Hamre et al.indd Drug Target Insights 2007: 2 209–219 209 ORIGINAL RESEARCH Correspondence: Dr. med. Harald J. Hamre, IFAEMM e. V., Böcklerstr. 5, D-79110 Freiburg, Germany, Tel. +49 761 15 60 307, Fax +49 761 15 60 306. Email: harald.hamre@ifaemm.de Please note that this article may not be used for commercial purposes. For further information please refer to the copyright statement at http://www.la-press.com/copyright.htm Use and Safety of Anthroposophic Medications for Acute Respiratory and Ear Infections: A Prospective Cohort Study Harald J. Hamre1, Anja Glockmann1, Michael Fischer2, David S. Riley3, Erik Baars4 and Helmut Kiene1 1Institute for Applied Epistemology and Medical Methodology, Freiburg, Germany. 2ClinResearch GmbH, Cologne, Germany. 3University of New Mexico School of Medicine, Santa Fe, New Mexico, U.S.A. 4Louis Bolk Instituut, Driebergen, The Netherlands. Abstract Objective: Anthroposophic medications (AMED) are widely used, but safety data on AMED from large prospective stud- ies are sparse. The objective of this analysis was to determine the frequency of adverse drug reactions (ADR) to AMED in outpatients using AMED for acute respiratory and ear infections. Methods: A prospective four-week observational cohort study was conducted in 21 primary care practices in Europe and the U.S.A. The cohort comprised 715 consecutive outpatients aged �1 month, treated by anthroposophic physicians for acute otitis and respiratory infections. Physicians’ prescription data and patient reports of adverse events were analyzed. Main outcome measures were use of AMED and ADR to AMED. Results: Two patients had confi rmed ADR to AMED: 1) swelling and redness at the injection site after subcutaneous injec- tions of Prunus spinosa 5%, 2) sleeplessness after intake of Pneumodoron® 2 liquid. These ADR lasted one and two days respectively; both subsided after dose reduction; none were unexpected; none were serious. The frequency of confi rmed ADR to AMED was 0.61% (2/327) of all different AMED used, 0.28% (2/715) of patients, and 0.004% (3/73,443) of applications. Conclusion: In this prospective study, anthroposophic medications used by primary care patients with acute respiratory or ear infections were well tolerated. Abbreviations: A-: anthroposophy; ADR: adverse drug reactions; AE: adverse events; AM: anthroposophic medicine; AMED: AM medication; C-: conventional; ENE-patients: eligible, not enrolled patients; IIPCOS: International Primary Care Outcomes Study Keywords: Adverse effects, complementary therapies, drug monitoring, otitis media, respiratory tract infections Introduction Anthroposophic medicine (AM) is a system of medicine founded by Rudolf Steiner and Ita Wegman (Steiner and Wegman, 2000). AM is provided by physicians in 56 countries worldwide. A cornerstone of AM therapy is AM medication (AMED). AMED includes more than 2,000 different products of mineral, botanical or zoological origin as well as chemically defi ned substances. AMED are prepared in concentrated form or in homeopathic potencies (IAAP 2005). All AMED are manufactured according to Good Manufacturing Practice and national drug regulations; quality standards of raw materials and manufacturing methods are described in the Anthroposophic Pharmaceutical Codex (IAAP 2005). Almost all AMED in current use have been on the market since the 1970s, some AMED even since the 1920s. Pre-clinical testing, pharmacovigilance reports, surveys, and 190 clinical studies suggest that adverse drug reactions (ADR) to AMED are infrequent and mostly mild to moderate (Kienle et al. 2006). However, safety data from the clinical trials are often sparse, and in two-thirds of the trials, the number of patients using AMED was less than 100. The study IIPCOS-Anthroposophy (International Integrative Primary Care Outcomes Study (Hamre et al. 2005)) provided an opportunity to investigate the use and safety of AMED in a large patient sample. 210 Hamre et al Drug Target Insights 2007: 2 IIPCOS-Anthroposophy was a prospective, obser- vational comparative study of patients with acute respiratory or ear infections seeing AM (n = 715 A-patients) or conventional physicians (n = 301 C- patients). Compared to C-patients, A-patients had more favorable clinical outcomes: adjusted odds ratios were 1.54 (95% confi dence interval 1.03– 2.31) for fi rst improvement within 24 hours, 1.61 (1.16–2.22) for fi rst improvement within 3 days, 1.50 (1.07–2.11) for response (major improvement or complete recovery) within 7 days, and 1.29 (0.82–2.00) for response within 14 days. A-patients were also more satisfi ed with therapy (odds ratio for “very satisfi ed”: 1.39 (0.98–1.95)). Nineteen (2.7%) A-patients and 18 (6.0%) C-patients reported adverse events (AEs) with a possible or probable relationship to medication taken during the study. In the primary analysis (Hamre et al. 2005), these AEs were not further investigated but were all clas- sifi ed as ADR. Here we present a more detailed analysis of AMED use and safety in A-patients from