance in connection with the standardization of prescription bases and prescription in Germany is given to the effective pharmacopoeia - possibly also to former editions including the pharmacopoeia of the ex-German Democratic Republic (GDR) - and in addition to the DAC and the NRF. We speak of individual prescription if such data is not made use of.
As far as pharmaceutical quality and benefit-risk-assessment is concerned, physicians and pharmacists fulfil their responsibility towards their patients for dermatological extemporaneous preparations in a special way by orienting as far as possible in agreement with actual principles and transforming them into professional practice. The benefit thereby consists in the treatment of skin organ diseases aiming at their elimination; there may be a risk of local and systemically mediated unwanted drug effects at the patient treated and/or a pollution of the human environment.
An essential importance in the field of dermatological prescription is attached to the Quality Management. In this context the individual physicians and pharmacists bear equally responsibility as chambers, specialized societies, professional associations and drug manufacturers, who provide components. The quality of the dermatological prescription is to be looked at under the aspects of structure- , process and result quality individually as well as in its entirety. Measures of internal and external quality control (ring experiments) have to be strived for.
The guidelines integrate important demands which had already been formulated as priorities from the medical point of view in the form of a commission resolution "extemporaneous preparations" of the DDG (see references) in 1997. They combine moreover the interests of the dermatological prescription and drug therapy with the pharmaceutical possibilities and the principles of the good pharmaceutical practice within the frame of effective laws.
1) Therapeutical concept - Extemporaneous preparations open up for a wide spectrum for individual approaches within the dermotherapy. The therapy conception chosen by the physician defines the quality requirement to the prescription drug and has to be recognizable in essence from the prescription; this also includes indications regarding the application by the pharmacist. If this is not the case a check back towards the physician is required (refer to chapter 2).
The pharmacist has to support this conception of preparation and sale of the prescription. This applies in particular by considering the non-objection of the components for the mode of application in question, tolerance, galenic characteristics, hygiene, sufficient preservation, stability, marking, applicability and packaging. He is to further the patient's compliance. If necessary lacks of clarity and objections have to be cleared up jointly by physician and pharmacist.
2) Interdepartmental cooperaton and protection from errors - In order to avoid delays and errors, dermatological prescriptions have to be made out in a precise and unequivocal manner. Salts respectively solvates or derivatives of components have to be named correctly in order to avoid misdosage or inefficiency. In case of recognizable errors, the pharmacist has to eliminate the lack of clarity by getting in contact with the physician before starting of the preparation process. Also in the case that the real intention of the prescribor is sufficiently perceptible, at least a subsequent information should follow in order to avoid repetitions.
Furthermore, consultations on a regular basis are necessary before preparing of such extemporaneous preparations containing contested drug substances (refer to chapter 4) which consist partly of ingredients whose quality can only be conditionally secured (refer to chapter 3). This also applies to extemporaneous preparations the exact mode of application of which is indistinct (refer to chapter 1 and 10), resp. no or only insufficient effectiveness can be expected due to interactions of ingredients or their pharmaceutical quality would be unsatisfactory without modification of the prescription formula due to various reasons (refer to chapter 7 and 9).
A restriction to one or few drug concentrations at ready-to-use drugs for topical application is an essential motive for the prescription of extemporaneous preparations with individually varying concentrations. In this context deviations from the standard concentration may be intended or based on an error. Due to the fact that drugs at too high a concentration may considerably endanger patients, selected dermatic active substances with so-called upper therapeutical recommended concentrations are listed in the NRF (table 1.6-1) on suggestion of the DDG commission of extemporaneous preparations. If these concentrations in prescriptions are exceeded the physician is to stress his intention by making an exclamation mark. In case such an indication is missing, the pharmacy has to eliminate the lack of clarity before preparing the drug.
3) Quality of ingredients -The quality of prescription components which the pharmaceutic laws call for has to be realized and given reference for. This is why in principle only raw materials and preparations certified according to ApBetrO (Pharmacists'Rules and Regulations), authorized or registered and prepared according to PharmBetrV (pharmacists' directive) ready-to-use drugs or substances prepared in pharmacies in accordance with approved pharmaceutical instructions (e.g. purified water) may be prescribed for prescriptions, processed and marketed.
When processing other components (e.g. brand bases) the decision lies with the pharmacist whether the required quality is available. Technical products as prescription components are generally unsuitable.
