GD — Society for Dermopharmacy
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Extemporaneous Preparations
Risks for Physicians and Pharmacists
Prescriptions at the Limits of the Freedom of Therapy
The Gesellschaft für Dermopharmazie (Society for Dermopharmacy) also tackles "hot issues". This was shown in a workshop organized by its department Extemporaneous Preparations at the beginning of the GD's 4th Annual Meeting in Freiburg in May of last year. The subjects of the workshop, chaired by the department leader Dr. Bernd Hünerbein, were dermatologic "niche drugs" and prescriptions at the limits of the freedom of therapy. Besides dermatologic and pharmaceutical aspects also legal aspects came up for discussion to be taken into account for the prescription or production and dispensing of such formulations.
In compliance with the GD's interdisciplinary character, the organizers had invited two dermatologists and two pharmacists as lecturers: professor Dr. med. Max Gloor, director of the Hautklinik at the Städtische Klinikum Karlsruhe (Dermatological Clinic at the Municipal Clinical Center), and professor Dr. med. Rudolf Happle, director of the Dermatologische Klinik of the Phillips-University Marburg (Dermatological Clinic), as well as Dr. Holger Reimann, leader of the Pharmazeutische Laboratorium of the Neue Rezeptur-Formularium in Eschborn [NRF] (Pharmaceutical Laboratory of the New Prescription Formulatory) and pharmacy-director Rudolf Völler, department head at the regional council in Darmstadt. Gloor expounded in his lecture the difference between standardized and individual extemporaneous preparations and made clear that the individual prescription should be exceptional for the cases in which the therapy target cannot be achieved in a different way.
 GD-member of the board Dr. Holger Reimann (right) reported about his experience with the Rezeptur-Hotline of the NRF (prescription-hotline). |
Reimann informed of his experience with the NRF Rezeptur-Hotline (prescription-hotline). This hotline is at the pharmacists' disposal mainly as coordinating body for galenic problems in everyday's prescription routine as well as for questions regarding the pharmaceutical quality of prescription drugs. The majority of the questions concern unstandardized individual prescriptions and prescriptions of medicinal agents which are either not at all available in ready-to-use drugs or only in completely different concentration, indication or preparation (please refer to annex 1 of this online-version). Such exceptional prescriptions are not only challenging for the pharmacist in the pharmaceutical-technical sense but they also oblige him to check the legal admissibility of the prescription and to eliminate any lack of clarity by consulting of the prescribing physician.
| Fax-Hotline
of the Neue Rezeptur-Formularium [NRF] (new prescription formulatory): +49/6196/928-330 |
Legal Aspects of
Prescriptions
In his lecture Völler touched upon the penal and liability risks relevant for physician and pharmacist in this context (the lecture is also available as article in this German online-version of DermoTopics).
As opposed to the Anglo-American linguistic region, there is no explicit regulation on how to proceed if drugs and substances are to be applied in the individual case which have not yet been subject to testing in a certain indication field. The prescribing physician has to perform an individual benefit-risk assessment in any case according to the medicinal state-of-the art. The pharmacy fulfils the constituent facts of the commercialization with the dispensing of the prescription. The responsible pharmacist has to check, therefore, whether or not the prescribed drug is qualified for commerce. If the test, however, reveals that the drug has to be rated as critical after assessing of all facts, then the pharmacist has to refuse the dispensing of the drug and to inform the physician accordingly. The prohibition of the commercialization of critical drugs according to § 5 of the Arzneimittelgesetz (drug act) has priority over the physician's freedom of therapy in such a case.
 Pharmacy-director Rudolf Völler is responsible for the field of pharmaceutical products and preparations at the regional council of Darmstadt. An abrigded version of his lecture can be looked up as annex 2 of this online-version of DermoTopics under the title "Off-label Use and Compassionate Use in Dermatology - Penal and Liability Risks for Physicians and Pharmacists". The complete version of the article is also available in this online-version in German. |
An example for a treatment not yet established in dermatology is the local therapy of the alopecia areata with diphenyl-cyclopropenone (DCP), presented by Happle. As Happle reported, DCP is applied for the topical immune therapy of the alopecia areata without the drug having an authorization as medicinal substance. Whereas the effectivity proof according to scientific standards can be considered as being accomplished, the question as to the safety profile of the substance cannot be answered in a satisfactory manner until today. Due to the fact, however, that similarly effective treatment alternatives are not available, the ethics commissions, consulted in Germany, have consented to the application of this substance with humans in general. The treatment method is, however, relatively demanding and should therefore be reserved to pharmacists having sufficient experience. Unwanted attendant symptoms are exuberant eczema reactions, haematogenic dispersion to other parts of the body as well as a hyper- or hypopigmentation in rare cases, sometimes also in combination as "dyschromia in confetti". Children below ten years of age should be excluded from this treatment due to general safety reasons.