the IIPCOS-Anthroposophy study. Material and Methods Objective and design The primary objective was to investigate the use and safety of AMED. In this study, AMED was defi ned as any medication produced by the phar- maceutical companies Weleda AG, Arlesheim, Switzerland or Wala-Heilmittel GmbH, Eckwälden, Germany. The secondary objective was to investi- gate the safety of all (AMED + non-AM) medica- tions used in AM settings. For this purpose we analyzed physicians’ prescription data and patient reports of AEs in the AM arm of a prospective observational comparative study of AM vs. conven- tional treatment of respiratory and ear infections. Setting, physicians, patients, and therapy The study was conducted 1999–2000 in primary care practices in Austria, Germany, The Netherlands, U.K., and U.S.A. Participating AM physicians were recruited through national AM physicians’ associations. All participating physicians had at least 5 years’ clinical experience and were regularly prescribing at least 75% AMED in acute respiratory and ear infections. Physicians were also required to have computers with internet access available, in order to collect data by remote data entry. The physicians enrolled consecutive outpatients fulfi lling the eligibility criteria. Inclusion criteria were (1) age �1 month, (2) chief complaint of sore throat, ear pain, sinus pain, runny nose or cough, (3) onset of chief complaint within seven days. Exclusion criteria were dementia, schizophrenia, psychosis, spinal cord injury, stroke, renal failure, severe hepatic disease, ongoing immunosuppres- sive treatment, chemotherapy or radiotherapy, alcohol or drug abuse. Patients were treated according to the physician’s discretion. Outcomes Medication use Medication use was assessed (for AMED and for non-AM medications, respectively) by the number of different medications used, the number of users and the number of applications. Patient self- reporting of compliance with medication prescrip- tion was also recorded. Medication safety For each AE the causal relationship of AE to all medication used by the patient between study entry and end of the AE was assessed (probable, possible, improbable, no relationship, unable to evaluate). In addition, the most probable cause of the AE (AMED, non-AM medication, primary illness, intercurrent illness, other) was noted. AEs with probable or possible causal relationship to any medication, confi rmed by this analysis, were clas- sified as confirmed ADR and described as follows: • Name and duration of the ADR, intensity: mild/moderate/severe = no/some/complete impairment of normal daily activities. • Necessary actions taken against the ADR: none, dose reduction/withdrawal/change of medica- tion, admit to hospital, therapeutic counter actions, others. • Outcome of the ADR: subsided, still being treated, uncertain—still under observation, patient lost to follow-up, permanent health damage, patient died. • ADR serious: yes/no (Yes: necessary action: “admit to hospital” or outcome: “permanent health damage” or “patient died”). • ADR expected: yes/no (Yes: ADR previously 211 Anthroposophic medications Drug Target Insights 2007: 2 reported or may be expected because of a known mechanism of action of ingredients). The frequency of ADR (to AMED and to any medication) was assessed in relation to the number of different medications, the number of users, and the number of applications. Data collection On Day 0, the physicians documented primary and concomitant diseases, ongoing medication, and all medication or non-medication therapy prescribed: name, dose, medication form, dosing frequency, number of days prescribed. On Days 7, 14, and 28, patients (for children: legal guardians) were interviewed by telephone. The interviews included the degree of compliance with medication prescription, change in medica- tion, and AEs. AEs were defi ned as any disorders of health, subjective and objective symptoms of illness including changes in laboratory fi ndings, intercurrent medical problems, and accidents observed during the study, regardless of a possible causal relationship to any medication. For patients with complete recovery on Days 7 or 14, study participation was terminated and no further follow- up interviews were performed. Data collection, follow-up interviews, and queries were performed by the Institute for Numerical Statistics (now: Omnicare Clinical Research), Cologne, Germany. Except for patients’ Day 0 questionnaire, all items were documented by remote data entry. For patients with AEs with a probable or possible causal relationship to any medication, according to patient response, the study physicians were contacted by telephone and the following items were checked: diagnosis of chief complaint; complaint-related symptoms and concomitant disease present at study entry; prescribed therapy (name, duration); any consultation between study entry and end of the AE; beginning, end, outcome, and necessary actions against the AE. Information about previously reported