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    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]

    FIGURE

    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