Consumer medicine information

Pentasa Sachets

Mesalazine

BRAND INFORMATION

Brand name

Pentasa Oral

Active ingredient

Mesalazine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Pentasa Sachets.

What is in this leaflet

This leaflet answers some common questions about PENTASA.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

Please read this leaflet before you start using PENTASA.

All medicines have risks and benefits. Your doctor has weighed the risks of you using PENTASA against the benefits they expect it will have for you.

If you have any concerns about using this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What PENTASA is used for

This medicine is used to treat Crohn's disease and ulcerative colitis, diseases associated with inflammation, ulcers and sores in the bowel causing bleeding, stomach pain, and diarrhoea.

The active ingredient in PENTASA is mesalazine. It is an anti-inflammatory agent, similar to aspirin, and is thought to work by reducing inflammation in the bowel.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

There is no evidence that PENTASA is addictive.

It is available only with a doctor's prescription.

It is not expected to affect your ability to drive a car or operate machinery.

Before you take PENTASA

When you must not take it

Do not take PENTASA if you have an allergy to:

  • any medicine containing mesalazine or aspirin-like medicines
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take PENTASA if you have a severe kidney or liver problem.

Do not take PENTASA after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

Do not give PENTASA to a child 12 years old or under. The safety and effectiveness of PENTASA in this age group have not been established.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • a known allergy to PENTASA, sulfasalazine or aspirin-like medicines, or any of the ingredients listed at the end of this leaflet
  • a kidney or liver problem
  • a bleeding disorder
  • a history of asthma.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved. PENTASA should be used with caution during pregnancy and breast-feeding and only if the potential benefits outweigh the possible risks in the opinion of the doctor. The underlying condition itself (inflammatory bowel disease) may increase risks for the pregnancy outcome.

If you have not told your doctor about any of the above, tell him/her before you start using PENTASA.

Taking other medicines

Tell your doctor or pharmacist if you are using any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

There is no information available on interactions between PENTASA and other medicines. However, mesalazine belongs to a group of medicines called salicylates that may interfere with the following types of medicines:

  • anti-coagulants, used to thin blood or stop blood clots (e.g. warfarin)
  • glucocorticoids, used to treat inflammation, swelling or allergies (e.g. prednisolone)
  • sulphonylureas, used to lower blood sugar and treat diabetes (e.g. glibenclamide, glipizide)
  • methotrexate, used to treat some kinds of cancers and arthritis
  • probenicid or sulfinpyrazone, used to treat gout
  • spirinolactone or frusemide, used to increase the amount of urine produced, and to lower blood pressure
  • rifampicin, used to treat tuberculosis
  • azathioprine, used to suppress the immune system
  • mercaptopurine and thioguanine, used to treat leukaemia.

Ask your doctor or pharmacist if you are unsure about taking any of these medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take PENTASA

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the packaging, ask your doctor or pharmacist for help.

How much to take

Adults:

Ulcerative Colitis
For active ulcerative colitis, take up to 4 g PENTASA once a day or in divided doses.

For long term treatment of ulcerative colitis, take 2 g PENTASA once a day or in divided doses.

Crohn's Disease
For active Crohn's disease, take up to 4 g PENTASA daily in divided doses.

For long term treatment of Crohn's disease, take up to 4 g PENTASA daily in divided doses.

For some conditions, your doctor may prescribe a different dose.

How to take it

Tear or cut to open the sachet along the dotted line.

Empty the contents (granules) of the sachet onto the tongue and wash down with water or juice.

Swallow the PENTASA granules whole without chewing or crushing.

When to take it

Take your medicine the same time each day. This will help you remember when to take it.

You can take PENTASA with or without food.

How long to take it

Continue using your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep using your medicine even if you feel well.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking PENTASA as you would normally.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take PENTASA, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have used too much PENTASA. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking PENTASA

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking PENTASA.