or expected ADR was obtained from the manufacturers. AEs were coded according to the World Health Organization Adverse Reaction Terminology. Quality assurance, adherence to regulations The study was approved by local ethics commit- tees and conducted according to the Helsinki Declaration, the International Conference on Harmonisation Good Clinical Practice guide- lines, and legal requirements. Written informed consent was obtained from all patients before enrolment. Data analysis Medication use Patients fulfi lling all eligibility criteria with at least one follow-up interview were included in the prescription analysis. The statistical analysis (SPSS® 13.0.1) was descriptive. For the prescrip- tion analysis, AMED with identical ingredients and dosage form but different concentrations were grouped together. Medication safety The safety analysis comprised all AEs reported by the patient (or legal guardian) as having a possible or probable causal relationship to any medication. For each medication used between study entry and end of the AE, the causal relationship to the reported AE was classifi ed by the fi rst author (HJH) according to criteria formulated in the study protocol (Table 1) as probable, possible, improbable, no relationship or “unable to evaluate”. Results Patient recruitment 26 AM physicians (19 general practitioners, three internists and four pediatricians) from 21 different practices in 20 different municipalities partici- pated. The physicians had an average of 18.0 (SD 8.8) years in practice. 853 patients were enrolled: 715 patients were evaluable for prescription analysis; 138 were not evaluable (protocol violations: n = 98, no follow- up interview: n = 40). The last follow-up interview was performed an average of 16.2 (SD 8.5) days after inclusion. A total of 878 patients were screened but not enrolled: 111 patients refused to participate; 306 did not fulfi ll all eligibility criteria; 461 (100%) screened patients fulfi lled all eligibility criteria (“eligible, not enrolled patients” = ENE-patients). Reasons for non-enrolment of ENE-patients were: physician too busy (68.1%, 314/481 patients), 212 Hamre et al Drug Target Insights 2007: 2 practical/technical (12.1%), ongoing therapy for chief complaint (2.0%), special diagnoses, e.g. mental handicap or scarlet fever (5.6%), other or not specifi ed (12.1%). ENE-patients (n = 461) did not differ from evaluable patients (n = 715) regarding gender or chief complaint severity; ENE- patients were median 1.13 years younger (95% confi dence interval: 0.38–1.95, p = 0.0036) and more ENE-patients were prescribed antibiotics on Day 0 (2.8% vs. 0.8%, p = 0.0153). A total of 83.1% (383/461) of screened, not enrolled patients were prescribed AMED. Patient characteristics The patients were recruited from Germany (50.6%, 362/715 patients), The Netherlands (21.3%), Austria (14.1%), U.K. (7.3%), and the U.S.A. (6.7%). Fifty-three percent (382/715 patients) were females; age groups were 0–17 years (68.1%, 487/715 patients), 18–64 years (30.2%), and � 65 years (1.5%). Patients’ chief complaint was cough (39.9%, 285/715 patients), sore throat (26.3%), ear pain (20.0%), sinus pain (7.0%), and runny nose (6.9%). Physicians’ diagnosis of chief complaint was pharyngitis/ tonsillitis (25.9%, 185/715 patients), bronchitis (19.3%), otitis media (17.2%), laryngitis/tracheitis (15.1%), rhinitis/common cold/upper respiratory infection unspecifi ed (14.4%), sinusitis (7.4%), and other (0.7%). Medication use At study entry, 10.5% (75/715) of patients were using AMED for concomitant diseases, and all patients were prescribed AMED for their chief complaint. During follow-up (Day 1–28), 18.2% (130/715) of patients had at least one further AMED prescription. Altogether 73,443 applica- tions of 327 different AMED were documented, thereof 265 different AMED prescribed on Day 0–28 (Table 2). Eight AMED were prescribed to at least 50 patients each (Table 3), 53 AMED were prescribed to at least ten patients each. The most frequent administration forms were liquids (35.4%, n = 830 of 2,346 prescriptions Day 0–28), pillules (11.2%), powders (11.0%), ointments (8.7%), ampoules (5.8%), tablets (4.7%), and eardrops (3.8%). The most common indications for AMED were acute otitis (18.9%, 467 of 2,468 prescriptions Day 0–28 + ongoing medication), bronchitis (15.7%), laryngotracheitis (14.4%), pharyngitis (9.6%), tonsillitis (9.2%), sinusitis (7.0%), and the common cold (5.4%). In addition to AMED, patients used 12,130 applications of 218 different non-AM medications Table 1. Criteria for classifi cation of causal relationship between adverse events and medication. Probable • Rational temporal relationship to the time of intake of the medication. • AE is already known to be a side effect of the medication or may be expected. • Regression or disappearance of the AE after discontinuation of medication or dose reduction. • Reappearance of the AE after repeated exposure. • AE cannot be explained in a reasonable manner by the clinical