Pentasa Sachets: Indications, Dosage, Precautions, Adverse Effects
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Pentasa Sachets - Product Information

Manufacture: Ferring Pharmaceuticals
Country: Australia
Condition: Crohn's Disease, Maintenance, Crohn's Disease, Diarrhea, Stomach Ulcer (Gastric Ulcer), Ulcerative Colitis, Ulcerative Colitis, Active
Class: 5-aminosalicylates
Form: Tablets
Ingredients: mesalazine, ethylcellulose, povidone

Name of the Medicine

Mesalazine (5-ASA)

Synonyms

5-aminosalicylic acid

5-amino 2-hydroxybenzoic acid

C7H7NO3

CAS No. 89-57-6

MW: 153.14


Description

PENTASA Tablets contain 500mg or 1g mesalazine as the active ingredient as well as the following inactive excipients: magnesium stearate, purified talc, povidone, ethylcellulose, microcrystalline cellulose.

PENTASA Sachets contain 1g, 2g and 4g mesalazine as the active ingredient as well as the following inactive excipients: ethylcellulose, povidone.

Pharmacology

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

Actions

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.

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. Mesalazine has invitro 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) (see CLINICAL TRIALS).

Pharmacokinetics

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 and tablet disintegration, 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 co-administration. 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 1-4 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 0.3µg/mL, 1.2µg/mL and 1.9µg/mL after 1.5g, 4g and 6g daily dosages, respectively. For acetyl-mesalazine the corresponding concentrations are approximately 1.1µg/mL, 2.5µg/mL and 3.1µg/mL.

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

Metabolism

Mesalazine is metabolised both pre-systemically 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. Acetyl-mesalazine is thought to be clinically, as well as toxicologically, inactive but this still remains to be confirmed.

Distribution

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

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.

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 1g, 2g, or 4g daily for 8 weeks, given orally as 250mg slow release capsules. Three primary efficacy parameters were assessed at baseline and weeks 1, 4 and 8;

  • 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).
Primary Efficacy Results (intent-to-treat population)
n = 374Placebo
(n=90)
1g daily
(n=92)
2g daily
(n=97)
4g daily
(n=95)
Physician Global Assessment
% of patients with complete or marked
Improvement of symptoms from baseline
to last visit
36%45%57%*59%*
Sigmoidoscopic Index
Mean improvement in Index score from
baseline to last visit (Mean+SE)
-2.5 ± 0.45-3.4 ± 0.45-4.3* ± 0.43-5.0* ± 0.44
Treatment Failure22%17%18%9%*

* P < 0.05 vs placebo

In an investigator-blinded, randomised, controlled multi-centre study (MOTUS trial) conducted in adult patients with active mild to moderate ulcerative colitis, 4g PENTASA once daily was shown to be non-inferior to 2g PENTASA twice daily in induction of remission after 8 weeks of treatment. In this trial a non-inferiority margin of 15% was calculated based on previously published studies. This margin is similar to those retained in comparable non-inferiority 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 the table below.

Remission Rate (UC-DAI score ≤1) at Week 8 (ITT, mITT, PP; LOCF)
 4g once daily
N (Weighted rate %)
2g twice daily
N (Weighted rate %)
Difference
(%) [95% CI]
P value
ITT population52/101 (52.1)42/101 (41.8)10.4 [-3.4; 24.1]0.1402 (NS)
mITT population52/89 (58.8)42/90 (46.8)12.0 [-2.6; 26.6]0.1061 (NS)
PP population48/79 (61.0)37/77 (48.3)12.8 [-2.7; 28.2]0.1047 (NS)

CI 95%: 95% confidence interval; LOCF: Last observation carried forward

The results showed that PENTASA 4g once daily was non-inferior to the reference regimen, PENTASA 2g twice daily in patients with active UC treated for 8 weeks in all three study populations.

Ulcerative Colitis: Maintenance of Remission

A double-blind study, double-dummy, randomised study comparing PENTASA 1.5g daily (administered as 250mg slow release tablets, three times a day ) with sulfasalazine 3g daily (administered as 500mg enteric coated tablets, three times daily) 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 (fig 1). No significant differences between the two treatments were revealed (c2 = 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%.

Figure 1. Remission rates


In an investigator-blinded, randomised, controlled multi-centre study (PODIUM trial) conducted in adult patients with mild to moderate ulcerative colitis in remission, 2g PENTASA once daily was non-inferior to 1g 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 PHARMACOLOGY).

