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

Manufacture: Ferring Pharmaceuticals
Country: Canada
Condition: Crohn's Disease, Maintenance, Crohn's Disease, Inflammatory Bowel Disease, Ulcerative Colitis, Ulcerative Colitis, Active, Ulcerative Proctitis
Class: 5-aminosalicylates
Form: Tablets
Ingredients: mesalazine (also known as mesalamine, 5-ASA or 5-aminosalicylic acid), microcrystalline cellulose, ethylcellulose, magnesium stearate, povidone, talc

Summary Product Information

Route of Administration Dosage Form / Strength Clinically Relevant Nonmedicinal Ingredients
Oral 500 mg and 1g None*
Rectal 1 g and 4 g Enema None*
Rectal 1 g Suppository None*

* For a complete listing see Dosage Forms, Composition and Packaging section of the Product Monograph 

Indications and Clinical Use

PENTASA (5-ASA, also called mesalazine or mesalamine) extended-release tablets are indicated for:

  • Treatment of mild to moderate active ulcerative colitis and for long-term maintenance therapy in order to maintain remission and prevent relapse of active disease.
  • Management of mild to moderate Crohn’s Disease and maintenance of Crohn’s Disease in remission induced by surgery or medication

PENTASA (5-ASA) rectal suspension is indicated for the treatment of acute distal ulcerative colitis extending to the splenic flexure and for long-term maintenance therapy in order to maintain remission and prevent relapse of active disease. Clinical experience has shown that topical PENTASA (i.e. enemas/suppositories) is superior to oral PENTASA (i.e. tablets) with regard to therapeutic efficacy in distal ulcerative colitis (see Table 2 - Clinical experience from pivotal trials).

PENTASA (5-ASA) suppositories are indicated for the treatment of acute ulcerative proctitis and for long-term maintenance therapy in order to maintain remission and prevent relapse of active disease.

Pediatrics (< 18 years of age)

The safety and effectiveness of 5-ASA have not been established in children.

Contraindications

PENTASA (5-ASA) is contraindicated in:

  1. Patients with existing gastric or duodenal ulcer;
  2. Patients with urinary tract obstruction, renal parenchymal disease or severe renal impairment. Very rarely, 5-ASA may induce nephrotoxicity which would be additive in these patients. Renal function should be determined prior to beginning therapy (e.g. serum creatinine), and the benefits of therapy versus the increased risk of nephrotoxicity carefully assessed. See WARNINGS.
  3. Patients who have demonstrated hypersensitivity to derivatives of salicylate.
  4. Patients with severe hepatic impairment
  5. Infants under 2 years of age

Warnings and Precautions

General

Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to PENTASA or other compounds that contain or are converted to 5-ASA. Therefore, caution should be exercised when treating patients allergic to sulfasalazine due to the potential risk of cross sensitivity reactions between sulfasalazine and 5-ASA.

5-ASA has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlled clinical trials of 5-ASA or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache and rash. If acute intolerance syndrome is suspected, prompt withdrawal is required.

In patients with mild to moderate renal impairment, 5-ASA products should be used only if the benefits outweigh the risks. Therefore, caution should be exercised, and it is recommended that all patients have an evaluation of renal function prior to initiation of therapy, and periodically while on treatment (see Renal).

In patients with mild to moderate impaired liver function, 5-ASA products should be used only if the expected benefits outweigh the risks to the patient. Caution should be exercised (see Hepatic/Biliary/Pancreatic).

PENTASA extended-release tablets should not be chewed, broken or crushed but should be swallowed whole.

Gastrointestinal

Organic or functional obstruction in the upper gastrointestinal tract may delay onset of action of the product. Acute intolerance syndrome: See WARNINGS AND PRECAUTIONS - General.

Cardiovascular

5-ASA induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported rarely with 5-ASA and other 5-ASA-containing preparations. Caution should be taken in prescribing this medication to patients with conditions predisposing to the development of myocarditis or pericarditis.

Hematologic

Following 5-ASA treatment, serious blood dyscrasias (including myelosuppression) have been reported rarely. The risk is further increased when 5-ASA products are used concomitantly with 6-mercaptopurine or azathioprine (see Drug Interactions Drug-Drug Interactions). If the patient develops unexplained bleeding, bruising, purpura, anaemia, fever or sore throat, haematological investigations should be performed. If there is suspicion of blood dyscrasia, 5-ASA treatment should be discontinued.

