Linoforce granules THR 13668-0021 - Medicines and ... Expert Safety Report was provided, which includes reviews of some non-clinical data. The Expert Safety Report was written by a

MHRA PAR; Linoforce granules THR 13668/0021

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Linoforce granules

THR 13668/0021

UKPAR

TABLE OF CONTENTS

Lay summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

Page 13

Summary of Product Characteristics

Page 14

Patient Information Leaflet

Page 24

Labelling Page 26


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Linoforce granules

THR 13668/0021

LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Bioforce (UK) Ltd a Traditional Herbal Registration Certificate for the traditional herbal medicinal product Linoforce granules (Traditional Herbal Registration number: THR 13668/0021) on 22nd June 2012. This product is available without prescription and can be bought from pharmacies and other outlets. Linoforce is a traditional herbal medicinal product for the short term relief of occasional constipation based on traditional use only. Linoforce contains the herbs Linseed, Senna leaf and Frangula bark which are all known for their laxative effect. Linseed helps bulk and soften the stool whilst Senna leaf and Frangula bark stimulate the muscles of the bowel to help bowel movement. This registration is based exclusively upon the longstanding use of Linseed, Senna leaf and Frangula bark as traditional herbal medicines and not upon data generated from clinical trials. There is no requirement under the Traditional Herbal Registration scheme to prove scientifically that the product works. No new or unexpected safety concerns arose from this application and it was, therefore, decided that a Traditional Herbal Registration Certificate could be granted.


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Linoforce granules

THR 13668/0021

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 4

Pharmaceutical assessment

Page 5

Non-clinical assessment

Page 9

Clinical assessment

Page 10

Overall conclusions and benefit-risk assessment Page 12


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INTRODUCTION

The MHRA granted a Traditional Herbal Registration Certificate for the traditional herbal product Linoforce granules (THR 13668/0021) to Bioforce (UK) Ltd on 22nd June 2012. This product is on the general sales list (GSL). This application was submitted according to Article 16.c of Directive 2001/83 EC, as amended, as part of the Traditional Herbal Medicines Registration Scheme. Linoforce granules are a traditional herbal medicinal product used for the short term relief of occasional constipation based on traditional use only. The data supplied by the applicant demonstrate 30 years of traditional use of Linseed, Senna leaves and Frangula bark in the European Community. A satisfactory review of the available safety data on these herbal preparations has also been provided, together with an Expert Report supporting the proposed product.


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PHARMACEUTICAL ASSESSMENT

HERBAL SUBSTANCE: LINSEED Scientific name of plant: Linum usitatissimum L. English name of plant: Flax Part of plant used: Seeds

Manufacture of the Herbal Substance The plants are cultivated in Europe, North- or South-America. The ripe seeds are harvested mechanically (threshing) in the summer and dried. Foreign matters are removed mechanically. The dry seeds are stored in sacks in a cool and dry place, free of insects and protected from light. The seeds are neither irradiated nor fumigated. The plants are collected in accordance with Good Agricultural and Collection Practice (GACP) guidelines. No pesticides are used. Only organic fertilisation is performed. Cultivation, harvesting and documentation are done according to GACP.

Control of Herbal Substance An appropriate specification based on the Ph Eur monograph for Linseed is applied and is acceptable. The specification is supported by the batch data provided. Container Closure System The seeds are stored in PP-/PE woven bags consisting of an outer PP cloth and an inside PE liner. The specification including technical data and a confirmation of compliance with the relevant EC legislation is provided. Stability This herbal substance is further processed within a month. Therefore no stability testing was done. HERBAL PREPARATION: LINSEED The herbal preparation is the same as the herbal substance. Therefore, there are no critical steps or intermediates, which have to be controlled. The specifications, analytical procedures, validations of analytical procedures as well as certificates of analysis have been provided. These are satisfactory. HERBAL SUBSTANCE: SENNA LEAVES Scientific name of plant: Cassia senna L. / Cassia angustifolia Vahl Synonyms: Cassia acutifolia Delile English name of plant: Alexandrian senna plant

