Well-established use

Traditional use

With regard to the marketing authorisation application of Article 10(a) of Directive 2001/83/EC, as amended

Active ingredients

Frangula bark in the crude or processed state in appropriate dosage units

Definition

Frangula bark consists of the dried, whole or fragmented bark of the stems and branches of Rhamnus frangula L. (Frangula alnus Miller). It contains not less than 7.0 per cent of glucofrangulins, expressed as glucofrangulin A (C₂7H₃₀Oi₄; M_r 578.5) and calculated with reference to the dried herbal substance.¹

Constituents

The constituents with known therapeutic activity of Frangula bark are emodin-di- and monoglycosides viz. the diglycosides glucofrangulin A (emodin-6-O-a-L-rhamnosyl-8-O-P-D-glucoside) and glucofrangulin B (emodin-6-O-P-D-apiosyl-8-O-P-D-glucoside) and the monoglycosides frangulins A, B, C (emodin-6-O-a-L-rhamnoside, emodin-6-O-P-D-apioside, emodin-6-O-P-D-xyloside) and emodin-8-O-P-D-glucoside.

There are also small quantities of other anthraquinone glycosides, dianthrones and the aglycones emodin and emodin-9-anthrone.

3. PHARMACEUTICAL FORM

With regard to the registration application of Article 16d(1) of Directive 2001/83/EC, as amended

Well-established use

Standardised crude or processed herbal substance

Traditional use

Well-established use

Patients taking cardiac glycosides, antiarrhythmic medicinal products, medicinal products inducing QT-prolongation, diuretics, adrenocorticosteroids or liquorice root, have to consult a doctor before taking frangula bark concomitantly.

Like all laxatives, frangula bark should not be taken by patients suffering from faecal impaction and undiagnosed, acute or persistent gastrointestinal complaints, e.g. abdominal pain, nausea and vomiting unless advised by a doctor because these symptoms can be signs of a 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.

Use for more than 1 - 2 weeks requires medical supervision. If stimulating laxatives are taken for longer than a brief period of treatment, this may lead to dependence requiring increasing quantities of the medicinal product, an atonic colon with impaired function and aggravation of the constipation. Frangula bark preparation should only be used if a therapeutic effect cannot be achieved by a change of diet or the administration of bulk forming agents.

When frangula bark preparations are administered to incontinent adults, pads should be changed more frequently to prevent extended skin contact with faeces.

Traditional use

Well-established use

The absorption of orally administered medicinal products may be reduced.

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 enhance electrolyte imbalance.

Traditional use

Well-established use 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. emodin, frangulin, chrysophanol and physcion, use is not recommended during pregnancy.

Lactation

Breastfeeding is not recommended as there are insufficient data on the excretion of metabolites in breast milk.

Small amounts of active metabolites (rhein) are excreted in breast milk after ingestion of a senna preparation. A laxative effect in breast fed babies has not been reported.

Traditional use

Well-established use Not known

4.8. Undesirable effects

Traditional use

Well-established use

Hypersensitive reactions may occur very rarely.

Very rarely frangula bark 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/abuse may lead to disorders in water equilibrium and electrolyte metabolism. Diarrhoea may cause potassium depletion, in particular. Potassium depletion may lead to cardiac disorders and muscular asthenia, particularly where cardiac glycosides, diuretics, adrenocorticosteroids or liquorice root are being taken at the same time. Chronic use 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.

Traditional use

Well-established use

Traditional use

The P-0-linked glycosides are not split by human digestive enzymes and therefore not absorbed in the upper gut to a large extent. They are converted by the bacteria of the large intestine into the active metabolite (emodin-9-anthrone). Mainly anthraquinone aglycones are absorbed and transformed into their corresponding glucuronides and sulphate derivatives. After oral administration of frangula bark extract, rhein, emodin and traces of chrysophanol are found in human urine.

Active metabolites, e.g. rhein, pass in small amounts into breast milk. Animal experiments demonstrated that placental-passage of rhein is small.

5.3 Preclinical safety data

Not required as per Article 16 c(1)(a) iii) of Directive 2001/83/EC, as amended

Well-established use

Traditional use

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 string inducer of UDS in primary hepatocytes. Emodin was has 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 (DNA) 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.

However, in vivo studies of other anthranoid-containing herbal substance (senna) in rat hepatocytes (chromosome aberration test, mouse spot test, in vivo/in vitro UDS (unscheduled DNA synthesis) showed no evidence of any genetic effects.

Commercial laxative use as a risk factor in colorectal cancer was investigated in some clinical trials. The results of the more recent studies are

Not required as per Article 16 c(1)(a) iii) of Directive 2001/83/EC, as amended