Crohn’s Disease: Treatment of active disease

A meta-analysis was conducted of three double-blind, placebo-controlled, randomised, multi-centre studies in 615 patients aged 18 and over, of whom 304 were treated with up to 4g/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.

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 well being ratings (per 7 days), use of loperamide or codeine, bodyweight, haematocrit, abdominal mass, Sum of symptoms.

Summary of intent-to-treat endpoint analysis of the CDAI Score for the 3 studies
Mean baseline
CDAI ± SD & (range)

PENTASA 4g
Change from
baseline
Placebo
Change from
baseline
PENTASA 4g - placebo
Trial PENTASA
Group
Placebo
Group
nMean ± SEnMean ± SEMean ± SE95%
confidenc
e interval
P value
Crohn’s I260±64
(86-381)
277±66
(112-460)
75-72±1380-21±13-52±18(-88, -16)0.005
Crohn’s II248±76
(129-474)
255±79
(67-440)
75-41±1275-35±12-6±17(-40, 27)0.7
Crohn’s III265±53
(136-431)
265±58
(118-428)
154-72± 9156-64±9-8±13(-33, 16)0.5
Overall effect
(Meta-Analysis)


-63± 6-45± 6-18±9(-35, -1)0.04

The meta-analysis demonstrated that the use of PENTASA 4g/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 3g dose of PENTASA was administered as 250mg 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).

Indications

Treatment of mild to moderate Ulcerative Colitis and Crohn’s Disease and maintenance of remission.

Contraindications

Hypersensitivity to mesalazine or any other component of the product or salicylates. Severe liver or renal impairment.

Precautions

Most patients who are intolerant or hypersensitive to sulfasalazine are able to take PENTASA without risk of similar reactions. However, caution is recommended when treating patients allergic to sulfasalazine because of risk of allergy to salicylates (also see Contraindications).

Treatment should be discontinued in the event of symptoms suggestive of hypersensitivity such as rash, fever, nausea, headache, abdominal discomfort or pain or exacerbation of diarrhoea.

Caution is recommended in patients with impaired liver function (also see Contraindications).Liver function parameters like ALT or AST should be assessed prior to and during treatment, at the discretion of the treating physician.

Mesalazine is not recommended for use in patients with renal impairment (see also 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.

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 Adverse Effects). Also, blood test for differential blood count is recommended prior to and during treatment, at the discretion of the treating physician. As stated in the Interactions with Other Medicines section, concomitant treatment with mesalazine can increase the risk of blood dyscrasia in patients receiving azathioprine, or 6-mercaptopurine or thioguanine. Treatment should be discontinued on suspicion or evidence of these adverse reactions (also see Adverse Effects).

Mesalazine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported rarely.

Effects on Fertility

Oral administration of mesalazine at doses up to 400mg/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.

Use in Pregnancy (Category C)

Oral administration of mesalazine during organogenesis in rats and rabbits at respective doses up to 1000 and 800mg/kg/day was associated with concomitant embryofetal toxicity and maternotoxicity. At a dose of 1000mg/kg/day in rats, fetuses showed enlarged brain ventricles. Non-embryofetal toxic and non-maternotoxic dosages were 500 and 400 mg/kg/day in rats and rabbits, respectively.

Adequate human data on use of mesalazine during pregnancy are not available. Mesalazine is known to cross the placental barrier but the limited data available on the use of this compound in pregnant women do not allow assessment of possible adverse effects.

Non-steroidal anti-inflammatory drugs 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 non-steroidal anti-inflammatory drugs 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 5-ASA during pregnancy were prospectively collected and pregnancy outcome was compared with that of a control group. The investigators concluded that 5-ASA does not represent a major teratogenic risk, as the reported rate of major malformations was within the expected baseline risk of the general population.

Use in Lactation

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 800mg/kg/day was associated with maternotoxicity and toxicity in offspring; a dose of 200mg/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 risks outweigh the possible hazards in the opinion of the physician. Hypersensitivity reactions, such as diarrhoea, in the nursing infant cannot be excluded.

Paediatric Use

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

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 800mg/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.

Effect 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.

Interactions with Other Medicines

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

  • Courmarin type anticoagulants – 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 frusemide – possible attenuation of the diuretic effects
  • Rifampicin – possible attenuation of the tuberculostatic effects.

Combination therapy with PENTASA and azathioprine, or 6-mercaptopurine or thioguanine 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 dosage regime of thiopurines should be adjusted accordingly.

The concomitant use of mesalazine with other known nephrotoxic agents, such as NSAIDs and azathioprine, may increase the risk of renal reactions.

