Summary for UKPID
Sulphasalazine
Dr Alan Worsley Bsc(hons) PhD MRPharmS
National Poisons Information Service (Newcastle Centre)
Regional Drug & Therapeutics Centre
Wolfson Building
Claremont Place
Newcastle upon Tyne
NE1 4LP
UK
This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.
Peer review group: Directors of the UK National Poisons Information
Service.
Summary
Sulphasalazine.
Type of product
For the treatment of ulcerative colitis.
Ingredients
Sulphasalazine tablets 500mg
suspension 250mg/5ml
Suppositories 500mg
Toxicity
Probably not very toxic. A 33 year old adult took 10-15g and had
no symptoms.
Features
Nausea and vomiting, dizziness, ataxia, drowsiness and dysuria.
Urine and other body fluids may be coloured orange. Contact
lenses may be stained.
Treatment
Supportive
1. Empty the stomach if more than 10 tablets ingested.
2. Liberal fluids.
3. Other measures are indicated by patients' clinical condition.
References
ABPI Data Sheet Compendium. Datapharm publications Limited 1996-1997
British National Formulary. Number 32 (september 1996). British
medical Association and Royal Pharmaceutical Society.
Dollery C. Therapeutic Drugs. (Pt 2). Churchill Livingstone (1994).
UKPID MONOGRAPH - JANUARY 1996
SULPHASALAZINE
Brand Name
Salazopyrin
Generic Name
Sulphasalazine
Chemical group/family
treatment of chronic diarrhoea
BNF 1.4
Reference number1
(CAS) 599-79-1
Manufacturer/supplier2
Pharmacia & Upjohn Ltd,
7 Windermere Rd
West Wickham,
Kent
BR4 9AN
01908 661101
Presentation
sulphasalzine 500mg tablets
pack size 100,
sulphasalazine enteric coated 500mg tablets
pack size 100,
sulphasalazine suspension 250mg/5ml
pack size 500ml,
sulphasalazine suppositories 500mg
pack size 10 & 50,
sulphasalazine retention enema 3g in 100ml
pack size 7x 100ml.
Physicochemical properties (Dollery)3
2-Hydroxy-4'-(2-pyridylsulphamoyl)azobenzene-3-carboxylic acid
Molecular Weight
398.39
pKa
2.4, 8.3, 11.0
Solubility
in water insoluble
in alcohol 1 in 2900
octanol/water partition coefficient
0.75
USES
Indications2
Induction and maintenance of remision in ulcerative colitis; active
Crohn's disease; rheumatoid arthritis.
Therapeutic Dosage (BNF)6
Adults (by mouth)
Acute attack 1-2 g 4 times daily until remission occurs, reducing to
maintenance dose of 500mg 4 times daily.
Child (by mouth)
Over 2 years, acute attack 40-60mg/kg daily, maintenance dose 20-
30mg/kg daily.
Adults (by rectum)
In suppositories, alone or in conjunction with oral treatment 0.5-1g
morning and night after bowel movement. As an enema, 3g at night,
retained for at least 1hr.
Contraindications
Salicylate and sulphonamide hypersensitivity. CHILD under 2 years of
age.
Precautions
History of allergy; hepatic and renal disease; G6PD deficiency; slow
acetylator status; risk of haematological and hepatic toxicity
(differential white cell, red cell and platelet counts initially and
at monthly intervals for first 3 months, liver function tests at
monthly intervals for first 3 months; upper gastro-intestinal side
effects common over 4g daily; pregnancy and breast feeding; porphyria.
Pharmacokinetics (Dollery)3
Oral absorption 20-30%
Presystemic metabolism 70-80%
Plasma half-life
range 3-11hr
mean 6hr
Plasma half-life
(sulphapyridine)
range 6-17hr
mean 10hr
Plasma half-life
(acetyl-5-aminosalicylic acid)
range 4-10hr
mean 7hr
Volume of distribution -
Plasma protein binding 95-99%
Toxicokinetics
None available
Adverse effects (data sheet)
Overall about 75% of adverse drug reactions occur within 3 months of
starting therapy and over 90% by 6 months. Some undesirable effects
are dose dependant and symptoms can often be alleviated by reduction
of the dose. Since sulphasalazine is metabolised to sulphapyridine and
5-aminosalicylic acid, side effects of sulphonamides and salicylates
may occur. Patients with slow acetylator status are more likely to
experience adverse effects due to sulphapyridine. The most commonly
encountered reactions are nausea, headache, rash, loss of apetite and
raised temperature.
