Information for the Patient
Pentasa
Pharmacology
PENTASA (5-aminosalicylic acid or 5-ASA) is an ethylcellulose-coated, extended-release formulation of 5-ASA, an aminosalicylate, gastrointestinal anti-inflammatory agent. Aminosalicylates are considered to be first line therapy for inflammatory bowel diseases. 5-ASA is known to be therapeutically active in Crohn's Disease and ulcerative colitis.
5-ASA has in vitro and in vivo pharmacologic effects that decrease leukotriene production, scavenge for free radicals and inhibit leukocyte chemotaxis. While the exact mode of action is currently unknown, any of these biochemical mechanisms may play a role in the clinical effectiveness of 5-ASA.
Regardless of its mode of action, 5-ASA appears to exert its therapeutic effect by topical action on the affected areas of inflammation. The oral dosage form of PENTASA extended-release tablets allows a very predictable, uniform, and continuous release of drug in the small (duodenum, jejunum and ileum) and large bowel (colon), at all enteral pH conditions, which is not significantly compromised by diarrhoea 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.
Based on urinary excretion data, 20% to 30% of 5-ASA in PENTASA extended-release tablets is absorbed. It is rapidly acetylated to N-acetyl-5-ASA. Plasma 5-ASA concentration peaks at approximately 1 μg/mL three hours after a 1 g dose of PENTASA, and declines rapidly in a biphasic manner. N-acetyl-5-ASA peaks at approximately 1.8 μg/mL and its concentration also follows a biphasic decline. Pharmacological activities of N-acetyl-5-ASA are unknown and other metabolites have not been identified.
Under steady-state conditions, 15% of the 2 g daily dose was recovered in the urine (mostly as the acetylated metabolite) after administration of PENTASA (5-ASA) enema, with 10% urinary recovery observed after administration of PENTASA suppositories. 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. About 130 mg of free 5-ASA was recovered in the faeces following a single 1 g dose of PENTASA (2×500 mg tablets). Elimination of free 5-ASA and salicylates in faeces increased proportionately with dose. N-acetyl-5-ASA was the primary compound excreted in the urine (19%-30% of dose).
Local availability, as shown by recovery of free 5-ASA in the faeces, was higher for both the enema (mean 30%) and the suppositories (mean 45%) than for the oral dosage forms of 5-ASA.
Scintigraphic studies have shown that in the stomach, PENTASA tablets disintegrate immediately into discrete microgranules which are spread throughout the entire gastrointestinal 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 simultaneous 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 food intake since no statistically significant difference could be detected between fasted and fed conditions. 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.
Coadministration 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 were 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.
Indications
PENTASA (5-ASA) extended-release tablets are indicated for the 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. PENTASA (5-ASA) extended-release tablets are also indicated for the management of mild to moderate Crohn's Disease, and as maintenance therapy for patients with 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.
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.
Precautions
A potential risk of myelosuppression, particularly leucopenia when aminosalicylates are coadministered with azathioprine or 6-mercaptopurine.
A potential risk of renal failure when aminosalicylates are coadministered with other nephrotoxic agents such as NSAIDs and azathioprine.
5-ASA has been associated with the production of an acute intolerance syndrome which may be difficult to distinguish from a flare-up of inflammatory bowel disease. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache and rash. If acute intolerance syndrome is suspected, prompt withdrawal is required. If a rechallenge is performed later in order to validate the hypersensitivity, it should be carried out under close medical supervision at reduced dose and only if clearly needed.
In ulcerative colitis studies, most patients who were intolerant or hypersensitive to sulfasalazine were able to take PENTASA (5-ASA) without evidence of allergic reaction (e.g., rash, fever, pruritus) or intolerance. Nevertheless, since rash is more often seen in PENTASA-treated patients than in placebo-treated patients (1.6% vs 0.6%), caution should be exercised when PENTASA is used in patients known to be allergic to sulfasalazine. These patients should be instructed to discontinue therapy if signs of rash or fever become apparent.