Have all blood tests recommended by your doctor. PENTASA may cause kidney, liver or blood problems in a few people. You should have regular blood tests to check your kidney function.

Kidney stones may develop while taking PENTASA. Symptoms may include pain in the sides of the abdomen and blood in the urine.

Take care to drink plenty of fluids while you are being treated with PENTASA.

Tell any other doctors, dentists, and pharmacists who treat you that you are using this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are using this medicine. It may affect other medicines used during surgery.

If you become pregnant while using this medicine, tell your doctor immediately.

Things you must not do

Do not take PENTASA to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop using your medicine or lower the dosage without checking with your doctor. If you stop taking it suddenly, your condition may worsen.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking PENTASA.

This medicine helps most people but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you experience some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • headache
  • diarrhoea
  • abdominal or stomach pain
  • flatulence (stomach discomfort or fullness, relieved by passing wind)
  • nausea (feeling sick)
  • vomiting
  • mild skin rash.

The above list includes the more common side effects of your medicine (affecting between 1 in 10 and 1 in 100 patients). They are usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following:

  • dizziness
  • bruising easily, unusual bleeding (e.g. nosebleeds), signs of infection such as fever, chills, sore throat and mouth ulcers
  • muscle aches and pains
  • painful or swollen joints
  • severe upper stomach pain, nausea and vomiting
  • changes in kidney function/kidney disease, and or urine discolouration
  • numbness, tingling or weakness of the arms and legs
  • yellowing of the skin or eyes, dark coloured urine
  • hair loss (this is reversible)
  • worsening of your condition.

The above list includes serious side effects which may require medical attention. Serious side effects are usually rare or very rare (affecting less than 1 in 1,000 patients).

If you notice any of the following, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • sudden signs of allergic reactions such as rash, itching or hives, shortness of breath, wheezing, coughing, or swelling of limbs, face, lips, mouth, tongue or throat which may cause difficulty swallowing or breathing
  • severe stomach cramps and/or pain, bloody diarrhoea, fever, severe headache and skin rash
  • rash with severe blisters and bleeding of the eyes, mouth, lips, nose and genitals e.g. erythema multiforme or Stevens-Johnson Syndrome (SJS)
  • lupus erythematosus-like reactions (a disease affecting the skin, joints and kidneys with symptoms such as joint pain, fever and skin rash)
  • chest pain and/or pain behind the breast bone sometimes spreading to the neck and shoulders, or with fever.

The above list includes very serious side effects, which may need urgent medical attention or hospitalisation. These side effects are usually rare or very rare (affecting less than 1 in 1,000 patients).

Other very rare side effects that have been reported with PENTASA include:

  • changes in kidney function
  • changes in liver function e.g. raised liver enzymes
  • changes in the blood e.g. a decrease in the number of red/white blood cells, and/or platelets
  • low sperm count (this is reversible).

As a precaution, your doctor may do blood tests to check if there are any changes in your blood, kidney or liver function.

Very rare side effects occur in less than 1 in 10,000 patients.

Kidney stones may develop while taking PENTASA. Symptoms may include pain in the sides of the abdomen and blood in the urine.

The frequency of this side effect is not known.

Other side effects not listed above may also occur in some people.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

After taking PENTASA

Storage

Keep your PENTASA in the packaging until it is time to take your next dose. If you take PENTASA out of the packaging it may not keep well.

Keep your PENTASA in a cool dry place where the temperature stays below 25°C.

Do not store PENTASA or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can damage some medicines.

Keep PENTASA where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking PENTASA or the expiry date has passed, ask your pharmacist what to do with any granules that are left over.

Product description

What it looks like

PENTASA Sachets contain short and cylindrical (or tube) shaped granules that are white-grey to pale white brown in colour.

PENTASA 1 g Sachets are supplied in packs of 30, 100 and 120.

PENTASA 2 g Sachets are supplied in packs of 15 and 60.

