Ulcerative colitis or Crohn's Disease affecting the rectum.

The dose is adjusted according to the severity of the disease and the patient's tolerance of the drug.

Acute attack or relapse - Adults and the Elderly

Two suppositories are to be inserted in the morning and two at bedtime after defecation. After three weeks the dosage is gradually reduced as improvement occurs.

Adjustment to oral therapy - Adults and the Elderly

In severe generalised ulcerative colitis of the rectum or recto sigmoid, or in cases who are responding slowly to oral therapy, one or two suppositories may be given in the morning and at bedtime additional to oral therapy.

Paediatric population

The adult dose is reduced on the basis of body weight.

General

Because of lower absorption levels and shorter retention time in the body, suppositories give rise to fewer adverse events than equivalent treatment by mouth. However, because of the theoretical possibility that serious adverse events can arise from treatment from either route, the details below are based on adverse event reports to both oral and rectal treatment.

i) A known hypersensitivity to sulfasalazine, its metabolites or any of the excipients as well as sulfonamides or salicylates.

ii) Use in infants under two years old.

iii) Porphyria.

Serious infections associated with myelosuppression, including sepsis and pneumonia, have been reported. Patients who develop a new infection while undergoing treatment with sulfasalazine should be monitored closely. Administration of sulfasalazine should be discontinued if a patient develops a serious infection. Caution should be exercised when considering the use of sulfasalazine in patients with a history of recurring or chronic infections or with underlying conditions which may predispose patients to infections.

Complete blood counts, including differential white cell count and liver function tests, should be performed before starting sulfasalazine, and every second week during the first three months of therapy. During the second three months, the same tests should be done once monthly and thereafter once every three months, and as clinically indicated. Baseline assessment of renal function (including urinalysis) is required to be performed in all patients initiating treatment with sulfasalazine. For patients with baseline renal impairment, treatment with sulfasalazine should only be initiated if the benefits are considered to outweigh risk. Thereafter, periodic renal function monitoring, especially in the early months of treatment, should be conducted based on clinical judgment taking baseline renal function into account. Treatment should be discontinued if renal function deteriorates. The patient should also be counselled to report immediately with any sore throat, fever, malaise, pallor, purpura, jaundice or unexpected non-specific illness during sulfasalazine treatment, this may indicate myelosuppression, haemolysis or hepatoxicity. Treatment should be stopped immediately while awaiting the results of blood tests. Please see section 4.4 “ Interference with laboratory testing” .

Sulfasalazine should not be given to patients with impaired hepatic function or with blood dyscrasias, unless the potential benefit outweighs the risk.

Sulfasalazine should be given with caution to patients with severe allergy or bronchial asthma.

Severe hypersensitivity reactions may include internal organ involvement, such as hepatitis, nephritis, myocarditis, mononucleosis-like syndrome (i.e., pseudomononucleosis), hematological abnormalities (including hematophagic histiocytosis), and/or pneumonitis including eosinophilic infiltration.

Severe, life-threatening, systemic hypersensitivity reactions such as Drug rash with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking various drugs including sulfasalazine. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately.

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of sulfasalazine. Patients appear to be at highest risk for these events early in the course of therapy, the onset of the event occurring in the majority of cases within the first month of treatment.

Sulfasalazine should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Sulfasalazine should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Use in children with the concomitant condition systemic onset juvenile rheumatoid arthritis may result in a serum sickness like reaction; therefore sulfasalazine is not recommended in these patients.

Since sulfasalazine may cause haemolytic anaemia, it should be used with caution in patients with G-6-PD deficiency.

Oral sulfasalazine inhibits the absorption and metabolism of folic acid and may cause folic acid deficiency (see section 4.6), potentially resulting in serious blood disorders (e.g., macrocytosis and pancytopenia), this can be normalised by administration of folic acid or folinic acid (leucovorin).