state of the patient. Possible • Rational temporal relationship to the time of intake of the medication. • AE is already known as a side effect of the medication or may be expected. • AE could be explained by numerous other factors. Improbable • Rational temporal relationship to the time of intake of the medication. • AE has not been reported so far as a side effect of the medication or cannot be expected. • AE persists after discontinuation of the medication or dose reduction. • Repeated exposure does not lead to reappearance of the AE. • AE could be explained by numerous other factors. No relationship • No rational temporal relationship to the time of intake of the medication. • AE is evidently caused by other factors, e.g. symptom of a concomitant disease. Unable to evaluate • Amount and content of data do not permit a judgment of the relationship to the medication. 213 Anthroposophic medications Drug Target Insights 2007: 2 during the study, altogether 85,573 applications of 545 different (AMED + non-AM) medications. 89.7% (641/715) of patients reported taking their medication as prescribed at all evaluable follow-ups. Safety of anthroposophic medications Reported AEs AEs were reported by 136 patients. The relationship between the medication used and these AEs was, according to patient responses: probable (n = 9 patients), possible (n = 10), improbable (n = 7), no relationship (n = 97), unable to evaluate (n =13). AEs with possible or probable causal relation- ship to any medication, according to patient responses, (n = 19 patients aged 0–53 years, male/ female = 11/8, Table 4) were included in the safety analysis. The intensity of these AEs was mild (n = 17 patients), moderate (n = 1), and severe (n = 1). Median AE duration was 4 days (interquar- tile range 1–7 days). No AE was serious. Between study enrolment and end of the AE the 19 patients had used altogether 62 AMED (thereof 57 different AMED), 32 non-AM medications, and 13 non- medication therapies, with a median of 4 (range 0–8) medications/therapies per patient. For the 62 AMED in question, the causal relationship to the AE was classifi ed as probable (n = 0), possible (n = 2, Table 5), improbable (n = 28), and no rela- tionship (n = 32). The most probable cause of the AE was primary or intercurrent illness (n = 13 patients), non-AM medication (n = 3), AMED (n = 2), other (n = 1). Seven patients reported a total of 11 AE with improbable causal relationship to medication used, according to patient responses: asthma, coughing, diarrhea, dry skin, erythema, hay fever, mesenterial adenitis, rash, rhinorrhea, upper respiratory tract infection, and whooping cough. Ninety-seven patients reported a total of 151 AE with no relationship to medication used; the most common of these AE were: coughing (n = 22 patients), rhinitis (n = 22), diarrhea (n = 11), gastro- enteritis (n = 8), fever (n = 7), and viral infection (n = 7). Patients reporting AEs with no relationship to medication were asked about the suspected cause of their AEs; in 93% (97/104) of interviews, the reported cause was a concomitant illness. Frequency of confi rmed ADR to AMED Throughout the study, the patients used 327 different AMED, of which two (0.61%) AMED were associated with confi rmed ADR. A total of 715 patients used AMED; in two (0.28%) patients, ADR to AMED occurred. Overall, 73,443 AMED applications were documented; three applications (0.004% or one in 24,481 applications) were asso- ciated with an ADR. Two (0.003%) applications were associated with an ADR of severe intensity. Safety of all medication Description of confi rmed ADR to any medication Five ADR were confi rmed (Table 4). Median ADR duration was 2 (range 1–8) days; the fi ve ADR were observed in conjunction with altogether 25 medication applications. The ADR intensity was mild in four patients and severe in one patient. All fi ve ADR subsided after dose reduction (n = 2) or withdrawal (n = 3) of the causative medication. None of the ADR were serious, none were unexpected. No adverse reactions to non-medication therapies were found. Table 2. Overview of medication use. Patients with medication Different medications Applications Medication AMED Non-AM All AMED Non-AM All AMED Non-AM All A) Ongoing at study entry, 75 78 125 94 59 153 8,656 3,576 12,232 used Day 0–28 B) Prescribed at Day 0 715 255 715 223 76 299 59,090 3,842 62,932 C) Prescribed at Day 1–28 131 179 211 130 119 249 5,697 4,712 10,409 B+C) Prescribed at Day 0–28 715 377 715 265 171 436 64,787 8,554 73,341 A+B+C) Ongoing 715 429 715 327 218 545 73,443 12,130 85,573 + prescribed Day 0–28 214 Hamre et al Drug Target Insights 2007: 2 Ta bl e 3. M os t f re qu en tly p re sc rib ed a nt hr op os op hi c m ed ic at io ns o n D ay 0 –2 8. P at ie nt s w ith A pp lic at io ns pr es cr ip tio n* M ed ic at io n In gr ed ie nt s M an uf ac tu re r N % N % P la nt ag o B ro nc hi al B al m 10 0 g co nt ai ns : C am ph or a 2 g, C er a fl a va 1 5 g, D ro se ra r ot un di fo lia / W al a 11 7 16 .4 % 19 45 3. 