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1. Balzide 750mg Capsules
2. Balzide 750mg Capsules

SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

BALZIDE® 750 mg capsules, hard.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Balsalazide disodium 750 mg

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

For the full list of excipients, see section 6.1

3.    PHARMACEUTICAL FORM

Capsule, hard.

Size 00 gelatin capsules with white body and blue cap.

Each capsule is marked with the Menarini logo.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

BALZIDE is indicated for:

Treatment of mild-to-moderate active ulcerative colitis and maintenance of remission. BALZIDE is indicated in adults.

4.2    Posology and method of administration

Posology

Adults

Treatment of active disease: 2.25 g Balsalazide disodium (three capsules) three times daily (6.75 g 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 1.5 g Balsalazide disodium (two capsules) twice daily (3 g daily). The dose can be adjusted based on each patient’s response; there may be an additional benefit with a dose up to 6 g daily.

Older people

No dose adjustment is anticipated.

Paediatric Population

The safety and efficacy of BALZIDE in children and adolescents aged below the age of 18 years have not been established. No data are available. BALZIDE is not recommended in children.

Method of administration Oral use.

BALZIDE should be swallowed whole after food.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 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

BALZIDE 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 disordersDuring treatment with BALZIDE blood counts, BUN/creatinine and urine analysis should be performed. Patients receiving balsalazide 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.

Adequate fluid intake should be ensured during treatment, because balsalazide can cause crystalluria and kidney stone formation.

4.5 Interaction with other medicinal products and other forms of interaction

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

4.6 Fertility, pregnancy and lactation

Fertility

Animal studies on fertility and reproductive function did not reveal adverse effects of balsalazide (see section 5.3).

Pregnancy

Human experience with balsalazide is limited, therefore BALZIDE should not be given to pregnant women.

Breastfeeding

BALZIDE should not be given to breastfeeding 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.

4.8 Undesirable effects

The adverse effects are expected to be those of mesalazine.

The table below lists the potential undesirable drug experiences by body system in decreasing order of incidence.

System Organ Class	common (>1/100 to < 1/10)	uncommon (>1/1,000 to < 1/100)	rare (>1/10,000 to <1/1,000)	very rare (<1/10,000)
Blood and the lymphatic system disorders				Aplastic anaemia, leukopenia, neutropenia, agranulocytosis, thrombocytopenia
Immune system disorders			hypersensitivity
Nervous system disorders	headache		neuropathy
Cardiac disorders			myopericarditis
Respiratory, thoracic and mediastinal disorders			bronchospasm, alveolitis allergic
Gastrointestinal disorders	abdominal pain, diarrhoea, nausea, vomiting		colitis aggravated, pancreatitis acute
Hepato-biliary disorders		cholelithiasis	hepatitis
Skin and subcutaneous tissue disorders			alopecia, rash
Musculoskeletal and connective tissuedisorders			arthralgia, lupuslike syndrome, myalgia
Renal and urinary disorders			nephritis interstitial

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. Overdode with large amounts of balsalazide may result in symptoms resembling mild salycylate intoxication. Treatment should be symptomatic.

5 PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Aminosalicylic acid and similar agents ATC code: A07E C04.

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 anti-inflammatory 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 half-life 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, BALZIDE 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.

5.3    Pre-clinical 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

Capsule contents Magnesium stearate Colloidal anhydrous silica

Capsule shells

Gelatin

Shellac

Black iron dioxide (E172)

Titanium dioxide (E171)

Indigo carmine (E132).

6.2    Incompatibilities

Not Applicable

10 DATE OF REVISION OF THE TEXT

10/12/2015