The folowing adverese reactions have been reported:
Haematological: Potentially fatal leucopaenia, neutropaenia,
agranulocytosis, aplastic anaemia and thrombocytopaenia. Leucopaenia,
which is normally mild and transient, may occur in up to 1.5% of
patients and agranulocytosis in up to 1 in 700 patients during the
second month of therapy.
Heinz body anaemia, methaemaglobinaemia, hypoprothrombinaemia,
haemolytic anaemia, megaloblastic anaemia.
Hypersensitivity reactions: Generalised skin eruptions, Stevens-
Johnson syndrome, exfoliative dermatitis, epidermal necrolysis,
pruritis, urticaria, photosensitisation, anaphylaxis, serum sickness,
drug fever, periorbital oedema, conjunctival and scleral injection,
arthralgia, allergic myocarditis, polyarteritis nodosa, LE-phenomenon
and lung complications with dyspnoea, fever, cough, eosinophilia,
fibrosing alveolitis.
Gastro-intestinal reactions: Stomatitis, parotitis, pancreatitis,
hepatitis.
CNS Reactions: Vertigo, tinnitus, peripheral neuropathy, ataxia,
convulsions, insomnia, mental depression, aseptic meningitis and
hallucinations.
Fertility: Oligospermia, reversible on discontinuance of drug.
Renal reactions: Crystallurai, haematuria, proteinuria and nephrotic
syndrome. An acute attack may be precipitated in patients with
porphyria.
Pregnancy4
Long term clinical usage and experimental studies have failed to
reveal any teratogenic or icteric hazards.
No increase in congenital defects or newborn toxicity has bee observed
from its use in pregnancy. However, three reports, involving five
infants (two stillborn), have described congenital malformations after
exposure to this drug. It cannot be determined whether the observed
defects were related to the therapy, the disease, or a combination of
these or other factors.
Sulphasalazine and its metabolite, sulphapyridine, readily cross the
placenta to the fetal circulation. Fetal concentrations are
approximately the same as maternal concentrations.
Placental transfer of 5-amoinosalicylic acid is limited since only
negligible amounts are absorbed from the caecum and colon and these
are rapidly excreted in the urine.
Breast Milk
Sulphapyridine (metabolite of sulphasalazine) is excreted into breast
milk. Milk concentrations were approximately 40-60% of maternal serum
levels. One of the infant's urine contained 3-4 microg/ml of drug,
representing about 30-40% of the total dose excreted in the milk.
Interactions5
Sulphasalazine Interaction with ampicillin. Reduction in the
release of 5-ASA due to disturbance of gut flora.
Interaction with cholestyramine. Cholestyramine
has been shown to bind to sulphasalazine in the
gut, thereby reducing activity.
Interaction with digoxin. serum digoxin levels can
be reduced by the concurrent use of
sulphasalazine.
Interaction with ferrous sulphate. Sulphasalazine
and iron appear to bind together in the gut,
thereby reducing activity.
Interaction with folic acid. Sulphasalazine can
reduce the absorption of folic acid.
Interaction with iron preparations. Sulphasalazine
and iron appear to bind together in the gut,
thereby reducing activity.
Interaction with rifampicin. Reduction in the
release of 5-ASA due to disturbance of gut flora.
Interaction with talinolol. Sulphasalazine
markedley reduced the absorption of talinolol.
EPIDEMIOLOGY OF POISONING6
No specific data on sulphasalazine poisoning are available.