0% in te rm ed ia /a ng lic a e pl an ta to ta fe rm . D 3 1. 0 g, E uc al yp ti ae th er ol eu m 0 .5 g , P et as ite s hy br id us e r ad ic e fe rm . D 1 1. 0 g, P la nt ag o la nc eo la ta e fo lii s fe rm . D 1 1. 0 g, T er eb in th in a la ric in a 5. 0 g, T hy m i a et he ro le um 0 .5 g E ry si do ro n® 1 L iq ui d 10 g c on ta in s: A pi s m el lifi c a D 2 1 g, B el la do nn a D 2 1 g W el ed a 98 13 .7 % 36 05 5. 6% C in na ba r co m p. P ow de r 10 g c on ta in s: A pi si nu m D 5 3. 3 g, B el la do nn a D 3 3. 3 g, W el ed a 96 13 .4 % 30 37 4. 7% C in na ba r D 5, 3 .3 g P ne um od or on ® 1 L iq ui d 10 g ( = 10 .5 m l) co nt ai ns : A co ni tu m n ap el lu s. D 2 0. 5 g, W el ed a 70 9. 8% 17 89 2. 8% B ry on ia D 2 1 g C in na ba r/ P yr it Ta bl et s 1 ta bl et c on ta in s: C in na ba r D 20 1 76 m g, P yr it D 2 20 m g W el ed a 69 9. 7% 20 75 3. 2% B ol us E uc al yp ti co m p. 10 g c on ta in s: A pi s m el lifi c a ∅ ( = D 1) 0 .1 g , B el la do nn a ∅ 0 .0 02 g , W el ed a 59 8. 3% 22 23 3. 4% P ow de r E uc al yp tu s ∅ ( = D 1) 0 .1 g , W hi te c la y 9. 97 –1 0 g P in e R ev iv in g B at h M ilk C on ta in s: W at er ( A qu a) , P ot as si um o liv at e, A bi es a lb a W el ed a 53 7. 4% 45 9 0. 7% le af o il, A bi es S ib iri ca o il, L im on en e B er do ni a N os e S pr ay 1 g co nt ai ns : B er be ris v ul ga ris e fr uc tib us fe rm D 2 0. 1 g, C itr us W al a 50 7. 0% 15 99 2. 5% lim on e fr uc tib us fe rm D 1 0. 1 g, C yd on ia o bl on ga e fr uc tib us fe rm D 1 0. 1 g, Q ua rz ( S ili ce a) D 19 0 .1 g E ch in ac ea c om p. 10 0 g co nt ai ns : A rg en tu m n itr ic um D 13 1 .0 g , C al en du la o ffi ci na lis , W al a 49 6. 9% 10 62 1. 6% M ou th sp ra y fl o s re c. 1 0. 0 g, E ch in ac ea p al lid a, h er ba r ec . 1 0. 0 g, E uc al yp tu s gl ob ul us e fo lii s fe rm . D 1 1. 0 g, G in gi va b ov is G l D 4 1. 0 g, G in gi va b ov is G l D il. D 8 1. 0 g, S al vi a of fi c in al is , f ol iu m r ec . 1 0. 0 g, To ns ill ae p al at in ae b ov is G l D 4 1. 0 g, T on si lla e pa la tin ae b ov is G l D 8 1. 0 g S tic ta L iq ui d S tic ta D 3/ D 6 W el ed a 48 6. 7% 21 44 3. 3% H ep ar S ul fu ris P ow de r H ep ar s ul fu ris D 3/ D 4/ D 6/ D 12 /D 30 W el ed a 47 6. 6% 19 70 3. 0% C ha m om ill a co m p. 1 su pp os ito ry ( 1 g) c on ta in s: B el la do nn a D 3 20 m g, C ha m om ill a W el ed a 43 6. 0% 55 5 0. 9% S up po si to ry re cu tit a, r ad ix , e th an ol . d ec oc tu m D 2 20 m g, E ch in ac ea p ur pu re a, pl an ta to ta ∅ 1 35 m g, P ap av er s om ni fe ru m , f ru ct us im m at . D 3 20 m g, A rg en tu m m et al lic um p ra ep ar at um D 19 2 0 m g A co ni tu m c om p. E ar dr op s 10 g co nt ai ns : A co ni tu m n ap el lu s e tu be re fe rm . D 9 1. 0 g, W al a 42 5. 9% 16 80 2. 6% C am ph or a 0. 1 g, L av an du la e ae th er ol eu m 0 .1 g , Q ua rz ( S ili ce a) D 9 1. 0 g 215 Anthroposophic medications Drug Target Insights 2007: 2 Frequency of confi rmed ADR to any medication Throughout the study, the patients used 545 different (AMED + non-AM) medications, of which fi ve (0.92%) medications were associated with confi rmed ADR. A total of 715 patients used medication; in fi ve (0.70%) patients ADR occurred. ADR of severe intensity occurred in one (0.14%) patient. Overall, 85,573 medication applications were documented; 25 applications (0.03% or one in 3,423 applications) were associated with an ADR. Two (0.002%) applications were associated with an ADR of severe intensity. Discussion Overall study fi ndings This is one of the fi rst detailed analyses (Hamre et al. 2006) of use and safety of AMED within a large prospective cohort study. In outpatients with acute respiratory and ear infections we found a low frequency of confirmed ADR to AMED (0.28% of AMED users and 0.004% of AMED applications). Strengths and limitations This study has several strengths: Data collection was prospective with extensive quality assurance guaranteeing high data quality (100% source data verifi cation performed for all baseline prescription data, i.e. for 88% of AMED applications). Patients were recruited by experienced physicians (average 18 years in practice) in a range of healthcare settings (20 different municipalities in five countries). Follow-up rates were high (only 5% of otherwise evaluable patients were lost to follow-up). AEs were documented in all patients at all follow-ups (instead of relying on spontaneous reporting). In the safety analysis, AEs were investigated with respect to a causal relationship to all ongoing medication according to predefi ned criteria, checking each case with physicians and patients. Selection bias is unlikely for this study: Screening data suggest that enrolled patients are representative for eligible patients. Moreover, the percentage of eligible but not enrolled patients prescribed AMED (83%) was lower—and not higher—than the percentage of evaluable patients prescribed AMED (100%). Therefore, if any signifi cant “selection-out” of patients from the In fl u do ® L iq ui d 10 g ( = 11 .1 m l) co nt ai ns : A co ni tu m n ap el lu s D 3 1 g, B ry on ia W el ed a 40 5. 