Pentasa (5-Aminosalicylic Acid)

PENTASA®

Hoechst Marion Roussel

5-Aminosalicylic Acid

Gastrointestinal Anti-inflammatory

Action And Clinical Pharmacology: Pentasa is a unique, ethylcellulose-coated, delayed-release formulation of 5-ASA, an aminosalicylate, gastrointestinal anti-inflammatory agent for oral administration. 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.

Although the mechanism of action of 5-ASA is unknown, its therapeutic effect appears to be nonsystemic. 5-ASA has in vitro and in vivo pharmacologic effects that decrease leukotriene production, scavenge for free radicals, and inhibit leukocyte chemotaxis. It is currently unknown which, if any, of these mechanisms play a predominant role in the clinical effectiveness of 5-ASA.

Pentasa is designed to release therapeutic quantities of 5-ASA throughout the small (jejunum and ileum) and large (colon) bowel. Based on urinary excretion data, 20 to 30% of 5-ASA in Pentasa is absorbed. It is rapidly acetylated to N-acetyl-5-ASA. Plasma 5-ASA concentration peaks at approximately 1 g/mL 3 hours following a 1 g Pentasa dose, and declines rapidly in a biphasic manner. N-acetyl-5-ASA peaks at approximately 1.8 g/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.

About 130 mg free 5-ASA is recovered in the feces following a single 1 g Pentasa dose, which is comparable to the amount of 5-ASA recovered from a molar equivalent sulfasalazine dose of 2.5 g. Elimination of free 5-ASA and salicylates in feces increases proportionately with Pentasa dose. N-acetyl-5-ASA is the primary compound excreted in the urine (19 to 30% of dose).

Indications And Clinical Uses: For the treatment of acute ulcerative colitis and for long-term maintenance therapy in order to maintain remission and prevent relapse of active disease.

For the management of mild to moderate Crohn’s disease, and as a maintenance therapy for patients with Crohn’s disease in remission induced by surgery or medication.

Contra-Indications: Patients with existing gastric or duodenal ulcer, patients with urinary tract obstruction and patients who have demonstrated hypersensitivity to 5-ASA or salicylates.

Manufacturers’ Warnings In Clinical States: Impaired Renal or Hepatic Function: Caution should be exercised if 5-ASA is administered to patients with impaired renal or hepatic function.

Single reports of nephrotic syndrome and interstitial nephritis associated with 5-ASA therapy have been described in the literature. Animal studies have demonstrated a dose-dependent nephrotoxicity. Patients with pre-existing renal disease, increased BUN or serum creatinine, or proteinuria should be carefully monitored.

Pregnancy: 5-ASA should be used during pregnancy only if clearly needed.

5-ASA is known to cross the placental barrier.

Lactation: Caution should be exercised when 5-ASA is administered to a nursing woman.

Children: Safety and efficacy have not been established in children. The potential benefits of its use should be weighed against the possible risks.

Precautions: General: 5-ASA has been associated with the production of an acute intolerance syndrome which may be difficult to distinguish from flare 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 Crohn’s disease and ulcerative colitis studies, most patients who were intolerant or hypersensitive to sulfasalazine were able to take 5-ASA without evidence of allergic reaction (e.g., rash, fever, pruritus) or intolerance. Nevertheless, caution should be exercised when 5-ASA 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 5-ASA during controlled clinical trials. Semen quality significantly improved when patients were transferred from sulfasalazine to 5-ASA.

Drug Interactions: There are no known interactions between 5-ASA and other drugs.

Adverse Reactions: Ulcerative Colitis: In 2 placebo-controlled clinical trials involving over 600 patients, adverse event rates for 5-ASA were similar to, or less than, those seen in the placebo group (5-ASA 14% vs placebo 18%) and were not dose-related. No single event was reported at a rate greater than 4% in the patients who received 5-ASA. Of the most common events, only nausea, rash, and vomiting had a higher incidence in the 5-ASA group relative to placebo.

Crohn’s Disease: In 2 placebo-controlled clinical trials involving over 540 patients with acute Crohn’s disease, 21% of the 5-ASA patients and 12% of the placebo patients, reported treatment-related adverse events. The adverse event rate for the 5-ASA group was not dose-related. No single event was reported at a rate greater than 5% in patients who received 5-ASA.

The most commonly reported 5-ASA related events were nausea 4.9%, headache 4.4%, abdominal pain 3.9%, diarrhea 3.4%, rash 2.8%, vomiting 2.6%, stool abnormalities 1.6%, back pain 1.0%, asthenia 1.0%, dyspepsia 1.0%, and pruritus 1.0%.