Hepatic/Biliary

There have been reports of hepatic failure and increased liver enzymes in patients with pre-existing liver disease when treated with 5-ASA products. Therefore, 5-ASA is contraindicated in patients with severe hepatic impairment (see Contraindications). In patients with mild to moderate liver function impairment, caution should be exercised and 5-ASA products should only be used if the expected benefit clearly outweighs the risks to the patients. Appropriate assessment and monitoring of liver function should be performed.

Renal

Reports of renal impairment, including minimal change nephropathy, and acute or chronic interstitial nephritis have been associated with 5-ASA products and pro-drugs of 5-ASA. 5-ASA is contraindicated in patients with severe renal impairment (see Contraindications). In patients with mild to moderate renal dysfunction, caution should be exercised and 5-ASA products should be used only if the benefits outweigh the risks. It is recommended that all patients have an evaluation of renal function prior to initiation of therapy and periodically while on treatment. The concurrent use of other known nephrotoxic agents may increase the risk of renal reactions.

Respiratory

Patients with chronic lung function impairment, especially asthma, are at risk of hypersensitivity reactions with 5-ASA products and should be closely monitored.

Special Populations

Pregnant Women

There are no adequate and well controlled studies of 5-ASA in pregnant women. 5-ASA is known to cross the placental barrier. PENTASA should be used during pregnancy only if benefits outweigh the risks.

Blood disorders (leucopenia, thrombocytopenia, anemia) have been reported in new-borns of mothers being treated with PENTASA.

Nursing Women

In nursing mothers, 5-ASA is excreted in breast milk at concentration much lower than in maternal blood, but the metabolite N-acetyl-5-ASA appears in similar concentrations. Caution should be exercised, and PENTASA should be used in nursing mothers only if the benefits outweigh the risks. Hypersensitivity reactions like diarrhea in the infants cannot be excluded. No controlled studies with Pentasa during breast feeding have been carried out.

Fertility

Semen abnormalities and infertility in men, which are associated with sulfasalazine, have not been reported with PENTASA during controlled clinical trials. Semen quality significantly may improve when patients are transferred from sulfasalazine to PENTASA 5-ASA.

Decreased sperm count and impaired sperm motility have been only rarely reported with mesalazine (5-ASA). This effect may be reversible when treatment is discontinued.

Pediatric Use (<18 years of age)

The safety and efficacy of PENTASA have not been established in children. The potential benefits of therapy should be weighed against the possible risks.

Geriatrics (≥ 65 years of age)

There are no clinical efficacy studies of 5-ASA in geriatrics patients.

Results of a single-dose pharmacokinetic study indicate that following the administration of a mesalamine-containing product, the systemic exposure to mesalamine may be increased by up 2-fold in elderly subjects (> 65 year), as compared with younger adult subjects (18-35 years). Systemic exposures were inversely correlated with renal function. Therefore, dose selection for elderly patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy.

Adverse Reactions

The following adverse events (AEs) were reported in the CAMMP clinical study (Table-1) using the Pentasa extended release tablets in adult patients with mild to moderate ulcerative colitis. A total of 143 patients received Pentasa Extended-release tablets of which 93 patients received Pentasa 4g /day for 8-week (induction phase) and 70 went on to a 24 week maintenance phase at 2 g/day.

Table-1 Adverse events, occurring in ≥ 2% of patients treated with Pentasa Extended-release tablets formulation (CAMMP Study 2011)
Pentasa Extended-release tablets
N=143
Patients with any adverseevent 52.4%
Nasopharyngitis 8.4%
Headache 7.7%
Nausea 4.2%
Influenza 3.5%
Gastroenteritis 3.5%
Colitis ulcerative 2.8%
Abdominal pain 2.8%
Fatigue 2.8%
Cough 2.8%
Pyrexia 2.1%
Flatulence 2.1%
Back pain 2.1%
Dizziness 2.1%
Pharyngolaryngeal pain 2.1%

In this clinical trial, other AEs occurring in less than 2% of patients included rash & pruritus, dyspepsia, vomiting, diarrhoea, haemorrhoids, rectal haemorrhage, hepatic enzyme increased, myalgia/arthralgia, pain in extremity, otitis media, and pneumonia.

