Clinical-expert-report_final01-jov.doc

Clinical Expert Report
Eucarbon® Tablets
Regulatory Authorities
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Clinical Expert Report Eucarbon® Tablets, 2004-05-17 Table of Contents

Qualitative and quantitative Composition Therapeutic indications of proprietary drug PHARMACOLOGY OF EUCARBON® AND EUCARBON®- CONSTITUENTS CLINICAL PHARMACOLOGY OF EUCARBON® AND EUCARBON®- CONSTITUENTS Documentation of the Pharmacological Properties of Wood and Activated Charcoal Clinical Trials: Charcoal Studies in Man Clinical Expert Report Eucarbon® Tablets, 2004-05-17 Safety Profile of Anthranoids and Derivatives as Anticancer Agents Constipation and General Digestive Disorders 14.1.1 Tabular Overview of the Clinical Trials (Tables I) 14.1.3 Supportive Data with Eucarbon® Herbal 14.2 Tabular Summaries of the Clinical Trials (Tables II) Clinical Expert Report Eucarbon® Tablets, 2004-05-17 1 Introduction
Purpose of the Clinical Expert Report
The following Clinical Expert Report presents an update on pharmacology, toxicology, efficacy and tolerability of Eucarbon® tablets, which are considered appropriate for the relief of the Eucarbon® is a traditionally used combination of anthranoid drugs (Senna and Rhubarb) with vegetable charcoal (carbo ligni). The action of the preparation is due to the charcoal and the stimulatory action of anthraquinones, which are presented in a standardized dosage form. The use of vegetable charcoal, rather than activated charcoal, prevents the significant drug binding of anthranoids and potential interaction. The vegetable charcoal is applied for its adsorptive properties in reducing gaseous distension. The sennosides are given in a standardized dosage form, which is important in predicting the action of the product. The medicinal product Eucarbon® is well-established for traditional use, having an acceptable Eucarbon® stimulates the entire digestive system, has a mild laxative and spasmolytic effect and Because of the traditional use, the MAH, F. Trenka GmbH in Vienna, has not yet finished any GCP-conform clinical study with the combination preparation Eucarbon® tablets. Thus this expert report is based on the assessment of published literature concerning experience, scientific data, monographs, pharmacopoeias, clinical studies with other preparations that contain the main ingredients senna, rhubarb and carbo ligni as well as a number of small open trials and some drug monitoring trials with Eucarbon®. The efficacy of these substances is historically known and generally accepted. Likewise efficacy and tolerability of Eucarbon® has been known to be excellent for decades. Eucarbon® is a highly acknowledged and marketed product in Austria and in more than 40 The most important indication of Eucarbon® is treatment of constipation. The justification for this indication is based on the experience with this preparation, on pharmacological considerations, literature and study data from the Trenka company. Constipation is a common problem and an important cause of complications especially in western society. Constipation has been greatly underestimated as a health care issue in the population and extensive studies of the condition have not been made. Clinical Expert Report Eucarbon® Tablets, 2004-05-17 Most patients with constipation notice an improvement after minimum lifestyle interventions such as dietary modifications, fiber supplementation and exercise. Others have severe disabling symptoms that are refractory to conservative medical measures. They then become dependent About half of the patients admitted to specialist palliative care units report constipation and about 80% of patients require laxatives, i.e. laxative therapy. The aim of laxative therapy is to achieve comfortable defecation. The choice of laxatives depends on the nature of the stools, the cause of the constipation and acceptability of the Senna and rhubarb, which are constituents of Eucarbon®, are popular purgative crude drugs and have been employed for centuries as laxatives. This paper is a Clinical Expert Report made to justify the indication and therapy principle with Eucarbon® based on pharmacological considerations and clinical findings. The Expert Report on the Clinical Documentation of Eucarbon® is therefore based on: 1. The review of the literature on the target indication “constipation” as well as “irritable bowel syndrome” as a potential additional indication. 2. The review of the literature on the pharmacological and clinical properties of the 3 active ingredients senna, rhubarb and carbo ligni. 3. The review of the literature on Eucarbon®. 4. Drug monitoring and clinical studies with Eucarbon®. Clinical Expert Report Eucarbon® Tablets, 2004-05-17 Product Profile
1.2.1 Name of proprietary drug
1.2.2 Qualitative and quantitative Composition
Active ingredients: Fol. sennae – Senna Leaf (Vegetable charcoal) Sulfur depuratum – Sublimed Sulfur 1.2.3 Description of active ingredients
Scientific name of plant: Cassia angustifolia Vahl (Tinnevelly-Senna) and Cassia senna L. (= Cassia acutifolia De Lile) Synonym: Senna Leaf, Cassia Leaf (Engl.), Feuilles de séné, Folioles de séné (French) Extractum Rhei: Scientific name of plant: Rheum palmatum L. and / or Rheum officinale Baill. Synonym: Rhizoma Rhei, Rhubarb, Radix Rhei sineusis, Rheum (Engl.), Radix Rhabarbari, Racine de rhubarbe (French)Anthraquinone-content: Referring to the Chemical-, Pharmaceutical- and Biological Documentation of Eucarbon®, the total content of anthraquinone is 3,30 ± 0,65 mg/tablet (2,65 – 3,95 mg/tablet). Wood Charcoal: Synonym: Carbo Ligni, vegetable charcoal (Engl.) Sulfur: Synonym: Sublimed Sulfur (Sulfur USP), Sulfur depuratum, OEAB, CAS – 7704-34-9, S = 32.06 All active and inactive substances are the subject of Pharmacopoeial specification with the exception of vegetable charcoal which deviates from European Pharmacopoeia specification. 1.2.4 Mode of action
Eucarbon® tablets contain only vegetable and mineral ingredients. Eucarbon® stimulates the entire digestive system, increases colonic motility, has a mild laxative and spasmolytic effect, relieves gas pains and can also be regarded as a detoxifying agent (mild adsorbent). Clinical Expert Report Eucarbon® Tablets, 2004-05-17 1.2.5 Therapeutic indications of proprietary drug
Mild laxative, indicated for the relief of all forms of constipation haemorrhoidal obstipation fermenting and putrefying processes in the intestines meteorism flatulence intestinal autointoxication 1.2.6 Contraindications
In case of suspected stomach or intestinal ulcers, appendicitis or intestinal obstruction, any kind of laxative should be avoided; patient is to consult a doctor immediately. 1.2.7 Side effects
No side effects are to be expected, if the doses are properly adhered to. 1.2.8 Presentation and instructions for use
Presentation: 10, 30, 50 and 100 tablets, Hospital 500 tablets Instructions for use: adults 1 – 2 tablets 3 times a day (at or after meals) children from 2 years on: ½ – 1 tablet at meals 1.2.9 Name of the Company
F. TRENKA Chemisch-pharmazeutische Fabrik GmbH A-1040 Wien, Goldeggasse 5 Austria Telephone: 0043 1 505 03 41-0 Telefax: 0043 1 505 03 41-31 E-mail: office@eucarbon.at Clinical Expert Report Eucarbon® Tablets, 2004-05-17 Information on the Database
Public information available on clinical data was reviewed from 1960 up to April 2004. Investigations were carried out in the following databases: CancerLit, ETHMED, Medline, MEDIKAT, TOXLINE, toxLit, EMBASE. For this clinical expert report relevant original articles and reviews in scientific journals, oral or poster presentations with original data, which have been documented in congress proceedings, and other not yet published proprietary documents of the MAH were used in the All citations are listed in chapter 12 "References". Status of Approval
The herbal medicinal product Eucarbon® has been approved pursuant to the Austrian Drug Law, and already been marketed for several years in the following countries: Registration No.
Registration No.
Yemen A.R.+P.D.R. 43/86, 8/92, 8456, 0086 Clinical Expert Report Eucarbon® Tablets, 2004-05-17 2 Indications
Constipation
Chronic constipation, which has been defined as the delayed evacuation of dry, hard stools (51), is one of the most common complaints in clinical medicine, and has several possible causes. The most common ones are associated with nutritional factors such as the consumption of food with poor dietary fibre content, which results in the insufficient filling of the intestine, furthermore, the intake of readily absorbed food with a reduced water-binding Constipation is also defined as the passage of small hard faeces infrequently and with difficulty (22). Constipation is defined also as a frequency of defecation of twice weekly or less. Many of the associated symptoms may mimic features of the underlying disease. About half of the patients admitted to specialist palliative care units report constipation, but about The costs of constipation are considerable. In Germany e.g. 62 million EURO were spent for prescribed laxatives in the year 2002 (63). In addition a likewise considerable amount is spent year by year in OTC and self-medication preparations. No data exist regarding additional costs generated as a result of medical evaluations, diagnostic studies, surgery, and absences Constipation may be conceptually regarded as disordered movement through the colon or anorectum because, with few exceptions, transit through the more proximal regions of the gastrointestinal tract is normal. From a pathophysiological point of view, impairment of large intestine transit can occur due to a primary motor disorder, in association with a large number of diseases, or as a side effect of many drugs. Diseases associated with constipation include metabolic and endocrine disorders and those neurogenic disorders such as disorders of extrinsic innervation, disorders of the enteric nervous system, peripheral neurologic diseases, that affect the gastrointestinal tract (71). Chronic illnesses often lead to physical and mental impairments that can produce or exaggerate constipation. This may be further exacerbated by inactivity or physical immobility that can lead to fecal retention. A bedridden patient may be unable to respond to defecatory signals because of inadequate toileting arrangements; as a result, fecal retention may lead to megarectum, diminished rectal sensation, and fecal impaction. Other factors that may contribute to constipation in the bedridden patient include underlying illness, medications, and Clinical Expert Report Eucarbon® Tablets, 2004-05-17 dietary inadequacies. Generalized weakness or striated muscle diseases, such as dermatomyositis, may result in significant constipation because of poor expulsion efforts (71). Most constipated patients have an underlying disorder of colonic or anorectal motor function. Patients with idiopathic constipation can be classified into broad groups based on age at presentation, symptoms, duration of complaints, colonic transit characteristics, and anorectal Severe constipation in young to middle-aged adults: Chronic constipation in this age group is predominantly confined to women. Abdominal pain is uncommon, and megacolon is rare. Patients may complain of infrequent defecation, excessive straining when defecating, or both, and the condition often fails to improve with fiber supplements or mild laxatives (58). There are several subtypes within this group of patients who, despite similarities in respect to their clinical pictures, may be distinguished by studies of bowel function and psychological profiles (58). It is a problem that occurs in only a small percentage of persons in the non-elderly population but affects as many as 26% of men and 34% of women over 65 years of age (61). Some elderly individuals with chronic constipation had similar complaints when they were younger. Others develop constipation because of colonic or systemic disorders or as a side effect of medications. There are few data to suggest that ageing significantly affects colonic motor function. However, laxatives are used more commonly by elderly women, and physician visits for constipation are more frequent in individuals of 65 years of age and older (37). Irritable Bowel Syndrome