6% 11 30 1. 7% D 2 0. 6 g, E uc al yp tu s D 2 0, 5g , E up at or iu m p er fo lia tu m D 2 0. 4 g, P ho sp ho ru s D 4 1 g, S ab ad ill a D 3 1 g Le vi st ic um R h Li qu id Le vi st ic um D 2/ D 3/ D 4/ D 6/ D 10 W el ed a 40 5. 6% 12 69 2. 0% C ou gh E lix ir 10 0g ( = 76 m l) co nt ai ns : 5 g aq ue ou s ex tr ac t f ro m 0 .6 g W el ed a 34 4. 8% 91 6 1. 4% A lth ae ae r ad ix , 3 0 g aq ue ou s de co ct um fr om ( 0. 15 g S ol an um du lc am ar a, s tip ite s si cc .; 0. 35 g M ar ru bi um v ul ga re , h er ba s ic c. ; 0. 5 g A ni si fr uc tu s; 0 .3 5 g S er py lli h er ba ; 2 .8 5g T hy m i h er ba ), D ro se ra D 2 0. 1g , E xt ra ct um M al ti 5 g, Ip ec ac ua nh a, e th an ol . de co ct um ∅ ( = D 1) 0 .1 g , P ul sa til la v ul ga ris D 3 0. 01 g K al iu m c ar bo ni cu m L iq ui d K al iu m c ar bo ni cu m D 3/ D 4/ D 6/ D 10 /D 12 /D 20 /D 30 W el ed a 34 4. 8% 15 41 2. 4% S ili ce a (Q ua rz ) 1% E ar dr op s 10 g ( = 10 .9 m l) co nt ai ns : Q ua rz ( S ili ce a) 0 .1 g W el ed a 34 4. 8% 67 6 1. 0% N os e B al m fo r C hi ld re n 10 g c on ta in s: B al sa m um p er uv ia nu m 0 .0 5 g, B er be ris v ul ga ris W al a 32 4. 5% 61 1 0. 9% e fr uc tib us fe rm . ∅ 1 .0 0 g, P ru nu s s pi no sa , f ru ct us r ec . 0 .5 0 g, S ili ce a co llo id al is 0 .0 5 g C ap si cu m a nn uu m L iq ui d C ap si cu m a nn uu m D 3/ D 4/ D 6/ D 10 W el ed a 32 4. 5% 41 8 0. 6% O th er m ed ic at io ns ( n = 24 5) 34 08 3 52 .6 % To ta l 71 5 10 0. 0% 6 47 87 10 0. 0% *M ul tip le r es po ns es p os si bl e, s um o f p er ce nt ag es � 10 0% . D : D ec im al p ot en ci es ( 1: 10 d ilu tio n; e .g . D 3 = 1: 10 00 ). ∅ : m ot he r tin ct ur e. G L: M ot he r tin ct ur e pr ep ar ed u si ng g ly ce ro l./ : M ed ic a- tio n ex is ts in d iff er en t c on ce nt ra tio ns g ro up ed to ge th er . 216 Hamre et al Drug Target Insights 2007: 2 (C on tin ue d) Ta bl e 4. A dv er se e ve nt s (A E ) re po rt ed w ith p os si bl e or p ro ba bl e ca us al r el at io ns hi p to a ny m ed ic at io n, a cc or di ng to p at ie nt fo llo w -u p re sp on se . P at ie nt no . A ge Ye ar s S ex D ia gn os is C on co m ita nt di se as e N th er ap ie s A dv er se e ve nt N am e In te n- si ty D ur at io n D ay s M os t p ro ba bl e ca us e* 1 7 f A cu te to ns ill iti s P ur ul en t r hi ni tis 4 N as al c on ge st io n M ild � 1 In te rc ur re nt il ln es s 2 0 m A cu te o tit is m ed ia N o 7 C on di tio n ag gr a- va te d, fe ve r M ild 1 P rim ar y ill ne ss 3 23 f A cu te ph ar yn gi tis N o 2 S el f- cr iti ci sm M ild 2 O th er 4 45 f A cu te U R I un sp ec ifi ed D us t m ite a lle rg y 6 N au se a M ild 4 P rim ar y or in te rc ur re nt il ln es s 5 8 m A cu te to ns ill iti s N o 4 C ra m p ab do m in al , v om it- in g M ild � 1 P rim ar y Ill ne ss ( m es en te ria l ad en iti s) A bd om in al p ai n M ild � 26 6 2 m A cu te p ha ry n- gi tis N o 4 D ia rr he a M ild 1 C on co m ita nt m ed ic at io n (iv y le af e xt ra ct ) 7 6 m B ro nc hi tis A to pi c de rm at iti s 8 E ye lid e de m a M ild 3 C on co m ita nt m ed ic at io n (s od iu m c ro m og ly ca te a nd / or s al bu ta m ol ) 8 1 f A cu te la ry ng iti s an d tr ac he iti s N o 3 R es tle ss ne ss a t ni gh t M ild 8 P rim ar y ill ne ss 9 1 m A cu te o tit is m ed ia N o 6 F ac ia l r as h M ild � 7 In te rc ur re nt il ln es s 10 40 f A cu te s in us iti s N o 3 G as tr o- in te st in al di so rd er N O S M ild 8 C on co m ita nt m ed ic at io n (m yr to l) 11 8 m B ro nc hi tis A to pi c de rm at iti s 2 R es tle ss ne ss M ild 8 P rim ar y ill ne ss 12 39 f A cu te to ns ill iti s N o 3 R as h M ild 7 P rim ar y ill ne ss 13 53 f A cu te la ry ng iti s an d tr ac he iti s N o 2 M ou th d ry M ild 4 P rim ar y or in te rc ur re nt il ln es s 14 32 f A cu te to ns ill iti s N o 0 A bd om in al p ai n M ild � 1 P rim ar y or in te rc ur re nt il ln es s 15 39 f B ro nc ho - pn eu m on ia N o 3 S le ep d iffi c ul t S ev er e 2 P ne um od or on ® 2 L iq ui d, W el ed a* * 16 14 m A cu te to ns ill iti s N o 6 In je ct io n si te sw el lin g an d re dn es s M ild 1 P ru nu s S pi no sa 5 % In je ct io n, W el ed a* * 217 Anthroposophic medications Drug Target Insights 2007: 2 study took place, these would have been patients not prescribed AMED, which would not affect the present analysis. A limitation of our safety analysis is its restric- tion to AEs reported by patients as having a possible or probable causal relationship to any medication. Unidentifi ed ADR could be present among the other AEs. However, inspection of these AEs suggests that in the overwhelming majority of cases they were symptoms of primary disease or intercurrent illness. In the safety analysis, AEs were classifi ed as “confi rmed ADR” (probable/possible relationship to a medication) or “not confi rmed ADR” (improbable/ no relationship/unable to evaluate). False-negative classifications (true ADR is not confirmed) are