PENTASA 4 g Sachets are supplied in packs of 8 and 30.

Not all pack sizes are being distributed in Australia.

Ingredients

PENTASA Sachets contain 1 g , 2 g or 4 g of mesalazine as the active ingredient, as well as the following inactive ingredients:

  • ethylcellulose
  • povidone.

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

PENTASA Sachets are supplied in Australia by:

Ferring Pharmaceuticals Pty Ltd
Suite 2, Level 1, Building 1
20 Bridge Street
Pymble, NSW 2073, Australia

AUST R 161063 - PENTASA mesalazine 1 g prolonged release granules sachet

AUST R 161064 - PENTASA mesalazine 2 g prolonged release granules sachet

AUST R 216259 - PENTASA mesalazine 4 g prolonged release granules sachet

This leaflet was prepared in December 2019.

#14662-v16A

PENTASA® is a registered trade mark of Ferring B.V.

® = Registered trademark

By scanning the QR code with your smart phone or tablet, you can access a video on how to administer PENTASA® Sachets. Alternative access via www.myibd.com.au Access available only within Australia.

Published by MIMS March 2020

BRAND INFORMATION

Brand name

Pentasa Oral

Active ingredient

Mesalazine

Schedule

S4

 

1 Name of Medicine

Mesalazine.

2 Qualitative and Quantitative Composition

Pentasa prolonged release tablets contain either 0.5 g or 1 g mesalazine as the active ingredient, and the following inactive excipients: magnesium stearate, purified talc, povidone, ethylcellulose, microcrystalline cellulose.
Pentasa prolonged release granules in sachets contain either 1 g, 2 g or 4 g mesalazine as the active ingredient, and the following inactive excipients: ethylcellulose, povidone.

3 Pharmaceutical Form

Pentasa 0.5 g prolonged release tablets are presented as white grey to pale brown, speckled round tablets with break mark and embossing: 500 mg on one side, PENTASA on the other side.
Pentasa 1 g prolonged release tablets are presented as white-grey to pale brown, speckled, oval tablets. Embossing on both sides: PENTASA.
Pentasa 1 g, 2 g, and 4 g prolonged release granules are presented as cylindrical shaped granules that are white-grey to pale white brown in colour.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of mild to moderate ulcerative colitis and Crohn's disease and maintenance of remission.

4.2 Dose and Method of Administration

Ulcerative colitis.

Treatment of active disease.

Adults.

Individual dosage, up to 4 g given once daily or in divided doses.
Maintenance treatment.

Adults.

2 g once daily or individual dosage, starting with 1.5-2 g daily in divided doses.

Crohn's disease.

Treatment of active disease.

Adults.

Individual dosage, up to 4 g daily in divided doses.
Maintenance treatment.

Adults.

Individual dosage, up to 4 g daily in divided doses.

Method of administration.

Do not crush or chew the tablets or granules.

Tablets.

To facilitate swallowing, the tablets may be dispersed in 50 mL of cold water. Stir and drink immediately.

Sachets.

The content of the sachet should be emptied onto the tongue and washed down with some water or juice.
Alternatively, the entire content of the sachet can be taken with yoghurt and consumed immediately.

4.3 Contraindications

Hypersensitivity to mesalazine or any of the excipients or salicylates.
Severe liver or renal impairment.

