Well-established use

Traditional use

With regard to the marketing authorisation

With regard to the registration application of

application of Article 10(a) of Directive

Article 16d(1) of Directive 2001/83/EC as

2001/83/EC as amended

amended

Rhamnus purshianus D.C. (Frangula purshiana

(D.C.) A. Gray ex J.C. Cooper), cortex (cascara)

i) Herbal substance

dried, whole or fragmented bark, standardised

ii) Herbal preparations

cascara dry extract, standardised

Well-established use

Traditional use

Standardised herbal substance or herbal

preparation in solid or liquid dosage forms for

oral use.

The pharmaceutical form should be described by

the European Pharmacopoeia full standard term.

Well-established use

Traditional use

Herbal medicinal product for short-term use in cases of occasional constipation.

Well-established use Posology

The maximum daily dose of hydroxyanthracene glycosides is 30 mg. This is equivalent to ....(dose of the preparation).

The correct individual dose is the smallest required to produce a comfortable soft-formed motion.

Adolescents over 12 years of age, adults, elderly Herbal substance/preparation equivalent to 10 -30 mg hydroxyanthracene derivatives, calculated as cascaroside A, to be taken once daily at night. Normally it is sufficient to take this medicinal product up to two to three times a week.

The pharmaceutical form must allow lower dosages.

The use in children under 12 years of age is contraindicated (see section 4.3 Contraindications).

Duration of use

Use for more than 1 - 2 weeks requires medical supervision.

If the symptoms persist during the use of the medicinal product a doctor or a pharmacist should be consulted. (See section 4.4 Special warnings and precautions for use).

Method of administration

As described in the package leaflet corresponding to the pharmaceutical form.

4.3. Contraindications

Traditional use

Well-established use

Hypersensitivity to the active substance.

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.

Traditional use

Well-established use

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

Like all laxatives, cascara should not be taken by patients suffering from faecal impaction and undiagnosed, acute or persistent gastro-intestinal complaints, e.g. abdominal pain, nausea and vomiting 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. Cascara preparations should only be used if a therapeutic effect cannot be achieved by a change of diet or the administration of bulk forming agents.

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

Patients with kidney disorders should be aware of possible electrolyte imbalance.

Traditional use

Well-established use

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, corticosteroids 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. aloe-emodin, emodin, frangulin, chrysophanol and physcion, use is not recommended during pregnancy.

Lactation

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

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.

Traditional use

Well-established use Not relevant.

4.8. Undesirable effects

Traditional use

Well-established use

Hypersensitivity reactions may occur.

Cascara 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 pharmacist should be consulted.

Traditional use

Well-established use

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 cause potassium depletion, in particular. Potassium depletion may lead to cardiac disorders and muscular asthenia, particularly where cardiac glycosides, diuretics, corticosteroids or liquorice root are being taken at the same time. Treatment should be supportive with generous amounts of fluid. 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

Traditional use

Well-established use

Traditional use

Pharmaco-therapeutic group: contact laxatives ATC-code: A 06 AB

1,8-dihydroxyanthracene derivatives possess a laxative effect.

Cascarosides A and B are mixed anthrone-C- and O-glycosides, Cascarosides C, D, E and F are 8-O-p-D-glucosides, which are largely not split by human digestive enzymes in the upper gut and therefore not absorbed to a large extent. They are converted by the bacteria of the large intestine into the active metabolites (mainly emodin-9-anthrone).

There are two different mechanisms of action:

1.    stimulation of the motility of the large intestine resulting in accelerated colonic transit.

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.

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

Defaecation takes place after a delay of 6 - 12 hours due to the time taken for transport to the colon and metabolisation into the active compound.

5.2. Pharmacokinetic properties

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 (mainly emodin-9-anthrone). The absorbed anthraquinone aglycones are transformed into their corresponding glucuronides and sulphate derivatives.

It is not known to what extent aloe-emodin-9-anthrone is absorbed. However, in the case of senna, animal experiments with radio-labeled rhein-anthrone administered directly into the caecum show that only a very small proportion (less than 10%) of rhein-anthrone is absorbed.

After administration of other anthranoids, active metabolites, such as rhein, pass in small amounts into breast milk. Animal experiments demonstrated that placental-passage of rhein is low.

5.3. Preclinical safety data

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

Well-established use

Traditional use

There are no recent studies on single dose toxicity, on repeated dose toxicity, or on reproductive toxicity.

Experimental data, mainly in vitro tests showed a genotoxic risk of several anthranoids in the Salmonella microsome assay, aloe-emodin, 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 phy scion. Emodin was highly mutagenic in the V79-HGPRT mutation assay. In the UDS assay emodin was a string inducer of UDS in primary hepatocytes. Aloe-emodin showed a significant increase in net grains/nucleus. 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 (DNA) repair test of primary rat hepatocytes emodin and frangulin showed a dose-dependent increase in the mutation

Not required as per Article 16c(1)(a)(iii) of Directive 2001/83/EC as amended, unless necessary for the safe use of the product.

Well-established use

Traditional use

Not applicable.