Khartoum senna Nubian senna plant Tinnevelly senna East Indian senna leaves

Part of plant used: Leaves


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Manufacture of the Herbal Substance Cassia senna L. / Cassia angustifolia Vahl is a perennial plant. It is cultivated in India. Pest management is performed with a minimal necessary dose of herbicides, fungicides and insecticides which meet European legal requirements. Mineral fertiliser is used for fertilisation. Cultivation, harvesting and documentation are done according to GACP. It is also stated that the plants are not treated with chemicals or irradiation following harvesting. Control of Herbal Substance An appropriate specification based on the Ph Eur monograph for Senna leaves is applied and is acceptable. The specification is supported by the batch data provided. Container Closure System No data are needed. Stability No stability data are needed. HERBAL PREPARATION: SENNA LEAVES Apart from the fact that it is powdered, the herbal preparation is the same as the herbal substance. Therefore, there are no critical steps or intermediates, which have to be controlled. The specifications, analytical procedures, validations of analytical procedures as well as certificates of analysis have been provided. These are satisfactory. HERBAL SUBSTANCE: FRANGULA BARK Scientific name of plant: Rhamns frangula L. Synonyms: Frangula alnus MILL

Frangula frangula (L.) KARST English name of plant: Alder buckthorn

Frangula Buckthorn

Part of plant used: Bark

Frangulae cortex is collected in Europe. Neither pesticides are used nor is fertilisation performed. The plants are collected in accordance with GACP guidelines. The plants are not treated with chemicals or irradiation following harvesting. Control of Herbal Substance An appropriate specification based on the Ph Eur monograph for Frangula bark is applied and is acceptable. The specification is supported by the batch data provided. Container Closure System No data are needed. Stability No stability data is needed.


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HERBAL PREPARATION: FRANGULA BARK Apart from the fact that it is powdered, the herbal preparation is the same as the herbal substance. Therefore, there are no critical steps or intermediates, which have to be controlled. The specifications, analytical procedures, validations of analytical procedures as well as certificate of analysis have been provided. These are satisfactory. HERBAL PRODUCT: LINOFORCE GRANULES

Description and Composition of the Herbal Product The herbal product is a coated, glossy dark brown granulate consisting of Linseed (Linum usitatissimum L.), coated with a standardised mixture of pulverised Senna leaves (Cassia senna L.) and Frangula bark (Rhamnus frangula L.) and excipients. 1 dose [4.1 g] (one measuring spoon) contains: ● 1.76 g of Linseed, whole (Linum usitatissimum L., semen), ● 0.43 - 0.70 g of Senna leaf (Cassia senna L. and/or Cassia angustifolia VAHL, folium) ● 36 - 58 mg of Frangula bark (Rhamnus frangula L., cortex) The excipients used in the product are talc, sucrose, calcium carbonate, acacia, spray dried, Red iron oxide E172, calcium lactate pentahydrate, Black iron oxide E172, vanillin, ginger oil and beeswax, yellow. The function of all the excipients is described and its composition justified. All excipients used comply with their respective Ph Eur monographs with the exception of Red iron oxide E172 and Black iron oxide E172 which comply with an in-house specification. Manufacture A description and flow-chart of the manufacturing method has been provided. The manufacturing method is a standard uncomplicated procedure. In-process controls are appropriate considering the nature of the product and the method of manufacture. Process validation has been carried out on product batches and the results are satisfactory.

Control of Herbal Product The finished product specification is satisfactory. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and have been adequately validated, as appropriate. Batch data have been provided and comply with the release specification.

Container Closure System The herbal product is stored in cardboard cans, laminated with aluminium inside and sealed with a tear-off aluminium membrane and a PE closure. The bottom is made of a tin plate covered with varnish (type epoxyphenol acc. 175-300). Included in the packaging is a measuring spoon made of polystyrene for one dose of 4.1 g.