4.4 Special Warnings and Precautions for Use

Most patients who are intolerant or hypersensitive to sulfasalazine are able to take Pentasa without the risk of similar reactions. However, caution is recommended when treating patients allergic to sulfasalazine because of the risk of allergy to salicylates (also see Section 4.3 Contraindications). Severe cutaneous adverse reactions (SCARs), including drug reaction with eosinophilia and systematic symptoms (DRESS). Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment.
Treatment should be discontinued immediately in cases of acute intolerance reactions such as nausea, exacerbation of diarrhoea, abdominal cramps, acute abdominal pain, fever, severe headache, and/or the first appearance of signs and symptoms of severe skin reactions, such as skin rash, mucosal lesions, or any other signs of hypersensitivity.
Mesalazine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported rarely.
Serious blood dyscrasias have been reported rarely with mesalazine. Haematological investigations should be performed if the patient develops unexplained bleeding, bruising, purpura, anaemia, fever or sore throat. Treatment should be stopped if there is suspicion or evidence of blood dyscrasia (also see Section 4.8 Adverse Effects (Undesirable Effects)). Also, a blood test for differential blood count is recommended prior to and during treatment, at the discretion of the treating physician. As stated in Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, concomitant treatment with mesalazine can increase the risk of blood dyscrasia in patients receiving azathioprine, or 6-mercaptopurine or tioguanine. Treatment should be discontinued on suspicion or evidence of these adverse reactions (also see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients with inflammatory bowel disease are at risk of developing nephrolithiasis. Cases of nephrolithiasis have been reported with the use of mesalazine including kidney stones composed entirely of mesalazine. It is recommended to ensure adequate fluid intake during treatment.

Use in hepatic impairment.

Caution is recommended in patients with impaired liver function (also see Section 4.3 Contraindications). Liver function parameters like ALT or AST should be assessed prior to and during treatment, at the discretion of the treating physician.
Mesalazine may produce red-brown urine discolouration after contact with sodium hypochlorite bleach (e.g. in toilets cleaned with sodium hypochlorite contained in certain bleaches).

Use in renal impairment.

Mesalazine is not recommended for use in patients with renal impairment (also see Section 4.3 Contraindications). Renal function should be monitored regularly in all patients (e.g. serum creatinine, urinalysis for protein) especially during the initial phase of treatment. Mesalazine-induced nephrotoxicity should be suspected in patients developing renal dysfunction during treatment. The concurrent use of other known nephrotoxic agents should increase monitoring frequency of renal function.

Use in the elderly.

Age related factors (such as altered renal and hepatic function as described above and polypharmacy) should be taken into consideration.

Paediatric use.

Pentasa should not be used in children 12 years of age and under, as there is limited experience with this age group.

Effects on laboratory tests.

Use of mesalazine may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection, because of the similarity in the chromatograms of normetanephrine and mesalazine's main metabolite, N-acetyl-5-aminosalicylic acid. An alternative selective assay for normetanephrine should be considered.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Whilst there are no data on interactions between Pentasa and other medicines, in common with other salicylates, interactions may occur during concomitant administration of mesalazine and the following medicines:

Coumarin type anticoagulants (e.g. warfarin sodium).

Possible potentiation of the anticoagulant effect (increasing the risk of gastrointestinal haemorrhage).

Glucocorticoids.

Possible increase in undesirable gastric effects.

Sulfonylureas.

Possible increase in the blood glucose lowering effects.

Methotrexate.

Possible increase in toxic potential of methotrexate.

Probenecid or sulfinpyrazone.

Possible attenuation of the uricosuric effects.

Spironolactone or furosemide (frusemide).

Possible attenuation of the diuretic effects.

Rifampicin.