unlikely, since for all medication for which an ADR was not confirmed, there was either no rational temporal relationship to the AE, or another cause (primary or intercurrent illness or another medication) was much more likely. However, false-positive clas- sifi cations cannot be ruled out; the three “confi rmed ADR” to non-AM medication might instead be symptoms of primary or intercurrent illness. Implication for research Classifi cation of causal relationship between medication and AEs In this study most AEs were disease symptoms and other subjective symptoms of 1–7 days’ duration. Thus a major challenge of the safety analysis was to distinguish between true ADR and symptoms of primary or intercurrent illness. For example, in 13 analyzed patients the AE started the same day as the medication was first t a k e n o r w i t h i n t h e f o l l o w i n g 1 – 2 d a y s , suggesting a “rational temporal relationship to the time of intake of the medication” (Table 1). However, if the AE is a symptom of the primary disease for which treatment is sought, a temporal relationship between beginning of treatment and beginning of the AE does not in itself indicate a causal relationship between the treatment and the AE. The same applies to cases where the end of the AE coincided with end of treatment, since AM treatment of respiratory and ear infections is usually applied as long as symptoms persist. These problems will have to be addressed in future safety research into AMED. 17 35 f A cu te n as o- ph ar yn gi tis (c om m on c ol d) N o 5 D ry li ps M ild 4 P rim ar y ill ne ss 18 29 m A cu te to ns ill iti s N o 3 C on ce nt ra tio n im pa ire d, fe el in g ba d, u rin e ab no rm al M od e- ra te 5 P rim ar y ill ne ss 19 5 f B ro nc hi tis A st hm a 5 In cr ea se d bo w el m ov em en ts M ild 11 P rim ar y or in te rc ur re nt il ln es s N th er ap ie s: N um be r of d iff er en t m ed ic at io ns o r no n- m ed ic at io n th er ap ie s us ed b et w ee n st ud y en tr y an d en d of th e A E ( al l p at ie nt s ex ce pt n o. 1 4 us ed a nt hr op os op hi c m ed ic at io ns b et w ee n st ud y en tr y an d en d of A E ). C on fi r m ed a dv er se d ru g re ac tio ns in b ol d ty pe s. * M os t p ro ba bl e ca us e w as c la ss ifi ed b y th e au th or s; o th er it em s w er e do cu m en te d by p hy si ci an s an d pa tie nt s. ** S ee T ab le 5 . 218 Hamre et al Drug Target Insights 2007: 2 Table 5. Confi rmed adverse reactions to anthroposophic medications. Patient No. 15: A woman aged 39 with bronchopneumonia (including severe cough, very severe hemoptysis, moderate shortness of breath, moderate expiratory wheezing, severe sputum expectoration, moderate pain with coughing or breathing, severe discomfort, and fever � 39.5 °C) was treated with three AMED (Pneumodoron® 1 Liquid 10 drops hourly, Pneumodoron® 2 Liquid 10 drops hourly, Tabulettae calcarea cum ferro three times daily) and quark compresses twice daily. The fi rst two subsequent nights she experienced severe sleeplessness which subsided after she stopped taking Pneumodoron® 2 at night. Another possible explanation for this AE is severe illness present at study entry. She has however taken Pneumodoron® 2 once after the study upon which she experienced sleeplessness which again subsided after stopping taking Pneu- modoron® 2 at night. Pneumodoron® 2 (10 g = 11.1 ml contains: Phosphorus D4 1 g, Tartarus stibiatus D2 1g) was classifi ed as the most probable cause of the AE but her bronchopneumonia may have contributed to the intensity of the AE. According to the manufacturer’s information, this AE can be expected from Pneumodoron® 2 in sensitive individuals, but has not been previously reported. Patient No. 16: A 14-year old boy with acute tonsillitis was treated with daily subcutaneous injections of Prunus spinosa, Summitates 5% and three further AMED and developed mild swelling and redness at the injection site. The reaction was observed after the fi rst injection and subsided after subsequent dose reduction of Prunus (the dose of the other three AMED was not reduced). This ADR has not been reported to the manu- facturer previously, but has been observed repeatedly in other patients by the boy’s physician. Prescription profi le of AMED—implications for safety research A striking finding of this study is the broad prescription profi le of AMED: 715 patients were prescribed altogether 265 different AMED; 53 AMED were prescribed to at least 10 patients each. Safety analysis assessed AMED as a single package: 2.7% (19/715) of patients reported AEs suspected to be ADR and 0.3% (2/715) of patients had confi rmed ADR to AMED. A conventional approach, assessing safety of individual AMED would not have been possible: To detect ADR from a single medication in a hypothetical frequency of 1% with suffi cient power, at least 500 patients per medication are needed. To detect ADR from the 53 most common AMED with a frequency of 0.3% (as in this analysis), a sample size of approximately 90,000 patients would be required. If 