Mild to moderate ulcerative colitis

Posology
Ulcerative colitis:
Adults
Active disease:
Individual dosage, up to 4 g mesalazine once daily or divided into 2-4 doses.
Maintenance treatment:
Individual dosage. Recommended dosage, 2 g mesalazine once daily.
Paediatric population
The safety and efficacy in children below 6 years of age have not been established.
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.
Method of administration
Oral use
The granules must not be chewed. The contents of the sachet should be emptied onto the tongue and washed down with some water or orange juice.

Caution is recommended when treating patients allergic to sulphasalazine (risk of allergy to
salicylates). In case of acute symptoms of intolerance, i.e. abdominal cramps, abdominal
pain, fever, severe headache and rash, the treatment should be discontinued immediately.
Caution is recommended in patients with impaired liver function. Liver function parameters
like ALT or AST should be assessed prior to and during treatment, at the discretion of the
treating physician.
The drug is not recommended for use in patients with impaired renal function and in patients
with haemorrhagic diathesis. The renal function should be regularly monitored (e.g. serum
creatinine), especially during the initial phase of treatment. Urinary status (dip sticks) should
be determined prior to and during treatment at the discretion of the treating physician.
Mesalazine induced nephrotoxicity should be suspected in patients developing renal
dysfunction during treatment. The concurrent use of other known nephrotoxic agents, such
as NSAIDs and azathioprine, may increase the risk of renal reactions.
Caution is recommended in patients with active peptic ulcer.
Patients with pulmonary disease, in particular asthma, should be very carefully monitored
during a course of treatment; see section 4.8.
Mesalazine-induced cardiac hypersensitivity reactions (myo- and pericarditis) have been
reported rarely. Serious blood dyscrasias have been reported very rarely with mesalazine
(see section 4.5). Blood tests for differential blood counts is recommended prior to and
during treatment, at the discretion of the treating physician. Treatment should be
discontinued on suspicion or evidence of these adverse reactions.
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.

No interaction studies have been performed. Combination therapy with mesalazine and
azathioprine or 6-mercaptopurine or thioguanine has shown a higher frequency of
myelosuppressive effects. An interaction cannot be excluded, however, the mechanism of
interaction is unknown. Regular monitoring of white blood cells is recommended and dosage
of thiopurines should be adjusted accordingly.
There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin.

PENTASA prolonged release granules should not be used during pregnancy and lactation
except when the potential benefits of the treatment outweigh the possible hazards in the
opinion of the physician. The underlying condition itself (Inflammatory bowel disease (IBD))
may increase risks for adverse pregnancy outcome.
Pregnancy:
Mesalazine is known to cross the placental barrier and its concentration in umbilical cord
plasma is lower than the concentration in maternal plasma. The metabolite acetylmesalazine
is found at similar concentrations in umbilical cord and maternal plasma. Animal
studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to
pregnancy, embryo/foetal development, parturition or postnatal development. There are no
adequate and well controlled studies of PENTASA use in pregnant women. Limited
published human data on mesalazine show no increase in the overall rate of congenital
malformations. Some data show an increased rate of preterm birth, stillbirth, and low birth
weight; however, these adverse pregnancy outcomes are also associated with active
inflammatory bowel disease. Blood disorders (leucopenia, thrombocytopenia and anaemia)
have been reported in new-borns of mothers being treated with PENTASA prolonged release
granules.
In one single case after long-term use of a high dose of mesalazine (2-4g, orally) during
pregnancy, renal failure in a neonate was reported.
Lactation:
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. No controlled studies with PENTASA prolonged release granules
during breast-feeding have been carried out. Only limited experience during lactation in
women after oral application is available to date.
Hypersensitivity reactions like diarrhea in the infant cannot be excluded. If the infant develops diarrhoea, breast-feeding should be discontinued.
Fertility:
Animal data on Mesalazine show no effect on male and female fertility

PENTASA prolonged release granules has no or negligible influence on the ability to drive or use machines

The most frequent adverse reactions seen in clinical trials are diarrhoea, nausea, abdominal
pain, headache, vomiting, and rash.
Hypersensitivity reactions and drug fever may occasionally occur.

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

(*) The mechanism of mesalazine-induced myo- and pericarditis, pancreatitis, nephritis and
hepatitis is unknown, but it might be of allergic origin.
(**) Photosensitivity: More severe reactions are reported in patients with pre-existing skin
conditions such as atopic dermatitis and atopic eczema.
It is important to note that several of these disorders can also be attributed to the
inflammatory bowel disease itself.
 

Experience in animals: A single intravenous dose of mesalazine in rats of 920 mg/kg and
single oral doses of mesalazine in pigs up to 5 g/kg were not lethal.
Human experience: There is limited clinical experience with overdose of PENTASA
prolonged release granules which does not indicate renal or hepatic toxicity. Since
PENTASA is an amino salicylate, symptoms of salicylate toxicity may occur. Symptoms of
salicylate over dosage are well described in the literature.
There have been reports of patients taking daily oral doses of 8 g for a month without any
adverse events.
There is no specific antidote and treatment is symptomatic and supportive. The treatment at hospital includes close monitoring of renal function.