Some prescription base materials may vary considerably as to content or activity or show a significant short content, e.g. at a major drying loss. Is the actual share of active substances below 95 % of the raw material, then its weighing in the process of preparation should be corrected by the so-called "factorizing" as recommended in the NRF (NRF, Table 1.2.-1).
4) Concerns and pharmacologic-toxological contested components - Physicians and pharmacists are to consider the actual state of the art in the medical and pharmaceutical sciences when assessing any objections as it can - among others - be gathered from statements of the BfArM resp. the AMK and the AKdÄ as well as from scientific contributions in professional journals. The monographs which have been made known in public in connection with the subsequent approval of ready-to-use drugs by processing of scientific findings have to be considered for the assessment. In case of doubt information has to be obtained, e.g. from institutions as chambers, specialized societies and professional associations or competent authorities.
It is not allowed to prescribe, prepare nor sell contested prescriptions. Concerns - among other causes - can merely and directly result from the pharmacologic-toxicological properties of certain medicinal substances resp. other prescription components or develop from the interplay of components or come about against the background of intended doses, concentrations, type and duration of application.
A benefit-risk-assessment for pharmacologic-toxicological contested components resp. prescriptions has to be made against the background of therapeutical alternatives. For negative monographs or otherwise prevailing negatively classified components (or prescriptions) a benefit-risk assessment has to be carried out individually for each isolated case. Above all an exceptionally positive judgement should be documented in writing, e.g. by means of the pattern according to NRF, illustration 1.5-1. Economical aspects mustn't play a part in this context.
5) Medicinal agents and drug combinations - Extemporaneous preparations should be composed in accordance with rationally comprehensible points of view and always contain medicinal agents in therapeutical effective concentrations. Two or more pharmaceutical effective substances should only be used in well-founded exceptions for drugs used for topical applications.
In times of a permanently increasing number of medicinal agents, the use of multiple combinations is not only more and more difficult to understand but also complicated to assess and to safeguard as to their pharmaceutical quality. This refers in particular to the preparation of ready-to-use drugs in a prescription (see chapter 9).
For the dilution of a ready-to-use drug the identical base should ideally be used - at least for a base of the same type.
6) Packaging and safety of application - Extemporaneous preparations have to be packaged in a way to ensure the required drug quality within the designated application period and allow a safe use of the drug according to its intended purpose. Packaging recommendations by the AMK, the NRF and the ZL are to be considered. If available, primary packing material with certification according to up-to-date specific standards should be used, e.g. pursuant to enclosure H of the DAC or the ZL-packaging regulations.
7) Preservation and hygiene - Dermatologic extemporaneous preparations have to be prepared in a hygienical faultless manner and also stay in this state during the application period, i.e. in certain cases sterility, in general a germ number limitation of not more than 100 germs per gram resp. milliliter under exclusion of certain indicator organisms and pathogenic agents. This is why only hygienically safe base substances (including water) as well as packing materials and only approved working techniques may be used. The institutions of chambers, specialized societies and professional associations are called upon to establish detailed recommendations adapted to pharmacies' requirements in this connection.
Extemporaneous preparations susceptible to microbes should be protected from microbial perishing - as a matter of principle - by adding a suited preservative. In case a preservation cannot be employed, the physician has to make a note accordingly ("preservation free"). Contained preservations have to be marked (refer to chapter 10).
8) Stability - Missing long-term stability may be responsible for the lack of ready-to-use drugs with certain medicinal agents or on the basis of certain dermatic bases. This may be an essential reason for the prescription of such extemporaneous preparations. Extemporaneous preparations only have to be stable during the designated application period.
For ready-to-use drugs, stability and use-up deadline at the patient's have to be distinguished. Concerning individually prepared prescription, however, prescription, preparation, sale and starting of use coincide as a rule in such a short period of time that in this case stability before use and use-up deadline only play a part for sterile drug types. Prescriptions should be marked with a definite final date of the term of use for sale (see NRF, paragraph 1.4, general indications, especially tables 1.4.-2 and 1.4.3), e.g. "not to be used after ....".
Drug master preparations and dermatic bases used in pharmacies underlie different systematics (see NRF). The use of opened packs of ready-to-use drugs for prescription purposes in pharmacies is to be limited in time in a reasonable way; for example the NRF approximative values for terms of consumption as from starting of use may alternatively be used without, however, overstepping the expiry date stipulated by the manufacturer.