Other Clinical Studies and Post Marketing Data

Table 2 - Frequency of adverse effects, based on other clinical trials reports with other Pentasa formulations, and from post-marketing surveillance data with all Pentasa formulations

Frequency of adverse effect Organ system affected Symptom
Common (> 1% and < 10%) Nervous system disorders Headache
Idiopathic intracranial hypertension
Anxiety
Hypoesthesia
Cardiovascular System Hypertension
Gastro-intestinal disorders Diarrhea
Abdominal pain
Abdominal pain, upper
Nausea
Vomiting
Gastroenteritis viral
Proctalgia
Skin and subcutaneous tissue
disorders/infections
Rash including urticaria
Exanthema

Varicella
Respiratory Bronchitis
Dyspnoea
Renal Urinary Tract Infection
Rare (> 0.01% and < 0.1%) Cardiac disorders Myocarditis*
Pericarditis*
Gastro-intestinal disorders Increased amylase
Pancreatitis
Very rare (< 0.01%) Skin and subcutaneous tissue Reversible alopecia
Hepato-biliary disorders Increased liver enzymes and bilirubin, hepatotoxicity (including hepatitis,
cirrhosis, hepatic failure)
Renal and urinary disorders Nephropathy including interstitial
nephritis
Nephrotic syndrome, urine discoloration
Respiratory, thoracic and
mediastinal disorders
Allergic lung reactions (including.
dyspnea, coughing, allergic alveolitis,
pulmonary eosinophilia, pulmonary
infiltration, pneumonitis), pleurisy
Musculo-skeletal, connective
tissue and bone disorders
Myalgia
Arthralgia
Isolated reports of lupus-erythematosus-
like reactions
Blood and lymphatic system
disorders
Eosinophilia (as part of an allergic
reaction), anemia, aplastic anemia,
leucopenia (including granulocytopenia),
thrombocytopenia, agranulocytosis,
pancytopenia,
Nervous system disorders Peripheral neuropathy

* The mechanism of 5-ASA-induced myocarditis and pericarditis, pancreatitis, nephritis and hepatitis is unknown, but may be of allergic origin. It is important to note that several of these disorders may also be attributable to the underlying inflammatory bowel disease itself. Following rectal administration, local reactions such as pruritus, rectal discomfort and urgency may occur.

Gastrointestinal

Abdominal distension, anorexia, duodenal ulcer, eructation, esophageal ulcer, fecal incontinence, bloody stools or diarrhea, intestinal obstruction, melena, dysphagia, mouth ulcer, oral moniliasis, pancreatitis, rectal bleeding, rectal urgency, thirst.

Diarrhea is a commonly reported adverse event (about 3% frequency in clinical trials; somewhat less from spontaneous post-market surveillance reports), which is not dose-related. Diarrhea is also a symptom of the underlying disease, and may indeed be indicative of inadequate dosage with PENTASA in some patients. Rarely 5-ASA may exacerbate the inflammatory bowel disease itself.

It may be noted that melena has been reported as an adverse event rarely during 5-ASA therapy, but it has not been definitely linked to treatment. Gastrointestinal bleeding has been assumed from observations of bloody diarrhea or stools. Again, blood in fecal matter may be a symptom of the underlying disease and has not been definitely linked to treatment.

Dermatological

Acne, alopecia, dry skin, eczema, erythema nodosum, erythematous rash, hirsuitism, nail disorder, photosensitivity, pruritus, skin discoloration, sweating.

Reversible alopecia has been reported in 5-ASA-treated patients, as well as in placebo-treated patients, indicating that hair loss could be part of the underlying disease. Two cases of alopecia in patients on treatment with 5-ASA at a dose of 4 g/day were confirmed by positive rechallenge. In one of the cases, the hair loss improved after dosage reduction to 2 g/day. However, the available data are insufficient to establish a dose relationship with 5-ASA treatment generally.

Three cases of erythema nodosum have been reported in connection with PENTASA therapy. The causality was assessed as probable (1 case), possible (1 case) and not related (1 case) due to negative dechallenge. Erythema nodosum is a well-known extra-intestinal manifestation of inflammatory bowel disease.

Nervous System

Anxiety, abnormal dreams, dizziness, insomnia, somnolence, pareesthesia.

Cardiovascular

Postural hypotension, tachycardia.