lrritable bowel syndrome (IBS) is a benign relapsing chronic disorder, characterised by recurrent abdominal pain and altered bowel function. It is estimated that 9 to 22% of the general population has clinical symptoms of IBS (68) but only about 5% seek medical care. IBS is the most common diagnosis made by gastroenterologists and accounts for approximately 50% of all referrals. lt contributes significantly to disability, days off work or school and health care costs; 69 to 85% of the patients report that they experienced difficulties in carrying out their daily activities (8). The economic impact is therefore high. Health care costs per patient per year are about 300 US$ greater than those for a matched comparable subject. Symptom subgroups (constipation predominant, diarrhoea predominant, Clinical Expert Report Eucarbon® Tablets, 2004-05-17 alternating constipation and diarrhoea, neither frequent constipation nor diarrhoea) have been described and are of similar frequencies. Patients complain of general symptoms of abdominal pain (most frequently located in the lower left quadrant), changes in bowel habits / stools, (e.g., stools may be soft-formed with pencil-size diameter), flatulence and / or abdominal distension with the onset of symptoms usually weeks or months prior to seeking medical attention. The cause of IBS is still unknown and abnormalities in gut motility fail to explain the diverse features of IBS. Symptoms of IBS may be related to stress (painless diarrhoea is often precipitated by stressful events and alleviated when the stressor is resolved), to depression, anxiety or other psychological manifestations, and food intolerance (most commonly lactose and gluten). IBS is also often triggered by enteric infections. For these reasons, IBS is considered as a complex disease whereby clinical and therapeutical management is particularly difficult. There is however no evidence that IBS predisposes to cancer or any other Treatment Considerations
The management of constipation extends well beyond the use of laxatives. There is a general agreement in selecting therapeutic strategies for treatment of constipation. Nonsurgical treatment can be separated into: dietary approaches such as fiber supplementation, behavioral approaches such as habit training, contingency management, and biofeedback, exercise as well as pharmacological approaches (71). The management of diarrhoea in irritable bowel syndrome is quite different, first bile acid- binding agents such as cholestyramine have been successfully used - which may be a result of the general constipation effect of the resin. Secondly others have proposed that elevated levels of short-chain fatty acids in the stools may mediate the diarrhoea in irritable bowel syndrome, however symptoms have not correlated with fecal levels (71). Charcoal such as carbo ligni, which is a component of Eucarbon®, has been successfully used alone or in combination with other drugs in treating diarrhoea for many decades. The aim of laxative therapy is to achieve comfortable defecation, rather than any particular frequency of evacuation. Although most laxatives are not very palatable, oral laxatives should be used whenever possible. The choice of laxative depends on the nature of the stools, the Clinical Expert Report Eucarbon® Tablets, 2004-05-17 cause of the constipation, and acceptability of the patient. Laxatives can be subdivided into • Predominantly softening • Predominantly peristalsis stimulating • Combination of the two. When choosing laxatives, knowledge of the main mechanism of action of laxatives is helpful. Many of the softeners increase stool bulk and lead to reflex stimulation of peristalsis, and, similarly, the peristalsis stimulators enhance intestinal fluid secretion and therefore improve Pharmacological Therapy of Constipation
The use of laxatives is deeply rooted in medical and social traditions. Laxatives are classified into five groups on the basis of their presumed mode of action (71): Such as natural (psyllium), synthetic (methyl cellulose) 2. Consist of mineral oil and docusate salts 3. Include mixed electrolyte solutions containing polyethylene glycol and nonabsorbable sugars such as lactulose and sorbitol 4. Contain relatively nonabsorbable ions and anions such as magnesium sulfate, magnesium citrate 5. Consist of castor oil, anthraquinones (cascara sagrada, senna, rheum, casanthranol, and danthron), and diphenylmethanes (phenolphthalein and bisacodyl). Three general mechanisms of laxatives can be described (24, 51): 1. Laxatives may cause retention of fluid in colonic contents due to their hydrophilic or osmotic properties thereby increasing bulk and softness and facilitating transit. 2. Laxatives may act, both directly and indirectlyon the colonic mucosa to decrease net absorption or water and sodium chloride. 3. Laxatives such as Eucarbon® may increase intestinal motility, causing decreased absorption of salt and water secondary to decrease transit time. Clinical Expert Report Eucarbon® Tablets, 2004-05-17 Pharmacology of Eucarbon® and Eucarbon®-Constituents
The pharmacology of the different components of Eucarbon® such as senna, rhubarb, carbo ligni (vegetable charcoal), sulfur as well as that of Eucarbon® as a composition preparation is described in detail in the “Expert Report on the Toxicological and Pharmacological In summary, the mentioned in vivo and in vitro studies are in compliance with the experience and long observations made during many decades with Eucarbon® and confirm that the combination of carbo ligni with senna and rhubarb is not only generally beneficial. It has also been proved to be pharmacologically effective in gastro-intestinal disturbances. The laxative effect of Eucarbon® stays as a major role of action. Thus no further information on experimental pharmacology of Eucarbon® and its constituents 4. Clinical Pharmacology of Eucarbon® and Eucarbon®-Constituents
In this chapter the clinical pharmacology of the different components of Eucarbon® such as senna, rhubarb, carbo ligni (vegetable charcoal), sulfur as well as that of Eucarbon® tablets is Clinical Pharmacology of Senna
Senna leaf consists of the dried leaflets of Cassia senna L. (C. acutifolia De Lile), known as Alexandrian or Khartoum senna, or Cassia angustifolia Vahl, known as Tinnevelly senna, or a mixture of the two species. It contains not less than 2,5 percent of hydroxyanthracene glycosides, calculated as sennoside B (C42H38O20; M, 863) with reference to the dried drug (27, 43). The material complies with the German Monograph “Sennae folium” of the Constituents: The main active constituents are sennosides A and B, which are rhein- dianthrone diglucosides. There are also small quantities of other dianthrone diglucosides, monoanthraquinone glucosides and aglycones. The constituents of senna, as a popular purgative crude drug, have been studied by several working groups. Sennosides C and D were isolated from senna and the structure of sennoside C was determined. Sennoside C was found to be the optical antipode of sennoside A. Further unknown sennosides may exist in senna in addition to sennosides A, B, C and D. Sennosides are glucosides possessing two moles of glucose and are easily hydrolyzed to give sennidins. The glycosides are not known in pure form, but their derivatives by hydrolysis are well known, such as emodin, rhamnetin, chrysophanic acid etc. (31, 36, 50). Clinical Expert Report Eucarbon® Tablets, 2004-05-17 1,8-dihydroxyanthracene derivatives possess a laxative effect (64). The β-linked glucosides (sennosides) are not absorbed in the upper gut; they are converted by the bacteria of the large intestine into the active metabolite (rhein anthrone). There are two different mechanisms 1) an influence on the motility of the large intestine (stimulation of peristaltic contractions and inhibition of local contractions) resulting in accelerated colonic transit, thus reducing fluid 2) an influence on secretion processes (stimulation of mucus and active chloride secretion) Defecation takes place after a delay of 8 – 12 hours due to the time taken for transport to the colon and metabolization into the active compound (43). The β-linked glucosides (sennosides) are neither absorbed in the upper gut nor split by human digestive enzymes. They are converted by the bacteria of the large intestine into the active metabolite (rhein anthrone). Aglycones are absorbed in the upper gut. Animal experiments with radioisotope-labeled rhein anthrone administered directly into the caecum demonstrated less than 10% absorption (43). In contact with oxygen, rhein anthrone is oxidized into rhein and sennidins, which can be found in the blood, mainly in the form of glucuronides and sulfates. After oral administration of sennosides, 3 – 6% of the metabolites are excreted in urine; some are excreted in bile. Most of the sennosides (ca. 90%) are excreted in faeces as polymers (polyquinones) together with 2 – 6% of unchanged sennosides, sennidins, rhein anthrone and rhein. In human pharmacokinetic studies with Senna pod powder (20 mg sennosides), administered orally for 7 days, a maximum concentration of 100 ng rhein/mL was found in the blood. An accumulation of rhein was not observed (43). Active metabolites, e.g. rhein, pass in small amounts into breast milk. Animal experiments demonstrated that passage of rhein through the For short-term use in cases of occasional constipation (19). Clinical Expert Report Eucarbon® Tablets, 2004-05-17 Mechanical preparation before colonic or rectal resection with senna is better and easier than with polyethylene glycol and should be considered in patients undergoing colonic or rectal resection, especially patients with stenosis (70). Posology and method of administration (19): Dosage: The correct individual dose is the smallest required producing a comfortable soft Adults and children over 10 years: preparations equivalent to 15 – 30 mg of hydroxyanthracene derivatives, calculated as sennoside B, to be taken once daily at night Not recommended for use in children under 10 years of age The pharmaceutical form must allow lower dosages. Method of administration: For oral administration. - Not to be used in cases of: intestinal obstruction and stenosis, atony, inflammatory colon diseases (e.g. Crohn’s disease, ulcerative colitis), appendicitis; abdominal pain of unknown origin; severe dehydration states with water and electrolyte depletion. Special warnings and special precautions for use: As for all laxatives, Senna leaf should not be given when any undiagnosed acute or persistent If laxatives are needed every day the cause of the constipation should be investigated. Long term use of laxatives should be avoided. Use for more than 2 weeks requires medical supervision. Chronic use may cause pigmentation of the colon (pseudomelanosis coli) which is harmless and reversible after drug discontinuation (54). Abuse with diarrhoea and consequent fluid and electrolyte losses may cause: dependence with possible need for increased dosages, disturbance of the water and electrolyte (mainly hypokalaemia) balance; an atonic colon with impaired function. Intake of anthranoid-containing laxatives for more than a short period of time may result in aggravation of constipation. Hypokalaemia can result in cardiac and neuromuscular dysfunction, especially if cardiac glycosides, diuretics or corticosteroids are taken. Chronic use may result in albuminuria and haematuria (43). Clinical Expert Report Eucarbon® Tablets, 2004-05-17 Interaction with other drugs and other forms of interaction: Hypokalaemia (resulting from long term laxative abuse) potentiates the action of cardiac glycosides and interacts with anti- arhythmic drugs or with drugs, which induce reversion to sinus rhythm (e.g. quinidine). Concomitant use with other drugs inducing hypokalaemia (e.g. thiazide diuretics, adrenocorticosteroids and liquorice root) may aggravate electrolyte imbalance. Pregnancy: There are no reports of undesirable or damaging effects during pregnancy or on the fetus when used in accordance with the recommended dosage schedule. However, in view of experimental data concerning a genotoxic risk from several anthranoids (e.g. emodin and aloe-emodin), avoid during the first trimester or take under medical supervision only (19). Lactation: Breastfeeding is not recommended, as there are insufficient data on the excretion of metabolites in breast milk. Small amounts of active metabolites (e.g. rhein) are excreted in breast milk. A laxative effect in breast-fed babies has not been reported (19). Undesirable effects: Abdominal spasms and pain, in particular in patients with irritable colon; yellow or red-brown (pH dependent) discoloration of urine by metabolites, which is not Clinical Pharmacology of Rhubarb