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Annex 1
Scientifically challenging, exceptional, indistinct, questionable or a cause for concern - dermatological prescriptions in the focus of the NRF-Rezeptur-Hotline (NRF-prescription hotline)
Dr. Holger Reimann, Laboratorium of the Neue Rezeptur-Formularium [NRF] (laboratory of the new prescription formulatory), Eschborn.
The pharmaceutical profession maintains several coordinating bodies for the support of suddenly emerging problems in the running prescription routine of pharmacies. The Rezeptur-Hotline (prescription hotline) of the NRF Pharmazeutische Laboratorium (Pharmaceutical Laboratory) mainly offers support regarding galenic difficulties and questions concerning the pharmaceutical quality. In this respect the prescriptions submitted to the hotline - predominantly medically prescribed - are not representative for the experienced dermatological prescriptions. However, they inform of the medicinal substances prescribed, not yet or no longer realized in ready-to-use drugs or only in considerably different concentration, indication or preparation in Germany respectively world-wide prefabricated available.
Pharmacies frequently face problems in this context in order to ensure the demands - pharmaceutical quality, effectiveness, safety and conformity with the prescription. Unusual prescriptions (in most cases not standardized individual prescriptions) not only challenge the pharmacist in a pharmaceutical-technical way. Since he has to eliminate lacks of clarity before the preparation, he can clear up doubts concerning the dosage and admissibility of the prescription in many cases only by consulting of the prescribing physician. Sometimes a decision is even then difficult if the type of application, the intended use and the indication are known. In this area of conflict between medical freedom of therapy for the well-being of the patient and legal provisions for the protection of the patient, appropriate solutions have to be found.
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Exceptional prescriptions |
Application; |
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Acetylsalicyl acid-solution/-ointment/- shaking mixture 5 % |
Postzosteroid neuralgias |
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Androstanolone gel 2,5 % |
Climacteric complaints |
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Allopurinol mouth-rinsing 0,1 % |
Fluorouracil-induced mucositis |
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Allyl mustard oil-solution 2 % / - ointment 0,1 % |
Local stimulation therapy |
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Aluminum acetate tartrate ear drops |
External otitis |
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Formic acid-solution |
Concentrated for the wart treatment |
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Aluminium chloride-hexahydrate-solution/-gel 20 % |
Antihidrotic agent |
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Amino-laevulinic acid-cream/-emulsion/-gel 20 % |
Cutaneous photodynamic
therapy ("PTD") |
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Anthrarobine solution 3 % (Arning solution) |
Antieczematic agent?; Antimycotic agent?;Anti psoriatic agent? |
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Benzalkoniumchloride- wound irrigation 1 % |
Antiseptic irrigation with dog bites |
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Betamethasone-21-dihydrogenphosphate-disodium-solution |
Oral immediate action for insect bite allergy |
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Brilliant green-solution 0,05 - 0,5 % |
Antimycotic, antiseptic |
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Calcium gluconate gel 2,5 % |
Antidote with hydrofluoric acid contamination |
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Canrenoate-gel/-cream 1,6 % |
Hirsutism |
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Capsaicin-gel/-cream 0,025 - 1 % |
Postzosteroid neuralgias |
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Chlorophylline-ointment |
Wound treatment |
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Ciclosporine mucous membrane contact gel 1 % |
Oral lichen planus |
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Clotrimazole ear drops 1 %, unctuous |
Antimycotic |
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Caffeine ointment |
Cellulite |
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Cyproteronacetate-gel/-emulsion 1 % |
Alopecia androgenetica, acne vulgaris, hirsutism |
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Dehydroepiandrosterone gel 2,5 % |
Climacteric complaints |
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Diphenylcyclopropenone-solution 2,5 % |
Topical immune therapy |
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Ferro(III)-chloride-solution, 1 - 10 % of iron |
Hemostasis |
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Eosin-solution 0,5 - 2 % |
Astringent, antiseptic |
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Acetic acid ear drops 0,7 % |
Otitis externa |
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Acetic acid irrigation 2 - 5 % |
Removal of nits |
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Fuchsine solution 0,05 - 0,5 % |
Antimycotic, antiseptic |
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Glyceroltrinitrate-cream 0,3 % |
Anal fissures |
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Glycolic acid-solution/-gel/-cream 0,06 - 70 % |
Peeling, sauriasis treatment |
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Wood tars (pix liquida, - juniperi, - betulina, - fagi) |
Antiprurigenic, Antieczematic |
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Hydroquinone-cream 2 - 5 % |
Bleaching agent |
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11-a-Hydroxyprogesterone-solution |
Alopecia androgenica |
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Iontophoresis gel with indometacine, lidocaine or anionic glucocorticosteroid-derivatives |
Intensification of the local effect |
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Isosorbide dinitrate-cream 1 % |
Anal fissures |
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Potassium iodide-ointment 50 % |
Onycholysis |
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Khellin-solution/-gel/-cream 2 % |
Vitiligo treatment |