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Specifications and certificates are provided from the manufacturers, along with confirmation that all components are safe for use in contact with foodstuffs and conform to Ph Eur standards. The product is licensed to come in pack sizes of 70, 200 and 300 g, although not all pack sizes may be marketed.

Stability Finished product stability studies have been conducted in accordance with current guidelines. Based on the results, a product shelf-life of 30 months with a storage condition ‘Do not store above 30°C’ is appropriate. Pharmaceutical Expert The Quality Overall Summary has been written by a pharmacist with suitable experience. Assessor’s comments on the Summary of Product Characteristics, product labelling and Patient Information Leaflet All product literature is satisfactory. A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. CONCLUSION There are no objections to granting of a Traditional Herbal Registration from a quality point of view.


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NON-CLINICAL ASSESSMENT NON-CLINCIAL OVERVIEW An Expert Safety Report was provided, which includes reviews of some non-clinical data. The Expert Safety Report was written by a suitably qualified professional. In addition, the Committee on Herbal Medicinal Products (HMPC) Community Monograph and assessment report for Linseed, Senna leaf and Frangula bark adequately cover the non-clinical safety issues for these herbal preparations. Due to a shortage of published data on Linseed, Senna leaf and Frangula bark, it is not possible to assess if the safety package for the phytochemical constituents of these active ingredients are acceptable to the standards of today’s GLP and safety testing requirements. However, the information supplied demonstrating traditional use is acceptable and thus the lack of provision of a complete standard safety package is acceptable and in compliance with guideline EMEA/HMPC/32116/05. Assurance was provided that the results of genotoxicity testing will be provided before renewal of the registration. The overview submitted in support of this application is satisfactory. SUMMARY OF PRODUCT CHARACTERISTICS (SmPC) The SmPC for this product is satisfactory from a non-clinical point of view. ENVIRONMENTAL RISK ASSESSMENT An environmental risk assessment is not required for herbal medicinal products according to guidance CPMP/SWP/4447/00. CONCLUSION There are no objections to granting of a Traditional Herbal Registration from a non-clinical point of view.


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CLINICAL ASSESSMENT

PROPOSED INDICATION The applicant has proposed the following: “A traditional herbal medicinal product for the short term relief of occasional constipation based on traditional use only.”

The proposed indication is acceptable. POSOLOGY AND METHOD OF ADMINISTRATION The applicant has proposed the following: “Adults, the elderly and children over 12 years: Using the measuring spoon provided take 1 level spoonful (4.1 g) in a single dose at night with a glass of water or other liquid. One measuring spoon (4.1 g) is equivalent to 20.5 mg of hydroxyanthracene derivatives expressed as sennoside B. The use in children under 12 years of age is not recommended (see section 4.3 Contraindications and section 4.4 Special warnings and precautions for use). Duration of use: If symptoms persist for more than 1 week, a doctor or a qualified health care practitioner should be consulted. For oral use only. The laxative effect occurs about 6-12 hours after oral administration and therefore the best administration time is at night to obtain the desired effect in the morning. Normally it is sufficient to take this medicinal product up to two to three times a week.” This is acceptable. EFFICACY No clinical efficacy data is required for registration of Traditional Herbal Medicinal Products (THMP). EVIDENCE OF TRADITIONAL USE Article 16 c 1 (c) requires the applicant to provide bibliographic or expert evidence to show that the medicinal product in question, or a corresponding product, has been in medicinal use throughout a period of at least 30 years, including at least 15 years within the European Community. Evidence has been presented to demonstrate that this product has been available since 1958 in Switzerland and has been available within the EU for at least 15 years. The information provided by the applicant is considered to satisfy the requirement to


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demonstrate the use of the product for at least 30 years of which at least 15 years have been in an EU Member State. Community Monographs have been adopted and assessment reports have been published by the HMPC for Linseed, Senna leaf and Frangula bark. The proposed indication for Linforce granules is in line with the traditional indications and HMPC monographs of the herbal preparations. The requirements of the Directive are, therefore, considered to be met. SAFETY REVIEW Article 16 c 1 (d) requires the applicant to provide a bibliography of the safety data together with an expert report. The HMPC Assessment Reports for Linseed, Senna leaf and Frangula bark cover the bibliographic data available and the safety of Linseed, Senna leaf and Frangula bark has been demonstrated. These are satisfactory. PRODUCT LITERATURE The SmPC, PIL and labelling for this product are medically satisfactory. CONCLUSION There are no objections to granting of a Traditional Herbal Registration from a clinical point of view.