Case report
A 23 yr old man ingested 50 x 500mg sulphasalazine tablets. He
developed a headache and felt dizzy. He was treated with Gastric
lavage, activated charcoal with sorbitol and I/V dextrose with sodium
bicarbonate. He survived with few ill effects7.
MECHANISM OF ACTION/TOXICITY
Range of toxicity (Poisindex)
Since many of the adverse effects appear to be hypersensitivity
reactions, there is no specific toxic dose. The incidence of the
adverse effects appears to increase with increased sulphonamide
dosage.
The majority of the 5-aminosalicylic acid (80%) is excreted in the
stool8. Thus toxicity due to salicylate is likely to occur only at
high levels of sulphasalazine ingestion. There are no data available
on the toxicity of 5-aminosalicylic acid.
Fatal level
Not Known
Toxicity of Sulphasalazine?
If toxic levels of aspirin are achieved in adults by an approximate
consumption of 5 to 30g, then toxicity may similarly be achieved with
salicylate by taking 3.8 to 22.8g (allowing for changes in atomic
mass). If Toxic levels of salicylate are then compared to
5-aminosalicylic acid , toxic levels could be achieved by ingestion of
4.22 to 25.5g of 5ASA.
The equivalent proportion of sulphasalazine needed to be taken to
cause toxic levels of toxicity as described above would be within the
range 11.1 to 66.66g. However the majority of sulphasalazine excreted
in the stool is approximately 80%. Therefore ingestion of 55.5g to
333.3g of sulphasalazine would be required in order to achieve toxic
levels of salicylate.
[This calculation is an approximation]
Sulphasalazine
FEATURES OF POISONING
Summary
Adverse reactions to sulphonamides involve nearly every organ system;
often in multiple fashion and in varying degree. Although there is a
difference as to the frequency of toxic effects between short acting
and long acting, there is considerable overlap. Many of the adverse
effects appear to be hypersensitivity reactions, the incidence of
which is dose related.
HEENT
Transient myopia, conjunctivitis and keratitis may occur in
association with hypersensitivity reaction.
GASTROINTESTINAL
Nausea and vomiting are likely to occur.
HEPATIC
Hypersensitivity reactions to sulphonamides may produce hepatic
injury.
HAEMATOLOGICAL
Haematological effects are uncommon, but sveral have been reported.
These include acute haemolytic anaemia, agranulocytosis,
thrombocytopaenia, aplastic anaemia and methaemoglobinaemia
MANAGEMENT
1. Administer activated charcoal within 1-2 hours of ingestion.
2. Treatment is symptomatic and supportive.
3. Hypotension- administer IV fluids.
4. Monitor renal function.
NPIS Newcastle
Dr Alan Worsley Bsc(hons) PhD MRPharmS
National Poisons Information Service (Newcastle Centre)
Regional Drug & Therapeutics Centre
Wolfson Building
Claremont Place
Newcastle upon Tyne
NE1 4LP
UK
This monograph was produced by the staff of the Newcastle Centre of
the National Poisons Information Service in the United Kingdom. The
work was commissioned and funded by the UK Departments of Health, and
was designed as a source of detailed information for use by poisons
information centres.
Peer review was undertaken by the Directors of the UK National Poisons
Information Service.
Last updated September 1997
References
1. Martindale: the Extra Pharmacopoeia. 30th edition. Pharmaceutical
Press (1993)
2. ABPI Data Sheet Compendium. Datapharm Publications Ltd (1995-6)
3. Therapeutic Drugs. Dollery C (Ed). Churchill Livingstone (1991)
4. Briggs GG et al. Drugs in pregnancy and lactation. Williams and
Wilkins Ltd (1993)
5. British National Formulary. No 32 (Sept 1996).
6. Medical Toxicology. 2nd Edition. Ellenhorn MJ (Ed) Elsevier 1992.
7. Minocha A, Dean HA & Mayle JE. Acute sulphasalazine overdose. Clin
Toxicol (1991);29:543-551
8. Hanngren A, Hansson E, Svartz N, Ullberg S. Distribution of studies
of salicylazosulphapyridine part I. Acta Medica Scandinavia (1963);
173:61-72