Possible attenuation of the tuberculostatic effects.
Combination therapy with Pentasa and azathioprine, or 6-mercaptopurine or tioguanine have in several studies shown a higher frequency of myelosuppressive effects, and an interaction seems to exist. However, the mechanism behind the interaction is not fully established. Regular monitoring of white blood cells is recommended and the dosage regime of the thiopurines should be adjusted accordingly.
The concomitant use of mesalazine with other known nephrotoxic agents, such as non-steroidal anti-inflammatory drugs (NSAIDS) and azathioprine, may increase the risk of renal reactions.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Oral administration of mesalazine at doses up to 400 mg/kg/day to male rats prior to mating and female rats from prior to mating through gestation and lactation did not affect fertility or elicit embryofetal toxicity.
(Category C)
Oral administration of mesalazine during organogenesis in rats and rabbits at respective doses up to 1000 and 800 mg/kg/day was associated with concomitant embryofetal toxicity and maternotoxicity. At a dose of 1000 mg/kg/day in rats, fetuses showed enlarged brain ventricles. Nonembryofetal toxic and nonmaternotoxic dosages were 500 and 400 mg/kg/day in rats and rabbits, respectively.
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 acetyl-mesalazine is found at similar concentrations in umbilical cord and maternal plasma. 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 birthweight; however, these adverse pregnancy outcomes are also associated with active inflammatory bowel disease.
Blood disorders (pancytopenia, leucopenia, thrombocytopenia, anaemia) have been reported in newborns of mothers being treated with Pentasa.
NSAIDS inhibit prostaglandin synthesis and, when given during the latter part of pregnancy, may cause closure of the fetal ductus arteriosus, fetal renal impairment, inhibition of platelet aggregation, and delay labour and birth. Continuous treatment with NSAIDS during the last trimester of pregnancy should only be given on sound indications. During the last few days before expected birth, agents with an inhibitory effect on prostaglandin synthesis should be avoided.
Data on 165 women exposed to mesalazine during pregnancy were prospectively collected and pregnancy outcome was compared with that of a control group. The investigators concluded that mesalazine does not represent a major teratogenic risk, as the reported rate of major malformations was within the expected baseline risk of the general population.
Pentasa should be used with caution during pregnancy only if the potential benefits outweigh the possible hazards in the opinion of the physician. The underlying condition itself (inflammatory bowel disease/ IBD) may increase risks for the pregnancy outcome.
 Mesalazine is excreted in breast milk. The concentration is lower than in maternal blood, whereas the metabolite acetyl-mesalazine appears in similar or increased concentrations.
In rats, oral administration of mesalazine during late gestation and lactation at doses of 400 and 800 mg/kg/day was associated with maternotoxicity and toxicity in offspring; a dose of 200 mg/kg/day was devoid of toxicity in either generation.
As data are very limited, Pentasa should be used with caution during lactation and only if the potential benefits outweigh the possible hazards in the opinion of the physician. Hypersensitivity reactions, like diarrhoea, in the nursing infant cannot be excluded.

4.7 Effects on Ability to Drive and Use Machines

Treatment with Pentasa is unlikely to affect the ability to drive and/or use machines.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

Hypersensitivity reactions and drug fever may occasionally occur. Severe cutaneous adverse reactions (SCARs), such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment (see Section 4.4 Special Warnings and Precautions for Use). Mesalazine may be associated with an exacerbation of the symptoms of colitis in those patients who have previously had such problems with sulfasalazine.
Table 1 represents the frequency of adverse effects based on clinical trials and reports from postmarketing surveillance for all formulations of Pentasa, including orals.
It is important to note that several of these disorders can also be attributed to the inflammatory process itself.
In the MOTUS study the incidences of nausea were 4.9% and 2.0% in the 4 g once daily and 2 g twice daily groups, respectively. All events of nausea were mild to moderate in intensity, and resolved; none led to withdrawal from the trial.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Acute experience in animals.

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

Human experience.

There is limited clinical experience with overdose of Pentasa. Since Pentasa is an aminosalicylate, symptoms of salicylate toxicity may occur. Symptoms of mild salicylate intoxication include nausea, vomiting, tinnitus or dizziness. Symptoms of more severe salicylate intoxication include hyperthermia, dehydration, disturbance of electrolyte balance and blood pH, seizures, dysrhythmias, coagulopathy, renal failure and coma.
There have been reports of patients taking daily doses of 8 g for a month without any adverse events.

Management of overdose in humans.

