Dipentum (Olsalazine Sodium)

DIPENTUM®

Pharmacia & Upjohn

Olsalazine Sodium

Lower Gastrointestinal Anti-inflammatory

Action And Clinical Pharmacology: The conversion of olsalazine to 5-aminosalicylic acid (5-ASA) in the colon is similar to that of sulfasalazine, which is converted into sulfapyridine and 5-ASA. On a weight basis olsalazine delivers twice the amount of 5-ASA to the colon compared with sulfasalazine and there is no residual carrier molecule (sulfapyridine) following olsalazine administration. It is thought that the 5-ASA component is therapeutically active in ulcerative colitis. The mechanism of action of 5-ASA (and sulfasalazine) is unknown, but appears to be topical rather than systemic.

After oral administration olsalazine has limited systemic bioavailability. Based on oral and i.v. dosing studies approximately 2.4% of a single 1 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 to 2 molecules of 5-ASA by colonic bacteria. The liberated 5-ASA is absorbed slowly resulting in very high local concentrations in the colon.

Systemically absorbed olsalazine is rapidly cleared from plasma with a half-time of 0.9 hour. The plasma 5-ASA and acetylated-5-aminosalicylic acid (Ac-5-ASA) are rapidly cleared via the kidneys. The elimination half-times are 45 and 80 minutes, respectively. In urine less than 1% is recovered as olsalazine, 20% as Ac-5-ASA and less than 1% as 5-ASA. The remaining 80% is eliminated via the feces as 5-ASA and Ac-5-ASA.

Indications And Clinical Uses: Long-term maintenance of patients with ulcerative colitis in remission.

Treatment of acute ulcerative colitis of mild to moderate severity, with or without the concomitant use of steroids.

Contra-Indications: Hypersensitivity to salicylates.

Manufacturers’ Warnings In Clinical States: All 5-ASA preparations have been reported to cause an exacerbation of colitis symptoms in less than 1% of patients with ulcerative colitis. This reaction may also occur with olsalazine treatment due to the pharmacological similarities among these drugs.

Pregnancy: Animal reproductive studies performed on the rat, rabbit and mouse were negative, thus there is no preclinical evidence of an adverse effect on the parent generation nor on its offspring.

Olsalazine does not pass the rat placental barrier, as shown in an autoradiography study.

Well-controlled studies with olsalazine in pregnant women assessing fetal risk in humans are not available. Because animal reproduction studies are not always predictive of the human response, this drug should be used in pregnancy only if clearly needed.

Lactation: No peri- and postnatal effects have been observed in animal studies. Olsalazine is not appreciably excreted in rat breast milk as shown in a study using radioactively labelled drug.

Well-controlled studies with olsalazine in lactating women are not available. Olsalazine should be used during lactation only if clearly indicated.

Children: For children there are to date no trials to support the use of olsalazine. The benefits of treatment should therefore be weighed against the risks.

Precautions: Dipentum can be used with or without concomitant steroids for treatment of acute ulcerative colitis of mild to moderate severity.

The following definitions may serve as guidelines for selection of patients: Remission is defined as 3 or fewer bowel movements a day without macroscopic blood admixture and without sigmoidoscopic evidence of inflammation. Mild disease is defined as 3 to 5 bowel movements a day or other symptoms of colitis including rectal bleeding, anorexia or nausea. Moderate disease includes patients with at least 6 and up to 10 bowel movements per day, with or without rectal bleeding, anorexia, or nausea. Severe disease is indicated by 10 or more bowel movements per day and 1 or more of the following signs: abdominal tenderness, pulse rate greater than 100 beats/minute, body temperature higher than 37.5°C.

Drug Interactions: None known.

Drug/Laboratory Test Interactions : None known.

General: Overall, approximately 15% of patients reported diarrhea when olsalazine was initially administered, resulting in treatment withdrawal in 6%. This diarrhea appears to be dose related although it may be difficult to distinguish it from the underlying symptoms of the disease. The diarrhea is temporary and may depend on the extent of colonic involvement. However, the severity of ulcerative colitis does not appear to influence its occurrence.

Drug-related diarrhea in patients in remission is defined as watery stools 4 or more times a day without blood or sigmoidoscopic signs of inflammation. Withdrawal of the drug results in prompt clinical improvement of the diarrhea.

Disease-induced diarrhea (i.e., relapse of the colitis) is defined as 4 or more bowel movements a day with visible blood in association with sigmoidoscopic evidence of inflammation.