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OVERALL CONCLUSION AND BENFIT-RISK ASSESSMENT

QUALITY The quality data submitted with this application are satisfactory. NON-CLINICAL No new non-clinical data were submitted with this application. However, the published HMPC assessment report and Community Monograph for Linseed, Senna leaf and Frangula bark adopted by the HMPC adequately cover the non-clinical safety issues associated with these herbal preparations. EFFICACY AND SAFETY No clinical efficacy data are required for registration of Traditional Herbal Medicinal Products (THMP). The published HMPC assessment report and Community Monograph for Linseed, Senna leaf and Frangula bark adopted by the HMPC adequately covers the evidence for traditional use of the extract in the product under assessment for at least 30 years and the clinical safety issues associated with these herbal preparations. The SmPC, PIL and labelling are satisfactory. RISK ASSESSMENT The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. The benefit: risk balance is acceptable and a Traditional Herbal Registration may be granted.


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Linoforce granules

THR 13668/0021

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the Traditional Herbal Registration application on 22nd October 2009

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 7th January 2010

3 Following assessment of the application the MHRA requested further information relating to the quality dossier on 4th August 2010, 22nd February 2011 and 21st June 2011

4 The applicant responded to the MHRA’s requests, providing further information on the quality dossier on 7th February 2011, 26th May 2011 and 30th April 2012

5 Following assessment of the application the MHRA requested further information relating to the clinical dossier on 7th May 2010

6 The applicant responded to the MHRA’s requests, providing further information on the clinical dossier on 7th February 2011

7 A THR was granted on 22nd June 2012


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SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Linoforce granules 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 dose [4.1 g] (one measuring spoon) contains: 1.76 g of Linseed, whole (Linum usitatissimum L., semen), 0.43 - 0.70 g of Senna leaf (Cassia senna L. and/or Cassia angustifolia VAHL, folium) 36 - 58 mg of Frangula bark (Rhamnus frangula L., cortex) corresponding to 20.5 mg of hydroxyanthracene derivatives, calculated as sennoside B. Excipients: One dose (4.1g) contains 480 mg sucrose For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Granules Glossy granulate of dark brown colour with an odour of vanillin and a sweetish taste.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

Traditional herbal medicinal product for the short term relief of occasional constipation based on traditional use only.

4.2 Posology and method of administration

Adults, the elderly and children over 12 years: Using the measuring spoon provided take 1 level spoonful (4.1 g) in a single dose at night with a glass of water or other liquid. One measuring spoon (4.1 g) is equivalent to 20.5 mg of hydroxyanthracene derivatives expressed as sennoside B. The use in children under 12 years of age is not recommended (see section 4.3 Contraindications and section 4.4 Special warnings and precautions for use). Duration of use: If symptoms persist for more than 1 week, a doctor or a qualified health care practitioner should be consulted. For oral use only. The laxative effect occurs about 6-12 hours after oral administration and therefore the best administration time is at night to obtain the desired effect in


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the morning. Normally it is sufficient to take this medicinal product up to two to three times a week.

4.3 Contraindications

Hypersensitivity to any of the active ingredients or to any of the excipients. Melanorrhoea, potential or existing intestinal blockage (ileus), paralysis of the intestine or megacolon. Sudden change in bowel habit that persists for more than 2 weeks, undiagnosed rectal bleeding and failure to defaecate following the use of a laxative. Abnormal constrictions in the gastro-intestinal tract, with diseases of the esophagus and cardia. Patients who have difficulty swallowing or have throat problems. Cases of intestinal obstructions and stenosis, atony, appendicitis, inflammatory colon diseases (e.g. Crohn’s disease, ulcerative colitis), abdominal pain of unknown origin, severe dehydration state with water and electrolyte depletion. Children under 12 years of age.

