This information is intended for use by health professionals

1. Name of the medicinal product

PENTASA® Slow Release Tablets 500mg

2. Qualitative and quantitative composition

Each tablet contains mesalazine 500mg

3. Pharmaceutical form

Tablet

White-grey to pale-brown, specked round tablets, scored and marked 500mg on one side and 'PENTASA' on the reverse side.

4. Clinical particulars
4.1 Therapeutic indications

PENTASA Slow Release Tablets 500mg are indicated for the treatment of mild to moderate exacerbations of ulcerative colitis. For the maintenance of remission of ulcerative colitis.

4.2 Posology and method of administration

Ulcerative Colitis

The tablets must not be crushed or chewed. They may be swallowed whole or broken up. To facilitate swallowing they may be dispersed in 50ml of cold water. Stir and drink immediately.

Adults:

Acute treatment: Individual dosage of up to 4g mesalazine once daily or in two or three divided doses.

Maintenance treatment: Individual dosage. Recommended dosage, 2g mesalazine once daily.

Paediatric population:

There is only limited documentation for an effect in children (age 6-18 years).

Children 6 years of age and older:

Active disease: To be determined individually, starting with 30-50 mg/kg/day in divided doses. Maximum dose: 75 mg/kg/day in divided doses. The total dose should not exceed 4 g/day (maximum adult dose).

Maintenance treatment: To be determined individually, starting with 15-30 mg/kg/day in divided doses. The total dose should not exceed 2 g/day (recommended adult dose).

It is generally recommended that half the adult dose may be given to children up to a body weight of 40 kg; and the normal adult dose to those above 40 kg.

Elderly Patients:

The usual adult dose applies.

Route of administration: oral.

4.3 Contraindications

PENTASA is contraindicated in:

- patients with known hypersensitivity to salicylates or any of the excipients.

- patients with severe liver and/or renal impairment

4.4 Special warnings and precautions for use

Blood tests (differential blood count; liver function parameters such as ALT or AST; serum creatinine) and urinary status (dip sticks) should be determined prior to and during treatment, at the discretion of the treating physician. As a guideline, follow-up tests are recommended 14 days after commencement of treatment, then a further two to three tests at intervals of 4 weeks.

If the findings are normal, follow-up tests should be carried out every three months. If additional symptoms occur, these tests should be performed immediately.

Caution is recommended in patients with impaired hepatic function.

PENTASA should not be used in patients with impaired renal function. Mesalazine-induced renal toxicity should be considered, if renal function deteriorates during treatment.

Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment with PENTASA.

Patients with a history of adverse drug reactions to preparations containing sulphasalazine (risk of allergy to salicylates), should be kept under close medical surveillance on commencement of a course of treatment with PENTASA. Should PENTASA cause acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever, severe headache and rash, the treatment should be discontinued immediately.

Mesalazine-induced cardiac hypersensitivity reactions (myo- and pericarditis) have been reported rarely. Treatment should be discontinued on suspicion or evidence of these reactions.

4.5 Interaction with other medicinal products and other forms of interaction

In patients who are concomitantly treated with azathioprine, or 6-mercaptopurine, or thioguanine, a possible increase in the myelosuppressive effects of azathioprine, or 6-mercaptopurine, or thioguanine should be taken into account.

There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin.

4.6 Fertility, pregnancy and lactation

PENTASA should be used with caution during pregnancy and lactation and only if the potential benefit outweighs the possible risks in the opinion of the physician.

Pregnancy

Mesalazine is known to cross the placental barrier. There is no adequate data on the use of PENTASA in pregnant women. However, data on a limited number of exposed pregnancies indicate no adverse effect of mesalazine on the pregnancy or on the health of the fetus/newborn child. To date no other relevant epidemiologic data are available.

In one single case after long-term use of a high dose of mesalazine (2-4 g, orally) during pregnancy, renal failure in a neonate was reported.

Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/fetal development, parturition or postnatal development.

Blood disorders (leucopenia, thrombocytopenia, anaemia) have been reported in new-borns of mothers being treated with PENTASA.

PENTASA should only be used during pregnancy if the potential benefit outweighs the possible risk.

Breast-feeding

N-acetyl-5-aminosalicylic acid and to a lesser degree mesalazine is excreted in breast milk. The mesalazine concentration in breast milk is lower than in maternal blood, whereas the metabolite, acetyl mesalazine appears in similar or increased concentrations. There is limited experience of the use of oral mesalazine in lactating women available to date. No controlled studies with PENTASA during breast-feeding have been carried out. Hypersensitivity reactions such as diarrhoea in the infant cannot be excluded. Therefore, PENTASA should only be used during breast-feeding, if the potential benefit outweighs the possible risk. If the infant develops diarrhoea, breast-feeding should be discontinued.

4.7 Effects on ability to drive and use machines

No effects on the ability to drive and use machines have been observed.

4.8 Undesirable effects

Table 1: Undesirable effects

Frequency of adverse effects, based on clinical trials and reports from post-marketing surveillance

SOC

Rare

≥1/10,000 to ≤1/1,000

Very rare

≤1/10,000

Blood and the lymphatic system disorders

Altered blood counts (aplastic anaemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia)

Nervous system disorders

Headaches

Dizziness

Peripheral neuropathy

Cardiac disorders

Myocarditis*

Pericarditis*

Respiratory, thoracic and mediastinal disorders

Allergic and fibrotic lung reactions (including dyspnoea, cough, bronchospasm, alveolitis pulmonary eosinophilia, lung infiltration, pneumonitis)

Gastrointestinal disorders

Abdominal pain, diarrhoea,

nausea,

vomiting

flatulence

Acute pancreatitis

Renal and urinary disorders

Impairment of renal function including acute and chronic interstitial nephritis* and renal insufficiency

Skin and subcutaneous tissue disorders

Alopecia

Musculoskeletal and connective tissue disorders

Myalgia

Arthralgia

Immune system disorders

Hypersensitivity reaction such as allergic exanthema, drug fever, lupus erythematosus syndrome, pancolitis

Hepato-biliary disorders

Changes in liver function parameters (increase in transaminases, and cholestasis parameters), hepatitis*, cholestatic hepatitis,

Reproductive system and breast disorders

Oligospermia (reversible)

(*) The mechanism of mesalazine-induced myo- and pericarditis, pancreatitis, nephritis and hepatitis is unknown, but it might be of allergic origin.

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

Acute experience in animals:

Single oral doses of mesalazine of up to 5g/kg in pigs or a single intravenous dose of mesalazine at 920mg/kg in rats were not lethal.

Human experience:

There are rare data on overdosage (e.g. intended suicide with high oral doses of mesalazine), which do not indicate renal or hepatic toxicity.

Management of overdose:

There is no specific antidote and the treatment is symptomatic and supportive. The treatment at hospital includes close monitoring of renal function.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Intestinal anti-inflammatory agents.

Mechanism of action and pharmacodynamic effects:

Mesalazine is recognised as the active moiety of sulphasalazine in the treatment of ulcerative colitis. It is thought to act locally on the gut wall in inflammatory bowel disease, although its precise mechanism of action has not been fully elucidated.

Increased leucocyte migration, abnormal cytokine production, increased production of arachidonic acid metabolites, particularly leukotriene B4 and increased free radical formation in the inflamed intestinal tissue are all present in patients with inflammatory bowel disease. Mesalazine has in-vitro and in-vivo pharmacological effects that inhibit leucocyte chemotaxis, decrease cytokine and leukotriene production and scavenge for free radicals. It is currently unknown which, if any of these mechanisms play a predominant role in the clinical efficacy of mesalazine.