Drug-induced hypersensitivity colitis presents with increasing diarrhea that is frequently bloody. Other signs of hypersensitivity such as fever, skin rash, cramping, abdominal pain, or nausea are often part of this type of acute exacerbation. Sigmoidoscopy reveals the macroscopic changes of an active colitis. Withdrawal of the drug results in prompt improvement of this hypersensitivity reaction.

Information for the Patient: Patients should be made aware that ulcerative colitis rarely remits completely and that the risk of relapse can be substantially reduced by continuous administration of olsalazine. Patients should be instructed to take olsalazine regularly, not to take more than 4 capsules at any one dosing interval and to take the capsules with meals. The drug should be taken in evenly divided doses. Patients should be informed that in approximately 15% of cases loose stools or diarrhea may result on initial administration and that they should contact their physician if severe diarrhea occurs.

Adverse Reactions: Olsalazine has been evaluated in ulcerative colitis patients in remission as well as those with acute disease. Both sulfasalazine-tolerant and intolerant patients have been studied in controlled clinical trials. Overall, 10.4% of patients discontinued olsalazine because of an adverse experience as compared with 6.7% of placebo patients (see Table I). In sulfasalazine-controlled trials in which all patients were already known to be sulfasalazine-tolerant, adverse experiences with this drug resulted in a similar rate of discontinuance of treatment (10.0%).

In general, olsalazine is well tolerated; adverse effects appear to be mild and transient, and may be difficult to differentiate from the symptoms of the underlying disease (see Table II). Olsalazine appears to induce loose stools in approximately 15% of patients. This incidence may be reduced if olsalazine is initially titrated and taken with food.

Severe adverse effects commonly attributed to the sulfapyridine moiety of sulfasalazine (agranulocytosis, Stevens-Johnson syndrome, pulmonary oesinophilia, etc.) have not been reported with olsalazine. In addition, there have been no reports of nephrotoxicity.

Over 2 500 patients have also been treated with olsalazine in various uncontrolled, compassionate-use programs. In these studies, olsalazine was administered mainly to patients intolerant to sulfasalazine. The adverse effects related to olsalazine reported in these uncontrolled studies were similar to those seen in the controlled clinical trials. In addition, there were rare reports of the following adverse effects in patients receiving olsalazine. There is currently not enough information to support an estimate of their frequency.

Digestive: pancreatitis, hepatitis, rectal discomfort, flatulence.

CNS: insomnia, mood swings, irritability.

Dermatologic: erythema nodosum, photosensitivity, erythema, hot flashes, alopecia.

Musculoskeletal: muscle cramps.

Cardiovascular: pericarditis, second degree heart block, hypertension, orthostatic hypotension, edema, tightness in chest.

Genitourinary: frequency, dysuria, impotence, heavy menstrual bleeding.

Hematologic: leukopenia, lymphopenia, anemia, reticulocytosis.

Laboratory: elevated liver enzymes.

Special Senses: dry mouth, dry eyes.

Drug Abuse and Dependency: Abuse: None reported.

Dependence: Drug dependence has not been reported with chronic administration of olsalazine.

Dosage And Administration: Dosage should be adjusted to the severity of the disease. Increase the dose gradually over a 1-week period, starting with 500 mg (2 capsules)/day. If no response is achieved with 2 g and the drug is well tolerated, the dose may be increased to 3 g daily. A single dose should not exceed 1 g.

The drug should be taken at regular intervals together with meals.

Patients experiencing watery diarrhea associated with increasing dosage can reduce the dose to the previously tolerated dose, for a 2-day period. The dose may then be increased again. Further subdivision of the dose may be necessary.

Usual Adult Dose (including elderly): Acute: 500 mg (2 capsules), 4 times daily.

Prophylaxis: 500 mg (2 capsules), 2 times daily.

Children: No specific dose has been defined for children. Dosage should be adjusted to individual weight and age of the child.

Concomitant therapy with oral or rectal steroids may be used.

Long-term maintenance therapy with olsalazine is recommended in order to avoid relapse and remain free from symptoms.

Availability And Storage: Each opaque, beige, hard gelatin capsule contains: olsalazine sodium 250 mg. Bottles of 100. Store at room temperature (15 to 30°C).

DIPENTUM® Pharmacia & Upjohn Olsalazine Sodium Lower Gastrointestinal Anti-inflammatory

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