There is no specific antidote. As Pentasa is an aminosalicylate, conventional therapy for salicylate toxicity may be beneficial. General supportive and symptomatic measures are recommended. Steps to prevent further gastrointestinal tract absorption may be appropriate. Fluid and electrolyte imbalance should be corrected by the administration of appropriate intravenous therapy. Renal function should be closely monitored.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

Pharmacotherapeutic group: intestinal anti-inflammatory agents (A07 EC02).

5.1 Pharmacodynamic Properties

Mechanism of action.

It has been established that mesalazine is the active component of sulfasalazine, which is used for the treatment of ulcerative colitis and Crohn's disease. Based on clinical results, the therapeutic value of mesalazine after oral as well as rectal administration appears to be due to a local effect on the inflamed intestinal tissue, rather than to systemic effects. There is information suggesting that the 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 mechanisms of action of mesalazine are 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 pharmacological effects that inhibit leukocyte chemotaxis, decrease cytokine production, scavenge for free radicals and also reduce leukotriene production via inhibition of the lipo-oxygenase pathway. Prostaglandin production is reduced via inhibition of the cyclo-oxygenase pathway. It is currently unknown which, if any, of these mechanisms play a predominant role in the clinical efficacy of mesalazine.
Observed effects of mesalazine in experimental models show downregulation of both inflammation dependent and non-inflammation dependent signalling pathways involved in the development of colitis associated colorectal cancer (CRC).

Clinical trials.

Ulcerative colitis: treatment of active disease.

In a placebo controlled, double blind, randomised study of 374 patients aged 18 and over, with active mild to moderate ulcerative colitis, patients were treated with either placebo, or Pentasa 1 g, 2 g or 4 g daily for 8 weeks, given orally as 250 mg slow release capsules. Three primary efficacy parameters were assessed at baseline and weeks 1, 4 and 8 (see Table 2).
Physician global assessment; an investigator rating of the patient's improvement of symptoms since baseline, based on a scale of 1 to 6 (e.g. 1 = complete relief of symptoms/ 6 = worsening in symptoms).
Sigmoidoscopic index (SI); an evaluation of the presence/ severity of erythema, friability, granularity/ ulceration, mucopus, and the appearance of mucosal vascular pattern, each assigned a value between 0 (normal) to 3 (severe) and totalled to provide an overall index score of between 0-15.
Treatment failure; which were those patients who were not receiving therapeutic benefit, defined as an increase of 5 points in SI and a worsening or no improvement in any symptoms (including trips to the toilet).
In an investigator blinded, randomised, controlled multicentre study (MOTUS trial) conducted in adult patients with active mild to moderate ulcerative colitis, 4 g Pentasa once daily was shown to be noninferior to 2 g Pentasa twice daily in induction of remission after 8 weeks of treatment. In this trial a noninferiority margin of 15% was calculated based on previously published studies. This margin is similar to those retained in comparable noninferiority studies dealing with treatment of mild to moderately active UC (either assessing topical or systemic treatments) which vary from -15% to -20%.
The primary efficacy endpoint was the percentage of patients in clinical and endoscopic remission after 8 weeks of treatment, defined as an Ulcerative Colitis Disease Activity (UC-DAI) score ≤ 1. The statistical analysis was based on the intention to treat (ITT), modified ITT (mITT), and per protocol (PP) analyses with equal importance; remission rates are presented in Table 3.
The results showed that Pentasa 4 g once daily was noninferior to the reference regimen, Pentasa 2 g twice daily in patients with active UC treated for 8 weeks in all three study populations.

Ulcerative colitis: maintenance of remission.