Rhubarb consists of the dried rhizome and root of Rheum officinal Baillon or of Rheum palmatum Linné (Fam. Polygonaceae), or of other species (excepting Rheum Rhaponticum Linné), or of hybrids of Rheum, grown in China, deprived of the periderm tissues. The rheum species contains 3 – 7,5% anthracene derivatives (30). The material complies with the German Monograph (Mono Rhei radix), DAB 10, ÖAB 90, Constituents: Six analogs of sennosides A, B, C, D, E and F have been isolated up to now I.e. the principal constituents of rhubarb are glycosides of two types: 1) The astringent principles (tannins like glucogallin and tetrarin) which yield glucose gallic acid and other products upon hydrolysis and 2) The anthraquinone derivatives which yield glucose and hydroxymethylanthraquinones upon Clinical Expert Report Eucarbon® Tablets, 2004-05-17 Rhubarb contains important quantities of emodin and chrysophanic acid, small quantities of rhein and aloe-emodin; gallic acid and catechin. About 7% of calcium oxalate; up to 15% total ash and about 0,2% acid – insoluble ash. The anthraquinones compounds may readily be separated from powdered rhubarb by 1,8-dihydroxyanthracene derivatives possess a laxative effect (21, 42). This effect is mainly contributed to stimulation and increases colonic motility, an effect attributed to stimulation of Auerbach’s plexus by anthraquinone derivatives. The laxative action is mainly due to interference of the colonic motility by inhibiting the stationary contraction and due to stimulation of propulsive contraction. This action leads to an accelerated transit time and to reduction of fluid resorption. In addition, a secretion of water and electrolytes occur due to stimulation of active chloride secretion. The laxative effect of rheum varies, depending upon the individual preparation as well as on the anthraquinone content and the ease of liberation of the active constituents from their precursor glycosides by the intestinal microflora. Since the laxative effects of anthraquinones are limited mainly to the large intestine, such agents like rheum are generally effective 6 hours or more after oral administration. Systematic clinical studies on the pharmacokinetics of rhubarb and rhubarb extracts with exact doses, mode of application and description of the test substance are not found in literature. In reference to other pharmacokinetic studies on anthranoids, it is assumed that the aglycones, which are contained in rhubarb, are absorbed through the upper intestine. The β- linked glucosides (sennosides) are prodrugs and these are neither absorbed nor degrated at the upper gastrointestinal tract, they are converted by the bacteria and bacterial enzymes of the large intestine into the active metabolite (rhein anthrone). Following an oral dose, the naturally occurring anthraquinone glycosides (prodrug) are poorly absorbed by the small intestine. After removal of the sugar (D-glucose or L-rhamnose) and reduction to the anthrol by colonic bacteria, the agents are absorbed to a moderate degree. Absorbed material may be excreted in the bile, with possible effects on the small bowel, and in Clinical Expert Report Eucarbon® Tablets, 2004-05-17 The systemic bioavailability of anthrones is very low. Animals studies have shown that the anthrones are excreted in urine at less than 5%. These are conjugated or oxidized products of rheum and sennidine. More than 90% of the anthrones are excreted in faeces as polymer The active metabolites are also found in other secretions including breast milk. Although anthraquinone derivatives or metabolites may be excreted in the milk of lactating mothers, following normal dosage the concentration is usually insufficient to affect the nursing infant. Anthrones pass neither the placenta nor the liquor barrier. Therapeutic indications: For short-term use in cases of constipation (48) Posology and method of administration (48): Dosage: The correct individual dose is the smallest required producing a comfortable soft- 20 – 30 mg hydroxyanthraquinone derivative per day calculated as rhein. The pharmaceutical form must allow lower dosages. Method of administration: For oral administration. Not to be used in cases of: intestinal obstruction and stenosis, atony, inflammatory colon diseases (e.g. Crohn’s disease, ulcerative colitis), appendicitis; abdominal pain of unknown origin; severe dehydration states with water and electrolyte depletion. Special warnings and special precautions for use: As for all laxatives, rhubarb should not be given when any undiagnosed acute or persistent Note: If laxatives are needed every day the cause of the constipation should be investigated. Long-term use of laxatives should be avoided. Use for more than 2 weeks requires medical supervision. Chronic use may cause pigmentation of the colon (pseudomelanosis coli), which is harmless and reversible after drug discontinuation. Abuse with diarrhoea and consequent fluid and electrolyte losses may cause: dependence with possible need for increased dosages: disturbance of the water and electrolyte (mainly hypokalaemia) balance; an atonic colon with impaired function. Intake of anthranoid-containing laxatives for more than a short period of time may result in an aggravation of constipation. Hypokalaemia can result in cardiac Clinical Expert Report Eucarbon® Tablets, 2004-05-17 and neuromuscular dysfunction, especially if cardiac glycosides, diuretics or corticosteroids are taken. Chronic use may result in albuminuria and haematuria. Interaction with other medicaments and other forms of interaction: Hypokalaemia (resulting from long term laxative abuse) potentiates the action of cardiac glycosides and interacts with antiarrhythmic drugs or with drugs, which induce reversion to sinus rhythm (e.g. quinidine). Concomitant use with other drugs inducing hypokalaemia (e.g. thiazide diuretics, adrenocorticosteroids and liquorice root) may aggravate electrolyte Pregnancy: There are no reports of undesirable or damaging effects during pregnancy or on the fetus when used in accordance with the recommended dosage schedule. However, rhubarb should be avoided during the first trimester or taken under medical supervision only Lactation: Breastfeeding is not recommended, as there are insufficient data on the excretion of metabolites in breast milk. Small amounts of active metabolites (e.g. rhein) are excreted in breast milk. A laxative effect in breast-fed babies has not been reported (48). Abdominal spasms and pain, in particular in patients with irritable colon; yellow or red-brown (pH dependent) discoloration of urine by metabolites, which is not clinically significant. Clinical Pharmacology of Sennosides
Sennosides are plant glycosides with laxative actions. Sennosides are laxative by virtue of the anthraquinone derivatives they contain. They are pro- drugs that produce an effect on the large intestine, having first been partly metabolized by gastrointestinal microflora. Peristalsis is stimulated via an increase in propulsive activity in the Sennosides have been shown to have no mutagenic or teratogenic effects. No carcinogenicity Clinical Expert Report Eucarbon® Tablets, 2004-05-17 Senna compounds in doses of 15 – 30 mg produce a laxative effect after about 6 h, since the drug has to reach the colon via the digestive tract and to a limited extent by recirculation after intestinal absorption. Induction of peristalsis has been demonstrated in man and the drug often causes griping abdominal pain. Stimulation of the intestinal secretions in both small and large intestines also occurs, and in larger doses an increased laxative effect is seen due to The preferred analytical method is by HPLC after alkali infusion. The sensitivity is 1 µg.1-1. A rapid urine test for qualitative detection is also available. Sennosides are pro-drugs requiring metabolic action by colonic bacteria to produce the active metabolites, rhein-9-anthrone and rhein. Systemic bioavailability is < 5%. Sennosides in the colon require bacterial degradation because they are pharmacologically inactive. Sennoside distribution outside body water is not known and likely to be small. Sennosides are not excreted in human breast milk in significant amounts. There is no known effect of altered disease states on sennoside kinetics, but where the colon is sterile a reduction in active metabolite formation may be expected. Sennosides are extensively metabolized within the gut lumen. Excretion is almost entirely as metabolites in faeces. Unchanged fecal excretion is slight (< 5%) as is urinary elimination (< Sennosides are hydrolyzed at the glycoside linkages to give sennidin A+B, which in turn are hydrolyzed at the C-C linkage, possibly by free radicals in the colon, to rhein and rhein-9- anthrone. Rhein is conjugated to a sulfate and a glucuronide. The main pharmacological activity of the sennosides may lie in the rhein-9-anthrone metabolite (27). Clinical Pharmacology of Wood Charcoal
Because of historical reasons 3 synonyms for the same product are used in the documentation and in this expert report: Wood charcoal= vegetable charcoal=Carbo Ligni In the context of these 3 synonyms the charcoal always is “non-activated” to distinguish it from Clinical Expert Report Eucarbon® Tablets, 2004-05-17 Charcoal is found in the pharmacological literature mainly under activated charcoal, though there is a difference in the adsorption capacity between wood and activated charcoal, the differentiation between these two is not always possible. The adsorptive capacity of vegetable charcoal is said and found to be less high than of activated charcoal (55). Charcoal is a fine odourless, tasteless, black powder, free from grittiness. Activated charcoal is described in the BP and USP. The vegetable matter is prepared by a carbonization process. Activated charcoal possesses a high adsorbing capacity. The BP specifies that it adsorbs not less than 40% of its own weight of phenazone, calculated with reference to the dried Wood charcoal as well as activated charcoal can adsorb a wide range of plant and inorganic poisons and many drugs including digoxin, yellow oleander, salicylates, paracetamol, barbiturates, and tricyclic antidepressants. Thus when administered by mouth, it reduces their systemic absorption from the gastrointestinal tract and is used in the treatment of acute oral poisoning. It is of no value in the treatment of poisoning by strong acids or alkalis and its adsorptive capacity is too low to be of use in poisoning with iron salts, cyanides, malathion, dicophane, and some organic solvents such as methyl alcohol or ethylene glycol. Adsorption characteristics can be influenced by charcoal’s particle size, thus different responses may be Activated charcoal is given by mouth usually as slurry in water. The usual dose if poisoning has occurred, is 50 g, but higher doses have been used. For maximum efficacy, charcoal should be administered as soon as possible after ingestion of the toxic compound. However, it may be effective several hours after poisoning with certain drugs that slow gastric emptying or undergo enterohepatic or enteroenteric recycling. Repeated doses of vegetable charcoal or activated charcoal are of value in enhancing the fecal elimination of such drugs including cardiac glycosides, barbiturates, salicylates, and theophylline. Repeated doses of 50 g may be given every 4 hours or 25 g every 2 hours (60). In the haemoperfusion treatment of poisoning, activated charcoal products may be used as adsorbent to remove drugs from the blood stream. Charcoal haemoperfusion may be of value