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BIOS
DIOCTYL PRE-CLINICAL AND CLINICAL EXPERT REPORT
PRE-CLINICAL AND CLINICAL EXPERT REPORT
- INTRODUCTION
The Dioctyl range of products has been marketed for at least 20 years. It includes Dioctyl Tablets containing 100 rag d o c u s a t e s o d i u m , Dioctyl Syrup' containing docusate sodium 1% w/v and Dioctyl Paediatric Syrup containing docusate sodium 0.25% w/v. The products are indicated for the prevention and treatment of chronic c o n s t i p a t i o n , although they are also used for bowel clearance prior to radiological procedures.
A r e v i e w o f s t a n d a r d r e f e r e n c e w o r k s a n d o t h e r published l i t e r a t u r e is presented in s u p p o r t of the w e l l known e f f i c a c y and t o l e r a b i l i t y of docusate sodium.
- PRE-CLINICAL DATA
D o c u s a t e sodium is a well-known s u b s t a n c e which has b e e n i n w i d e s p r e a d u s e f o r v e r y m a n y y e a r s. C o n s e q u e n t l y , p h a r m a c o l o g i c a l a n d toxicological information has not been included in this application.
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- CLINICAL EVIDENCE
3.1 SUMMARY OF PRODUCT CHARACTERISTICS
The following is a summary of proposed particulars:
3.1.1 Active constituents
Dioctyl Tablets:
Dioctyl Syrup:
Dioctyl Paediatric Syrup:
100 mg d o c u s a t e sodium
1% w/v d o c u s a t e sodium (50 mg in 5 ml)
0.25% w/v d o c u s a t e sodium (12.5 mg in 5 ml)
3.1.2 Uses
Docusate sodium is an anionic w e t t i n g agent which acts as a f a e c a l s o f t e n e r by a l l o w i n g penetration of accumulated, hard, dry faeces by w a t e r and f a t s. Used for the p r e v e n t i o n and treatment of chronic constipation.
BIOS O DIOCTYL PRE-CLINICAL AND CLINICAL EXPERT REPORT
3.1.3 Dosage and administration
For constipation
Adults: Up to 500 mg in divided doses daily. Treatment should be commenced with large doses which should be decreased as the patient improves.
Children: 12.5 to 25 mg three times daily
Infants over six months: 12.5 mg three times daily
For barium meals: 400 mg to be t a k e n w i t h the meal.
3.1.4 Contraindications, warnings etc.
A n t h r a q u i n o n e d e r i v a t i v e s should be taken in a reduced dose when a d m i n i s t e r e d w i t h docusate sodium as it increases their absorption. Do not use when abdominal pain, nausea or vomiting is present. Do not take concurrently with mineral oil. Not to be given to i n f a n t s u n d e r six months.
3.1.5 Pharmacological particulars
Docusate sodium acts as a f a e c a l s o f t e n e r by increasing the penetration of water and fats.
3.2 EFFICACY
3.2.1 Mode of Action
The m o d e of a c t i o n of d o c u s a t e s o d i u m is p o s t u l a t e d t o b e t w o - f o l d. F i r s t l y , t h e material is an anionic surfactant with wetting, d i s p e r s i n g , d e t e r g e n t and e m u l s i f y i n g actions ^. In vivo this allows w a t e r to p e n e t r a t e faecal masses, softening them and increasing bulk.
A s t i m u l a n t laxative has been d e f i n e d as any drug which may affect intestinal salt and water f l u x e s o r m a y s t i m u l a t e p e r i s t a l s i s. Docusate sodium has been shown to inhibit water absorption in both rats and humans and to alter the histological appearance of cells of rat colon and is t h e r e f o r e described in several texts as a stimulant laxative ( 2 > 5 » 6 '. it has also been suggested that the increased bulk of faeces, caused by absorption of w a t e r may help to stimulate peristalsis'.
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However, there was a trend which indicated that in postnatal women Normax and senna, might have been m o r e e f f i c a c i o u s t h a n the b u l k - f o r m i n g laxatives, but associated w i t h m o r e adverse effects, such as abdominal pain and diarrhoea.
F i n a l l y , an open label s t u d y ;• ' in post- operative patients showed that a combination of senna and docusate sodium gave good r e s u l t s in terms of safety and efficacy.
3.2.3 Dosage and Administration
The recommended dosages of docusate sodium, listed in s t a n d a r d r e f e r e n c e w o r k s are as follows:
Martindale^l^ ^:
Adults
Children
Rectally
British National Formulary ^.
Orally
Rectally
50-300 m g / d a y in divided doses. 500 mg has been used.
5 m g / k g d a i l y in divided doses.
use a 0.1% solution.
Adults: up to 500 mg daily in divided doses; i n i t i a l doses should be large and gradually reduced.
Children: 12.5 to 25 mg 3 times daily. With barium meal - 400 mg.
- A d u l t s : u s e D i o c t y l P a e d i a t r i c S y r u p 15- ml.
Children: up to 1 yr: 5- 10 ml Dioctyl P a e d i a t r i c Syrup.
