Acute episode of distal or left-sided ulcerative colitis.

Adults: If not prescribed otherwise, adults are treated as follows: 1 enema bottle with rectal suspension per day before going to bed.
Children: There are only few data and experience available on the use in children.
The duration of administration is up to the discretion of the treating physician.
It is advisable to empty the bowels before using PENTASA Enema.

Caution is recommended when treating patients allergic to sulphasalazine (risk of allergy to salicylates). Treatment with PENTASA Enema should only be commenced under careful medical supervision in these patients. In case of acute symptoms of intolerance, i.e. abdominal cramps, abdominal pain, fever, severe headache and rash, the treatment should be discontinued immediately.

Severe cutaneous adverse reactions
Severe cutaneous adverse reactions (SCARs), including Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment.
Mesalazine should be discontinued, at the first appearance of signs and symptoms of severe skin reactions, such as skin rash, mucosal lesions, or any other sign of hypersensitivity.

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.

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.

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.

Mesalazine may produce red-brown urine discoloration after contact with sodium hypochlorite bleach (e.g. in toilets cleaned with sodium hypochlorite contained in certain bleaches).

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 Enema 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 Enema should be given up. In doing so, the benefit of breast-feeding 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

Summary of the safety profile

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. Severe cutaneous adverse reactions (SCARs), including Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment (see section 4.4).
Local reactions such as pruritus, disorders in the rectal area and urge to empty one’s bowels may occur.
Frequency of side effects based on clinical studies and experience after market introduction:

(*)The mechanism of mesalazine-induced myocarditis and pericarditis, pancreatitis, nephritis and hepatitis 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.

(***) See section 4.4 for further information.
It is important to note that several of these disorders can also be attributed to the bowel disease itself.

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 to;
Bundesinstitut für Arzneimittel und Medizinprodukte
Abt. Pharmakovigilanz
Kurt-Georg-Kiesinger-Allee 3
D-53175 Bonn
Website: www.bfarm.de

Experience in animals:
Single oral doses of mesalazine of up to 5 g/kg in pigs and single intravenous doses 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 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 leucotriene 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.

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 Enema is designed to provide the distal part of the intestinal tract with high concentrations of mesalazine and a low systemic absorption. The Enema covers the distal part including the descending colon.
Absorption:
The absorption following rectal administration is low, and depends on the dose, the formulation and the extent of spread. Based on urine recoveries in healthy volunteers under steady-state conditions given a daily dose of 2 g (1 g x 2), approximately 15-20 % is absorbed after administration.
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 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.

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 i.v. administered uncoated mesalazine, which is approximately 40 minutes and for acetyl-mesalazine approximately 70 minutes.
Characteristics in patients:
The systemic exposure following administration of PENTASA Enema has been shown to be significantly decreased in patients with active ulcerative colitis as compared to those in remission.

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.

100 mg sodium metabisulphite (Ph. Eur.), sodium edetate (Ph. Eur), sodium acetate 3H2O, hydochloric acid 36 % and purified water

None known.

Store below 25°C. Do not refrigerate or freeze. The enema bottles should be stored only in the nitrogen-filled
plastic bags sealed by the manufacturer.

OP with 7 enema bottles with 100 ml rectal suspension each
OP with 21 enema bottles with 100 ml rectal suspension each

Shake before usage, use Enema immediately after opening the plastic bag.
Any unused product or waste material should be disposed of in accordance with local requirements.