SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Salazopyrin Suppositories

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Sulfasalazine EP 500mg

3 PHARMACEUTICAL FORM

Suppository

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Ulcerative colitis or Crohn's Disease affecting the rectum.

4.2 Posology and method of administration

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.

Children

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

4.3 Contraindications

General

Because of lower absorption levels and shorter retention time in the body, Salazopyrin 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.

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

•    Use in infants under two years old.

•    Porphyria.

4.4 Special warnings and precautions for use

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. Assessment of renal function (including urinalysis) should be performed in all patients initially and at least monthly for the first three months of treatment. Thereafter, monitoring should be performed as clinically indicated. 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.

Sulfasalazine should not be given to patients with impaired hepatic or renal 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.

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 know oligospermia has not occurred during therapy per rectum.

4.5 Interaction with other medicinal products and other forms of interaction

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 Salazopyrin, bone marrow suppression and leucopenia have been reported when the thiopurine 6-mercaptopurine or it’s prodrug, azathioprine, and oral Salazopyrin 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

Reproduction studies in rats and rabbits have revealed no evidence of harm to the fetus. Published data regarding use of sulfasalazine in pregnant women have revealed no evidence of teratogenic hazards. If sulfasalazine is used during pregnancy, the possibility of fetal harm appears remote. Oral sulfasalazine inhibits the absorption and metabolism of folic acid and may cause folic acid deficiency. Because the possibility of harm cannot be completely ruled out, sulfasalazine should be used during pregnancy only if clearly needed.

Lactation

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.

4.7 Effects on ability to drive and use machines

No specific effects.

4.8 Undesirable effects

Overall, about 75% of ADRs occur within 3 months of starting therapy, and over 90% by 6 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 ADRs to either sulfonamide or salicylate are possible. Patients with slow acetylator status are more likely to experience ADRs related to sulfapyridine. The most commonly encountered ADRs 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). 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 list below.

Not known	Pseudomembranous colitis
Blood and Lymphatic System Disorders
Common	Leukopenia
Uncommon	Thrombocytopenia*
Not known	Agranulocytosis, aplastic anemia, haemolytic anemia, Heinz body anaemia, hypoprothrombinaemia, lymphadenopathy, macrocytosis, megaloblastic anemia, methaemoglobinaemina, neutropenia, pancytopenia
Immune System Disorders:
Not known	Anaphylaxis, polyarteritis nodosa, serum sickness
Metabolism and Nutrition Disorders:
Not known	Loss of appetite
Psychiatric Disorders:
Common	Insomnia
Uncommon	Depression
Not known	Hallucinations
Nervous System Disorders:
Common	Dizziness, headache, taste disorders
Uncommon	Convulsions,
Not known	Aseptic meningitis, ataxia, encephalopathy, peripheral neuropathy, smell disorders
Ear and Labyrinth Disorders:
Common	Tinnitus
Uncommon	Vertigo
Eye Disorders:
Common	Conjuctivial and scleral injection
Cardiac Disorders:
Not known	Allergic myocarditis, cyanosis, pericarditis
vascular Disorders:
Uncommon	Vasculitis
Respiratory, Thoracic and Mediastinal Disorders:
Common	Cough

Dyspnoea

Fibrosing alveolitis, eosinophilic infiltration, interstitial lung disease

Gastrointestinal Disorders:

Very Common    Gastric distress, nausea

Common    Abdominal pain, diarrhoea, vomiting, stomatitis

Not known    Aggravation of ulcerative colitis, pancreatitis, parotitis

Hepato-biliary Disorders:

Not known    Hepatic failure, fulminant hepatitis, hepatitis*

Skin and Subcutaneous Tissue Disorders:

Common    Pruritus

Uncommon    Alopecia, urticaria

Not known    Epidermal necrolysis (Lyell’s syndrome), Stevens-Johnson

syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), toxic pustuloderma, erythema, exanthema, exfoliative dermatitis, periorbital oedema, lichen planus, photosensitivity Musculoskeletal and Connective Tissue Disorders:

Common    Arthralgia

Not known    Systemic lupus erythematosus

Renal and Urinary Disorders:

Common    Proteinuria

Not known    Nephrotic syndrome, interstitial nephritis, crystalluria*,

haematuria

Reproductive System and Breast Disorders:

Not known    Reversible oligospermia*

General Disorders and Administration Site Conditions:

Fever

Facial oedema

Yellow discoloration of skin and body fluids

Elevation of liver enzymes Induction of autoantibodies

* See Section 4.4 for further information

Overdose with suppositories is unlikely. In the event, evacuate the bowel and treat supportively. The toxicity of sulphasalazine is low in acute dosage.

There is no specific antidote.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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 1 5-prostaglandin dehydrogenase and slows prostaglandin metabolism. Lipoxygenase release in inflammatory cells is also depressed. NK cells and T cell proliferation are inhibited.

5.2 Pharmacokinetic properties

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 0.5g suppositories gave the following results:

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

5.3 Preclinical safety data

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 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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Povidone Adeps Solidus

6.2 Incompatibilities

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

Shelf life

Five years.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

PVC/Polyethylene laminate moulds. Pack sizes: 10 and 50.

6.6 Special precautions for disposal

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.

7    MARKETING AUTHORISATION HOLDER

Pfizer Limited Ramsgate Road Sandwich Kent

CT13 9NJ United Kingdom

MARKETING AUTHORISATION NUMBER(S)

PL 00057/1042

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12 January 1994

DATE OF REVISION OF THE TEXT

11/02/2014