Semen abnormalities and infertility in men, which are associated with sulfasalazine, have not been reported with PENTASA during controlled clinical trials. Semen quality significantly improved when patients were transferred from sulfasalazine to PENTASA.
Supplied
Each unit dose (100 mL) of rectal suspension enema contains: 5-ASA 1 g or 4 g. Nonmedicinal ingredients: hydrochloric acid (to adjust the pH to 4.8), purified water, sodium acetate, sodium edetate, sodium metabisulfite. Cartons of 7 enemas together with 7 hygienic bags. Store at controlled room temperature, preferably below 25°C. Dispense in the respective carton.
Each suppository contains: 5-ASA 1 g. Nonmedicinal ingredients: magnesium stearate, polyethylene glycol, povidone, talc. Cartons of 30 suppositories in individual foil pouches with finger protectors. Store at controlled temperature, preferably below 25°C. Dispense in the respective carton.
Each round, flat, speckled beige, extended-release tablet with beveled edges, one face debossed with “PENTASA”, other face scored, debossed with “500” above scoreline and with “mg” below scoreline, contains: 5-ASA 500 mg. Nonmedicinal ingredients: cellulose, ethylcellulose, magnesium stearate, povidone and talc. Gluten-free. Bottles of 240. Store at room temperature (15 to 30°C).
Contraindications
In patients with existing gastric or duodenal ulcer. In 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; patients who have demonstrated hypersensitivity to derivatives of salicylate.
Warnings
Caution should be exercised when PENTASA is administered to a nursing woman. 5-ASA is excreted in breast milk. The concentration of 5-ASA is much lower than in maternal blood, but the metabolite N-acetyl-5-ASA appears in similar concentrations. There is limited experience of the use of oral mesalazine in lactating women. No controlled studies with PENTASA during breast-feeding have been carried out. Hypersensitivity reactions like diarrhea in the infants cannot be excluded.
The safety and efficacy of PENTASA have not been established in children under 12 years of age. The potential benefits of therapy should be weighed against the possible risks.
PENTASA should be used during pregnancy only if clearly needed. 5-ASA is known to cross the placental barrier. However no teratogenic effects have been observed in animal studies.
Blood disorders (leukopenia, thrombocytopenia, anemia) have been reported in newborns of mothers being treated with PENTASA.
Adverse Effects
abdominal distention, 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.
albuminuria, urinary frequency, urinary infection, urination disorder, vaginitis, isolated cases of nephrotic syndrome and interstitial nephritis.
anxiety, abnormal dreams, dizziness, insomnia, somnolence, paresthesia.
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.
dyspnea, increased coughing, pharyngitis.
acne, alopecia, dry skin, eczema, erythema nodosum, erythematous rash, hirsutism, 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.
alkaline phosphatase increase, amylase increase, C reactive protein increase, creatinine increase, GGTP increase, LDH increase, proteinuria, AST increase, ALT 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.
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.
The following events have been reported infrequently during trials and represent sporadic, idiosyncratic or hypersensitivity reactions, to be expected rarely.
postural hypotension, tachycardia.
Overdose
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 i.v. 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 i.v. therapy. Close monitoring of renal function is required in order to maintain adequate renal function. No cases of overdose have been reported.
Dosage
Extended-release Tablets 500 mg: Management of mild to moderate active ulcerative colitis and maintenance therapy: Therapy should be initiated at 0.5 g 4 times daily (2 g daily dose). The dose may be increased to 1 g 4 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 4 times daily (4 g daily dose). For patients with Crohn's disease in remission, a dose of 0.75 g 4 times daily (3 g daily dose) is recommended.
PENTASA extended-release tablets should not be chewed, broken or crushed but should be swallowed whole.
PENTASA extended-release tablets may be taken before meals without affecting drug bioavailability. Taking PENTASA with food may be helpful in alleviating gastrointestinal pain and nausea if these symptoms have been reported after taking the product on an empty stomach.
Rectal Suspension: The recommended dose ranges from 1 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 1 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.
