Section

Change

3 PHARMACEUTICAL FORM

Update:

Red-brown, ellipsoidal, film-coated tablet (dimensions 20.5 × 9.5 × 7.5 mm), debossed on one side with S476.

4.1 Therapeutic Indications

Update:

Adults, including the elderly (>65 years)

For the induction and maintenance of clinical and endoscopic remission in patients with mild to moderate, active ulcerative colitis. For maintenance of remission.

Children and adolescents (weighing more than 50 kg and age 10 years or older)

For the induction and maintenance of clinical and endoscopic remission in patients with mild to moderate, active ulcerative colitis.

4.2 Posology and method of administration

Update:

Children and adolescents (weighing more than 50 kg and age 10 years or older)

For induction of remission (initial 8 weeks): 2.4 g to 4.8 g (two to four tablets) should be taken once daily.

For maintenance of remission: 2.4 g (two tablets) should be taken once daily.

Mesalazine 1200 mg tablets should not be used by paediatric patients weighing 50 kg or less and should not be used in paediatric patients below the age of 10 years due to a lack of data on safety and efficacy in these patients.

4.8 Undesirable effects

Addition:

The safety profile in the paediatric population is consistent with the safety profile in adult studies and in post marketing experience.

5.1 Pharmacodynamic properties

Addition:

A Phase 3, multicentre, randomized, double‑blind, parallel‑group study was conducted in 107 paediatric patients aged 5 to 17 years (inclusive) with mild to moderate ulcerative colitis to evaluate the safety and efficacy of Mezavant in both double‑blind acute (Double‑Blind Acute, DBA) and double‑blind maintenance (Double‑Blind Maintenance, DBM) phases. Subjects received a low or a high weight‑based dose of mesalazine in four weight groups: 18 kg to £23 kg (n=3), >23 kg to £35 kg (n=9), >35 kg to £50 kg (n=29), and >50 kg to £90 kg (n=66). The low dose ranged from 900 mg/day to 2,400 mg/day and the high dose ranged from 1,800 mg/day to 4,800 mg/day. Clinical effects of 1200‑mg mesalazine tablets were evaluated in 66 subjects >50 kg to £90 kg in the age range 10 to 17 years.

Primary endpoint of the double‑blind treatment phases was defined in terms of clinical response. Clinical response was defined as a partial Ulcerative Colitis Disease Activity Index (UC‑DAI) score of £1 with a score of 0 for rectal bleeding and £1 for stool frequency and physician’s global assessment = 0.

After 8 weeks of treatment in the DBA phase, 37.0% of subjects achieved a clinical response in the low‑dose arm compared to 65.4% of subjects in the high‑dose arm. The response rates at week 8 in these dose arms were 50.0% and 56.3% respectively in subjects weighing >50 kg to £90 kg who received 1200‑mg mesalazine tablets. In the DBM phase, after 26 weeks of treatment, 54.8% of subjects maintained a clinical response in the low‑dose arm compared to 53.3% in the high‑dose arm. The response rate at week 26 was 50% in both dose arms in subjects weighing >50 kg to £90 kg who received 1200‑mg mesalazine tablets. The study was not powered to assess differences between the low dose and high dose.

5.2 Pharmacokinetic properties

Addition

In a Phase 1, multicentre, open label study (SPD476 112) in paediatric subjects (aged 5 to 17 years) diagnosed with UC, dosing of mesalazine was stratified by weight. Subjects were randomized to 1 of 3 possible treatments: 30, 60, or, 100 mg/kg/day. Subjects received a total dose between 900 and 4,800 mg of mesalazine per day for 7 days.

Pharmacokinetic steady state was attained by Day 5 for all doses. On Day 7, systemic 5 ASA exposure, as measured by mean AUCss and Cmax,ss, increased in a dose proportional manner between 30 and 60 mg/kg/day of mesalazine. Between 60 and 100 mg/kg/day, systemic exposure of mesalazine increased in a sub proportional manner. The mean percentage of mesalazine absorbed (based on urinary recovery) was similar at 30 and 60mg/kg/day doses, being 29.4% and 27.0%, respectively. These results are similar to the percentage of mesalazine dose absorbed in adults from a previous study (SPD476 105), with values ranging from 17-22% for adult males and 24-32% for adult females.

The percentage of mesalazine absorbed was lower at 100 mg/kg/day 5 ASA (22.1%). There was no discernible difference of 5 ASA (and N Ac 5 ASA) systemic exposure between children (aged 5 through 12 years) and adolescents (aged 13 through 17 years) with this weight based (i.e., mg/kg) dosing paradigm.

…

In adults, the mean renal clearances (CLR) were 1.8 L/h and 2.9 L/h for single doses of 2.4 g and 4.8 g, respectively, and slightly higher on Day 14 of multiple dosing: 5.5 L/h and 6.4 L/h for 2.4 g/day and 4.8 g/day. Mean renal clearances for the metabolite were higher, at approximately 12 15 L/h following single and multiple doses of mesalazine 2.4 g/day and 4.8 g/day.

In paediatric patients, the mean renal clearance of 5 ASA at steady state ranged from approximately 5.0 6.5 L/h (83 108 mL/min), which is similar to that observed with adult volunteers. There was a trend for CLR to decrease with increasing dose, and individual CLR estimates were highly variable. The mean CLR of N Ac 5 ASA ranged from 10.0 16.2 L/h (166 270 mL/min), with a trend to decrease with increasing dose.

6.6 Special precautions for disposal

Updated:

Any unused medicinal product or waste material should be disposed of in accordance with local requirements. No special requirements.

10 Date of revision of the text

8^th July 2020

Section

Change

4.4          Special warnings and precautions for use

Addition of text:

Cases of nephrolithiasis have been reported with the use of mesalazine, including stones with a 100% mesalazine content. It is recommended to ensure adequate fluid intake during treatment.

4.8 Undesirable effects

Addition of adverse drug reaction under renal and urinary disorders:

Nephrolithiasis*

10 Date of revision of the text

21^st April 2020