A double blind, double dummy, randomised study comparing Pentasa 1.5 g daily (administered as two 250 mg slow release tablets, three times a day) with sulfasalazine 3 g daily (administered as two 500 mg enteric coated tablets, three times a day) treatment for 12 months, was conducted in 75 patients aged 18 years and over, with ulcerative colitis, who had been in remission for between 1 month and 5 years and had not taken steroids (either orally or as an enema) or azathioprine during at least 1 month before entry. Patients were assessed clinically, endoscopically and histologically before, and 3, 6, 9 and 12 months after the start of treatment. Endoscopy examined mucosal colour, vessel pattern, granularity, presence of valves, distention, polypoid structures, ulcers, spontaneous haemorrhage, and mucopurulent covering, and a wipe test was performed to determine friability. Endoscopy was scored as normal, mild, moderate, severe abnormality or very severe abnormality. Histological assessment was made on the basis of biopsy examination for oedema and haemorrhage in the mucosa and submucosa, for quality and quantity of mucosal cellular infiltrate, and for epithelial architecture of the crypts and was scored as normal, little inflammation, medium inflammation, severe inflammation, or UC in remission. Patients were assessed immediately if symptoms developed or if side effects occurred.
Patients were considered to have remained in remission if all data obtained at each visit were assessed as 'normal' or 'in remission'.
The data of 41 patients treated with Pentasa and 34 patients treated with sulfasalazine were included in life table analysis for calculating remission rates (see Figure 1). No significant differences between the two treatments were revealed (chi2 = 0.14, df = 1, p > 0.70). The final remission rates were 54% for Pentasa and 46% for sulfasalazine, with 95% confidence intervals of 38%-69% for Pentasa and 26%-64% for sulfasalazine. The difference is 8% in favour of Pentasa, with a 95% confidence interval of -16% to 31%.
In an investigator blinded, randomised, controlled multicentre study (PODIUM trial) conducted in adult patients with mild to moderate ulcerative colitis in remission, 2 g Pentasa once daily was noninferior to 1 g Pentasa twice daily with respect to relapse rate to 12 months.
The risk of colorectal cancer (CRC) is increased in ulcerative colitis, especially in patients with extensive disease, with a disease course > 8 years, with a first degree family history of CRC, or with comorbid primary sclerosing cholangitis. The risk for colitis associated CRC has been estimated to be 2% at 10 years, 8% at 20 years, and 18% at 30 years after onset of ulcerative colitis (see Section 5.1 Pharmacodynamic Properties).

Crohn's disease: treatment of active disease.

A meta-analysis was conducted of three double blind, placebo controlled, randomised, multicentre studies in 615 patients aged 18 and over, of whom 304 were treated with up to 4 g/day Pentasa administered as oral capsules and 311 were treated with placebo, for mild to moderate Crohn's disease for a period of 16 weeks (see Table 4).
The primary efficacy variable used in these trials was the Crohn's Disease Activity Index (CDAI), which included the following components: sum of liquid/ very soft stools (per 7 days), sum of abdominal pain rating (per 7 days), sum of general wellbeing ratings (per 7 days), use of loperamide or codeine, bodyweight, haematocrit, abdominal mass, sum of symptoms.
The meta-analysis demonstrated that the use of Pentasa 4 g/day for 16 weeks was associated with a statistically significant greater overall improvement in the CDAI from baseline to the final visit (p = 0.04) when compared with placebo.

Crohn's disease: maintenance of remission.

In a randomised, double blind, placebo controlled study conducted in 293 patients aged 18 years and over, with Crohn's disease in remission, a daily 3 g dose of Pentasa was administered as 250 mg capsules for a period of up to 48 weeks (with assessments at baseline and weeks 4, 12, 24, 36, 48). Relapse was defined as a Crohn's Activity Index of > 150, with at least a 60 point increase over baseline.
246 patients completed a minimum of 4 weeks treatment. Of these, thirty of the 118 patients (25%) who received Pentasa had a relapse compared with 47 of 128 (36%) receiving placebo (p = 0.056).

5.2 Pharmacokinetic Properties

The therapeutic activity of mesalazine appears to depend on local contact of the drug with the diseased area of the intestinal mucosa.
Pentasa prolonged release granules and tablets consist of ethylcellulose coated microgranules of mesalazine. Following administration of the tablets and granules, and the disintegration of the tablets, mesalazine is continuously released from the individual microgranules throughout the gastrointestinal tract in any enteral pH conditions.
The microgranules enter the duodenum within an hour of administration, independent of food coadministration. The average small intestinal transit time is approximately 3-4 hours in healthy volunteers.