9) Avoidance of incompatibilities and standardized prescriptions - Incompatibilities between prescription components and between prescriptions and their primary packaging materials can be avoided when reducing to ready-to-use drugs and standardized instructions, e.g. according to SR or NRF. As far as ready-to-use drugs or analogous NRF-prescriptions are available, individually composed prescriptions should only be made out in special justified cases.
When processing drugs in single composed dermatic bases from recognized and generally accessible instructions (for example from DAB, DAC, SR or NRF) possible incompatibilities may be predicted to a great extent and can be avoided by switching to alternatives.
Prescriptions on the basis of brand bases or ready-to-use drugs should only be prescribed if experimentally secured data concerning the physical, chemical and microbiological quality and stability on the part of the pharmaceutic producer can be presented for the scheduled treatment over an appropriate period.
As far as possible within a given context, priority should be given to those prescriptions which are contained in approved and generally accessible instructions (for instance in DAB, DAC, SR, NRF, standardized approvals or ADKA-regulations).
10) Marking and patient information - Extemporaneous preparations in prescriptive preparation are to be marked by the pharmacy according to ApBetr0 (pharmacy operation regulation). In precising and completing the mentioned obligatory declarations therein, it is recommendable to indicate the information in German language.
The designation of medicinal agents mustn't be abbreviated or indicated in a way that the patient respectively consignee might be deceived or mislead about the content. Drugs for topical applications containing glucocorticoids are to be marked "containing cortisone!".
Pharmaceutically effective ingredients have to be marked as to type and quantity. For standardized prescriptions from approved and generally accessible instructions, e.g. giving explicit reference to SR or NRF, the designation of the prescription is sufficient if it reflects unequivocally the contained medicinal agent (or the contained medicinal agents) concerning the type and concentration respectively dose.
All contained components for not standardized prescriptions have to be marked as to type and quantity. If a prescription base from approved and generally accessible regulations is employed (for example from DAB, DAC, SR or NRF) it is sufficient to indicate the designation of the processed prescription base; it is not necessary to mention the single components of the prescription base. When processing ready-to-use drugs as components of prescriptions it suffices to list the designation of the integrated ready-to-use drug; it is not required to indicate the medicinal agent (or the medicinal agents) of the ready-to-use drug and the other components.
Included preservatives have to be indicated in German as well for standardized prescriptions from authorized and generally accessible instructions (for example from NRF or SR), for medicinal-agent-free bases from authorized and generally accessible regulations (e.g. from DAB, DAC, SR or NRF) and in addition for prescriptions prepared on the basis of such bases regarding type and quantity.
Extemporaneous preparations which are obtainable on prescription have to contain instructions for use. These instructions have to be transfered to the drug in the pharmacy. This marking is to be adequate in order to exclude misuse with a sufficient certainty if a comprehensive written patient information is missing.
11) Unintended drug effects- Physicians and pharmacists are to document observations about not intended drug effects also for extemporaneous preparations (see recording form according to NRF, illustration 1.5-2). It is recommendable to document and deposit a copy in the pharmacy respectively doctor's practice.
12) Dermatological and pharmaceutical permanent training - An appeal is made to the institutions of chambers, specialized societies, professional associations and drug producers to incorporate the actual state of knowledge regarding a rational handling of dermatological extemporaneous preparations during university studies and permanent professional training of physicians, pharmacists and assistant professions concerned as well as to promote interdepartmental cooperation.
13) Glossary: ABDA: ABDA - Bundesvereinigung Deutscher Apothekerverbände (Federal Association of German Pharmacist Unions). ADKA: Bundesverband Deutscher Krankenhausapotheker (Federal Association of Hospital Pharmacists). AKdÄ: Arzneimittelkommission der deutschen Ärzteschaft (Drug Commission of the German Medical Profession). AMG: Arzneimittelgesetz (Drug act). AMK: Arzneimittelkommission der Deutschen Apotheker (Drug Commission of German Pharmacists). ApBetrO: Apothekenbetriebsordnung (Pharmacies' Rules and Regulations). BApÖD: Bundesverband der Apotheker im öffentlichen Dienst (Federal Association of Pharmacists in Civil Service). BfArM Bundesinstitut für Arzneimittel und Medizinprodukte (Federal Institute for Drugs and Medicinal Products). DAB: Deutsches Arzneibuch (German Pharmacopoeia). DAC: Deutscher Arzneimittel-Kodex (German Drug Code). DDG: Deutsche Dermatologische Gesellschaft (German Dermatological Society). GD: Gesellschaft für Dermopharmazie (Society for Dermopharmacy). NRF: Neues Rezeptur-Formularium (New Prescription Formulary). PharmBetrV: Betriebsordnung für pharmazeutische Unternehmer (Rules and Regulations for Pharmaceutical Entrepreneurs). SR: Standardrezepturen 1990 (DDR) (Standard Prescriptions 1990 (GDR)). Standardzulassungen (Standard Registrations): Sammlung von Monographien zu Arzneimitteln gemäß § 36 AMG, die von der Pflicht zur Einzelzulassung befreit sind (Collection of Monographs concerning drugs in accordance with § 36 AMG, which are released from individual registration). ZL: Zentrallaboratorium Deutscher Apotheker (Central Laboratory of German Pharmacists).