in acute severe poisoning by drugs such as barbiturate or theophylline when other measures fail to improve the condition of the patient. Charcoal is used in dressings for ulcera and suppurating wounds to reduce malodor and may improve the rate of healing. Charcoal has been used as an intestinal marker and has also been tried in the treatment of flatulence. Both activated charcoal and vegetable charcoal are used in preparations for various gastrointestinal disorders (60) Clinical Expert Report Eucarbon® Tablets, 2004-05-17 Technical grades of charcoal have been used as purifying and decolorizing agents, for the removal of residual gases in low-pressure apparatus, and in respirators as a protection Wood charcoal or activated charcoal is most commonly administered as slurry in water but this is often found to be unpalatable because of the color, gritty taste, lack of flavor, and difficulty in swallowing. Efforts have therefore been made to improve its palatability but studies in vitro or in healthy subjects have indicated that some foods such as ice cream, milk, and cocoa might inhibit the adsorptive capacity, whereas starches and jams appeared to have no effect. Carmellose has been demonstrated to improve palatability though it might also reduce the adsorptive power of charcoal. Activated charcoal formulations containing sorbitol, carmellose sodium, or starch were more palatable and essentially equivalent to the aqueous slurry formulation in efficacy. When chocolate syrup was used as a sweet flavoring agent it had to be added just before administration as the sweetness and flavor disappeared after a few minutes’ contact with the activated charcoal. The administration of a single dose of activated charcoal has become an accepted method of preventing the absorption of ingested compounds. In addition, multiple oral doses of activated charcoal have been found to enhance the elimination of some drugs and toxic substances even after systemic absorption. Mechanisms by which activated charcoal may increase drug elimination from the body, include interruption of the enterohepatic circulation of drugs excreted into the bileand reduction of the reabsorption of drugs. Repeated oral doses of activated charcoal may therefore be considered for compounds that undergo enterohepatic or enteroenteric circulation, have a small volume of distribution, are not extensively bound to plasma proteins, and have a low endogenous clearance. Anecdotal reports and studies in acutely poisoned patients indicate that a technique of giving multiple doses of charcoal may be effective for some drug overdoses and may offer an alternative to charcoal haemoperfusion or haemodialysis. However, while activated charcoal is generally well tolerated, major complications may occasionally occur, including pulmonary aspiration and bowel obstruction. Also some charcoal preparations contain sorbitol or sodium bicarbonate. Ingestion of large doses can result in electrolyte disturbances. Thus, some have questioned Wood charcoal as well as activated charcoal have been used to reduce gas in the intestines but reports on its efficacy have been conflicting. In a study involving 10 healthy subjects, oral Clinical Expert Report Eucarbon® Tablets, 2004-05-17 activated charcoal was found to be an effective anti-gas medication and significantly reduced symptoms of bloating and abdominal discomfort. In contrast, the study failed to show that simethicone was effective in reducing gas in the colon. Documentation of the Pharmacological Properties of Wood and Activated
Charcoal
The pharmacological properties of wood and activated charcoal in vitro as well as in vivo are related to its adsorbing capacity on numerous exogenic and endogenic substances and especially on those involved in diarrhoea. Adsorbing capacity in vitro: The capacity of charcoal to adsorb several substances form watery solutions was proven by numerous publications of studies (10, 60). The absorbing capacity of carbo ligni was studied in Zanzibar red colobus monkeys for Some examples are aspirin (280 mg/g), sodium salicylate (490 mg/g), atropine sulfate (700 mg/g), propoxyphen chlorohydrate (130 mg/g), chlorpromazine chlorohydrate (360 mg/g), promethazine chlorohydrate (330 mg/g), thioridazine (300 mg/g), amphetamine sulfate (180 mg/g), malathion (310 mg/g), morphine chlorohydrate (800 mg/g), sodium barbiturates (300- 350 mg/g), potassium cyanide (35 mg/g), mercurous chloride (1800 mg/g), strychnine nitrate (950 mg/g), ethanol (300 mg/g) (60) and phenylpropanol amine (100 mg/g) (69). Other substances are not as well adsorbed by activated charcoal, e.g. quinine, chloroquine, Beckett et al. 1980 (1) have shown that activated charcoal brought into contact with bacterial suspensions (B. subtilis, E. coli, P. aeruginosa, P. vulgaris, S. aureus, S. epidermis) caused a 3 to 5 log reduction of the size of the suspensions. Examination under an electronic sweep microscope showed the strong adherence of the bacteria to the activated charcoal, especially the gramnegative bacteria. By means of a Limulus test, Ditter et al. (13) have shown that E. coli entotoxin is adsorbed onto activated charcoal in a proportion of 10 to 75 (charcoal) at pH 3.0 of 10 to 100 at pH 7.4. Clinical Expert Report Eucarbon® Tablets, 2004-05-17 This suggests that activated charcoal could adsorb bacterial toxins in the intestinal Clinical Pharmacology of Sulfur
Sulfur is an element of molecular weight 32. It is yellow, tasteless and odorless and usually used in the form of precipitated sulfur, which is an amorphous or microcrystalline powder. It melts at around 118 - 120°C to form a yellow liquid which becomes dark and viscous at around 160°C. It is soluble only to a slight extent in water and alcohol, but soluble quite well in carbon disulfide, light petroleum and turpentine (59). The element is present in all living Sulfur has been used for centuries for the following indications (14, 59): - treatment of acne and seborrhoeic conditions - for the attachment of isotopes in diagnostic radiology. As a laxative drug, sulfur is prepared in the form of lozenge (14, 59). When taken by mouth, sulfur is converted in the gut to alkali sulfides whose irritant action produces a mild laxative Sublimed sulfur is one of the active ingredients of Eucarbon®, which has been used for nearly 100 years due to its mild laxative effect, antiseptic effect, and antibacterial action. There has been little research into the basis of the effects attributed to sulfur or mechanisms of action. Little work has been done in the field of pharmacokinetics. There is no evidence available to suggest significant absorption through the skin. After an oral load of methionine 80% of the sulfur content is reported to be converted to inorganic sulfur, which appears in the Sulfur is essential to human metabolism. Total body sulfur is approximately 100 g. This is mainly present in the amino acids methionine, cysteine and cystine and the mucopolysaccharide chondroitin sulfate, being predominantly localized to the skin, nails and hair. Metabolic balance is maintained through its absorption in the gut, and by losses in urine, A decrease in urinary sulfur has been demonstrated in conditions of increased epidermal Clinical Expert Report Eucarbon® Tablets, 2004-05-17 There is no risk of overdose from too much sulfur and no evidence exists for carcinogenic or 5. Toxicity Data of Eucarbon®
Information on the toxicity of the different components of Eucarbon® such as senna, rhubarb, carbo ligni (vegetable charcoal) as well as that of Eucarbon® tablets is described in detail in the “Expert Report on the Toxicological and Pharmacological Documentation of Eucarbon®” The results of the review and an acute toxicity study show that Eucarbon® was well tolerated without specific toxic effects. Eucarbon® caused no death among rats. In spite of the fact that Eucarbon® was a well-tolerated drug, a purgative or laxative effect of Eucarbon® was noticed and it was dose dependent. Pharmacokinetics of Eucarbon®
Since Eucarbon® is a combination product of senna, rhubarb, carbo ligni and sulfur, and since none of the active substances are absorbed and act in situ, no pharmacokinetic studies for Eucarbon® were conducted nor are available. In the “Expert Report on the Toxicological and Pharmacological Documentation of Eucarbon®” (23) the pharmacokinetics of the separate ingredients senna, rhubarb as well as that of sennosides are described in detail. Especially the pharmacokinetic knowledge of sennosides is of great interest and this enabled some insights and assumptions of the pharmacokinetic behavior of Eucarbon®. 7. Bioavailability of Eucarbon®
Information on bioavailability of senna, rhubarb, sulfur and carbo ligni as well as of Eucarbon® tablets is not available and will not be available until one (or more) therapeutically relevant pure substance(s) in the extracts is (are) known and examined. Adequate bioavailability can be supposed because efficacy has been shown for decades in daily practice and in several studies with the constituents as well as with Eucarbon®. 8. Pharmacodynamics of Eucarbon®
As a combination of senna, rhubarb and carbo ligni as well as sulfur Eucarbon®, by its pharmacological and pharmacodynamical properties, belongs to the stimulant laxatives, but due to the mild adsorptive activity of carbo ligni Eucarbon® also is a mild adsorbent and therefore a medicine against general digestive disorders. Clinical Expert Report Eucarbon® Tablets, 2004-05-17 For the laxative effect these agents stimulate accumulation of water and electrolytes in the colonic lumen, and enhance intestinal motility too. The effects of Eucarbon® as a stimulant laxative, on intestinal fluxes of electrolytes and water are readily demonstrated in vitro or in situ under conditions in which effects on motility are excluded. Concentrations of these agents that reduce net absorption of electrolytes and water also increase the permeability of the mucosa, possibly by making tight junctions leaky. The stimulant laxatives may inhibit intestinal Na+, K+-ATPase. This action could account for at least a portion of their laxative effect. Many of the stimulant laxatives also increase the synthesis of prostaglandin’s and cyclic AMP, and this action may contribute to increased secretion of water and electrolytes. Inhibition of prostaglandin synthesis with indomethacin does reduce the effects of many of these agents on net water flux (6). Clinical Expert Report Eucarbon® Tablets, 2004-05-17 9. Clinical Documentation of Eucarbon®
Clinical Trials: Charcoal Studies in Man