In a 48-week, placebo-controlled, maintenance therapy trial conducted in 293 patients with Crohn’s disease in remission, treatment-related events were reported by 31% of patients in both the 5-ASA and the placebo groups. The most commonly reported treatment-related events in the 5-ASA group were abdominal pain (5%), diarrhea (5%), nausea (3.5%), headache (3.5%), abdominal cramps (2.1%), loose stools (2.1%), dyspepsia (1.4%), heartburn (1.4%), exacerbation of headache (1.4%) and edema of the hands (1.4%).

When considering all clinical trials together (ulcerative colitis and Crohn’s disease), more than 2 600 patients have received 5-ASA therapy. Generally, 5-ASA was well tolerated. The most common events (i.e., greater than 1%) were: diarrhea (3.4%), headache (2.4%), nausea (2.3%), abdominal pain (2.4%), vomiting (1.7%), dyspepsia (1.6%), and rash (1.5%).

The following events were reported infrequently (i.e., less than 1%) during trials. In many cases the relationship to 5-ASA has not been established.

Gastrointestinal: abdominal distention, anorexia, duodenal ulcer, dysphagia, eructation, esophageal ulcer, fecal incontinence, gastrointestinal bleeding, gastrointestinal disturbances, increase in bowel movements, melena, mouth irritation, mouth ulcer, oral moniliasis, pancreatitis, rectal bleeding, rectal urgency, thirst.

Dermatological: acne, alopecia, dry skin, eczema, erythema nodosum, erythematous rash, hirsutism, nail disorder, photosensitivity, pruritus, skin discoloration, sweating.

Nervous System: anxiety, abnormal dreams, dizziness, insomnia, somnolence, paresthesia.

Cardiovascular: postural hypotension, tachycardia, vasodilation.

Respiratory: dyspnea, increased coughing, pharyngitis.

Metabolic: alkaline phosphatase increase, amylase increase, C reactive protein increase, creatinine increase, GGTP increase, LDH increase, proteinuria, AST increase, ALT increase, weight decrease, weight increase.

Other: albuminuria, anemia, appetite decreased, 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, urinary frequency, urinary infection, urination disorder, vaginitis, weakness.

Isolated case reports have described pericarditis, pancreatitis, nephrotic syndrome and interstitial nephritis associated with 5-ASA.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no clinical experience with 5-ASA overdosage. 5-ASA is an aminosalicylate and symptoms of salicylate toxicity may be possible, such as: tinnitus, vertigo, headache, confusion, drowsiness, sweating, hyperventilation, vomiting and diarrhea. Severe intoxication with salicylates can lead to disruption of electrolyte balance and blood pH, hyperthermia and dehydration. Since 5-ASA is an aminosalicylate, conventional therapy for salicylate toxicity may be beneficial in the event of acute overdosage. This includes prevention of further gastrointestinal tract absorption by emesis and, if necessary, by gastric lavage. Fluid and electrolyte imbalance should be corrected by the administration of appropriate i.v. therapy. Adequate renal function should be maintained.

Dosage And Administration: 5-ASA is effective as a single oral agent for the treatment of acute ulcerative colitis and for long-term maintenance therapy in order to maintain remission and prevent relapse of active disease.

5-ASA is also effective for the management of mild to moderate Crohn’s disease and as a maintenance therapy for patients with Crohn’s disease in remission induced by surgery or medication. Dosage should be adjusted for each patient’s needs consistent with achieving a satisfactory therapeutic response.

Ulcerative Colitis: Therapy should be initiated at 0.5 g 4 times daily (2 g daily dose). If additional therapeutic benefit is needed, the dose may be increased to 1 g 4 times daily (4 g daily dose).

Crohn’s Disease: The optimal dose for mild to moderate disease 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. The management of Crohn’s disease in remission should start as soon as remission is achieved.

5-ASA should be taken before meals and at bedtime with fluids. Pentasa should not be chewed, broken or crushed before being swallowed.

Availability And Storage: 250 mg: Each white to grey or light brown, speckled, scored, delayed-release tablet, with PENTASA on one side and 250 on the other, contains: 5-ASA 250 mg. Nonmedicinal ingredients: cellulose, ethylcellulose, magnesium stearate, povidone and talc. Gluten-free. Bottles or blister packs of 240 and 480.

500 mg: Each white to grey or light brown, speckled, scored, delayed-release tablet, with PENTASA on one side and 500 on the other, contains: 5-ASA 500 mg. Nonmedicinal ingredients: cellulose, ethylcellulose, magnesium stearate, povidone and talc. Gluten-free. Bottles or blister packs of 240 and 480.

Store at room temperature (15 to 30°C). (Shown in Product Recognition Section)

PENTASA® Hoechst Marion Roussel 5-Aminosalicylic Acid Gastrointestinal Anti-inflammatory

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