Respiratory

Dyspnea, increased coughing, pharyngitis.

Metabolic

Alkaline phosphatase increase, amylase increase, C reactive protein increase, creatinine increase, GGTP increase, LDH increase, proteinuria, SGOT increase, SGPT increase, weight decrease, weight increase.

Rise in liver enzymes by 3 to 5 times the normal range may be expected in a small percentage of patients treated with PENTASA. This variable and transient occurrence is difficult to relate definitely to drug treatment due to the concomitant drug therapy usual with patients, and due to enzyme fluctuations caused by the disease itself. In many cases, the enzyme increases resolve without drug discontinuation or reduction. In most cases, enzyme abnormalities are reversed on discontinuation of therapy. Rarely, increase in liver enzymes is indicative of developing hepatitis.

Similarly, increases in serum amylase and lipase levels by 3 to 5 times the normal range may occur, and are usually reversible upon dosage reduction or discontinuation. Very rarely, patients develop pancreatitis.

Weight loss is an expected consequence of inflammatory bowel disease. Weight gain is usually indicative of a positive clinical response to PENTASA therapy.

Renal/genitourinary

Albuminuria, urinary frequency, urinary infection, urination disorder, vaginitis, isolated cases of nephrotic syndrome and interstitial nephritis.

Hematologic

Agranulocytosis.

Immunological

Anaphylactic reaction, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson Syndrome (SJS).

Other

Anemia, appetite decrease, arthralgia, breast pain, chest pain/pressure, chills, conjunctivitis, dry eyes, eye pain, ecchymosis, edema, eosinophilia, ESR increase, fatigue, fever, flu syndrome, leg cramps, malaise, menorrhagia, myalgia, scotoma, sore throat.

Drug Interactions

Overview

There is a potential risk of myelosuppression, particularly leucopenia when aminosalicylates are co-administered with azathioprine or 6-mercaptopurine.

There is a potential risk of renal failure when aminosalicylates are co-administered with other nephrotoxic agents such as NSAIDs and azathioprine.

Drug-Drug Interactions

No investigations of interaction between PENTASA and other drugs have been performed. However, there have been reports of interactions between products containing 5-ASA and other drugs. The concurrent use of 5-ASA with known nephrotoxic agents, including non-steroidal anti-inflammatory drugs (NSAIDS) and azathioprine may increase the risk of renal reactions. In patients receiving azathioprine or 6-mercaptopurine, concurrent use of 5-ASA can increase the potential for blood disorders, especially leucopenia.

Caution should be exercised when 5-ASA and sulfonyl ureas are prescribed concomitantly since the blood-sugar reducing effect of sulfonyl ureas may be enhanced. Interactions with coumarin, probenecid, sulfinpyrazone, spironolactone, furosemide and rifampicin cannot be excluded. 5-ASA may delay the excretion of methotrexate.

Drug-Food Interactions

The effect of food on the new formulation of PENTASA 500 mg extended release tablets has not been established. The new formulation was only administered under fed conditions (after a high fat meal) in a comparative bioavailability study comparing the new and former PENTASA extended release tablet formulations for safety purposes [for results see CLINICAL TRIALS, ORAL DOSAGE FORMS, Comparative Bioavailability Data]. In addition, PENTASA 500 mg extended release tablets were administered mainly with food, as part of an unrestricted diet in the pivotal phase 3 trial that was submitted for approval of the new Pentasa 500 mg extended release tablet formulation.

For this reason, PENTASA 500 mg extended release tablets should be taken with food. See DOSAGE AND ADMINISTRATION, Extended-release tablets 500 mg.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Test Interactions

Several reports of possible interference with measurement, by liquid chromatography, of urinary normetanephrine causing a false-positive test result have been observed in patients exposed to sulfasalazine or its metabolite, mesalazine/mesalamine/5-ASA.

Dosage and Administration

Extended-release tablets 500 mg and 1g

Management of mild to moderate active ulcerative colitis and maintenance therapy: Therapy should be initiated at 0.5 g four times daily (2 g daily dose). The dose may be increased to 1 g four times daily (4 g daily dose) if additional therapeutic benefit is needed.

Management of mild to moderate Crohn’s disease: The optimal dose is 1 g four times daily (4 g daily dose). For patients with Crohn’s Disease in remission, a dose of 3 g daily in divided doses is recommended.