Because sulfasalazine causes crystalluria and kidney stone formation, adequate fluid intake should be ensured during treatment.

Oligospermia and infertility may occur in men treated with sulfasalazine. Discontinuation of the drug appears to reverse these effects within 2 to 3 months. As far as is known oligospermia has not occurred during therapy per rectum.

Interference with laboratory testing

Several reports of possible interference with measurements, by liquid chromatography, of urinary normetanephrine causing a false-positive test result have been observed in patients exposed to sulfasalazine or its metabolite, mesalamine/ mesalazine.

Sulfasalazine or its metabolites may interfere with ultraviolet absorbance, particularly at 340 nm, and may cause interference with some laboratory assays that use NAD(H) or NADP(H) to measure ultraviolet absorbance around that wavelength. Examples of such assays may include urea, ammonia, LDH, α -HBDH and glucose. It is possible that alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase-muscle/brain (CK-MB), glutamate dehydrogenase (GLDH), or thyroxine may also show interference when sulfasalazine treatment is given at high doses. Consult with the testing laboratory regarding the methodology used. Caution should be exercised in the interpretation of these laboratory results in patients who are receiving sulfasalazine. Results should be interpreted in conjunction with clinical findings.

There have been no adverse interactions reported, due to the drug largely remaining confined to the rectum. However, there is a potential for interaction as follows:

Reduced absorption of digoxin, resulting in non-therapeutic serum levels, has been reported when used concomitantly with oral sulfasalazine.

Sulfonamides bear certain chemical similarities to some oral hypoglycemic agents. Hypoglycemia has occurred in patients receiving sulfonamides. Patients receiving sulfasalazine and hypoglycemic agents should be closely monitored.

Due to inhibition of thiopurine methyltransferase by sulfasalazine, bone marrow suppression and leucopenia have been reported when the thiopurine 6-mercaptopurine or it's prodrug, azathioprine, and oral sulfasalazine were used concomitantly.

Coadministration of oral sulfasalazine and methotrexate to rheumatoid arthritis patients did not alter the pharmacokinetic disposition of the drugs. However, an increased incidence of gastrointestinal adverse events, especially nausea, was reported.

Several reports of possible interference with measurements, by liquid chromatography, of urinary normetanephrine causing a false-positive test result have been observed in patients exposed to sulfasalazine or its metabolite, mesalamine/ mesalazine.

Pregnancy

Reproduction studies in rats and rabbits have revealed no evidence of harm to the fetus. Oral sulfasalazine inhibits the absorption and metabolism of folic acid and may cause folic acid deficiency. There have been reports of babies with neural tube defects born to mothers who were exposed to sulfasalazine during pregnancy, although the role of sulfasalazine in these defects has not been established. Because the possibility of harm cannot be completely ruled out, sulfasalazine should be used during pregnancy only if clearly needed.

Breast-feeding

Sulfasalazine and sulfapyridine are found in low levels in breast milk. Patients should avoid breastfeeding while taking this medicine.

There have been reports of bloody stools or diarrhoea in infants who were breastfeeding from mothers on sulfasalazine. In cases where the outcome was reported, bloody stools or diarrhoea resolved in the infant after discontinuation of sulfasalazine in the mother.

Sulfasalazine has no influence on the ability to drive and use machines.

The following have been reported to sulfasalazine given orally or rectally. The drug rectally is well tolerated. Overall, about 75% of adverse drug reactions occur within three months of starting therapy and over 90% by six months. Some undesirable effects are dose-dependent and symptoms can often be alleviated by reduction of the dose.

General

Sulfasalazine is split by intestinal bacteria to sulfapyridine and 5-amino salicylate so adverse drugs reactions to either sulfonamide or salicylate are possible. Patients with slow acetylator status are more likely to experience adverse drug reactions related to sulfapyridine. The most commonly encountered adverse drugs reactions are nausea, headache, rash, loss of appetite and raised temperature.