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Copper(II)-sulphate-solution 1 % (aqua d´Álibour) |
Astringent |
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Lidocaine-DMSO-ear drops 5 % |
Local anaesthetic (eardrum) |
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Methylrosanilinechloride-solution 0,05 - 0,5 % |
Antimycotic, antiseptic |
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Metronidazole-gel/-cream 0,5 to 5 % |
Rosacea |
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Metronidazole-solution 1 % |
Wound treatment |
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Minoxidil-solution 2 % |
Hair restorer |
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Nandrolone decanoate-cream 0,04 % |
Phimosis treatment of children |
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2-naphthol-ointment 8 % |
Wart treatment |
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Sodium nitrite-5% / ascorbic acid -5% - gel |
Raynaud-syndrome |
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Oxytetracycline hydrochloride-cream 1 % |
Acne vulgaris |
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Paromomycine sulphate vaseline 15 % with methylbenzethoniumchloride |
Cutaneous leishmaniasis |
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Permethrine-cream 2,5 - 5 % |
Antiscabetic agent |
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Phenol-oil 5 % |
Sclerotherapy; neurolytic agent |
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Phenylalanine-suspension 20 % (m/V) |
Orally before ray treatment with vitiligo |
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Podophylline-solution/-gel/-ointment 2 - 20 % |
Condyloma |
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Polyhexanide-solution/-gel 0,04 % |
Wound treatment |
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Povidone iodine sugar paste |
Wound treatment |
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Povidone iodine eye drops 5 % |
HIV postexpositional infection prophylaxis |
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Squaric acid dibutylester-solution |
Topical immune therapy |
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Scopolaminehydrobromide-ointment 0,1 - 5 % |
Frey-syndrome (gustatory perspiration) |
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Silver nitrate-solution/-ointment 0,5 - 1 % |
Astringent |
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SKAT-solution (Papaverine phentolamine mesylate injection-solution |
SKAT (erectile impotence) |
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Sulphanilamide-solution/-ointment; also other sulphonamides |
Cutaneous application |
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Tacrolimus-gel |
Neurodermitis |
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Tannic acid-solution 40 % |
Anal fistulae |
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Testosteronepropionate-cream/-ointment 2 % |
Lichen sclerosus et atrophicus Pre-operative enlargement of the penis with congenital malformations |
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Tetracycline hydrochloride cream 3 % |
Acne vulgaris |
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Tiabendazole-cream 10 % |
Cutaneous Larva migrans |
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Tretinoine-ointments (lipophil); - mucous membrane contact gel |
Presbyderma; lichen ruber planus |
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Tribromphenolbismut-formulations |
Antiseptic, astringent |
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Triclosane-cream 3 % |
Antiseptic |
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Zinc chloride-solutions 0,1 - 50 % |
Wound treatment; caustic agents. Sclerotherapy with hemorrhoids |
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Annex 2
Off-Label Use and Compassionate Use in Dermatology - Penal and Liability Risks for Physician and Pharmacist
Government pharmacy-director Rudolf Völler, department II 15 D, regional council, Darmstadt
The drug law explicitly provides the use of unauthorized drugs. The dispensing is intended to take place exclusively in pharmacies, disregarding drugs scheduled for clinical examination. Differently than in the Anglo-American linguistic region there is no special regulation on how to proceed if drugs and substances which have not yet been tested in a certain indication field are to be used in an individual case.
First of all it has to be determined that the individual rededication of a drug by the physician is in general covered by medical freedom. It has to be emphasized, however, that also in this case the regulations as usual in the profession and standards of the criminal law are to be applied. The drug law, however, is not valid here. Yet in the moment when the physician or patient obtains drugs by a third party, the latter performs the constituent fact of commercialization. The facts of the case of the Arzneimittelgesetz (drug law) - the correct name of which is Gesetz über den Verkehr mit Arzneimitteln (Law of Drug Commercialization) are pertinent. The manufacture of drugs in the individual case and on prescription by physicians through pharmacies is anchored in history. Thus there have been recognized formulatories or collections of formulations in both parts of Germany for years, the pharmacopoe contain formulations with acknowledged benefit-risk relations. Penal and civil law problems are at best discernible when elementary errors have occurred in the course of the production or application. The drugs without authorization can be prepared by the pharmacy in the individual case and dispensed to the patient in the pharmacy. Further details are regulated in the Apothekenbetriebsordnung (Pharmacy Operation Procedure). In case of frequent prescription of these drugs, the exception of the so-called 100-rule (§ 21 chapter 2 no. 1 AMG) applies which allows pharmacies to prepare limited quantities of ready-to-use drugs. Particularly the stipulation that the preparation in its essential manufacture steps has to take place in a pharmacy makes clear that a large-scale production of preliminary stages outside of pharmacies is not intended. The risk liability of §§ 84 f. Arzneimittelgesetz [AMG] (Drug Law) is excluded for these drugs. Claims as to liability and damages can however be asserted under civil law.