Absorption.

Based on urinary recovery in healthy volunteers, 30-50% of the ingested dose is absorbed following oral administration, predominantly from the small intestine. Mesalazine is detectable in plasma 15 minutes after administration.
Maximum plasma concentrations are seen 1-6 hours post-dose. Dosage regimens of 2 g twice daily and 4 g once daily of mesalazine result in comparable systemic exposures (AUC) over 24 hours and indicate the 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 (see Table 5).
Mean steady-state plasma concentrations of mesalazine are approximately 0.3 microgram/mL, 1.2 microgram/mL and 1.9 microgram/mL after 1.5 g, 4 g and 6 g daily dosages, respectively. For acetyl-mesalazine the corresponding concentrations are approximately 1.1 microgram/mL, 2.5 microgram/mL and 3.1 microgram/mL.
The transit and release of mesalazine after oral administration are independent of food coadministration, whereas the systemic absorption will be reduced.

Distribution.

Protein binding of mesalazine is approximately 50% and of acetyl-mesalazine about 80%.

Metabolism.

Mesalazine is metabolised both presystemically by the intestinal mucosa and systemically in the liver to N-acetyl mesalazine (acetyl-mesalazine). 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 x 3 and 2 g x 3, respectively, implying a dose dependent acetylation which may be subject to saturation.
Acetyl-mesalazine is thought to be clinically, as well as toxicologically, inactive but this still remains to be confirmed.

Excretion.

After intravenous administration, the plasma half-life of mesalazine is approximately 40 minutes and for acetyl-mesalazine approximately 80 minutes. Due to the 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 the urine and faeces. The urinary excretion consists mainly of acetyl-mesalazine and the faecal excretion consists mainly of mesalazine.

Characteristics in patients.

The delivery of mesalazine to the intestinal mucosa after oral administration is only slightly affected by pathophysiologic changes, such as diarrhoea and increased bowel acidity 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. Likewise, a corresponding increase in faecal excretion has been seen.
In patients with impaired liver and kidney function, 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

Genotoxicity.

Mesalazine was negative in bacterial assays of gene mutation and in a mouse micronucleus test.

Carcinogenicity.

There is no evidence of carcinogenicity in mice or rats treated with mesalazine in the diet at respective doses up to 2500 and 800 mg/kg/day for two years. These doses were associated with plasma concentrations of mesalazine and its metabolite N-acetyl-5-aminosalicylic acid of 7-fold (mice) and 3-fold (rats) the peak plasma concentrations of these compounds at the maximal recommended human dose of the granules and the tablets.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

Prolonged release tablets: 3 years.
Prolonged release granules: 2 years.

6.4 Special Precautions for Storage

Store below 25°C. Keep in original container.

6.5 Nature and Contents of Container

Pentasa prolonged release tablets.

Pentasa 0.5 g tablets are supplied in blister packs of 30 and 100 tablets.
Pentasa 1 g tablets are supplied in blister packs of 20, 60 and 120 tablets.

Pentasa prolonged release granules.

Pentasa 1 g granules are supplied in packs of 30, 50, 100, 120 and 150 sachets.
Pentasa 2 g granules are supplied in packs of 10, 15 and 60 sachets.
Pentasa 4 g granules are supplied in packs of 8 and 30 sachets.
Not all pack sizes are being distributed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


Molecular Formula: C7H7NO3. Molecular Weight: 153.13.
Synonyms: 5-aminosalicylic acid; 5-amino 2-hydroxybenzoic acid; mesalamine.

CAS number.

89-57-6.

7 Medicine Schedule (Poisons Standard)

(S4) Prescription Only Medicine.

Summary Table of Changes