PENTASA extended-release tablets should not be chewed, broken or crushed but should be swallowed whole.

PENTASA extended-release tablets should be taken with meals.

Rectal suspension

The recommended dose ranges from 1 g to 4 g of 5-ASA, depending on disease activity. PENTASA may be self-administered once daily at bedtime. Dosage may be adjusted according to the individual patient's needs consistent with therapeutic goals.

Prolonged retention is expected to achieve the best therapeutic response.

Suppositories

The usual dose of PENTASA suppositories is one suppository containing 1 g of 5-ASA, self-administered once daily at bedtime. Prolonged retention is expected to achieve the best therapeutic response. The frequency of dosage may be adjusted according to the individual patient's needs consistent with therapeutic goals.

Overdosage

For management of a suspected drug overdose, contact your Regional Poison Control Centre.

Symptoms of Overdosage

There is no clinical experience with PENTASA (5-ASA) overdosage. Single oral doses of 5-ASA up to 5 g/kg in pigs and a single intravenous dose of 5-ASA at 920 mg/kg in rats were not lethal.

In cases of suspected overdose, symptomatic treatment at hospital is required. Fluid and electrolyte, as well as acid/base imbalances, should be corrected by the administration of appropriate intravenous therapy. Close monitoring of renal function is required in order to maintain adequate renal function. No cases of overdose have been reported.

Action and Clinical Pharmacology

Mechanism of Action

5-ASA is an aminosalicylate, gastrointestinal anti-inflammatory agent. Aminosalicylates are considered to be one of the first line therapy(s) for inflammatory bowel diseases.

Mesalazine is the active component of sulfasalazine, which has been used for a long time in the treatment of ulcerative colitis and Crohn’s disease.

The therapeutic value of mesalazine appears to be due to local effect on the inflamed intestinal tissue, rather than to systemic effect.

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 in-vitro and in-vivo pharmacological effects that inhibit leukocyte chemotaxis, decrease cytokine and leukotriene production and scavenge for free radicals. The mechanism of action of mesalazine is, however, still not understood.

Pharmacodynamics

Regardless of its mode of action, 5-ASA appears to exert its therapeutic effect by topical action on the affected areas of inflammation.

PENTASA tablets are composed of 5-ASA extended-release granules that allows for a predictable, uniform, and continuous release of drug throughout the small (duodenum, jejunum and ileum) and large bowel (colon), at all enteral pH conditions. The release is not

significantly compromised by diarrhea or increased bowel acidity, conditions which accompany active inflammatory bowel disease.

The PENTASA dosage forms designed for rectal administration, enemas and suppositories, are well suited to deliver the active ingredient, 5-ASA, directly to affected areas along the mucosal lumen of the rectum, sigmoid and distal large bowel.

Pharmacokinetics: Oral Dosage Forms

Absorption

Based on urinary excretion data, 20% to 30% of the 5-ASA in PENTASA is absorbed. In contrast, when 5-ASA is administered orally as an unformulated 1 g aqueous suspension, 5-ASA is approximately 80% absorbed. Plasma 5-ASA concentration peaked at approximately

1 μg/mL three hours after a 1 g dose of PENTASA, and declined in a biphasic manner.

N-acetyl-5-ASA, the major metabolite of 5-ASA, peaked at approximately 3 hours at

1.8 μg/mL and its concentration followed a biphasic decline. Pharmacological activities of N-acetyl-5-ASA are unknown and other metabolites have not been identified.

Oral 5-ASA pharmacokinetics were non-linear when PENTASA capsules were dosed from 250 mg to 1 g four times daily, with steady-state 5-ASA plasma concentrations increasing about nine times, from 0.14 μg/mL to 1.21 μg/mL, suggesting saturable first-pass metabolism. N-acetyl-5-ASA pharmacokinetics was linear.

Co-administration of 5-ASA tablets and a high fat meal was found to inhibit 5-ASA and N-acetyl-5-ASA systemic absorption. Bioavailability of 5-ASA decreased by about 70% and peak concentration decreased by about 60% as compared to the fasting state. N-acetyl-5-ASA pharmacokinetics was affected to a lesser extent, i.e., a 24% decrease in bioavailability and peak concentration. When food was present, less free 5-ASA was eliminated in the feces (33%), although 15.2% more salicylates were eliminated in the feces than under fasting conditions. The same effect was observed after administration of 5-ASA in a suspension, indicating that the interaction involves 5-ASA, not the PENTASA delivery system.