The individual terms of the § 21 chapter 2, no. 1 AMG are as follows:
- Intended for the application with humans
- on the basis of proven frequent medicinal or dental prescription
- in essential preparation steps in a pharmacy
- in a quantity up to hundred sale packets per day
- prepared in the course of the usual pharmacy routine
- intended for the dispensing in pharmacies.
The situation, however,
gets completely different if developments of new substances rouse the
expectation to use the substance as early as possible. The responsibility
cannot be taken on to apply substances for which a benefit-risk assessment
is not possible. Also in single exceptions it has to be made a rule to
implement the procedure steps for the development of new drugs (GLP, GCP,
GMP) until a safe clinical assessment is possible. It has to be emphasized
in this context that the clinical checks can evaluate effects but a safe
determination of unwanted effects (incidence 1:1000 upwards) is not possible.
Procedural steps for the development of new drugs are:
- Evaluation according to GLP
- In the preclinic according to GLP
- Clinical examination phases 1 - 3
- Authorization
- Specific observation and reporting obligations
Hence a reliable benefit-risk assessment is the no. 1 problem for new substances. Planning and implementation of the application should furthermore come up to the essential conditions of clinical tests in principle. An information of the patients as well as his consent are inalienable. The preparation of the medication is effected by the pharmacy dispensing the drug.
This commercialization raises questions in the case if there is a sponsor behind the treatment concept who propagates a systematical application of new drugs. In this case the individual treating physician is no longer the initiator rather at least an initial suspicion comes about that the new treatment concept is to be used without thorough scientific testing (e.g. preparation steps have been excluded artificially in order to avoid the clinical test or authorization procedure). But clinical tests are also possible if a treatment concept is to be tested and the authorization is not the target.
As soon as a drug
is applied for a different indication or group of people (children) (off-label-use),
a new authorization or amendment of the authorization is required. In
this case an assessment of the benefit-risk relationship is often easier,
as an extensive amount of data is already available. The regulations of
the risk liability of the drug act are not applicable in the damages case
as the use as directed, designates the application in the indication field.
This does not exclude the pharmaceutical entrepreneur reaching an agreement
with the insurance company in question in the individual case before.
Concluding it must be referred to the Heilmittelwerbegesetz (Medicine
Advertising Law).
Law about the advertising in the field of health care 3
§ 3a
Advertising for drugs subject to the obligation of authorization and not
authorized according to the stipulations contained in the drug law or
considered as being authorized is inadmissible.
In general the penal code permits deviations from laws in exceptional
situations: justifying / legal emergency (§ 34 StGB): "Who commits
an offence out of a present hazard for life, limb, liberty, honor, property
or another legal asset not preventible in a different way in order to
avert the hazard from oneself or another person, does not act illicitly
if after pondering of the conflicting interests, namely of the legal assets
affected and the degree of the threatening hazards, the protected interest
considerably predominates the impaired one. This, however, is only valid
as far as the offence is an appropriate means to avert the hazard."
It is recommendable
in such cases to involve the responsible authorities or to get in contact
with the public prosecutor's office and bring about an agreement. Incidentally
after that, an immediate dispensing of the medication by the pharmaceutical
entrepreneur to the physician is possible (analogy with the channel of
distribution for clinical tests).
The legislator is called upon to reflect on possibilities, include individual
cases for which an application of a not yet finally tested substance is
necessary and a default can also be legally prosecuted (exposure). An
example is the regulation in the US (compassionate use) in which the principles
of responsible acting are formulated, however, in Germany not yet implemented
in effective law.
Compassionate Use
Compassionate or named patient use of a drug
- should be strictly controlled by the company responsible for providing the drug and
- should ideally be the subject of the protocol.
The company should
- provide the prescribing physician with suitable forms and remind him / her of the
- the requirement to report suspected adverse drug reactions to the company and / or to the appropriate competent authority.
Companies should
- continuously monitor the balance of benefit and risk of drugs used under such conditions and
- follow the national
requirements for reporting to the appropriate
competent authorities.