Olsalazine Sodium Capsules

The active ingredient in DIPENTUM Capsules (olsalazine sodium) is the sodium salt of a salicylate, disodium 3,3'-azobis (6-hydroxybenzoate) a compound that is effectively bioconverted to 5-aminosalicylic acid (5-ASA), which has anti-inflammatory activity in ulcerative colitis. Its empirical formula is C14H8N2N2O6 with a molecular weight of 346.21.

The structural formula is:

Olsalazine sodium is a yellow crystalline powder, which melts with decomposition at 240°C. It is the sodium salt of a weak acid, soluble in water and DMSO, and practically insoluble in ethanol, chloroform, and ether. Olsalazine sodium has acceptable stability under acidic or basic conditions.

DIPENTUM (olsalazine sodium capsules) is supplied in hard gelatin capsules for oral administration. The inert ingredient in each 250 mg capsule of olsalazine sodium is magnesium stearate. The capsule shell contains the following inactive ingredients: black iron oxide, caramel, gelatin, and titanium dioxide.

Olsalazine is indicated for the maintenance of remission of ulcerative colitis in patients who are intolerant of sulfasalazine.

No overdosage has been reported in humans. The knowledge of overdosage is limited. Possible overdose symptoms include nausea, vomiting and diarrhea. It is recommended to check hematology, acid-base, electrolyte, liver and kidney status, and to provide supportive treatment. There is no specific antidote to DIPENTUM (olsalazine sodium capsules) .

Maximum single oral doses of 5g/kg in mice and rats and 2 g/kg in dogs were not lethal. Symptoms of acute toxicity were decreased motor activity and diarrhea in all species tested. In addition, vomiting was reported in dogs.

After oral administration, olsalazine has limited systemic bioavailability. Based on oral and intravenous dosing studies, approximately 2.4% of a single 1.0 g oral dose is absorbed. Less than 1% of olsalazine is recovered in the urine. The remaining 98 to 99% of an oral dose will reach the colon, where each molecule is rapidly converted into two molecules of 5-aminosalicylic acid (5-ASA) by colonic bacteria and the low prevailing redox potential found in this environment. The liberated 5-ASA is absorbed slowly resulting in very high local concentrations in the colon.

The conversion of olsalazine to mesalamine (5-ASA) in the colon is similar to that of sulfasalazine, which is converted into sulfapyridine and mesalamine. It is thought that the mesalamine component is therapeutically active in ulcerative colitis (A.K. Azad-Kahn et al, LANCET, 2: 892-895, 1977). The usual dose of sulfasalazine for maintenance of remission in patients with ulcerative colitis is 2 grams daily, which would provide approximately 0.8 gram of mesalamine to the colon. More than 0.9 gram of mesalamine would usually be made available in the colon from 1 gram of olsalazine.

The mechanism of action of mesalamine (and sulfasalazine) is unknown, but appears to be topical rather than systemic. Mucosal production of arachidonic acid (AA) metabolites, both through the cyclooxygenase pathways (i.e., prostanoids) and through the lipoxygenase pathways (i.e., leukotrienes [LTs] and hydroxyeicosatetraenoic acids [HETEs]) is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin (PG) production in the colon.

Pharmacokinetics

The pharmacokinetics of olsalazine are similar in both healthy volunteers and in patients with ulcerative colitis. Maximum serum concentrations of olsalazine appear after approximately 1 hour and, even after a 1.0 g single dose, are low (e.g., 1.6 to 6.2 µmol/L). Olsalazine has a very short serum half-life, approximately 0.9 hour. Olsalazine is more than 99% bound to plasma proteins. It does not interfere with protein binding of warfarin. The urinary recovery of olsalazine is below 1%. Total recovery of oral 14C-labeled olsalazine in animals and humans ranges from 90 to 97%. Approximately 0.1% of an oral dose of olsalazine is metabolized in the liver to olsalazine-O-sulfate (olsalazine-S). Olsalazine-S, in contrast to olsalazine has a half-life of 7 days. Olsalazine-S accumulates to steady state within 2 to 3 weeks.

Patients on daily doses of 1.0 g olsalazine for 2 to 4 years show a stable plasma concentration of olsalazine-S (3.3 to 12.4 µmol/L). Olsalazine-S is more than 99% bound to plasma proteins. Its long half-life is mainly due to slow dissociation from the protein binding site. Less than 1% of both olsalazine and olsalazine-S appears undissociated in plasma.

Serum concentrations of 5-ASA are detected after 4 to 8 hours. The peak levels of 5-ASA after an oral dose of 1.0 g olsalazine are low (i.e., 0 to 4.3 µmol/L). Of the total 5-ASA found in the urine, more than 90% is in the form of N-acetyl-5-ASA (Ac-5-ASA). Only small amounts of 5-ASA are detected.

N-acetyl-5-ASA (Ac-5-ASA), the major metabolite of 5-ASA found in plasma and urine, is acetylated (deactivated) in at least two sites, the colonic epithelium and the liver. Ac-5-ASA is found in the serum, with peak values of 1.7 to 8.7 µmol/L after a single 1.0 g dose. Approximately 20% of the total 5-ASA is recovered in the urine, where it is found almost exclusively as Ac-5-ASA. The remaining 5-ASA is partially acetylated and is excreted in the feces. From fecal dialysis, the concentration of 5-ASA in the colon following olsalazine has been calculated to be 18 to 49 mmol/L. No accumulation of 5-ASA or Ac-5-ASA in plasma has been detected. 5-ASA and Ac-5-ASA are 74 and 81%, respectively, bound to plasma proteins.

Animal Toxicology

Preclinical subacute and chronic toxicity studies in rats have shown the kidney to be the major target organ of olsalazine toxicity. At an oral daily dose of 400 mg/kg or higher, olsalazine treatment produced nephritis and tubular necrosis in a 4-week study; interstitial nephritis and tubular calcinosis in a 6-month study, and renal fibrosis, mineralization, and transitional cell hyperplasia in a 1-year study.

Clinical Studies

Two controlled studies have demonstrated the efficacy of olsalazine as maintenance therapy in patients with ulcerative colitis. In the first, ulcerative colitis patients in remission were randomized to olsalazine 500 mg B.I.D. or placebo, and relapse rates for a six month period of time were compared. For the 52 patients randomized to olsalazine, 12 relapses occurred, while for the 49 placebo patients, 22 relapses occurred. This difference in relapse rates was significant (p < 0.02).

In the second study, 164 ulcerative colitis patients in remission were randomized to olsalazine 500 mg B.I.D. or sulfasalazine 1 gram B.I.D., and relapse rates were compared after six months. The relapse rate for olsalazine was 19.5% while that for sulfasalazine was 12.2%, a non-significant difference.

Patients should be instructed to take olsalazine with food. The drug should be taken in evenly divided doses. Patients should be informed that about 17% of subjects receiving olsalazine during clinical studies reported diarrhea sometime during therapy. If diarrhea occurs, patients should contact their physician.

Follow your doctor's instructions about any restrictions on food, beverages, or activity while you are using olsalazine.

Avoid getting a varicella (chickenpox) vaccine within 6 weeks after you stop taking olsalazine.