Children: over 1 yr: 7.5- 15 ml D i o c t y l P a e d i a t r i c Syrup.
or use D i o c t y l S y r u p , as a b o v e , d i l u t e d w i t h 3 parts water.
BIOS DIOCTYL PRE-CLINICAL AND CLINICAL EXPERT REPORT
Medo's dosage recommendations correspond w e l l , with the exception that the use of the syrup as an enema is not recommended by the manufacturer.
3.2.4 Tablet vs. Syrup Presentation
No e v i d e n c e i s a v a i l a b l e t o c o m p a r e t h e availability or efficacy of docusate sodium when p r e s e n t e d in a s y r u p as opposed to a t a b l e t f o r m u l a t i o n. However, extensive l i t e r a t u r e searches have been performed which have failed to reveal any evidence that e f f i c a c y of the s y r u p d i f f e r s f r o m that of the tablets. Since efficacy depends upon a physical effect and not upon a b s o r p t i o n , it is b e l i e v e d t h a t the two p r e s e n t a t i o n s can be c o n s i d e r e d to have essentially equivalent e f f e c t s in vivo.
3.2.5 Comment
The D i o c t y l range of p r o d u c t s all contain docusate sodium which is a well-known substance and has been w i d e l y used for the t r e a t m e n t of constipation for many years. Its effectiveness in softening stools depends upon its surfactant p r o p e r t i e s. D e s p i t e a r e l a t i v e lack of f o r m a l clinical e v i d e n c e , docusate sodium is referred to in many a c c e p t e d , s t a n d a r d r e f e r e n c e works. M e d o P h a r m a c e u t i c a l ' s recommended indications and dosages correspond satisfactorily with those quoted in the above sources.
3.3 SAFETY
The dosages of docusate sodium recommended by Medo are w i t h i n w e l l - a c c e p t e d l i m i t s (see S e c t i o n 3.2.3), however a number of precautions and warnings need to be taken into account in the use of the product. Many of these cautions apply to the use of laxative drugs in general, however some are specific to surfactants, and docusate in particular.
3.3.1 Absorption and Possible Hepatic Toxicity
Originally, docusate sodium was believed to be non-absorbable, however Dujovne and Shoeman^ , in 1972 showed that patients given 100 mg or 200 mg of d o c u s a t e s o d i u m , excreted s i g n i f i c a n t amounts in bile. At the time concern had arisen that combinations of docusate with oxyphenisatin (a drug which is no longer available) had p r o d u c e d h e p a t i c t o x i c i t y i n some p a t i e n t s. Dujovne also investigated the cytotoxic effects of docusate and o x y p h e n i s a t i n on h u m a n liver cell cultures. They discovered t h a t docusate,
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DIOCTYL PRE-CLINICAL AND CLINICAL EXPERT REPORT
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3.3.2 Evidence from Published Literature
E x t e n s i v e l i t e r a t u r e searches have f a i l e d t o reveal r e p o r t s of s i g n i f i c a n t adverse e f f e c t s occurring with the use of docusate sodium.
One woman who suffered from delusions developed d u o d e n a l a d e n o c a r c i n o m a f o i l o w i n g ..the consumption of a bowl of soapy water every night f o r 2 0 y e a r s. S h e h a d a l s o b e e n t a k i n g neuroleptic agents for about 15 years. It was p o s t u l a t e d that her carcinoma m i g h t have resulted from a carcinogenic effect of detergent compounds. The authors further proposed that if this was a general property of detergents, then d o c u s a t e s o d i u m m i g h t also e x e r t s i m i l a r e f f e c t s. However, the evidence for a causal link in this case is weak.
In clinical trials described in Section 3.2. only a low incidence of adverse reactions was o b s e r v e d f o l l o w i n g a d m i n i s t r a t i o n o f a combination of docusate with senna to antenatal a n d p o s t p a r t u m p a t i e n t s ^. N o a d v e r s e reactions at all were observed in a study of d o c u s a t e v s. p l a c e b o i n e l d e r l y p a t i e n t s , however this study was not p a r t i c u l a r l y well reported.
In c o m m o n with all laxatives, docusate sodium should not be administered to patients suffering f r o m undiagnosed abdominal pain, nausea and v o m i t i n g o r i n t e s t i n a l o b s t r u c t i o n. Mortality is increased if given inadvertently in cases of a p p e n d i c i t i s , for example. Use of d o c u s a t e ' s o d i u m i n t h e s e s i t u a t i o n s i s contraindicated in the data sheet.
W i t h regard to the possible enhancement of a b s o r p t i o n o f o t h e r l a x a t i v e p r o d u c t s b y docusate, Medo have q u i t e rightly r e c o m m e n d e d r e d u c t i o n o f t h e d o s e o f a n t h r a q u i n o n e d e r i v a t i v e s (e.g. s e n n a b i s o c o d y l ) w h e n administered concurrently with Dioctyl.
In addition, absorption of liquid p a r a f f i n is known to-be increased by docusate and concurrent use is contra-indicated.
