SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

COLAZIDE® 750mg Capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Balsalazide disodium 750 mg INN:    balsalazide

Each capsule contains balsalazide disodium 750 mg corresponding to balsalazide 612.8 mg and to mesalazine 262.5 mg.

For a full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Capsule, hard.

Size 00 beige gelatin capsules.

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

Colazide is indicated for:

Treatment of mild-to-moderate active ulcerative colitis and maintenance of remission.

4.2    Posology and method of administration

To be swallowed whole with or after food.

Adults:    Treatment of active disease:

2.25g Balsalazide disodium (3 capsules) three times daily (6.75g daily) until remission or for 12 weeks maximum.

Rectal or oral steroids can be given concomitantly if necessary.

Maintenance treatment:

The recommended starting dose is 1.5g Balsalazide disodium (2 capsules) twice daily (3g daily). The dose can be adjusted based on each patient’s response; there may be an additional benefit with a dose up to 6g daily.

Elderly:    No dose adjustment is anticipated.

Children: Colazide is not recommended in children.

4.3    Contraindications

Hypersensitivity to any component of the product or its metabolites, including mesalazine. History of hypersensitivity to salicylates.

Severe hepatic impairment, moderate-severe renal impairment.

Pregnant and breast feeding women.

4.4    Special warnings and precautions for use

Colazide should be used with caution in patients with asthma, bleeding disorders, active ulcer disease, mild renal impairment or those with established hepatic disease.

Renal function should be monitored before starting an oral aminosalicylate, at 3 months of treatment, and then annually during treatment (more frequently in renal impairment). Blood disorders can occur with aminosalicylates (see recommendation below).

Blood disorders

During treatment with Colazide blood counts, BUN/creatinine and urine analysis should be performed. Patients receiving aminosalicylates should be advised to report any unexplained bleeding, bruising, purpura, sore throat, fever or malaise that occurs during treatment. A blood count should be performed and the drug stopped immediately if there is suspicion of a blood dyscrasia.

4.5 Interaction with other medicinal products and other forms of interaction

Formal interaction studies have not been performed with Colazide. Available data suggest that the systemically available amounts of balsalazide and its metabolites may be increased if Colazide is administered in the fasting as compared with the fed state. Therefore, Colazide should preferably be administered with food.

The acetylated metabolites of balsalazide are actively secreted in the renal tubule to a high degree. Therefore, plasma levels of co-prescribed drugs also eliminated by this route may be raised and this should be noted in the case of those with a narrow therapeutic range, such as methotrexate.

Pharmacodynamic interactions have not been studied. However, while balsalazide, mesalazine, and N-acetylmesalazine are salicylates chemically, their properties and kinetics make classical salicylate interactions such as those found with acetylsalicylic acid very unlikely.

The uptake of digoxin has been impaired in some individuals by concomitant treatment with sulphasalazine. Even if it is not known whether this would occur also during treatment with balsalazide, it is recommended that plasma levels of digoxin should be monitored in digitalised patients starting Colazide.

Mesalazine inhibits thiopurine methyltransferase. In patients receiving azathioprine or 6-mercaptopurine, caution is recommended for concurrent use of mesalazine as this can increase the potential for blood dyscrasias.

4.6    Pregnancy and lactation

Animal studies on fertility and reproductive function did not reveal adverse effects of balsalazide. Human experience with balsalazide is limited, therefore Colazide should not be given to pregnant women. Colazide should not be given to breast feeding women as the active metabolite mesalazine has produced adverse effects in    nursing    infants.

4.7    Effects on ability to drive    and use    machines

No evidence of any relevant effect. Presumed to be safe.

4.8    Undesirable effects

The adverse effects are expected to be those of mesalazine.

Reactions reported during treatment with oral mesalazine are listed in the table below.