4.4 Special warnings and precautions for use Patients taking cardiac glycosides, antiarrhythmic medicinal products, medicinal products inducing QT-prolongation, diuretics, adrenocorticosteriods or liquorice root, have to consult a doctor before taking this product concomintantly. Like all laxatives, Linoforce should not be taken by patients suffering from faecal impaction and undiagnosed, acute or persistent gastro-intestinal complaints, e.g. abdominal pain, nausea, vomiting and irregular bowel habits unless advised by a doctor because these symptoms can be signs of potential or existing intestinal blockage (ileus). If laxatives are needed every day the cause of the constipation should be investigated. Long-term use of laxatives should be avoided. If stimulant laxatives are taken for longer than a brief period of treatment, this may lead to impaired function of the intestine and dependence on laxatives. Linoforce should only be used if a therapeutic effect cannot be achieved by a change of diet or the administration of bulk forming agents. When this product is administered to incontinent patients, pads should be changed more frequently to prevent extended skin contact with faeces. Patients with kidney disorders should be aware of possible electrolyte imbalance. If abdominal pain occurs or in cases of any irregularity of faeces, the use of this product should be discontinued and medical advice should be sought.


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If the condition worsens or does not improve after 1week, a doctor or a qualified health care practitioner should be consulted. Take Linoforce with at least 150 ml of water or similar aqueous fluid. Taking this product without adequate fluid, may cause it to swell and block your throat or oesophagus and may cause choking. Intestinal obstruction may occur if adequate fluid intake is not maintained. If you experience chest pain, vomiting, or difficulty in swallowing or breathing after taking this product, seek medical attention immediately. The treatment of debilitated patients and elderly should be supervised. Investigations in healthy women suggest that linseed may have an oestrogenic effect, use of this product is therefore not recommended in women with hormonally dependent tumours. This medicinal product contains 480 mg of sucrose per measuring spoon (4.1 g). Patients with hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. The use of this product in children or adolescents under 12 years of age is not recommended because data are not sufficient and medical advice should be sought.

4.5 Interaction with other medicinal products and other forms of interaction

Enteral absorption of concomitantly administered medicines may be delayed by bulk forming laxatives such as Linoforce granules. For this reason Linoforce granules should not be taken ½ to 1 hour before or after intake of other medicinal products. In order to decrease the risk of gastrointestinal obstruction (ileus), this product should only be used together with medicinal products known to inhibit peristaltic movement (e.g. opiods, loperamide) under medical supervision. Hypokalaemia (resulting from long-term laxative abuse) potentiates the action of cardiac glycosides and interacts with antiarrhythmic medicinal products, with medicinal products which induce reversion to sinus rhythm (e.g. quinidine) and with medicinal products inducing QT-prolongation. Concomitant use with other medicinal products inducing hypokalaemia (e.g. diuretics, adrenocorticosteroids and liquorice root) may in case of abuse enhance electrolyte imbalance.

4.6 Fertility, Pregnancy and lactation Pregnancy There are no reports of undesirable or damaging effects during pregnancy and on the foetus when used at the recommended dosage. However, as a consequence of experimental data concerning a genotoxic risk of several anthranoids, e.g. aloe-emodin, emodin, frangulin, chrysophanol and physcion, the use is to be avoided during the first trimester and is not


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recommended in other phases of pregnancy as there is insufficient systematic data available. Investigations in healthy women suggest that one of the active ingredients, linseed, in this product may have an oestrogenic effect. Linoforce should only be used under medical supervision intermittently and if other actions such as behavioural modification, dietary changes and use of bulk forming agents failed. Lactation Use during breastfeeding is not recommended as there are insufficient data on the excretion of metabolites in breast milk and insufficient systematic data is available. After administration of other anthranoids, active metabolites (such as rhein) are excreted in breast milk in small amounts. A laxative effect in breast fed babies has not been reported. Fertility Studies on fertility have not been carried out.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