In common with all laxatives, inappropriate or excessive use of docusate can p r o d u c e adverse e f f e c t s , i n c l u d i n g s p a s t i c c o l i t i s a n d a b n o r m a l i t i e s resulting from excessive loss of water and electrolytes. For example, secondary aldosteronism, hypoalbuminaemia and excess
BIOS Q DIOCTYL PRE-CLINICAL AND CLINICAL EXPERT REPORT
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calcium excretion with osteomalacia. They may also .result in steatorrhoea and protein-losing enteropathy^. When taken in accordance w i t h the m a n u f a c t u r e r ' s r e c o m m e n d a t i o n s , however, there is no evidence that these severe syndromes are likely to occur. The exception to this is in i n f a n t s , who are particularly sensitive to a l t e r a t i o n s o f w a t e r a n d e l e c t r o l y t e balance^ '. For this reason Dioctyl is not recommended for i n f a n t s u n d e r the age of six months.
3.3.3 Use in the elderly /o
The study p e r f o r m e d by Hyland^ , discussed previously, was c a r r i e d out exclusively in e l d e r l y p a t i e n t s , w h o appeared t o receive s a t i s f a c t o r y b e n e f i t f r o m D i o c t y l w i t h o u t adverse effects.
No more recent clinical studies have been performed to assess the safety of Dioctyl in the e l d e r l y , but there is no evidence to suggest that this might d i f f e r from younger patients.
A suitable s t a t e m e n t to this e f f e c t has been included on the data sheet.
3.3.4 Use in Pregnancy and lactation
The c u r r e n t data sheet does not contain a s t a t e m e n t concerning the use of Dioctyl in pregnancy. Only very l i m i t e d data have been i d e n t i f i e d OIL the use of the p r o d u c t in pregnancy ^ '.
A s u i t a b l e s t a t e m e n t has been p r e p a r e d in a c c o r d a n c e w i t h g u i d e l i n e s i s s u e d b y t h e Committee on Review of Medicines, i.e.:
There is inadequate evidence of s a f e t y of the drug in human p r e g n a n c y , nor is there evidence f r o m a n i m a l work that i t i s f r e e f r o m h a z a r d , but it has been in w i d e use for many years w i t h o u t apparent i l l c o n s e q u e n c e. U s e i n pregnancy only if the b e n e f i t s o u t w e i g h the potential risks.
Docusate sodium is excreted in breast-milk and s h o u l d t h e r e f o r e b e u s e d w i t h c a u t i o n i n lactating mothers. A suitable s t a t e m e n t has been given on the data sheet.
BIOS DIOCTYL PRE-CLINICAL AND CLINICAL EXPERT REPORT
- CONCLUSIONS
D i o c t y l Tablets, Dioctyl Syrup and Dioctyl Paediatric Syrup have been marketed by Medo Pharmaceuticals Ltd. for at least 20 years. The active ingredient, docusate s o d i u m , is a well-established s u b s t a n c e having been used in indications s i m i l a r to those proposed for Dioctyl for very many years.
The recommended dosages, uses and precautions etc. of Dioctyl are well in accordance with those described in published l i t e r a t u r e a n d s t a n d a r d r e f e r e n c e w o r k s , although there i s very l i t t l e evidence f r o m f o r m a l clinical trials to substantiate conclusively the drug's efficacy.
D e s p i t e some evidence t h a t d o c u s a t e may produce hepatotoxic e f f e c t s , these concerns have not been supported in practice, since widespread use over many years has failed to reveal any clinically significant adverse effects. Medo Pharmaceuticals Ltd. have given a p p r o p r i a t e c e n t r a - i n d i c a t i o n s , p r e c a u t i o n s a n d w a r n i n g s etc. o n t h e d a t a s h e e t s o a s t o a v o i d inappropriate use with agents whose toxicity might be enhanced as a result of increased absorption.
In s u m m a r y Dioctyl products have p r o v e d a s a f e and p o p u l a r remedy for a common c o m p l a i n t for v e r y many years. The s y r u p s have also b e e n used s u c c e s s f u l l y prior to radiological procedures. They are considered to be suitable for retention in the U.K. marketplace.
- REFERENCES
- M a r t i n d a l e. The E x t r a P h a r m a c o p o e i a , 2 8 t h E d i t i o n. E d. J.E.F. R e y n o l d s. L o n d o n. T h e Pharmaceutical Press. 1982.
- The P h a r m a c o l o g i c a l B a s i s of T h e r a p e u t i c s. Goodman and Oilman. Seventh Edition. MacMillan Publishing Company. New York. 1985.
- The Merck Manual. 14th. Ed. M e r c k Sharp and Dohme Ltd. Herts. 1982.
- The B r i t i s h P h a r m a c o p o e i a 1988. London. Her Majesty's Stationery Office.
- SAUDERS D.R., SILLERY J. RACHMILFWITZ D. E f f e c t of Dioctyl Sodium Sulfosuccinate on Structure and f u n c t i o n o f R o d e n t a n d H u m a n I n t e s t i n e. Gastroenterology 1975; 69: 380-386.
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