Considering the clinical trials with charcoal discussed in this chapter, it is sometimes difficult to indicate in publications what kind of charcoal (either wood or activated charcoal) was used. Nevertheless the publications supply important evidence of the essential use of charcoal in In 6 healthy subjects, Neuvonen and Karkkainen (53) showed that charcoal (50 g p.o.) administered simultaneously with chlorpropamide (250 mg p.o.) reduced its absorption by In 5 healthy subjects the administration of charcoal (2 g) as a powder or as tablets immediately after phenylpropanolamine (50 mg) diminished significantly the bioavailability of Recent studies showed that charcoal administered immediately after amlodipine, fluoxetine, verapamil or pholcodine also diminished the absorption of these drugs, but delayed administration of charcoal has reduced or only a slight effect (11, 39, 40, 41). In a cross-over study on 6 healthy subjects, Berg et al. (4) administered a single dose of phenobarbital (200 mg i.v.) followed by oral ingestion of activated charcoal (60 g/day for 3 days) or not. Compared to the reference group of phenobarbital alone, the administration of charcoal caused a triplication of the total body clearance of the barbiturate, without an effect on renal clearance or distribution volume. This suggests an increased intestinal secretion of phenobarbital followed by binding to the activated charcoal. According to a similar procedure, Berlinger et al. (5) studied the influence of activated charcoal (140 g over 12 h) on the kinetics of theophyllin (Aminophyllin 6 mg/kg i.v.). With activated charcoal the half-life decreased from 6.4 to 3.3 hours and the AUC0-24 was Hall et al. (28) studied the effect of activated charcoal on the production of intestinal gas in 13 healthy subjects. Intestinal gas is composed of O2, N2, CO2, H2 and CH4 of which only the last two are produced by bacterial fermentation. Because of its easy passage from the intestines to the blood and its elimination through the lungs, hydrogen, measured in the expired air, was used to study the intestinal gas production. The authors also measured the number of post- Clinical Expert Report Eucarbon® Tablets, 2004-05-17 prandial episodes of flatulence for 7 hours. The subjects received a standard meal enriched with fermentable carbohydrates (beans) followed by administration of activated charcoal (320 mg every 30 minutes for 2 hours) or a placebo (cross-over). The enriched meal, without addition of charcoal, brought about a 5-fold increase of flatulence compared to a standard meal. The administration of charcoal, on the contrary, diminished significantly (p < 0,001) the flatulence caused by enriched meal, which was brought back to a value not significantly different from the one observed after a standard meal. The measurement of expired hydrogen confirmed these results. After 4 hours the quantities of hydrogen in the expired breath were significantly (p < 0,001) higher after an enriched meal than after a standard meal. The addition of activated charcoal brought the hydrogen production back to a value not significantly different from that after the standard meal. The authors have also observed that the administration of a lower dose of activated charcoal (388 mg) 2 hours after the meal caused a similar reduction of flatulence as the high dose of activated charcoal, which only had effect 2 h after administration. Thus it can be assumed that charcoal only has effect in situ after a latency time corresponding to the duration of intestinal transit and that lower doses could be sufficient. In a similar study protocol on 10 healthy subjects, Potter et al. (57) have seen a lower hydrogen production when the enriched meal was supplemented with activated charcoal (4 g), but the difference was not significant (p < 0,2). Wood charcoal (carbo ligni) and/or activated charcoal present non-specific adsorption properties for a large number of drugs and substances possibly related to the etiology of diarrhoea (bacteria, bacterial metabolism products) as well as to the production of intestinal It could also have an indirect favorable effect by sequestration of endogenic substances involved in the pathogenesis of certain intestinal lesions. 9.2. Clinical Efficacy of Eucarbon®
Introduction
Eucarbon® is a combination of well-established agents for the treatment of constipation. The safety and efficacy of these active ingredients have been known and accepted for centuries. The clinical studies (studies and uncontrolled investigations) which are reported, were carried out in order to provide evidence for the clinical safety and efficacy of the combination preparation. The number of recently conducted studies is limited, as is frequently the case with drugs employed in phytotherapy. But on the other hand the „accepted“ efficacy of the Clinical Expert Report Eucarbon® Tablets, 2004-05-17 ingredients for the treatment of various symptoms and intestinal complaints has been known from clinical experience for decades in daily practice and is well documented in the literature. Eucarbon® has been on the market for nearly 100 years. The safety and efficacy of the ingredients per se is accepted by German Commission E monographs, European Pharmacopoeias and their inclusion on the General Sales List in UK. Thus no rigorous testing of efficacy was made with Eucarbon®, as is common for traditionally used herbal preparations whose efficacy and safety is accepted beyond doubt – as mentioned The applicant company presents a number of clinical evaluations in different indications and some testimonials by various physicians from different countries on the safety and obvious Due to the fact that some of the studies were performed already some years ago and others have the character of drug monitoring studies, they lack to fulfill current GCP-requirements. Clinical Studies with Eucarbon®
In the following clinical studies and systematically collected clinical data for Eucarbon® are Main outcome variables were Likert scales for severity of complaints, symptomatology, well- being as well as global assessment for efficacy and safety/tolerance, modified Clinical Global Impressions Score (CGI) and modified Francis IBS-Score (25), which summarises the actual complaints, incorporating pain, distension, bowel dysfunction, classified as mild, moderate or Document 1: Ref. (7) Breier, H.: An open study in general practice of 102 patients, Vienna, 1980: Klinische Untersuchungsergebnisse nach Verabreichung von Eucarbon®. In an open clinical study with 102 patients in a general practice, Eucarbon® was found to be effective in over two thirds of the patients treated at a dose of (usually) two tablets daily (or higher doses – up to six tablets daily – in 31 subjects). The patients’ age ranged from 35 – 90 years (mean 71 years). The observation period was one week. The assessment of symptomatology was focused on constipation, abdominal distension, colicky abdominal pain, nausea, flatulence, vomiting, diarrhoea and insomnia. Five symptoms were significantly improved by treatment with Eucarbon® during the study: constipation, abdominal distension, colicky abdominal pain, nausea and flatulence, p-values being from <0,01 to <0,001 for the individual symptoms. The improvements were maintained for the whole study period. There were no reports of intolerance to the medication. Clinical Expert Report Eucarbon® Tablets, 2004-05-17 Document 2: Ref. (56) Pezzoli, A.: Treatment of in-hospital patients with Eucarbon®. An open evaluation, Trieste, 1981 Open Evaluation with in-hospital patients from the Clinica Medica Generale, University of Trieste. In this evaluation 31 patients admitted to hospital with general medical complaints, suffering additionally from intestinal complaints, constipation or bellyache, were treated with Eucarbon® at doses of 3 – 6 tablets per day for 6 to 26 days. The case study was not randomized or controlled. The patients’ age ranged from 48 to 96 years, the mean age was 68. Best results were obtained in patients with persistent constipation. The effects of Eucarbon® were found to be satisfactory, especially in cases of constipation and meteorism with no reports of side effects at this dosage. Document 3: Ref. (62) Schmidbauer, C.P., Schuster, F.X.: Vienna, 1985 A randomized controlled study as a bowel preparation in urology: Darmreinigung vor Uroradiologie und Urosonographie. Eine klinische Prüfung mit Eucarbon®. In a parallel group, prospective, monocentric study Eucarbon® was taken at a dosage of four tablets each at midday and in the evening, before urological investigation - compared to the usual but varied laxative preparations. There were 28 patients in the Eucarbon® and 30 patients in the control group of the study. Evaluation was made by investigators’ assessment of the preparations, by patient symptoms and blood biochemistry. The investigators rated the preparation as “very good” in 13 Eucarbon® patients and in 8 control patients, with results being “good” in 7 Eucarbon® and in 16 control subjects. Four patients taking Eucarbon® had watery stools with tolerable intestinal spasm, compared to five patients on comparator treatments. No abnormality of hematology or biochemistry was attributed to Eucarbon®. Document 4: Ref. (52) N’Dri Yoman: The use of Eucarbon® in preparing radiology (unprepared abdominal x-ray, echography). Assessments on 15 patients from Prof. Yoman, University Hospital Center of Yopougon / Ivory Coast, 1993 An open non-comparative assessment of the use of Eucarbon® in ten outpatients (mean age 43 years) with severe constipation, treated with six tablets of Eucarbon® daily, and five patients before abdominal echocardiography. Eucarbon® is reported as having a satisfactory clinical effect (disappearance of gases and improvement of echographies) and no serious side effects. It was necessary to administer a minimum dosage of 6 tablets/day for 3 days or more, if necessary (in case of protracted immobilization, previous severe constipation, dyspeptic troubles). Document 5: Ref. (18) El Mirini, M.: An evaluation of 80 patients undergoing urological investigations. Evaluation of the clinical efficacy of Eucarbon® in the preparation of the intestine for urography and for enterocystoplastic surgery, Central Hospital, Casablanca, Morocco, 1994 Evaluation in radiology: Eighty patients (72 men, 8 women, aged between 53 and 75 years, mean age 64) with urinary tract disorders were treated either with Eucarbon® or with a low residue diet for three days prior to urological investigation. The study was prospective but it is Clinical Expert Report Eucarbon® Tablets, 2004-05-17 not clear whether the subjects were randomized. Eight patients who underwent an enterocystoplastic surgery were given both, a low residue diet and Eucarbon® as well as metronidazole. In the two main groups the results were as follows: Improvement in the interpretation of urographic radiograms: (n=36) The clinical efficacy in the Eucarbon® group was excellent. The well-being of the patients was improved. Document 6: Ref. (46) Machavariani, A. et al. : Use of Eucarbon® for the treatment of patients suffering from irritable bowel syndrome and from constipation, Tiflis, 2003 The efficacy of Eucarbon® was investigated on a group with 35 patients (18 men, 17 women, average age 45,2 years). 15 patients were with irritable bowel syndrome, 10 patients with atonic constipation and 10 with spastic constipation. The dose was 2 tablets twice a day for 12 weeks. The authors came to the conclusion, that Eucarbon® is an active remedy for the treatment of colon dysfunction. It works equally effectively in all forms of constipation in colon diseases. The atonic constipation treatment is especially effective. The IBS and spastic constipation is also influenced by Eucarbon®, but an optimum result was achieved after the addition of sedative and spasmolytic drugs. Document 7: Ref. (15) Dumitrascu, D.L. et al. : A combination of charcoal and Senna improves the accuracy of abdominal ultrasonographic investigation, Cluj/Romania, 2003 24 patients (15 men, 9 women, mean age 46 years) with inaccurate images at abdominal ultrasonography were included in a prospective, parallel group, randomized, open, controlled trial. Group I (n=14) received Eucarbon® three times daily one tablet, group II (n=10) charcoal in the same quantity. The quality of the ultrasonographic pictures was evaluated according to a Likert scale from 1 (minimum) to 5 (maximum). Eucarbon® improved the quality of the ultrasonographic pictures from 1.9+/-0.4 to 3.3+/-1.7 (p<0.01). Simple charcoal improved the quality score from 1.5+/-0.7 to 2.6+/-11.1 (p=0.07). Thus the effect of Eucarbon® was superior to that of simple charcoal. No case of diarrhoea as side effect was recorded. Document 8: Ref. (33) Hübner, W.D. and Alken, R.G.: Treatment of Patients Suffering from Constipation with Eucarbon® Tablets, 2004 In a drug-monitoring study efficacy and safety of Eucarbon® tablets were investigated in patients suffering from constipation, especially those with spasmodic complaints. After the 12-week treatment period, 61 patients were available for analyses, whereby the following questionnaires were used: global assessment for efficacy and safety/tolerance, modified Clinical Global Impressions Score (CGI) and modified Francis Score (IBS-Score). The majority of patients took 3x2 tablets daily. Clinical Expert Report Eucarbon® Tablets, 2004-05-17 All major symptoms and complaints like abdominal pain, altered frequency of stool, flatulence, hyperperistalsis, tenderness on pressure, tympatitic resonance decreased during treatment. The medication was very well tolerated. In conclusion the efficacy and safety of the natural drug Eucarbon® in the indication constipation could be confirmed. All mentioned clinical studies are presented as tabular survey in order to give quick information on design, results, and further details in chapter 14. Annex. Supportive Data