Hypersensitivity reactions (pruritus, urticaria, local or generalised exanthema) may occur. The frequency is not known. Meteorism occurring with use of the product is common. May produce abdominal pain and spasm and passage of liquid stools, in particular in patients with irritable colon. However, these symptoms may also occur generally as a consequence of individual overdosage. In such cases dose reduction is necessary. Chronic use may lead to disorders in water equilibrium and electrolyte metabolism and may result in albuminuria and haematuria. Furthermore, chronic use may cause pigmentation of the intestinal mucosa (pseudomelanosis coli), which usually recedes when the patient stops taking the preparation. Yellow or red-brown (pH dependent) discolouration of urine by metabolites, which is not clinically significant, may occur during the treatment. If other adverse reactions not mentioned above occur, a doctor or a qualified health care practitioner should be consulted.


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4.9 Overdose The major symptoms of overdose / abuse are griping pain and severe diarrhoea with consequent losses of fluid and electrolytes, which should be replaced. Diarrhoea may especially cause potassium depletion, which may lead to cardiac disorders and muscular asthenia, particularly where cardiac glycosides, diuretics, adrenocorticosteroids or liquorice root are being taken at the same time. Abdominal discomfort, flatulence and possibly intestinal obstruction may occur. Treatment should be supportive with generous amounts of fluid and management should be symptomatic. Electrolytes, especially potassium, should be monitored. This is especially important in the elderly. Chronic ingested overdoses of anthranoid containing medicinal products may lead to toxic hepatitis.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: contact laxatives ATC-code: A 06 AB Senna leaf and Frangula bark The action of the actives Senna leaf and Frangula bark is due to the content of 1,8-dihydroxyanthracene derivatives (mainly sennosides, frangulins, glucofrangulins), which possess a laxative effect. Glucofrangulins (O-diglycosides), frangulins (O-monoglycosides) and sennosides (β-O-glycosides) are neither absorbed as such nor largely split by human digestive enzymes in the upper gut and therefore are not absorbed to a large extent. They are converted by the bacteria of the large intestine into the active aglyca (glucofrangulins / frangulins: emodin-9-anthrone, sennosides: rhein anthrone). Defaecation takes place after a delay of 8 – 12 hours due to the time taken for transportation to the colon and metabolisation into the active compound. There are two different mechanisms of action:

1. Stimulation of the motility of the large intestine resulting in accelerated colonic transit. The motility effects are mediated by direct stimulation of colonic neurons and possibly by prostaglandins. 2. Influence on secretion processes by two concomitant mechanisms viz. inhibition of absorption of water and electrolytes (Na+, Cl-) into the colonic epithelial cells (antiabsorptive effect) and increase of the leakiness of the tight junctions and stimulation of secretion of water and electrolytes into the lumen of the colon (secretagogue effect) resulting in enhanced concentrations of fluid and electrolytes in the lumen of the colon.


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Linseed The seeds contain nearly 25 % of bulk materials (3 – 6 % of mucilage, 4 – 7 % of alimentary fibres). The laxative effects of linseed have long been recognised empirically and shown in animal and clinical investigations. These effects are attributed to the bulk materials and in particular to the mucilage that binds with water and swells to form a demulcent gel in the intestine. Water is held back in the intestine due to the swelling of the mucilage. Faeces become softer. The volume of the intestinal content increases and causes a stretch stimulus, which results in a decrease in transit time. The swollen mass of mucilage forms a lubrication layer facilitating the transit of intestinal content. The laxative effect of linseeds usually occurs within 12 to 24 hours. Sometimes the maximum effect is not reached before 2 or 3 days. The use of linseed as a laxative is made plausible by information from clinical studies and pharmacological data. The use in conditions, in which easy defaecation with soft stool is desirable, is scientifically substantiated on the basis of the laxative effects but there are no special data available.