Adverse Effects

The following table represents the frequency of adverse effects based on clinical trials and reports from post-marketing surveillance for all formulations of PENTASA, including oral:

Common >1% and <10% Nervous system disordersHeadache 
Gastrointestinal disordersDiarrhoea, abdominal pain, nausea, vomiting
Skin and subcutaneous tissue disordersRash (incl urticaria, erythematous rash) 
Rare >0.01% and <0.1%Cardiac disorders Myo- and pericarditis 
Gastro-intestinal disordersIncreased amylase, pancreatitis 
Very rare <0.01%Skin and subcutaneous tissue disordersReversible alopecia, bullous skin reactions including erythema multiforme and Stevens-Johnson syndrome
Hepato-biliary disordersIncreased liver enzymes and bilirubin, hepatotoxicity (incl. hepatitis, cirrhosis, hepatic failure)
Renal and urinary disordersRenal function impairment (incl. interstitial nephritis, nephrotic syndrome, renal insufficiency urine discolouration)
Respiratory, thoracicand mediastinal disordersAllergic and fibrotic lung reactions (incl. dyspnoea, coughing, allergic alveolitis, pulmonary eosinophilia, interstitial lung disease, pulmonary infiltration, pneumonitis)
Musculo-skeletal, connective tissue and bone disordersMyalgia, arthralgia, Isolated reports of lupus erythematous-like reactions
Blood and the lymphatic system disordersEosinophilia (as part of an allergic reaction), anaemia, aplastic anaemia, leukopenia (incl. granulocytopenia and neutropenia), thrombocytopenia, agranulocytosis, pancytopenia
Nervous system disordersPeripheral neuropathy 

In the MOTUS study the incidences of nausea were 4.9 % and 2.0 % in the 4g once daily and 2g twice daily groups respectively. All events of nausea were mild to moderate in intensity, and resolved; none led to withdrawal from the trial.

It is important to note that several of these disorders can also be attributed to the inflammatory process itself. The mechanism of mesalazine-induced myo- and pericarditis, pancreatitis, nephritis and hepatitis is unknown, but it might be of allergic origin. Hypersensitivity reactions and drug fever may occasionally occur. Mesalazine may be associated with an exacerbation of the symptoms of colitis in those patients who have previously had such problems with sulfasalazine.

Dosage and Administration

Ulcerative Colitis

Treatment of active disease:
Adults:

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

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

Crohn’s Disease

Treatment of active disease:
Adults:

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

Individual dosage, up to 4g daily in divided doses

The contents of the sachet should be emptied onto the tongue and washed down with some water or juice.

To facilitate swallowing, the tablets may be dispersed in 50mL of cold water. Stir and drink immediately. Do not crush or chew the tablets or granules.

Overdosage

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

Human experience: No overdoses have been reported.

Management of overdose in man: There is no specific antidote. General supportive and symptomatic measures are recommended. Renal function should be closely monitored.

Presentation and Storage Conditions

PENTASA 500mg prolonged release tablets are white-grey to pale brown, speckled round tablets with breakmark and embossing: ‘500 mg’ on one side, ‘PENTASA’ on the other side. They are supplied in blister packs of 30 and 100 tablets.

PENTASA 1g prolonged release tablets are white-grey to pale brown speckled oval tablets with

‘PENTASA’ embossed on both sides. They are supplied in blister packs of 20, 60 and 120 tablets.

PENTASA 1g Sachets contain mesalazine 1g prolonged release granules. They are supplied in packs of 30, 50, 100, 120 and 150 sachets.

PENTASA 2g Sachets contain mesalazine 2g prolonged release granules. They are supplied in packs of 10, 15 and 60 sachets.

PENTASA 4g Sachets contain mesalazine 4g prolonged release granules. They are supplied in packs of 8 and 30 sachets.

PENTASA Sachets contain cylindrical shaped granules that are white-grey to pale white brown in colour.

Not all pack sizes are being distributed in Australia.

Store below 25°C. Keep in original container.

Name and Address of the Sponsor

Ferring Pharmaceuticals Pty Ltd

Suite 2, Level 1, Building 1

20 Bridge Street

Pymble NSW 2073, Australia

Poison Schedule of the Medicine

Prescription Medicine (S4)

Date of First Inclusion in the Australian Register of Therapeutic Goods (the artg)

Tablets 500mg: 2 January 2007 Tablets 1g: 16 April 2010

Sachets 1g and 2g: 21 November 2006 Sachets 4g: 14 August 2014

Date of Most Recent Amendment

19 January 2015