In the following supportive data are discussed which resulted from clinical studies with modified Eucarbon® tablets (containing as active ingredients 180mg Carbo ligni, 105mg Fol. sennae, 25mg Extr. rhei) without sulfur (“Eucarbon® Herbal”, which is registered in some Eastern European, some Asian and some African countries). Although the tablets are modified by taking out sulfur, the remaining composition is unchanged and thus may give strong evidence for efficacy and safety in the used indications in conformance with the original Document 9: Ref. (34) Irnius et al.-I: Press release by Fa. Trenka: Herbal intestinal regulator for radiological examinations by contrast media, Vilnius, 2003 The preparation Eucarbon® was administered to 19 patients (15 women, 4 men, median 63 years) at the Santariske Hospital of the University Vilnius to prepare the bowel for contrast examinations. The main complaints of the patients were IBS, chronic hepatitis, chronic constipation, and diverticulitis. The majority of the patients (in total 10 patients) received 4 tablets each in the morning and in the evening prior to the day of the examination. In 14 cases out of 19 (74%) the desired effect was obtained by Eucarbon® alone. 5 patients (26%) needed to be given an enema in addition. Eucarbon® was very well tolerated by all patients. Side effects have not been observed. Document 10: Ref. (35) Irnius et al.-II: Press release by F. Trenka: Herbal intestinal regulator for the treatment of IBS, the Irritable Bowel Syndrome, Vilnius, 2003 At the Santariske Hospital of the University Vilnius 21 patients suffering from recurrent symptoms of IBS (20 women, 1 man, median 63 years) received treatment with the herbal intestinal regulative agent Eucarbon®. The medication was given at doses decreasing from 3x2 and 4x1 to 3x1 and 1x1 tablets per day. The treatment was conducted over a period of 25-45 days (median 37 days). The evaluation showed an excellent effect in 5 cases and a good/sufficient therapeutic effect in the remaining 16 cases, which was generally reached after 2 to 3 weeks (median 14 days). In all cases the preparation was well tolerated. Clinical Expert Report Eucarbon® Tablets, 2004-05-17 Document 11: Ref. (32) Hübner, W.D. and Moser, E.H.: Charcoal Tablets in the Treatment of Patients With Irritable Bowel Syndrome, 2002 In a double blind, controlled, randomised, multi-centre, prospective clinical trial efficacy and tolerance of modified Eucarbon® tablets (containing as active ingredients 180mg Carbo ligni, 105mg Fol. sennae, 25mg Extr. rhei) was compared to carbo ligni (C.l.) containing tablets. 284 patients between 19-70 years suffering from IBS started treatment (“Eucarbon” group 145, C.l. group 139). After the 12-weeks treatment period 262 patients were available for ITT analysis whereby changes of the disease have been evaluated with the IBS-score (Francis et al. 1997) as the primary efficacy parameter. Symptoms decreased in the ITT population under “Eucarbon” treatment by about 60%, but surprisingly the relative gain in terms of efficacy over the control group was only about 9%. On the other hand a number of clinical observations and subgroup analyses showed that Eucarbon has been much more effective, e.g. in the subgroup of patients suffering from constipation. Both treatments were well tolerated, adverse events occurred with similar frequency in both groups (22% of patients treated with „Eucarbon” vs. 17% treated with C.l.). In most cases it was not possible to distinguish the event from symptoms of IBS. The results of this trial are regarded as supportive data as the test preparation “Eucarbon” had a modified composition compared to the original commercially available Eucarbon® containing no sulfur. Nevertheless regarding drug safety the data from this trial support the traditionally well known good tolerance of Eucarbon®. Testimonials
Over the decades of successful use of Eucarbon® again and again “Testimonials” of well- recommended physicians from various countries have been sent to the applicant to bear witness to efficacy and safety of this traditional preparation. These documents give important knowledge on the benefits of Eucarbon® tablets in daily practice. As they have not the relevance of clinical trials or systematically collected clinical data, they are not discussed in detail but are mentioned in the references (2, 3, 17, 29). Safety of Eucarbon®
The over all tolerability and safety of Eucarbon® is worldwide known and traditionally documented. Using Eucarbon® as a drug of choice in constipation has never been associated with life-threatening adverse reactions. In the usual dosage regime i.e. at the recommended doses Eucarbon® does not even show preparation-related side effects, neither in the daily There are no findings on drug interactions so far nor any restrictions on the ability to drive or The MCA report "Safety of Herbal Medicinal Products" published in July 2002 (47) mentioned for rhubarb and senna as potential adverse events only “purgative, irritant to GI tract” – thus Clinical Expert Report Eucarbon® Tablets, 2004-05-17 known effects - and recommended to avoid non-standardised preparations during pregnancy. Thus confirming the excellent safety of the drug. Safety of Anthranoid Laxatives
Overviewing the medical literature concerning anthranoid laxatives and negative association with cancer risk following studies are available: Kune (38), Nusko et al. (54), Siegers et al. Safety Profile of Anthranoids and Derivatives as Anticancer Agents
A literature research in the data banks “CancerLit, Database, Medline, Toxline” showed no evidence for toxicity of anthranoid laxatives. On the contrary, in recent literature many publications and issues were found to prove the use of anthranoids and derivatives as anticancer agents (16). Wiseman et al. (72) showed in their publication the antitumor effect of the anthrachinon mitoxantrone in prostatic cancer. The antineoplastic agent mitoxantrone in combination with a corticosteroid (either prednisone or hydrocortisone) has shown clinical efficacy as palliative treatment for a proportion of patients (about 35 to 40%) with hormone-resistant advanced Sufficient studies are published in the literature to prove the safety of anthranoids and the anticancer properties of anthranoid derivatives. Post-Marketing Experience
The product Eucarbon® has already been marketed for several years or is currently marketed in the following countries (for the countries in which Eucarbon® is marketed at present, Clinical Expert Report Eucarbon® Tablets, 2004-05-17 Pharmacovigilance reports date back to the early 1960´s and no side-effect of Eucarbon® has been reported since then or even before. Which is very remarkable as year by year about 1 million packs (at 100 tablets) are sold worldwide. There are no findings on drug-drug interactions, deliberate or accidental overdose, and drug abuse or misuse. Since Eucarbon® is not indicated during pregnancy and lactation period, no findings have been reported so far. No untoward findings from long-term treatment, which may frequently occur in medical practice, exist either. Clinical Expert Report Eucarbon® Tablets, 2004-05-17 General Conclusions
11.1. Constipation and General Digestive Disorders
Chronic constipation is one of the most common complaints in clinical medicine. It is a rising problem in modern society. Approximately one-fifth of all adults in industrialized countries Chronic constipation, which has been defined as the delayed evacuation of dry, hard stools, has several possible causes. The most common ones are associated with nutritional factors such as the consumption of food with poor dietary fibre content, which results in the insufficient filling of the intestine, the intake of readily absorbed food with a reduced water- Other causes include factors related to organ dysfunction or organ damage including gastro- intestinal disorders, changes in the intestinal wall (due to a tumour or chronic inflammation e.g.), metabolic and endocrine disorders (diabetes mellitus e.g.), functional and organic disturbances of the nervous system, such as Parkinson’s disease, or may be caused by the side-effects of drugs such as analgesics, antidepressants, antispasmodics or sedatives. Constipation per se is diagnosed if no bowel movements occur for three days or more and if this irregularity persists for longer than six days. In addition to the adverse effect on the patients’ well-being, the following symptoms may also occur: sluggishness of the bowels, putrefaction, headache, fatigue, skin rashes and halitosis. In many patients there is a smooth transition to other functional gastro-enterologic disorders like irritable bowel syndrome (IBS) also known as spastic colon, which is a benign relapsing chronic disorder, characterized by recurrent abdominal pain and altered bowel function. Constipation and diarrhoea often alternate, and abdominal cramping, gassiness, and bloating It is a problem that occurs in only a small percentage of persons in the non-elderly population but affects as many as 26% of men and 34% of women over 65 years of age. Chronic constipation can lead to physical and mental impairments. There is a persistent demand on a laxative and/or antidiarrhoeal medicine with the possibility of easy modulation of dosage for this very complex illness. 11.2. Eucarbon®
Eucarbon® is a combination of anthranoid drugs (senna and rhubarb), sulfur, and the mild adsorbent vegetable charcoal (carbo ligni) - ingredients which as single drugs/substances or in different combinations have been used as remedies for centuries in patients with intestinal Clinical Expert Report Eucarbon® Tablets, 2004-05-17 complaints, mainly with constipation. In the unique combination of this preparation the proven and generally accepted effects of the single ingredients have additional beneficial effects – presented in a standardized dosage form. It is a medicinal product with mainly laxative effects. The action of the preparation is due to the content of vegetable charcoal and the stimulatory action of anthraquinones and sulfur. The use of vegetable charcoal, rather than activated charcoal, avoids the significant drug binding of anthranoids and potential interactions. The adsorption properties of carbo ligni are regarded for the effect to cure complaints due to intestinal gases and supports the antiputrefactive action of sulfur. This adsorbant activity of carbo ligni, although definitely lower compared to activated charcoal has been extensively studied in the last 20 years. It could be demonstrated that carbo ligni adsorbs many chemical entities, but does not inhibit the release and efficacy of the anthrachinone glycosides from Eucarbon®. The detoxifying effect also has been studied and shown in in-vivo studies from study groups outside the applicant company The efficacy and safety of Eucarbon® have been established and highly acknowledged for nearly 100 years. There are no preparation-specific contra-indications known for Eucarbon®. Longtime experience and clinical studies have demonstrated that patients taking Eucarbon® for one or two weeks get relief of abdominal swelling and of dyspeptical troubles. The action of Eucarbon® is gradual, mild and prolonged. This determines its value. Eucarbon® is a well-tolerated product. Nevertheless patients have to take care – as for every Since Eucarbon® is a traditional product, the documentation failed to exhibit new clinical studies especially according to GCP. In spite of this fact Eucarbon® has proven to be an effective and excellent tolerated drug. Eucarbon® possesses unique properties and is a valuable tool in the therapy of general digestive disorders with special regard to the indications (chronic) constipation, irritable bowel syndrome and in the preparation or improvement of x-ray and/or ultrasonic abdominal investigations. To give stronger evidence, new clinical studies with extensive protocols using modern study designs and analytical laboratory methods should be considered in these indications. From the data collected in this Clinical Expert Report it must be concluded that Eucarbon® tablets are an effective and safe drug, suited for the treatment of the proposed indications with Clinical Expert Report Eucarbon® Tablets, 2004-05-17 the suggested dosages. It is recommended that marketing authorization be granted for this Clinical Expert Report Eucarbon® Tablets, 2004-05-17 12. References