5.2 Pharmacokinetic properties Senna leaf and Frangula bark The β-O-linked glycosides from Senna leaf and Frangula bark are not split by human digestive enzymes and therefore are not absorbed in the upper gut to a large extent. They are converted by the bacteria of the large intestine into the active aglyca (glucofrangulins / frangulins: emodin-9-anthrone, sennosides: rhein anthrone). The aglyca are absorbed in the upper gut. Animal experiments with radio-labeled rhein anthrone administered directly into the caecum demonstrated absorption <10%. In contact with oxygen, rhein anthrone is oxidised into rhein and sennidins, which can be found in the blood, mainly in the form of glucuronides and sulphates. 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 antron and rhein. In human pharmacokinetic studies with Senna pods 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. After administration of anthranoids, active metabolites, such as rhein, pass in small amounts into breast milk. Animal experiments demonstrated that placental passage of rhein is low. Linseed One part of the bulk materials in linseed is defaecated, the other part is fermented in the colon by bacteria. This process of fermentation can produce gas and flatulence. The predominant products of fermentation are short chain


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fatty acids (SCFA), which are mainly resorbed and can act as nutrients for cells of the colonic mucosa.

5.3 Preclinical safety data

Senna leaf Since the spectrum of constituent of Senna leaf and fruit is comparable the data can be transferred to Senna leaf. Most data refer to extracts of Senna pods containing 1.4 to 3.5 % of anthranoids, corresponding to 0.9 to 2.3 % of potential rhein, 0.05 to 0.15 % of potential aloe-emodin and 0.001 to 0.006 % of potential emodin or isolated active constituents, e.g. rhein or sennosides A and B. The acute toxicity of Senna pods, specified extracts thereof, as well as of sennosides in rats and mice was low after oral treatment.

As a result of investigations with parenteral applications in mice, extracts are supposed to possess a higher toxicity than purified glycosides, possibly due to the content of aglyca. In a 90-day rat study, Senna pods were administered at dose levels from 100 mg/kg up to 1,500 mg/kg. The tested drug contained 1.83 % sennosides A-D, 1.6 % potential rhein, 0.11 % potential aloe-emodin and 0.014 % potential emodin. In all groups epithelial hyperplasia of the large intestine of minor degree was found and was reversible within the 8-week recovery period. The hyperplastic lesions of the forestomach epithelium were reversible as well. Dose-dependent tubular basophilia and epithelial hypertrophy of the kidneys were seen at a dose of, or greater than 300 mg/kg per day without functional affection. These changes were also reversible. Storage of a brown tubular pigment led to a dark discoloration of the renal surface and still remained to a lesser degree after the recovery period. No alterations were seen in the colonic nervous plexus. A no-observable-effect-level (NOEL) could not be obtained in this study. Sennosides displayed no specific toxicity when tested at doses up to 500 mg/kg in dogs for 4 weeks and up to 100 mg/kg in rats for 6 months. An extract and aloe-emodin were mutagenic in in vitro tests, sennoside A, B and rhein gave negative results. Comprehensive in vivo examinations of a defined extract of Senna pods were negative. In vivo studies of Senna herbal substance in rat hepatocytes (chromosome aberration test, mouse spot test, in vivo/in vitro UDS (unscheduled DNA synthesis) showed no evidence of any genetic effects. A 104-week study on rats of both genders did not reveal any carcinogenic effects with the same Senna pods preparation at oral dosages of up to 300 mg/kg. A specified Senna extract given orally for 2 years was not carcinogenic in male or female rats. The extract investigated contained approximately 40.8 %


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of anthranoids from which 35 % were sennosides, corresponding to about 25.2 % of potential rhein, 2.3 % of potential aloe-emodin and 0.007 % of potential emodin and 142 ppm free aloe-emodin and 9 ppm free emodin. There is no evidence of any embryo lethal, teratogenic or foetotoxic actions in rats or rabbits after oral treatment with sennosides. Furthermore, there was no effect on the postnatal development of young rats, on rearing behaviour of dams or on male and female fertility in rats. Data for herbal preparations are not available. Frangula bark There are no studies on single dose toxicity, on repeated dose toxicity, on reproductive toxicity or on carcinogenicity.

