- Acute treatment of ulcerative colitis as well as treatment for avoidance of recurrence.
- Treatment for symptomatic recovery in patients with active Crohn’s disease.

If not prescribed otherwise, the following general dosing recommendations apply:
Ulcerative colitis:
Adults:
Acute therapy: individual dose up to 4 g mesalazine daily, divided into 2 single doses, i.e. 2 times daily
2 PENTASA 1g controlled-release tablets each.
Maintenance therapy: recommended dose 1.5 g mesalazine daily, divided into 2 – 3 single doses, e.g. 3
times daily 1 PENTASA 500 mg controlled-release tablets.
Children and adolescents:
There are only limited data on the effect in children (6 – 18 years).
Children from the age of 6 years:
Acute therapy:
The dose should be determined on an individual basis, initially with 30 – 50 mg/kg body weight/day,
divided into single doses.
Maximum dose: 75 mg/kg body weight/day, in single doses. The total dose should not exceed 4 g/day
(maximum adult dose).
Maintenance therapy:

The dose should be determined on an individual basis, initially with 15 – 30 mg/kg body weight/day,
divided into single doses. The total dose should not exceed 1.5 g/day (recommended adult dose).

Crohn’s disease:
Adults:
Acute therapy: up to 4 g mesalazine daily, divided into 2 – 3 single doses, e.g. 2 times daily 1 - 2
PENTASA 1g controlled-release tablets each or 3 times daily 2 – 3 PENTASA 500 mg controlledrelease
tablets each (30 – 50 mg/kg body weight/day).
Children and adolescents:
There are only limited data on the effect in children (6 – 18 years).
Children from the age of 6 years:
Acute therapy:
The dose should be determined on an individual basis, initially with 30 – 50 mg/kg body weight/day,
divided into single doses.
Maximum dose: 75 mg/kg body weight/day, in single doses. The total dose should not exceed 4 g/day
(maximum adult dose).
It is usually recommended that children with a body weight of up to 40 kg should receive half the dose
given to adults and children above 40 kg should receive the normal adult dose.
Take the controlled-release tablets without chewing, preferably between meals, with sufficient fluid or
put them into water or fruit juice, stir and drink.
The duration of administration is up to the discretion of the treating physician. It depends on the course
of the disease. PENTASA 1g controlled-release tablets are suitable for long-term use.

Caution is recommended when treating patients allergic to sulphasalazine (risk of allergy to salicylates).
In these patients treatment with PENTASA 1g controlled-release tablets should only be commenced
under careful medical supervision. 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.
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.
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 PENTASA and azathioprine or
6-mercaptopurine or thioguanine have shown a higher frequency of myelosuppressive effects, and an
interaction cannot be ruled out, however, the mechanism behind the interaction is not established.
Regular monitoring of white blood cells is recommended and the dosage regimen of thiopurine should
be adjusted accordingly.

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

Pregnancy:
There is only limited experience in the use of mesalazine in pregnant women. Except one case of renal
failure after long-term use of high doses of mesalazine (2-4 g, orally) in a pregnant woman, until now no
negative effects on pregnancy became known.
The underlying condition „Inflammatory bowel disease“ itself may increase risks for preterm birth and
stillbirth as well as a lower birth weight in the pregnancy.
Animal studies showed no reproductive toxicity (see section 5.3).
Mesalazine and the metabolite acetyl-mesalazine are known to cross the placental barrier. Blood
disorders (pancytopenia, leucopenia, thrombocytopenia and anemia) have been reported in new-borns of
mothers being treated with mesalazine.
PENTASA 1g controlled-release tablets 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.
Lactation:
Mesalazine and the metabolite acetyl-mesalazine are excreted in breast milk. There is only insufficient
information if mesalazine has effects on new-borns or infants. Hypersensitivity reactions like diarrhea in
the infant cannot be excluded. It must be decided if breast-feeding is to be interrupted or if treatment
with PENTASA 1g controlled-release tablets should be given up. In doing so, the benefit of breastfeeding
for the infant as well as the benefit of therapy for the woman has to be considered.
Fertility:
There is no human data in terms of effects of mesalazine on female and male fertility. Animal studies did
not indicate any negative impact on female and male fertility (see section 5.3).

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

The most frequent adverse reactions seen in clinical trials are diarrhea, nausea, abdominal pain,
headache, vomiting and rash.
Occasionally, hypersensitivity reactions and drug fever may occur.
Frequency of side effects, based on clinical studies and experience after market introduction:

(*)
Tmechanism of mesalazin-induced myocarditis and pericarditis, pancreatitis, nephritis andhepatitis is unknown, but 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 bowel disease itself.

Experience in animals:
Single oral doses of mesalazine of up to 5 g/kg in pigs and a single intravenous dose of mesalazine at
920 mg/kg in rats were not lethal.
Human experience:
There is limited clinical experience on overdosage of PENTASA which do not indicate renal or hepatic
toxicity. But since PENTASA is an amino salicylate, symptoms of salicylate toxicity such as acid-base

balance disorder, hyperventilation, pulmonary edema, vomiting, dehydration and hypoglycaemia may
occur. Symptoms of salicylate overdosage is well described in the literature.
There have been reports of patients taking oral daily doses of 8 grams for a month without any adverse
events.
There is no specific antidote and the management of overdose is supportive and symptomatic. The
treatment at the hospital includes close monitoring of renal function.

Pharmacotherapeutic group: Intestinal anti-inflammatory agents, aminosalicylic acid and similar agents
ATC code: A07 EC 02
Mesalazine is the active moiety of sulphasalazine which has already been used in the treatment of
ulcerative colitis and Crohn’s disease for a long time. Clinical examinations show that the therapeutic
efficacy of both oral and rectal mesalazine is rather due to a local effect at the inflamed intestinal wall
than to a 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 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. 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 has been implicated. 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.
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 colitisassociated
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 efficacy of mesalazine most likely depends on a local
contact of the active substance with the diseased area of the intestinal mucosa.
PENTASA 1g controlled-release tablets consist of mesalazine microgranules coated with ethyl cellulose.
After administration and decay of the tablets, 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.

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%.
Biotransformation:
Mesalazine is metabolised both pre-systemically by the intestinal mucosa and systemically in the liver to Nacetyl
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 acetyl-mesalazine to mesalazine in plasma after oral administration ranges from
3.5 to 1.3 after daily doses of 500 mg×3 and 2 g×3, respectively, implying a dose-dependent acetylation
which may be subject to saturation.
Elimination:
Due to the continuous release of mesalazine in the entire gastrointestinal tract, the elimination half-life is
not determinable 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 acetylmesalazine
approximately 70 minutes.

Characteristics in patients
Pathophysiological 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.

Definitive nephrotoxicity and possible gastrointestinal toxicity is demonstrated in all species examined.
Nephrotoxicity is evident with doses 5-10 times those used in humans.
In animal studies, no significant toxicity has been observed in the gastrointestinal tract, in the liver or in
the hemopoietic system.
In-vitro test systems and in-vivo studies showed no evidence of mutagenic effects. Studies on the
tumorigenic potential carried out in rats showed no evidence of any substance-related increase in the
incidence of tumors.
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.

Povidone K30, ethyl cellulose, magnesium stearate (Ph. Eur.), talcum, microcrystalline cellulose

Not applicable.

Do not store above 30°C. Do not freeze. Store in the original package in order to protect from light.

Package with 60 controlled-release tablets (6 x 10 tablets)
Package with 150 controlled-release tablets (15 x 10 tablets)

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