BECKETT, R., COOMBS, T.J., FROST, M.R., McLEISH, J., THOMPSON, K.: Charcoal cloth and malodorous wounds. Lancet, 9: 594 (1980) BELSASSO, E. et al.: Testimonials from five Heads of Departments at the University of Trieste. Data on file (1993) BENDA, L.: Testimonials on EUCARBON. Data on file (1969) BERG, M.J., BERLINGER, W.G., GOLDBERG, M.J., SPECTOR, R., JOHNSON, G.F.: Acceleration of the body clearance of phenobarbital by oral activated charcoal. N. Eng. J. Med. 307: 642-644 (1982) BERLINGER, W.G., SPECTOR, R., GOLDBERG, M.J., JOHNSON, G.F., QUEE, C.K., BERG, M.J.: Enhancement of theophylline clearance by oral activated charcoal. Clin. Pharmacol. Ther., 33: 351-354 (1983) BEUBLER, E., KOLLAR, G.: Prostaglandin-mediated action of sennosides. Pharmacology 36 (1): 85-91 (1988) BREIER, H.: An Open Study in general practice of 102 patients: Klinische Untersuchungsergebnisse nach Verabreichung von EUCARBON. Biomed 5/81: 1-4 (1981) CHASSANY, O., MARQUIS, P., SCHERRER, B. et al.: Validation of a specific quality of life questionaire for functional digestive disorders. Gut 44: 527-533 (1999) COONEY, D.O., STRUHSAKER, T.T.: Adsorptive Capacity of Charcoals Eaten by Zanzibar Red Colobus Monkeys: Implications for Reducing Dietary Toxins. International Journal of Primatology, 18 (2): 235-246 (1997) COONEY, D.O.: In vitro adsorption of phenobarbital, chlorpheniramine maleate, and theophylline by four commercially available actvated charcoal suspensions. J Toxicol Clin Toxicol. 33(3): 213-7 (1995) COONEY, D.O.; THOMASON, R.: Adsorption of fluoxetine HCl by activated charcoal. Journal of pharmaceutical sciences; VOL: 86 (5 )642-4 (1997) DE SILVA, HA; Fonseka MM; Pathmeswaran A; Alahakone DG; Ratnatilake GA; Gunatilake SB; Ranasinha CD; Lalloo DG; Aronson JK; de Silva HJ : Multiple-dose activated charcoal for treatment of yellow oleander poisoning: a single-blind, randomised, placebo-controlled trial. Lancet; VOL: 361 (9373) 1935-8 (2003) DITTER, B., URBASCHEK, R., URBASCHEK, B.: Ability of various adsorbents to bind endotoxins in vitro and to prevent orally induced endotoxemia in mice. Gastroenterology, 84: 1547-1552 (1983) Clinical Expert Report Eucarbon® Tablets, 2004-05-17 DOLLERY, C.: Sulphur. In: Therapeutic Drugs, Churchill Livingstone, Edinburgh, London, Melbourne, New York, Tokyo, Madrid:145-146 (1981) DUMITRASCU, D.L., SIMON, B., DUMITRASCU, D.I.: A combination of Charcoal and Senna Improves the Accuracy of Abdominal Ultrasonographic Investigation. Modern Medicine 11/2003 (2003) DUNN, CH.J., GOA, K.L.: Mitoxantrone: A Review of its Pharmacological Properties and Use in Acute Nonlymphoblastic Leukaemia. Drugs & Aging 9 (2): 122-147 (1996) ELLIDER, R.M.:Testimonial: Preliminary Report on Eucarbon, 21-11-1989 Data on file (1989) El MIRINI, M., ABOU TAIEB, R., BENJELLOUN, S.: Evaluation of the clinical efficacy of EUCARBON in the preparation of the intestine for urography and for enterocystoplastic surgery. Central Hospital, Casablanca, Marocco Data on file (1994) EWE, K., UEBERSCHAER, B., PRESS, A.G.: Influence of Senna, Fibre, and Fibre + Senna on Colonic Transit in Loperamide-Induced Constipation. Pharmacology 47 (1): 242-248 (1993) FAIRBAIRN, J.W., MOSS, M.J.R.: The relative purgative activities of 1,8-dihydroxyanthracene derivatives. J. Pharm. Pharmacol. 22: 584-593 (1970) FALLON, M., O’NEILL, B.: ABC of palliative care: Constipation and diarrhoea. BMJ 315: 1293-1296 (1997) FARR, C., MAHY, P.: Expert Report on the Toxicological and Pharmacological Documentation of Eucarbon, 16-02-1999 Data on file (1999) FORTH, W., HENSCHLER, D., RUMMEL, W., STARKE, K.: Einteilung der Laxantien. Allg. u. spez. Pharmakologie und Toxikologie, 7. Auflage, Spektrum-Verlag, Heidelberg: 532-535 FRANCIS, C.Y., MORRIS, J., WHORWELL, P.J.: The irritable bowel severity scoring system: a simple method of monitoring irritable bowel syndrome and its progress. Aliment Pharmacol Ther 11: 395-402 (1997) HAGERS HANDBUCH der Pharmazeutischen Praxis, 5. vollständig neubearbeitete Auflage; Herausgeber: VON BRUCHHAUSEN, F., DANNHARDT, G., EBEL, S., FRAHM, A.W., HACKENTHAL, E., HOLZGRABE, U., Springer Verlag: Rheum: 411-439 (1993) HAGERS HANDBUCH der Pharmazeutischen Praxis, 5. vollständig neubearbeitete Auflage; Herausgeber: VON BRUCHHAUSEN, F., DANNHARDT, G., EBEL, S., FRAHM, A.W., HACKENTHAL, E., HOLZGRABE, U., Springer Verlag: Senna: 705-715 (1993) Clinical Expert Report Eucarbon® Tablets, 2004-05-17 HALL, R.G., THOMPSON, H., STROTHER, A.: Effects of orally administered activated charcoal on intestinal gas. Am. J. Gastroent. 75: 192-196 (1981) HALPERN, Z.: Testimonial on Eucarbon, 15-07-2002 Data on file (2002) HÖLZL, J., KREUSCH, D.: Rhabarber In: Das große Arzneipflanzen – Kompendium. Auszug CD-ROM (1999) HOLZSCHUH, L., KOPP, B., KUBELKA, W.: Physcion-8-O-β-D-gentiobiosid, ein neues Hauptglykosid aus Radix Rhei. Planta Medica, Journal of Medicinal Plant Research, Hippokrates Verlag GmbH., 46: 159-161 (1982) HÜBNER, W.D., MOSER, E.H.: Charcoal Tablets in the Treatment of Patients With Irritable Bowel Syndrome. Advances in Therapy 19(5): 245-252 (2002) HÜBNER, W.D., ALKEN, R.G.: Treatment of Patients Suffering from Constipation with Eucarbon® Moderne Medicin (2004), submitted for publication Irnius, A.: Herbal Intestinal Regulator for radiological examinations by contrast media, Press release Fa. Trenka I Z f Phytother 2: 58 (2003) Irnius, A.: Herbal intestinal regulator for the treatment of IBS, the Irritable Bowel Syndrome, Summary 14-08-2002 Press release Fa. Trenka II (in preparation) KINJO, J., IKEDA, T., WATANABE, K., NOHARA, T.: An Anthraquinone Glycoside from Cassia angustifolia Leafes. Phytochemistry, 37 (6): 1685-1987 (1994) KINNUNEN, O., WINBLAD, I., KOISTINEN, P., SALOKANNEL, J.: Safety and Efficacy of a Bulk Laxative Containing Senna versus Lactulose in the Treatment of Chronic Constipation in Geriatric Patients. Pharmacology 47 (1): 253-255 (1993) KUNE, G.A.: Laxative use not a risk for colorectal cancer: data from the Melbourne colorectal cancer study. Z. Gastroenterol. 31: 140-143 (1993) LAINE, K.; Kivistö KT; Pelttari S; Neuvonen PJ : The effect of activated charcoal on the absorption of fluoxetine, with special reference to delayed charcoal administration. Pharmacology & Toxicology; VOL: 79 (5): 270-3 (1996) LAINE, K.; Kivistö KT; Neuvonen PJ: Effect of delayed administration of activated charcoal on the absorption of conventional and slow-release verapamil. Journal of Toxicology. Clinical toxicology; VOL: 35 (3): 263-8 (1997) LAPATTO-REINILUOTO, O.; Kivistö KT; Neuvonen PJ: Efficacy of activated charcoal versus gastric lavage half an hour after ingestion of moclobemide, temazepam, and verapamil. European journal of clinical pharmacology; VOL: 56 (4): 285-8 (2000) Clinical Expert Report Eucarbon® Tablets, 2004-05-17 LENG-PESCHLOW, E.: Dual effect of orally administered sennosides on large intestine transit and fluid absorption in the rat. J. Pharm. Pharmacol. 38: 606-610 (1986) LENG-PESCHLOW: Senna and its Rational Use. Pharmacology 44 (suppl. 1): 1-52 (1992) LENNARD-JONES, J.E.: Clinical Management of Constipation. Pharmacology 47 (1): 216-223 (1993) LYDEN-SOKOLOWSKI, A., NILSSON, A., SJOBERG, P.: Two-year carcinogenicity study with sennosides in the rat: emphasis on gastrointestinal alterations. Pharmacology 47 (Supp. 1): 209-215 (1993) MACHAVARIANI, A., Maisaia, B.K., Kekelidze, N., Shashiashvili, T., Mamulashvili, M.: Use of „Eucarbon“ for the treatment of patients suffering from irritable bowel syndrome and from constipation. Modern Medicine 20: 53-59 (2003) Medicines Control Agency (MCA) London: Report on Safety of Herbal Medicinal Products, July 2002 (2002) Monograph Rhei radix, German Kommission E, Banz Nr. 133: 21-07-1993 (1993) Monograph Sennae folium, German Kommission E, Banz Nr. 133: 21-07-1993 (1993) MÜLLER, B.M., KRAUS, J., FRANZ, G.: Chemical Structure and Biological Activity of Water-Soluble Polysaccharides from Cassia angustifolia Leaves. Planta Medica 55: 536-539 (1989) MUTSCHLER, E.: Laxantien Arzneimittelwirkungen – Lehrbuch der Pharmakologie und Toxikologie, 7. Auflage, Stuttgart: 483-489 (1991) N’DRI YOMAN: The use of EUCARBON in preparing radiology (unprepared abdominal x-ray, echography). Assessments on 15 patients from Prof. Yoman, University Hospital Centre of Yopougon/Ivory Coast. Data on file (1993) NEUVONEN, P.J., KARKKAINEN, S.: Effects of charcoal, sodium bicarbonate, and ammonium chloride on chlorpropamide kinetics. Clin. Pharmacol. Ther. 33: 386-393 (1983) NUSKO, G., SCHNEIDER, B., ERNST, H., WITTEKIND, C., HAHN, E.G.: Melanosis coli – a harmless pigmentation or a precancerous condition? Z. Gastroenterol. 35 (5): 313-318 (1997) PALUMBO, M., ZAGOTTO, G., GUIOTTO, A.: Evaluation of Adsorption Properties of Carbo Ligni used for Eucarbon and of Norit activated Carbon. Universita di Padova, Trenka, Data on file (1994) PEZZOLI, A.: Treatment of hospital in-patients with EUCARBON. An open evaluation. A report on 31 hospital in-patients from the Clinica Medica Generale, University of Trieste. Data on file (1981) Clinical Expert Report Eucarbon® Tablets, 2004-05-17 POTTER, T., ELLIS, C., LEVITT, M.: Activated charcoal: In vivo and in vitro studies of effect on gas formation. Gastroenterology 88: 620-624 (1985) RANTIS Jr., P.C., VERNAVA III, A.M., DANIEL, G.L., LONGO, W.E.: Chronic Constipation – Is the Work-Up Worth the Cost? Dis. Colon Rectum 40: 280-286 (1997) REYNOLDS, J.E.F., PRASAD, A.B.: Sulphur Martindale: The Extra Pharmacopoeia, 30th Edition, The Pharmaceutical Press, London: 504-506 (1993) REYNOLDS, J.E.F.: Activated Charcoal Martindale – The Extra Pharmacopoeia, 31st Edition, London: Royal Pharmaceutical Society: 973-974 (1996) SCHAEFER, D.C., CHESKIN, L.J.: Constipation in the Elderly. American Family Physician, Sept. 15,1998 (www.aafp.org/afp/980915ap/schaefer) SCHMIDBAUER, C.P., SCHUSTER, F.X.: Darmreinigung vor Uroradiologie und Urosonographie. Eine klinische Prüfung mit EUCARBON. Data on file (1985) SCHWABE, U., PAFFRATH, D.: Arzneiverordnungsreport 2003. Laxantien: 607-609. Springer Verlag, Berlin, Heidelberg, New York (2004) SIEGERS, C.P., VON HERTZBERG-LOTTIN, E., OTTE, M., SCHNEIDER, B.: Anthranoid laxative abuse a risk for colorectal cancer? Gut 34 (8): 1099-1101 (1993) SONNENBERG, A., MULLER, A.D.: Constipation and cathartics as risk factors of colorectal cancer: a meta-analysis. Pharmacology 47 (Suppl. 1): 224-233 (1993) SONNENBERG, A., KOCH, T.R.: Epidemiology of constipation in the United States. Diseases of the colon and rectum 32 (1): 1-8 (1989) STRUHSAKER, T.T., COONEY, D.O., SIEX, K.S.: Charcoal Consumption by Zanzibar Red Colobus Monkeys: Its Function and Its Ecological and Demographic Consequences. International Journal of Primatology 18 (1): 61-72 (1997) THOMPSON, W.G., GICK, M.: Irritable bowel syndrome. Semin Gastrointest Dis. 7(4):217-229 (1996) TSUCHIYA, T., LEVY, G.: Drug adsorption efficacy of commercial activated charcoal tablets in vitro and in man. J. Pharm. Sc. 61(4): 624-625 (1972) VALVERDE, A., Hay JM; Fingerhut A; Boudet MJ; Petroni R; Pouliquen X; Msika S;
Flamant Y: Senna vs polyethylene glycol for mechanical preparation the evening before
elective colonic or rectal resection: a multicenter controlled trial. French Association for
Surgical Research. Archives of surgery:
Official publication for the Central Surgical Association and the Western Surgical
Association; VOL: 134 (5): 514-9 (1999)
Clinical Expert Report Eucarbon® Tablets, 2004-05-17 WALD, A.: Approach to the Patient With Constipation. Textbook of Gastroenterology, 2nd Edition, edited by Tadataka Yamada, JB Lippinott Company, Philadelphia: 864-880 (1995) WISEMAN, L.R., SPENCER, C.M.: Mitoxantrone: A review of its pharmacology and clinical efficacy in the management of hormone-resistant advanced prostate cancer. Drugs & Aging 10 (6): 473-485 (1997) Clinical Expert Report Eucarbon® Tablets, 2004-05-17 Qualification of the Expert