Experimental data, mainly in vitro tests showed a genotoxic risk of several anthranoids in the Salmonella microsome assay, emodin, chrysophanol and physcion were weakly mutagenic. No mutagenic effects were observed in the V79-HGPRT mutation assay and in the unscheduled DNA synthesis (UDS) assay for chrysophanol and physcion. Emodin was highly mutagenic in the V79-HGPRT mutation assay. In the UDS assay emodin was a strong inducer of UDS in primary hepatocytes. Emodin was also tested with respect to its transforming activity in C3H/M2 mouse fibroblasts in vitro. In the in vitro salmonella/microsome mutagen test and the deoxyribonucleic acid (DAN) repair test of primary rat hepatocytes emodin and frangulin, an alcoholic extract of “Rhamnus frangula”, and a commercial Frangula bark preparation showed a dose-dependent increase in the mutation rate or the induction of DNA repair. 2-year studies on male and female rats and mice with emodin gave no evidence of carcinogenic activity for male rats and female mice and equivocal evidence for female rats and male mice. Hydroxyanthracene laxative use, as a risk factor in colorectal cancer (CRC), was investigated in some clinical trials. Some studies revealed a risk for CRC associated with the use of anthraquinone-containing laxatives, some studies did not. However, a risk was also revealed for constipation itself and underlying dietary habits. Further investigations are needed to assess the carcinogenic risk definitely. Linseed Linseed contains 20-50 mg cyanide / 100 g in form of the cyanogenic diglycosides linustatin, neolinustatin and small amount of the monoglucoside linamarin. Neither a single dosage of 100 g linseed nor a chronic dose of 45 – 50 g daily for 4 –6 weeks cause intoxication signs in man. The enzyme thiosulphate sulphur transferase (rhodanase) catalyzes the change of cyanide into thiocyanate (rhodanide), which is 200 times less toxic than cyanide. The chronic use of linseed causes accumulation of thiocyanate, which can be compared with the blood level of thiocyanate in heavy smokers.


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Investigations in healthy women suggest that there might be an oestrogenic effect of linseed due to the lignan-precursors in linseed, which are converted to mammalian-lignans and might interfere with the metabolism and activity of oestrogens. Tests on reproductive toxicity, genotoxicity and carcinogenicity have not been performed.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Talc Sucrose Calcium carbonate Acacia, spray dried Red iron oxide E172 Calcium lactate pentahydrate Black iron oxide E172 Vanillin Ginger oil Beeswax, yellow

6.2 Incompatibilities Not applicable.

6.3 Shelf life

30 months unopened. 6.4 Special precautions for storage

Do not store above 30°C. 6.5 Nature and contents of container

Cardboard cans, laminated with aluminium inside and sealed with a tear-off aluminium membrane and a PE closure. The bottom is made of a tin plate covered with varnish (type epoxyphenol acc. 175-300). Included in the packaging is a measuring spoon made of polystyrene for one dose of 4.1 g. The package leaflet is inserted between the polyethylene lid and the upper aluminium seal. Pack sizes: 70 g 200 g 300 g Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.


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7 MARKETING AUTHORISATION HOLDER Bioforce (UK) Ltd 2 Brewster Place Irvine, Ayrshire KA11 5DD, United Kingdom Tel: 01294 277344 [email protected]

8 MARKETING AUTHORISATION NUMBER(S) THR 13668/0021

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 22/06/2012

10 DATE OF REVISION OF THE TEXT

22/06/2012


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PATIENT INFORMATION LEAFLET


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LABELLING

Labels:


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Cartons:


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Documents

Linoforce granules THR 13668-0021 - Medicines and ... Expert Safety Report was provided, which includes reviews of some non-clinical data. The Expert Safety Report was written by a