14) References: 1. Meigel, W.N., Altmeyer, P., Jahn, S., und die DDG-Kommission "Magistrale Rezepturen", Empfehlungen zu "Magistralen Rezepturen" erarbeitet, Hautarzt 48, 702 (1997). Siehe auch Dt. Derm. 45, 600 (1997). 2. ABDA - Bundesvereinigung Deutscher Apothekerverbände (Hrsg.), Abbildungen 1.5.-1 und 1.5.-2 sowie Tabellen 1.6.-1,1.2.-1,1.4.-2 und 1.4.-3, Kapitel Allgemeine Hinweise, Neues Rezeptur-Formularium (NRF), Bände 3 und 4 zum Deutschen Arzneimittel-Codex (DAC), Loseblattsammlung auf dem Stand der 14. Ergänzung 1998, Govi-Verlag, Eschborn / Deutscher Apothekerverlag, Stuttgart. 3. Fachgruppe "Magistralrezepturen" der GD, Hygiene-Richtlinie für die Herstellung von Arzneimitteln in der Apotheke (in Bearbeitung).
15)Participants of the GD-Consensus Conference "extemporaneous preparations" - Prof., Dr. med. Peter Altmeyer, Bochum, Vorsitzender der DDG-ad hoc-Kommission "Magistrale Rezepturen". Prof. Dr. Volker Dinnendahl, Eschborn, Leiter der Arzneimittelkommission der Deutschen Apotheker. Apothekerin Rosemarie Eifler-Bollen, Eschborn, ZL - Zentrallaboratorium Deutscher Apotheker. Dr. med. Joachim von Essen, Hamburg, Sonderreferent für Dermatologische Rezepturen im Berufsverband der Deutschen Dermatologen. Prof., Dr. med. Max Gloor, Karlsruhe, GD-Fachgruppe Magistralrezepturen. Apotheker Dr. Bernd Hünerbein, Naumburg, Vorsitzender der GD-Fachgruppe Magistralrezepturen. Dr. med. Winfried Klövekorn, Gilching, Vorstand der GD; Vorsitzender des Bezirksverbandes Oberbayern im Berufsverband der Deutschen Dermatologen. Prof. Dr. med. Hans Christian Korting, München, Stellvertr. Vorsitzender der GD; Vorsitzender der Kommission Therapie der DDG. Apotheker Dr. Joachim Kresken, Viersen, Vorsitzender der GD. Prof., Dr. Bernhard. C. Lippold, Düsseldorf, Institut für Pharmazeutische Technologie der Heinrich-Heine-Universität. Apotheker Jürgen Maurer, Wetzlar, Zentralapotheke im Klinikum Wetzlar; Leiter Arbeitskreis Herstellung und Analytik ADKA Hessen. Apotheker Dr. Holger Reimann, Eschborn, Pharmazeutisches Laboratorium des NRF; Schriftführer der GD. Apotheker Dr. Hans W. Reinhardt, Offenbach, Stiefel Laboratorium GmbH. Apotheker Dr. Rainer Rogasch, Waldeck, Repräsentant der APV-Fachgruppe Arzneimittelinformation und Apothekenpraxis. Apotheker Dr. Hartmut Schmall, Trier, Präsident der Bundesapothekerkammer. Regierungspharmaziedirektor Rudolf Völler, Darmstadt, Repräsentant BApÖD. Dr. Petra ZaDeutschn-Muncke, Eschborn, Wissenschaftliches Sekretariat der Arzneimittelkommission der Deutschen Apotheker. Prof. Dr. Jochen Ziegenmeyer, Berlin, BfArM - Bundesinstitut für Arzneimittel und Medizinprodukte.
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