Curriculum vitae Dr. Wolf-Dietrich Hübner

Name
Education and Graduation: 1958 – 1972 High school and Grammar school in Berlin 1972 – 1979 Study of medicine, Free University Berlin Dr. med. (MD), Free University Berlin,1980 Board Certification as Urologist, Berlin, 1990 Member of the Faculty of Pharmaceutical Medicine, London,1996 Clinical education in University and teaching hospitals in neurosurgery, surgery and urology in Berlin and Heidelberg R + D Department, Lichtwer Pharma AG, Berlin Vice President Medical Affairs, Berolina Drug Development GmbH, Berlin papers in different journals, poster presentations, abstracts, oral presentations: more than 100 Berlin, 12-May-2004 ____________________________ Clinical Expert Report Eucarbon® Tablets, 2004-04-30 I 14. ANNEX
14.1.1 Tabular Overview of the Clinical Trials (Tables I)
14.1.2 Eucarbon®
(Please see Tabulated Study Reports: Study 1 – Study 8, chapter 14.2)
Study
Number (Ref.-No)
Patients
treated with
Eucarbon®
Clinical Results after the Application of Clinical report on the Tolerance and efficacy Intestinal Cleaning before Uroradiology and Eucarbon® in the Preparation of Urography 14.1.3 Supportive Data with Eucarbon® Herbal
(The following studies are discussed in chapter 9.2.3. but not listed as Tabulated Study Reports, as they are not performed with Eucarbon® tablets in the applied composition) Patients
treated with
Eucarbon®
Herbal Intestinal Regulator for Radiological Herbal Intestinal Regulator for the Treatment Charcoal Tablets in the Treatment of Patients 145 Clinical Expert Report Eucarbon® Tablets, 2004-04-30 I 14.2 Tabular Summaries of the Clinical Trials (Tables II)
Clinical Expert Report Eucarbon® Tablets, 2004-04-30 I Clinical Expert Report – Study 1

Name of the company:
TABULAR FORMAT
(For National
F. Trenka GmbH
REFERRING TO PART IV B
Authority Use
OF THE DOSSIER
Name of the finished product:
Eucarbon® tablets
Name of the active substance(s):
Fol. Sennae, Extr. Rhei, Carbo ligni, Sulfur depur. Page:
Title of the study: Clinical Results after the Application of Eucarbon®
Investigator: Breier, H
Study centre: General Practice in Vienna

Publication (reference): Breier, H.: Klinische Untersuchungsergebnisse nach Verabreichung von EUCARBON.
Biomed 5/81: 1-4 (1981)
Studied period (years):
Clinical Phase:
Objectives
Methodology
Number of subjects (total and for each treatment): 102 out-patients
Diagnosis and criteria for inclusion:
Test product, dose, mode of administration, batch No.:
Eucarbon® tablets, two tablets daily (or higher doses – up to six tablets daily – in 31 subjects) Duration of treatment: 1 week
Clinical Expert Report Eucarbon® Tablets, 2004-04-30 Clinical Expert Report – Study 1

Name of the company:
TABULAR FORMAT
(For National
F. Trenka GmbH
REFERRING TO PART IV B
Authority Use Only)
OF THE DOSSIER
Name of the finished product:
Eucarbon® tablets
Name of the active substance(s):
Fol. Sennae, Extr. Rhei, Carbo ligni, Sulfur depur. Page:
Reference therapy, dose, mode of administration, batch No.: --
Criteria for evaluation:
Improvement of constipation, meteorism, colicky pains, flatulence, nausea, vomiting, diarrhoea, sleep disorders, Measured with Likert scales, general assessment of efficacy and tolerance Statistical methods:
SUMMARY - CONCLUSIONS:
(a supplementary sheet may be used if necessary)
Five symptoms were significantly improved by treatment with Eucarbon® during the study: constipation, abdominal distension, colicky abdominal pain, nausea and flatulence, p-values being from <0,01 to <0,001 for the individual symptoms. The improvements were maintained for the whole study period. Efficacy results: Global assessment of efficacy (Number of Patients)
Safety results
Conclusions: Good efficacy in two third to three fourths, good tolerance of nearly 100%
Date of report
Clinical Expert Report Eucarbon® Tablets, 2004-04-30 Clinical Expert Report – Study 2

Name of the company:
TABULAR FORMAT
(For National
F. Trenka GmbH
REFERRING TO PART IV B
Authority Use
OF THE DOSSIER
Name of the finished product:
Eucarbon® tablets
Name of the active substance(s):
Fol. Sennae, Extr. Rhei, Carbo ligni, Sulfur depur. Page:
Title of the study: Clinical Report on the Tolerance and Efficacy of Eucarbon®
Investigators: Pezzoli, A., Feruglio, F.S.
Study centre: Clinica Medica Generale, University of Trieste

Publication (reference): Pezzoli, A.: Treatment of in hospital in-patients with Eucarbon®. An open evaluation. A
report on 31 hospital in-patients from the Clinica Medica Generale, University of Trieste.
Data on file (1981)
Studied period (years):
Clinical Phase:
Objectives
Methodology
Number of subjects (total and for each treatment):
Diagnosis and criteria for inclusion:
Patients with general medical complaints, suffering additionally from intestinal complaints, constipation or bellyache Test product, dose, mode of administration, batch No.:
Eucarbon® tablets at doses of 3 – 6 tablets per day Duration of treatment:
Clinical Expert Report Eucarbon® Tablets, 2004-04-30 Clinical Expert Report – Study 2

Name of the company:
TABULAR FORMAT
(For National
F. Trenka GmbH
REFERRING TO PART IV B
Authority Use Only)
OF THE DOSSIER
Name of the finished product:
Eucarbon® tablets
Name of the active substance(s):
Fol. Sennae, Extr. Rhei, Carbo ligni, Sulfur depur. Page:
Reference therapy, dose, mode of administration, batch No.: --
Criteria for evaluation:
General assessment of symptomatology and well-being Statistical methods:
SUMMARY - CONCLUSIONS:
(a supplementary sheet may be used if necessary)
Best results were obtained in patients with persistent constipation.
The effects of Eucarbon® were found to be satisfactory, especially in cases of constipation and meteorism
Efficacy results
In 77% of the patients good results, in 6% moderate, in 17% insufficient results
Safety results
No ADRs or drug-drug interactions reported Conclusions
The product Eucarbon® is effective and save and is appropriate in all cases, where its multifunctional efficacy can be used to relieve symptoms like constipation or meteorism Date of report
Clinical Expert Report Eucarbon® Tablets, 2004-04-30 Clinical Expert Report – Study 3

Name of the company:
TABULAR FORMAT
(For National
F. Trenka GmbH
REFERRING TO PART IV B
Authority Use
OF THE DOSSIER
Name of the finished product:
Eucarbon® tablets
Name of the active substance(s):
Fol. Sennae, Extr. Rhei, Carbo ligni, Sulfur depur. Page:
Title of the study: Intestinal Cleaning before Uroradiology and Urosonography
Investigators: Schmidbauer, C.P., Schuster, F.X.:
Study centre: Clinic for Urology, General Polyclinic, Vienna

Publication (reference): Schmidbauer, C.P., Schuster, F.X.: A randomised controlled study as a bowel
preparation in urology: Darmreinigung vor Uroradiologie und Urosonographie. Eine klinische Prüfung mit
Eucarbon®.
Data on file (1985)
Studied period (years):
Clinical Phase:
Objectives
Intestinal Cleaning before Uroradiology and Urosonography to improve the interpretation of the examination Methodology
Randomized, controlled, prospective, parallel group study Number of subjects (total and for each treatment):
58 (28 patients in the Eucarbon® and 30 patients in the control group) Diagnosis and criteria for inclusion:
Patients to undergo uroradiology and urosonographie Test product, dose, mode of administration, batch No.:
Eucarbon® tablets at doses of 4 tablets each at midday and in the evening , before urological examination Duration of treatment:
Clinical Expert Report Eucarbon® Tablets, 2004-04-30 Clinical Expert Report – Study 3

Name of the company:
TABULAR FORMAT
(For National
F. Trenka GmbH
REFERRING TO PART IV B
Authority Use Only)
OF THE DOSSIER
Name of the finished product:
Eucarbon® tablets
Name of the active substance(s):
Fol. Sennae, Extr. Rhei, Carbo ligni, Sulfur depur. Page:
Reference therapy, dose, mode of administration, batch No.:
Usual but varied laxative preparations, enemas Criteria for evaluation:
Improvement of the conditions for urological examinations Statistical methods:
SUMMARY - CONCLUSIONS:
(a supplementary sheet may be used if necessary)
Efficacy results: conditions for urological examinations (number of patients)
Safety results
Conclusions
Premedication with Eucarbon® to clean the intestine before uroradiology and urosonography is as effective as common measures like laxatives or enemas Date of report
Clinical Expert Report Eucarbon® Tablets, 2004-04-30 Clinical Expert Report – Study 4

Name of the company:
TABULAR FORMAT
(For National
F. Trenka GmbH
REFERRING TO PART IV B
Authority Use
OF THE DOSSIER
Name of the finished product:
Eucarbon® tablets
Name of the active substance(s):
Fol. Sennae, Extr. Rhei, Carbo ligni, Sulfur depur. Page:
Title of the study: The Use of Eucarbon® in Preparing Radiology
Investigators: N’Dri Yoman
Study centre: University Hospital Centre of Yopougon/Ivory Coast

Publication (reference): N’Dri Yoman: The use of Eucarbon® in preparing radiology (unprepared abdominal x-
ray, echography). Data on file (1993)
Studied period (years):
Clinical Phase:
Objectives: To improve the radiological examinations of the abdominal organs and the rachis
Methodology
Number of subjects (total and for each treatment):
Diagnosis and criteria for inclusion:
Undefined abdominal pain, suspected ascites, intestinal lymphoma, acute lumbalgia with suspected lesions of the rachis Test product, dose, mode of administration, batch No.:
Eucarbon® tablets at doses of 6 (3x2) tablets daily Duration of treatment:
Clinical Expert Report Eucarbon® Tablets, 2004-04-30 Clinical Expert Report – Study 4

Name of the company:
TABULAR FORMAT
(For National
F. Trenka GmbH
REFERRING TO PART IV B
Authority Use Only)
OF THE DOSSIER
Name of the finished product:
Eucarbon® tablets
Name of the active substance(s):

Source: http://www.eucarbon.at/PDF3/Clinical-Expert-Report_Final01-jov.pdf