escription: Olsalazine, a salicylic acid derivative, is used in the treatment of ulcerative colitis. Olsalazine, administered orally, is a prodrug that is converted to mesalamine, which is the active moiety. Mesalamine (see separate monograph) is also commercially available in oral and rectal preparations. Even though mesalamine is a metabolite of olsalazine, mesalamine blood levels are lower when administered as olsalazine. Because the action of mesalamine is believed to be due to its local effects, side effects can be minimized by administering mesalamine in the form of its prodrug olsalazine. Olsalazine was approved by the FDA in July 1990. Mechanism of Action: Although the mechanism of action of olsalazine has not been fully elucidated, it appears to be local rather than systemic. Olsalazine is converted to mesalamine in the GI tract by colonic bacteria. The antiinflammatory mechanism of mesalamine is believed to occur, at least in part, through the inhibition of prostaglandin production in the bowel mucosa by inhibition of cyclooxygenase. This effectively diminishes the production of arachidonic acid metabolites, thereby reducing colonic inflammation. Production of arachidonic metabolites appears to be increased in patients with inflammatory bowel disease. Mesalamine also inhibits leukotriene synthesis, possibly through the inhibition of lipoxygenase, which catalyzes the production of arachidonic acid. This activity has been suggested as a major component of the drug's antiinflammatory effects. Inhibition of colonic mucosal sulfidopeptide leukotriene synthesis and chemotactic stimuli for polymorphonuclear leukocytes also may occur. Other possible mechanisms include alterations in colonic fluid balance, immunosuppression, and alteration of the GI bacterial flora. Pharmacokinetics: Olsalazine is administered orally. Approximately 99% of olsalazine reaches the colon after oral administration. Once in the colon, each molecule of olsalazine is rapidly converted into two molecules of mesalamine by colonic bacteria. Serum concentrations of mesalamine are seen 4�8 hours after oral administration. Mesalamine is acetylated to N-acetyl-5-ASA (Ac-5-ASA). Ac-5-ASA is then acetylated by the liver and the colonic epithelium. Olsalazine and mesalamine are 99% and 74% bound to plasma proteins, respectively. It is unknown whether olsalazine or its metabolites cross the placenta or are distributed into breast milk (see Contraindications). The elimination half-life of mesalamine is 0.5�1.5 hours after rectal administration, but it can vary from 2�15 hours after oral administration of olsalazine. Less than 1% of the drug is excreted in the urine, but 90% of the total urinary mesalamine is excreted as Ac-5-ASA. About 80% of mesalamine (some acetylated) is eliminated in the feces.

Indications...Dosage For the treatment of ulcerative colitis: Oral dosage: Adults: The recommended dosage for maintenance of remission is 500 mg PO twice daily. In a dose-ranging study, olsalazine doses of 0.5 g, 1 g, or 2 g/day PO maintained remission in 60%, 70%, and 78% of patients, respectively, with the higher dose (2 g/day) more effective than lower doses in patients with proctitis or those in remission for less than 12 months before study enrollment.[1920] Olsalazine has also been used to induce remission in patients with mild to moderate active ulcerative colitis. Up to 3 g/day PO has been used. Do not exceed 1 g/dose.[1921] Children: The safety and efficacy of olsalazine was compared to sulfasalazine in a randomized, double-blind study of 56 children (ages 2�18 years) with mild to moderate ulcerative colitis. The dosage of olsalazine used in this study was 30 mg/kg/day PO (maximum: 2 g/day), in two divided doses. Although patients treated with olsalazine had less adverse effects than those treated with sulfasalazine (39% vs 46%), fewer patients treated with olsalazine demonstrated clinical improvement (39% vs 79%).[1922] Patients with renal impairment: Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Oral Administration �Administer orally with food.

Contraindications Although olsalazine has not been reported to cause renal disturbances, it should be used with caution in patients with preexisting renal disease due to the potential risk of developing renal tubular damage. Monitoring parameters should include urinalysis, BUN, and creatinine clearance. Olsalazine is a salicylate derivative; therefore, patients sensitive to mesalamine or who have a history of severe salicylate hypersensitivity can demonstrate cross-sensitivity. Olsalazine should be avoided in these patients. Olsalazine is classified as pregnancy category C and has been shown to produce fetotoxic effects in animal studies. Well-controlled studies in humans have not been conducted, so olsalazine should be used during pregnancy only when the benefits outweigh the potential harm to the fetus. It is unknown whether olsalazine or its metabolites distribute into breast milk. Use caution when administering this drug during breast-feeding.

Interactions Mesalamine, the metabolite of olsalazine, can decrease the GI absorption of digoxin; however, this has not been confirmed by well-controlled clinical trials.

Adverse Reactions Blood dyscrasias, characterized by fever, pallor, sore throat, fatigue, and unusual bleeding and bruising, have been reported rarely during therapy with olsalazine and require discontinuation of the drug. Exacerbation of ulcerative colitis has occurred during therapy with olsalazine, with symptoms such as bloody diarrhea, fever, and skin rash. This complication is believed to originate from an effect caused by olsalazine. The manufacturer reports that in a double-blind, placebo-controlled study, increased frequency and severity of diarrhea were reported in patients randomized to olsalazine 500 mg twice daily with concomitant radiation. GI disturbances are frequently associated with olsalazine. Diarrhea is the most common adverse reaction, occurring in about 17% of patients, with 6% requiring discontinuation of the drug. This adverse reaction appears to be dose-related, but it can be difficult to distinguish from symptoms of the disease. Abdominal pain or cramps occur in 10.1%, followed by nausea/vomiting in 5% of patients. Less commonly reported gastrointestinal effects include bloating and anorexia. Olsalazine and related products that are metabolized to (or contain) mesalamine have been reported in post-market use to cause rare cases of elevated hepatic enzymes, hepatitis, hyperbilirubinemia, jaundice, cholestasis with jaundice, cirrhosis, and possible hepatocellular damage including hepatic necrosis and hepatic failure. The incidence of hepatic adverse events is not known. In some cases, the reactions were fatal. One case of Kawasaki-syndrome, which included hepatic changes, was also reported. CNS disturbances, such as dizziness, depression, and headache, occur less frequently than GI effects during therapy with olsalazine and may not be clinically significant when compared with placebo-controlled groups. Rash and pruritus occur in 2.3% and 1.3% of patients, respectively, during therapy with olsalazine. Arthralgia has been reported with a frequency of 4%.

Olsalazine Dipentum�

1920. Travis SP, Tysk C, de Silva HJ, et al. Optimum dose of olsalazine for maintaining remission in ulcerative colitis. Gut 1994;35:1282�6.

1921. Zinberg J, Molinas S, Das KM. Double-blind placebo-controlled study of olsalazine in the treatment of ulcerative colitis. Am J Gastroenterol 1990;85:562�6.

1922. Ferry GD, Kirschner BS, Grand RJ, et al. Olsalazine versus sulfasalazine in mild to moderate childhood ulcerative colitis: results of the Pediatric Gastroenterology Collaborative Research Group Clinical Trial. J Pediatr Gastroenterol Nutr 1993;17:32�8.