Pharmacotherapeutic group: Intestinal anti-inflammatory agents, aminosalicylic acid and
similar agents
ATC code: A07E C02
Mesalazine is the active component of sulfasalazine, which has been used for a long time in
the treatment of ulcerative colitis and Crohn’s disease.
The therapeutic value of mesalazine appears to be due to local effect on the inflamed
intestinal tissue, rather than to systemic effect.
There is information suggesting that severity of colonic inflammation in ulcerative colitis
patients treated with mesalazine is inversely correlated with mucosal concentrations of
mesalazine.
Increased leukocyte 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. The mechanism of action of mesalazine is not fully understood although
mechanisms such as activation of the γ-form of peroxisome proliferator-activated receptors
(PPAR-γ) and inhibition of nuclear factor-kappa B (NF-κB) in the intestinal mucosa have
been implicated. Mesalazine has in-vitro and in-vivo pharmacological effects that inhibit leukocyte 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.
The risk of colorectal cancer (CRC) is slightly increased in ulcerative colitis.
Observed effects of mesalazine in experimental models and patient biopsies support the role
of mesalazine in prevention of colitis-associated CRC, with down regulation of both
inflammation dependent and non-inflammation dependent signalling pathways involved in
the development of colitis-associated CRC. However data from meta-analyses, including
both referral and non-referral populations, provide inconsistent clinical information regarding
the benefit of mesalazine in the carcinogenesis risk associated with ulcerative colitis.

General characteristics of the active substance
Disposition and local availability:
The therapeutic activity of mesalazine most likely depends on a local contact of the drug with
the diseased area of the intestinal mucosa.
PENTASA prolonged release granules consist of ethylcellulose coated microgranules of
mesalazine. The coated microgranules enter the duodenum within an hour of administration,
independent of food co-administration. Mesalazine is continuously released from the coated
microgranules throughout the gastrointestinal tract in any enteral pH conditions.
Absorption: Bioavailability of PENTASA after oral administration can be estimated to approx.
30%, based on urine recovery data in healthy volunteers. Maximum plasma concentrations
are seen 1-6 hours post-dose. A once-daily dosing regimen of mesalazine (1 × 4 g/d) and a
twice-daily dosage (2 × 2 g/d) results in a comparable systemic exposure (AUC) over 24
hours and indicate a continuous release of mesalazine from the formulation over the
treatment period. Steady-state is reached after a treatment period of 5 days following oral administration.

Molecular weight of mesalazine: 153.13 g/moL; Ac-mesalazine: 195.17 g/moL.
*BID=twice daily
**OD=once daily
The transit and release of mesalazine after oral administration are independent of food coadministration,
whereas the systemic exposure may be increased.
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%.
Metabolism: Mesalazine is metabolised both pre-systemically by the intestinal mucosa and
systemically in the liver to N-acetyl-mesalazine (acetyl-mesalazine) principally by NAT-1.
Some acetylation also occurs through the action of colonic bacteria. The acetylation seems
to be independent of the acetylator phenotype of the patient. The metabolic ratio of acetylmesalazine
to mesalazine in plasma after oral administration ranges from 3.5 to 1.3 after
daily doses of 500 mg x 3 and 2 g x 3, respectively, implying a dose-dependent acetylation which may be subject to saturation.
Elimination: Due to the continuous release of mesalazine throughout the gastrointestinal
tract, the elimination half-life cannot be determined after oral administration.
However, once the formulation is not present in the GI tract elimination will follow the plasma
half-life of orally or iv administered uncoated mesalazine, which is approximately 40 minutes
and for acetyl-mesalazine approximately 70 minutes.
Characteristics in patients
Pathophysiologic changes such as diarrhoea and increased bowel acidity observed during
active inflammatory bowel disease have only a minor impact on the delivery of mesalazine to
the intestinal mucosa after oral administration. A urine excretion 20-25% of the daily dose
has been observed in patients with accelerated intestinal transit. Likewise, a corresponding increase in faecal excretion has been seen.

Toxic renal effects have been demonstrated in all species tested. Rat and monkey dosages
and plasma concentrations at the No Observed Adverse Effect Levels (NOAELs) exceed
those used in humans by a factor of 2-7.2.
In vitro test systems and in-vivo studies showed no evidence of mutagenic effects. Studies
on the tumourigenic potential carried out in rats showed no evidence of any substancerelated
increase in the incidence of tumours.
Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with
respect to fertility, pregnancy, embryo-foetal development, parturition or postnatal development.

Ethylcellulose
Povidone

Not applicable

Store below 30°C Store in the original package in order to protect from light.

Polyester/Aluminium/LD polyethylene sachet.

Pack sizes:
PENTASA Sachet 4 g prolonged release granules:
1 x 20 sachets
1 x 30 sachets
1 x 50 sachets
1 x 100 sachets
Not all pack sizes may be marketed.

Any unused product or waste material should be disposed of in accordance with local requirements.