2.7% of patients report AEs suspected to be ADR (as here), a study of this size would necessitate examining more than 2,000 AEs. This task would, if performed as in the present analysis, hardly be feasible. Therefore, safety studies of AMED for indications with broad prescription profi les will generally have to assess AMED as a package rather than as single medications. Implications for risk-benefi t assessment For most individual AMED, scientifi c evidence of effectiveness is limited. This study evaluated the effectiveness and safety of AM treatment (265 individual AMED, adjunctive non-AM medication, and adjunctive non-medication therapies) of respiratory and ear infections (Hamre et al. 2005). Using a conventional approach, focusing on each of the 265 individual AMED, a benefi t-risk assess- ment would not have been possible: Effectiveness was not proven for any individual AMED (the study was not designed for this purpose) and ADR from two AMED were found, leading to a negative benefi t-risk profi le for two AMED and inconclusive data for the remaining 263 AMED. Instead, all AM treatment was analyzed as one therapy package, thus a benefi t-risk assessment in comparison to conven- tional treatment was possible. A broad AMED prescription profi le is typical not only for respiratory and ear infections but for many other indications (Husemann and Wolff 1987; Ritchie et al. 2001). Therefore, therapy package evaluation will probably have an impor- tant role in future benefit-risk assessments of AMED. Implications for practice Safety of AM This study of acute respiratory and ear infections demonstrated an excellent safety profi le, both for comprehensive AM treatment (ADR in 0.7% of patients and 0.03% of applications with a median duration two days; severe intensity ADR in 0.1% of patients and 0.003% of applications) and for AMED (ADR in 0.3% of patients and 0.004% of 219 Anthroposophic medications Drug Target Insights 2007: 2 applications; severe intensity ADR in 0.1% of patients and 0.003% of applications). Comparative risk-benefi t assessment In the primary analysis of this study (Hamre et al. 2005), AM treatment had a signifi cantly lower frequency of reported ADR (2.7%, n = 19/715 patients) than conventional (C-) treatment (6.0%, n = 18/301) (Fisher ’s exact test, 2-tailed, p = 0.0157). For practical reasons, the present more precise secondary safety analysis was restricted to A-patients, confi rming ADR in 0.7% (5/715) of A-patients. In C-patients the frequency of confi rm- able ADR may be between 0/301 and 18/301. At both ends of this range, this frequency will not be lower but will either be comparable to (p = 0.3295) or signifi cantly higher (p � 0.00005) than the frequency in A-patients. In other words: AM had comparable or lower risk than conventional treat- ment. Since AM had more favorable clinical outcomes, AM had a more favorable benefi t-risk profi le than conventional treatment. Conclusion In this prospective study of 715 outpatients with acute respiratory and ear infections, we found a low frequency of ADR and no serious ADR to AMED. Study results suggest that short-term AMED therapy for acute respiratory and ear infec- tions is well tolerated. Acknowledgments This analysis was funded by grants from Weleda and Wala. The sponsors had no infl uence on study design or planning; on the collection, analysis, or interpretation of data; on the writing of the manu- script; or on the decision to submit the manuscript for publication. We thank Peter Vögele, Wala and Jasmin Peschke, Weleda for providing safety data on AMED, and Gunver S. Kienle and Wilfried Tröger for valuable help and advice. Our special thanks go to the study physicians and their patients for participating. Confl ict of interest: All authors declare that they have no confl icts of interest. References Hamre, H.J., Fischer, M., Heger, M. et al. 2005. Anthroposophic vs. conventional therapy of acute respiratory and ear infections: a pro- spective outcomes study. Wien Klin Wochenschr., 117:256–68. Hamre, H.J., Witt, C.M., Glockmann, A. et al. 2006. Use and safety of anthroposophic medications in chronic disease: a 2-year prospective analysis. Drug Saf., 29:1173–89. Husemann, F. and Wolff, O. 1987. The anthroposophical approach to medicine. Volume 2. London: Rudolf Steiner Press. IAAP. 2005. Anthroposophic Pharmaceutical Codex APC. Dornach: The International Association of Anthroposophic Pharmacists. Kienle, G.S., Kiene, H. and Albonico, H.U. 2006. Anthroposophic medicine: effectiveness, utility, costs, safety. Stuttgart, New York: Schattauer Verlag. Ritchie, J., Wilkinson, J., Gantley, M. et al. 2001. A model of integrated primary care: anthroposophic medicine. London: Department of General Practice and Primary Care, St Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary Uni- versity of London. Steiner, R. and Wegman, I. 2000. Extending practical medicine. Fundamen- tal principles based on the science of the spirit. GA 27. 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