The effect of food on the new formulation of Pentasa 500 mg extended release tablets has not been established.

Distribution

Scintigraphic studies have shown that in the stomach, PENTASA extended release tablets disintegrate immediately into discrete extended release microgranules which are spread throughout the entire gastro-intestinal tract. The microgranules are emptied from the stomach within 17 + 5 minutes under fasted conditions and within about 30 minutes when a breakfast meal is served 5 minutes post-dose. Therefore the residence time in the stomach is not affected by post-dose food intake. The transit time through the small intestine has been shown to be 213 + 45 minutes after which the microgranules arrive in the caecum. The small intestinal transit is not affected by post-dose food intake since no statistically significant

difference could be detected between conditions in which subjects were fasted and those in which a meal was administered 5 minutes post-dose. The small intestinal transit time was 3.7 hours in fasted subjects and 3.1 hours in a fasted subject that had a breakfast meal 5 minutes post-dose. The microgranules reside in the colon for about 8 hours. The independence of food intake and intestinal transit has also been shown in another study, where the gastric emptying and small intestinal transit of 5-ASA microgranules occurred within the digestive period and synchronous with the meal.

Metabolism

5-ASA is rapidly acetylated to N-acetyl-5-ASA. Pharmacological activities of N-acetyl-5-ASA are unknown and other metabolites have not been identified.

Excretion

In published single dose studies of PENTASA tablets, Rasmussen (1982) and Rijk (1988), both reported total combined fecal and urinary excretion to be 77% of total dose. Total fecal recovery varied slightly between reports. About 130 mg of free 5-ASA was recovered in the feces following a single 1 g PENTASA dose. Forty-six percent of the dose was eliminated in the feces as 5-ASA and N-acetyl-5-ASA. Elimination of free 5-ASA and salicylates in feces increased proportionately with the dose of PENTASA. N-acetyl-5-ASA was the primary compound excreted in the urine (19% - 30%) following PENTASA dosing.

The literature describes a mean terminal half-life of 42 minutes for 5-ASA following intravenous administration. Because of the continuous release and absorption of 5-ASA from PENTASA throughout the gastrointestinal tract, the true elimination half-life cannot be determined after oral administration.

Pharmacokinetics: Rectal Dosage Forms

Absorption

The local and systemic bioavailability of PENTASA (5-ASA) enema and PENTASA suppositories were assessed in 12 healthy volunteers under steady-state conditions. Systemic absorption of 5-ASA was low. 15% of the 2 g daily dose was recovered in the urine (mostly as the acetylated metabolite) after administration of the enema, with 10% urinary recovery observed after administration of the suppositories. This compares to 20% to 30% of the 5-ASA dose being absorbed systemically following oral administration.

Maximum plasma concentrations of 5-ASA and of N-acetyl-5-ASA (approximately 0.7 μg/mL and 1.2 μg/mL respectively for the enema; 0.3 μg/mL and 0.8 μg/mL respectively for the suppositories) were reached 2 hours following administration of the enema and 5 to 6 hours following administration of the suppositories.

Local availability, as shown by recovery of free 5-ASA in the feces, was higher for both the enema (mean 30%) and the suppositories (mean 45%) than for the oral dosage forms of 5-ASA.

Bondesen et al demonstrated that systemic absorption from 5-ASA enemas was pH dependent, showing a significantly greater absorption at pH 7.4 (mean Cmax in plasma 1.18 μg/mL for 5-ASA, 0.55 μg/mL for N-acetyl-5-ASA) than at pH 4.8 (Cmax 0.35 μg/mL for 5-

ASA, 0.55 μg/mL for N-acetyl-5-ASA). In another study, Bondesen et al demonstrated that systemic absorption of 5-ASA occurred to a similar degree in the right and the left parts of the colon, both being significantly lower than the absorption from the small intestine.