Specific

The adverse reactions observed during clinical studies conducted with Sulfasalazine have been provided in a single list below by class and frequency (very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon (≥ 1/1000 to <1/100); rare (1/10000 to <1/1000); very rare (<1/10000); not known (cannot be estimated from available data)). Where an adverse reaction was seen at different frequencies in clinical studies, it was assigned to the highest frequency reported.

Additional reactions reported from post-marketing experience are included as frequency Not known (cannot be estimated from the available data) in the table below.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Overdose with suppositories is unlikely. In the event, evacuate the bowel and treat supportively. The toxicity of sulfasalazine is low in acute dosage. There is no specific antidote.

Pharmacotherapeutic group: Aminosalicylic acid and similar agents, ATC code: A07EC01

Therapeutic benefit of sulfasalazine in ulcerative colitis and Crohn's Disease appears to be due to a local action of the sulfasalazine and its split product 5-aminosalicylic acid on the mucous membrane and deeper colonic structures. Pharmacological actions noted for these compounds include inhibition of neutrophil activation, free radical scavenging, inhibition of superoxide production, inhibition of bacterial growth. Sulfasalazine inhibits 15-Prostaglandin dehydrogenase and slows prostaglandin metabolism. Lipoxygenase release in inflammatory cells is also depressed. NK cells and T cell proliferation are inhibited.

There are considerable individual differences in the retention time of suppositories in volunteer studies. Consequently, uptake values vary widely also. Given that the effect of the drug is almost certainly due to a local effect pharmacokinetics becomes less relevant to therapeutic action than to possible adverse effects related to systemic levels.

A study of five volunteers over three days following insertion of 2 x 500 mg suppositories gave the following results:

Retention time: mean 8.9 hours (s.d. 5.2), serum concentration at 10 hours: sulfasalazine 1.7 mcg/ml (s.d. 0.46), sulfapyridine less than 1 mcg/ml. Percentage renal excretion: 10.2 (s.d. 4.3). Uptake as reflected by excretion is much below that of the oral rate and may explain the good tolerance of the dose form.

In two-year carcinogenicity studies in rats and mice, sulfasalazine showed some evidence of carcinogenicity. In rats, there was a small increase in the incidence of transitional cell papillomas in the urinary bladder and kidney. The tumours were judged to be induced mechanically by calculi formed in the urine rather than through a direct genotoxic mechanism. In the mouse study, there was a significant increase in the incidence of hepatocellular adenoma or carcinoma. The mechanism of induction of hepatocellular neoplasia has been investigated and attributed to species-specific effects of sulfasalazine that are not relevant to humans.

Sulfasalazine did not show mutagenicity in the bacterial reverse mutation assay (Ames test) or in the L51784 mouse lymphoma cell assay at the HGPRT gene. It did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells, and in vivo mouse bone marrow chromosomal aberration tests were negative. However, sulfasalazine showed positive or equivocal mutagenic responses in rat and mouse micronucleus assays, and in human lymphocyte sister chromatid exchange, chromosomal aberration and micronucleus assays. The ability of sulfasalazine to induce chromosome damage has been attributed to perturbation of folic acid levels rather than to a direct genotoxic mechanism.

Based on information from non-clinical studies, sulfasalazine is judged to pose no carcinogenic risk to humans. Sulfasalazine use has not been associated with the development of neoplasia in human epidemiology studies.

Povidone

Hard fat

Certain types of extended wear soft contact lenses may be permanently stained during therapy.

5 years

Do not store above 25° C.

PVC/Polyethylene laminate moulds

As the suppositories melt at body temperature they should be kept below 25° C and handled as little as possible before insertion so that they are firm.

Sulfasalazine is an orange dye, and care should thus be taken with clothing, bedding etc., with regard to seepage or spillage.

Insertion

Empty the bowel if possible. Push the suppository through the anus with a finger, as far as possible. The urge to expel them will pass in a few minutes, once they have melted.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.