1. Name Of The Medicinal Product
Dual Lax Extra Strong Coated Tablets
Lanes Modern Herbals Laxative Coated Tablets
Boots Alternatives Laxative Coated Tablets
2. Qualitative And Quantitative Composition
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Excipients: Sucrose (92mg/tablet), sodium propyl parahydroxybenzoate E217 and sodium methyl parahydroxybenzoate E219.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Coated tablet.
Brown circular biconvex sugar coated tablet.
4. Clinical Particulars
4.1 Therapeutic Indications
For the relief of temporary constipation.
4.2 Posology And Method Of Administration
For oral use.
Adults and children aged 12 and over: Swallow 1 or 2 tablets with water at night.
Not recommended for children under 12 years old.
4.3 Contraindications
Children under 12 years old.
Hypersensitivity to the active substances or to any of the excipients.
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.
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
4.4 Special Warnings And Precautions For Use
This product contains sodium propyl parahydroxybenzoate (E217) and sodium methyl parahydroxybenzoate (E219) and should not be used by patients who are allergic to these ingredients.
Patients taking cardiac glycosides, antiarrhythmic medicinal products, medicinal products inducing QT-prolongation, diuretics, corticosteroids or liquorice root, have to consult a doctor before taking senna leaves or cascara concomitantly.
Like all laxatives, senna leaves 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. Senna leaf or 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 senna leaf or 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.
If symptoms worsen or do not improve after 7 days, contact a doctor.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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.
4.6 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, 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.
4.7 Effects On Ability To Drive And Use Machines
This product has no influence on the ability to drive and use machines.
4.8 Undesirable Effects
Hypersensitivity reactions (pruritus, urticaria, local or generalised exanthema) may occur.
Senna leaves and 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 overdose. 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.
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.
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, 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
Pharmaco-therapeutic group: contact laxatives
ATC-code: A 06 AB
1,8-dihydroxyanthracene derivatives possess a laxative effect. The β-Ο-linked glycosides (sennosides) are not absorbed in the upper gut; they are converted by bacteria of the large intestine into the active metabolite (rhein anthrone).
Cascarosides A and B are mixed anthrone-C- and O-glycosides, Cascarosides C, D, E and F are 8-O-β-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.
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
The β-Ο-linked glycosides (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). 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 anthrone 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. Active metabolites, e.g. rhein, pass in small amounts into breast milk. Animal experiments demonstrated that placental passage of rhein is low
The β-0-linked glycosides (cascarosides) 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
Senna
There are no new, systematic preclinical tests for senna leaves or preparations thereof. Data derive from investigations with senna pods. Since the spectrum of constituents of senna leaf and fruit is comparable these data can be transferred to senna leaves. 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 application 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.
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.
In addition a specified senna extract given orally for 2 years was not carcinogenic in male or female rats. The extract investigated contained approximately 40.8% 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.
Further 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.
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.
There was no evidence of any embryolethal, 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.
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.
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
Cascara
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 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. 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 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.
In in vivo studies (micronucleus assay in bone marrow cells of NMRI mice; chromosome aberration assay in bone marrow cells of Wistar rats; mouse spot test [DBA/2J x NMRI]) no indication of a mutagenic activity of aloe emodin was found.
Further 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.
Dietary exposure of rats to high doses of the anthraquinone glycosides of cascara for 56 successive days did not cause appearance of aberrant crypti foci (ACF) or increase of incidence of ACF induced by 1,2-dimethyl-hydrazine (DMH). However, in rats treated with both DMH and the highest dose of glycosides, the average number of aberrant crypts per focus, considered a consistent predictor of tumour outcome, was higher than in rats given DMH alone.
Rats were treated with azoyxmethane (AOM) and 140 and 420 mg/kg cascara (alone or in combination) for 13 weeks. Cascara did not induce the development of colonic aberrant crypti foci (ACF) and tumours and did not modify the number of AOM-induced ACF and tumours in both doses.
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.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Core:
Calcium Phosphate E341
Magnesium Stearate E572
Maize Starch, Pregelatinised
Silicon Dioxide E551
Sodium Starch Glycolate
Stearic Acid E570
Coating:
Acacia, Spray-Dried E414
Calcium Carbonate E170
Carnauba Wax E903
Mastercote Brown SP0830 (containing Red and Black Iron Oxide E172, hydrochloric acid E507, sodium propyl parahydroxybenzoate (E217) and sodium methyl parahydroxybenzoate (E219))
Opaseal (Polyvinyl Acetate Phthalate, Ethyl Acetate, Stearic Acid)
Talc E553b
Sucrose
Titanium Dioxide E171
Yellow Beeswax E901
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
3 years (bottles)
2 years (blisters)
6.4 Special Precautions For Storage
Keep out of the reach and sight of children.
Do not store above 25ºC.
6.5 Nature And Contents Of Container
14 tablets and 60 tablets packaged into PVDC-aluminium/polyethylene laminate blister packs.
100 tablets are packaged into amber glass bottles (USP type III glass) fitted with white HDPE tamper evident caps.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
G. R. Lane Health Products Limited
Sisson Road
Gloucester
GL2 0GR
United Kingdom
Tel: +44 (0)1452 524012
Fax: +44 (0)1452 507930
Email: info@laneshealth.com
8. Marketing Authorisation Number(S)
PL 1074/5015R
9. Date Of First Authorisation/Renewal Of The Authorisation
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10. Date Of Revision Of The Text
November 2008.
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