5.2 Pharmacokinetic properties

General characteristics of the active substance

Disposition and local availability:

PENTASA tablets consist of ethylcellulose-coated microgranules of mesalazine. Following administration and tablet disintegration the microgranules act as discrete slow-release formulations which allow a continuous release of drug from duodenum to rectum at all enteral pH conditions. The microgranules enter the duodenum within an hour of administration, independent of food co-administration. In healthy volunteers the average small intestinal transit time is approximately 3-4 hours.

Biotransformation:

Mesalazine is metabolised both pre-systemically by the intestinal mucosa and systemically in the liver to N-acetyl mesalazine (acetyl mesalazine). The acetylation seems to be independent of the acetylator phenotype of the patient. Some acetylation also occurs through the action of colonic bacteria.

Acetyl mesalazine is thought to be clinically as well as toxicologically inactive, although this remains to be confirmed.

Absorption:

Based on urine recovery data in healthy volunteers, 30-50% of the ingested dose is absorbed following oral administration, predominantly from the small intestine. Mesalazine is detectable in plasma approximately 15 minutes following administration. Maximum plasma concentrations are seen 1 - 4 hours post-dose. After a gradual decrease, mesalazine will no longer be detectable 12 hours post-dose. The plasma concentration curve for acetyl mesalazine follows the same pattern, but the concentrations are generally higher and the elimination is slower.

The metabolic ratio of acetyl mesalazine to mesalazine in plasma after oral administration ranges from 3.5 to 1.3 after daily doses of 500mg x 3 and 2g x 3 respectively, implying a dose-dependent acetylation which may be subject to saturation.

Mean steady-state plasma concentrations of mesalazine are approximately 2 micromoles/l, 8 micromoles/l and 12 micromoles/l after daily doses of 1.5g, 4g and 6g respectively.

For acetyl mesalazine the corresponding concentrations are 6 micromoles/l, 13 micromoles/l and 16 micromoles/l respectively.

The transit and release of mesalazine after oral administration are independent of food co-administration, whereas the systemic absorption is reduced.

Distribution:

Mesalazine and acetyl mesalazine do not cross the blood-brain barrier. Protein binding of mesalazine is approximately 50% and of acetyl mesalazine about 80%.

Elimination:

The plasma half-life of pure mesalazine is approximately 40 minutes and for acetyl mesalazine approximately 70 minutes. Due to continuous release of mesalazine from PENTASA throughout the gastrointestinal tract, the elimination half-life cannot be determined after oral administration. However, steady-state is reached after a treatment period of 5 days following oral administration. Both substances are excreted in urine and faeces. The urinary excretion consists mainly of acetyl mesalazine.

Characteristics in patients:

The delivery of mesalazine to its site of action after oral administration is only slightly affected by pathophysiological changes such as diarrhoea and increased bowel activity observed during active inflammatory bowel disease. A reduction in systemic absorption to 20 – 25% of the daily dose has been observed in patients with accelerated intestinal transit. A corresponding increase in faecal excretion has been seen.

In patients with impaired liver and kidney functions, the resultant decrease in the rate of elimination and increased systemic concentration of mesalazine may constitute an increased risk of nephrotoxic adverse reactions.

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical particulars
6.1 List of excipients

Povidone

Ethylcellulose

Magnesium stearate

Talc

Microcrystalline cellulose

6.2 Incompatibilities

None known

6.3 Shelf life

36 months

6.4 Special precautions for storage

Do not store above 25°C.

Store in the original package.

6.5 Nature and contents of container

Blister: Double aluminium foil

Pack size: 100 Tablets

6.6 Special precautions for disposal and other handling

None

Administrative data
7. Marketing authorisation holder

Ferring Pharmaceuticals Ltd.

Drayton Hall

Church Road

West Drayton

UB7 7PS

United Kingdom

8. Marketing authorisation number(s)

PL 3194/0044

9. Date of first authorisation/renewal of the authorisation

30th March 2004

10. Date of revision of the text

October 2017