Organ group	Adverse Event
Blood and lymphatic system disorders	Blood dyscrasias Aplastic anaemia Leucopenia Neutropenia Agranulocytosis Thrombocytopenia
Nervous system disorders	Headache Neuropathy
Cardiac disorders	Myocarditis Pericarditis
Respiratory, thoracic and mediastinal disorders	Bronchospasm Allergic alveolitis Eosinophilic pneumonia
Gastrointestinal disorders	Abdominal pain Diarrhoea Nausea, vomiting Aggravation of ulcerative colitis Acute pancreatitis
Hepatobiliary disorders	Hepatitis Cholelithiasis
Skin and subcutaneous tissue disorders	Alopecia Angioedema Rash
Musculoskeletal and connective tissue disorders	Systemic lupus erythematosus-like syndrome Arthralgia Myalgia
Renal and urinary disorders	Interstitial nephritis Acute renal failure Renal insufficiency Renal impairment
Immune system disorders	Hypersensitivity

See Section 4.4 Special warnings and special precautions for use

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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, Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

To date, there are no reports of overdosage with mesalazine-releasing products. Overdose with large amounts of balsalazide may result in symptoms resembling mild salicylate intoxication. Treatment should be symptomatic.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC-code: A07 EC.

Balsalazide consists of mesalazine linked to a carrier molecule (4-aminobenzoyl-B-alanine) via an azo bond.

Bacterial azo-reduction releases mesalazine as an active metabolite in the colon. Mesalazine is an intestinal anti-inflammatory agent acting locally on the colonic mucosa. Its precise mechanism of action is unknown. Balsalazide and the carrier do not contribute to the pharmacodynamic action.

5.2 Pharmacokinetic properties

The pharmacokinetics of balsalazide and its metabolites have been studied in healthy subjects and patients in remission. The systemic uptake of balsalazide itself is low (<1%) and the major part of the dose is split in the colon by bacterial azoreductase. This cleavage results in the primary metabolites 5-aminosalicylic acid (5-ASA), responsible for the antiinflammatory action, and 4-aminobenzoyl-beta-alanine (4-ABA), considered to be an inert carrier.

Most of the dose is eliminated via the faeces but about 25% of the released 5-ASA appears systemically predominantly as the N-acetylated metabolite (NASA) after inactivation in the colonic mucosa and liver. The systemic uptake of 4-ABA is only 10-15% of that of 5-ASA and also this metabolite is grossly N-acetylated (to NABA) in the first pass.

In urine, virtually only NASA and NABA are recovered and their renal clearances are high: 0.2-0.3 L/min and 0.4-0.5 L/min, respectively. The halflife of NASA is in the order of 6-9 hours. The half-life of 5-ASA itself is very short: about 1 hour.

Because of the great importance of renal clearance for the elimination, Colazide should be used with caution in renal impairment. No studies have been performed in patients with hepatic disease.

Protein binding of 5-ASA is about 40% and that of NASA about 80%. Available data suggest that the pharmacokinetics of balsalazide is not affected by genetic polymorphism, nor does age seem to be an important factor. Fasting slightly increases the systemic uptake of balsalazide and its metabolites.

Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of genotoxicity, carcinogenic potential, toxicity to reproduction, safety pharmacology and validating kinetics and metabolism. In repeated dose toxicity studies, nephrotoxicity, an effect known to occur following mesalazine, was observed particularly in rats.

6. PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Magnesium stearate, colloidal anhydrous silica, gelatin, shellac, titanium dioxide (E171), yellow, red and black iron oxide (E172).

6.2    Incompatibilities

Not applicable

6.3. Shelf life

3 years.

6.4    Special precautions for storage

No special precautions for storage.

6.5    Nature and contents of container

High density polyethylene container fitted with tamper-evident, child-resistant, high density polyethylene screw caps.

Pack sizes are: 50, 54, 56, 100, 112, 130, 224 (2 x 112), 260 (2 x 130), 300 (3 x 100), 500 (10 x 50), 672 (6 x 112) and 780 (6 x 130) capsules.

Not all pack sizes will be marketed in all Member States.

6.6    Special precautions for disposal

None.

7 MARKETING AUTHORISATION HOLDER

ALMIRALL S.A Ronda General Mitre 151 Barcelona

E-08022

Spain

8    MARKETING AUTHORISATION NUMBER(S)

PL 16973/0019

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

18/12/2007

10    DATE OF REVISION OF THE TEXT

05/05/2015