Systemic absorption of 5-ASA was shown to be dose and volume dependent. Using a concentration of 4 g of 5-ASA in 100 mL enema, Campieri et al observed mean plasma levels of approximately 4 μg/mL for total (free and acetylated) 5-ASA, which was approximately double of the level observed with 2 g of 5-ASA enema. Systemic absorption was also increased when the volume of the enema was doubled, as shown by significant increase in urinary recovery. These same authors also showed that systemic absorption of 5-ASA was significantly decreased in patients with active disease as compared to those in remission. They found no evidence of accumulation of total 5-ASA in plasma after repeated daily administration of 2 g or 4 g enemas for 15 days to patients with active disease. This was also confirmed by Almer and collaborators with patients in remission, given 4 g enemas once a day for 7 days. Low systemic absorption of 5-ASA from the suppository dosage form was also confirmed by Norlander et al who found mean peak plasma levels of 0.2 μg/mL for 5-ASA, 0.6 μg/mL for N-acetyl-5-ASA and urinary excretion of 10.8% (almost all as N-acetyl-5-ASA) following a single 500 mg dose of 5-ASA given as a suppository to 12 healthy, fasting volunteers.

Distribution

The extent of colonic distribution of 5-ASA was studied in patients with active left-sided ulcerative colitis, using scintigraphic imaging of 99mTc-labelled enemas and suppositories. These studies showed that the retrograde spread of 5-ASA from 100 mL enemas, containing either 1 g or 4 g of the active compound, usually extended beyond the rectosigmoid, reliably reaching the areas of inflammation up to and including the splenic flexure. With the suppositories, the spread of 99mTc-labelled 5-ASA was confined to the rectum and adjacent sigmoid colon, thereby acting on the inflamed mucosa in patients whose disease was localized in those areas.

Excretion

With regard to the clinically important local availability of free 5-ASA, the values, measured in terms of fecal excretion, ranged from 26% (48-hour recovery) to 29.4% (24-hour recovery) and 30% (48-hour recovery), following administration of the enema and from 45% (48-hour recovery) to a high of 64.8% (72-hour recovery) following administration of suppositories. This compares to approximately 13% of the orally administrated dose of 5-ASA being excreted in the feces as free 5-ASA.

Storage and Stability

Storage and Stability Information

PENTASA extended-release tablets (500 mg and 1 g) should be stored between 15oC and 30oC. Protect from light.

PENTASA (5-ASA) rectal suspension (enema) and PENTASA (5-ASA) suppositories should be stored at controlled room temperature, preferably below 25 C. They should be dispensed in their respective containers.

Keep out of the reach of children.

Dosage Forms, Composition and Packaging

NOTE: ALL PENTASA PRODUCTS ARE PHTHALATE FREE

Extended-release Tablets

Contains either 500 mg or 1 g of 5-ASA with the following non-medicinal ingredients: Microcrystalline cellulose, ethylcellulose, magnesium stearate, povidone, talc.

Pentasa tablets do not contain gluten, phthalates, or lactose.

PENTASA 500 mg Extended Release Tablets are round, white-grey to pale brown speckled tablets with a scoreline on one side and embossed “500 mg” on one side and “PENTASA” on the other. They are available in HDPE bottles containing 240 tablets, 500 tablets and 40 tablet samples and in unit dose blister strips of 10 tablets, in packages of 10 strips.

PENTASA 1g Extended Release Tablets are oblong, white-grey to pale brown speckled tablets embossed PENTASA on both sides. They are available in HDPE bottles containing 120 tablets, 20 tablet samples and in unit dose blister strips of 10 tablets, in packages of 6 strips.

Rectal Suspension

Is available in strengths of 1 g or 4 g per 100 mL with the following non-medicinal ingredients: sodium acetate, sodium edetate, sodium metabisulfite, purified water, with hydrochloric acid to adjust the pH to 4.8. Each unit dose of rectal suspension enema contains 5-ASA in concentrations of either: 1 g/100mL or 4 g/100 mL. Each carton contains 7 enemas together with 7 hygienic bags.

PENTASA rectal suspension is supplied in a low density polyethylene (LDPE) bottle.

Suppositories

Contain 1 g of 5-ASA with the following non-medicinal ingredients: polyethylene glycol, povidone, talc, magnesium stearate. Each suppository contains 1 g of 5-ASA. Suppositories are packaged in blister cards of 5 suppositories per card. Each carton contains 6 cards of 5 suppositories for a total of 30 suppositories and finger protectors.

PENTASA suppositories are sealed in aluminium blisters made of double aluminium push through foils.