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ENTOCORT® Enema
Astra
Budesonide
Glucocorticosteroid
 
Action And Clinical Pharmacology: Budesonide is a potent nonhalogenated synthetic glucocorticosteroid with strong topical and weak systemic effects.

Budesonide has a high topical anti-inflammatory potency. It undergoes an extensive degree (approximately 90%) of biotransformation in the liver to metabolites with low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6b-hydroxybudesonide and 16a-hydroxyprednisolone, is less than 1% of that of budesonide.

The favorable separation between topical anti-inflammatory and systemic effect is due to strong glucocorticosteroid receptor affinity and an effective first-pass metabolism with a short half-life.

A glucocorticosteroid with such a profile is of particular importance for the local treatment of inflammatory bowel diseases (IBD) such as ulcerative colitis (UC). With regard to treatment of these diseases with glucocorticosteroids, it is essential to achieve a high local anti-inflammatory activity in the bowel wall with systemic side effects, for example, on the hypothalamic-pituitary-adrenal (HPA) axis function, as low as possible. At the recommended doses, budesonide enema causes no or small suppression of plasma cortisol.

Pharmacokinetics: Absorption in healthy subjects after rectal dosing of 2 mg budesonide low viscosity enema is rapid and essentially complete within 3 hours. The mean maximal plasma concentration after rectal administration is 3 ± 2 nmol/L, reached within 1.5 hours. Similar results are obtained in patients suffering from distal ulcerative colitis. The mean systemic availability after rectal dosing is 15 ± 12%. The plasma half-life is between 2 and 3 hours in adults.

Indications And Clinical Uses: In the management of distal ulcerative colitis (rectum, sigmoid and descending colon).

Contra-Indications: Budesonide is contraindicated for the following: Local contraindications to the use of budesonide include imminent bowel perforation as well as the probability of obstruction, abscess or other pyogenic infection, fresh intestinal anastomoses, extensive fistulas and sinus tracts; systemic or local bacterial, fungal or viral infections; known hypersensitivity to any of the ingredients; active tuberculosis; ocular herpes simplex, and acute psychosis. tag_WarningWarnings

Manufacturers' Warnings In Clinical States: Special care is demanded in treatment of patients transferred from systemic steroids to budesonide as disturbances in the hypothalamic-pituitary-adrenal axis could be expected in these patients.

Precautions: Glucocorticosteroids may mask some signs of infections and new infections may appear. A decreased resistance to localized infection has been observed during corticosteroid therapy. Viral infections such as chickenpox and measles can have a more serious or fatal course in patients on immunosuppressant corticosteroids. In adults who have not had these diseases, particular care should be taken to avoid exposure. If exposed to chickenpox or measles, therapy with varicella zoster immune globulin (VZIG) or pooled i.v. immunoglobulin (IVIG), as appropriate, may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.

At recommended doses, budesonide enema causes no clinically important changes in basal plasma cortisol levels or in the response to stimulation with ACTH. The effects on morning plasma cortisol and adrenal function are significantly less compared with prednisolone enema 25 mg daily. However, knowledge with regard to treatment of the following conditions is limited and therefore cautioned: active or lateral peptic ulcer, osteoporosis, acute glomerulonephritis, myasthenia gravis, exanthematous diseases, diverticulitis, thrombophlebitis, psychic disturbances, diabetes, hypertension, hyperthyroidism, acute coronary disease, limited cardiac reserve and pregnancy. In such cases the benefits of a corticosteroid enema must be weighed against the risks.

There are still insufficient data on the long-term systemic effect of budesonide. With the recommended therapeutic doses, the risk/benefit ratio seems to be very low. However, as with any other glucocorticosteroid, patients should be carefully followed up for systemic adverse effects. During long-term therapy, pituitary-adrenal function and hematological status should be periodically assessed.

Some patients feel unwell in a nonspecific way during the withdrawal phase, e.g., pain in muscles and joints. A general insufficient glucocorticosteroid effect should be suspected if, in rare cases, symptoms such as tiredness, headache, nausea and vomiting should occur. In these cases a temporary increase in the dose of systemic glucocorticosteroids is sometimes necessary.

Glucocorticosteroid enemas should be administered with caution in patients with severe ulcerative colitis because these patients are predisposed to perforations of the bowel wall.

Patients should be advised to inform subsequent physicians of the prior use of glucocorticosteroids.

Aggravation of diabetes mellitus or stimulation of manifestations of latent diabetes mellitus may be caused by corticosteroid therapy.

There may be an enhanced effect of budesonide in patients with liver cirrhosis and, as with other glucocorticosteroids, there may be enhanced effects in those with hypothyroidism. Reduced liver function may affect the elimination of corticosteroids. The i.v. pharmacokinetics of budesonide are, however, similar in cirrhotic patients and in healthy subjects. The pharmacokinetics after oral ingestion of budesonide were affected by compromised liver function as evidenced by increased systemic availability.

Glucocorticosteroid therapy may cause hyperacidity of peptic ulcer.

ASA should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.

Glucocorticosteroids may cause elevation of intraocular pressure in glaucoma patients.

Pregnancy: Administration of budesonide during pregnancy should be avoided unless there are compelling reasons. In experimental animal studies, budesonide was found to cross the placental barrier. Like other glucocorticosteroids, budesonide is teratogenic to rodent species. High doses of budesonide administered s.c. produced fetal malformations, primarily skeletal defects, in rabbits, rats, and in mice. The relevance of these findings to humans has not yet been established. In the absence of further studies in humans, budesonide should be used during pregnancy only if the potential benefits clearly outweigh the risk to the fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for hypoadrenalism.

Lactation: Glucocorticosteroids are secreted in human milk. It is not known whether budesonide would be secreted in human milk, but it is suspected to be likely. The use of budesonide in nursing mothers requires that the possible benefits of the drug be weighed against the potential hazards to the mother, or infant.

Children: The safety and effectiveness of budesonide in children have not been established; therefore, use in this age group is not recommended.

Drug Interactions: To date, budesonide has not been observed to interact with other drugs used for the treatment of intestinal bowel diseases.

Cimetidine: The kinetics of budesonide were investigated in healthy subjects without and with cimetidine, 1 000 mg daily. After a 4 mg oral dose the values of Cmax (nmol/L) and systemic availability (%) of budesonide without and with cimetidine (3.3 vs 5.1 nmol/L and 10 vs 12%, respectively) indicated a slight inhibitory effect on hepatic metabolism of budesonide, caused by cimetidine. This should be of little clinical importance.

Ketoconazole: Ketoconazole, a potent inhibitor of cytochrome P450 3A, the main metabolic enzyme for corticosteroids, increases plasma levels of orally ingested budesonide.

Omeprazole: At recommended doses, omeprazole has no effect on the pharmacokinetics of oral budesonide.

Adverse Reactions: No major side effects attributable to the use of budesonide have been reported. During clinical trials, the frequency of subjectively reported side effects in a total of 247 patients and healthy volunteers given 2 mg budesonide, once daily in the morning, was low.

The most common adverse reactions are gastrointestinal disturbances, e.g., flatulence, nausea, diarrhea. These symptoms were reported in 23 of the 247 patients (9%) receiving 2 mg of budesonide. Psychiatric symptoms (insomnia, agitation, anxiety, depression, dysphoria, emotional lability, somnolence) were reported in 7 patients (3%) receiving 2 mg budesonide. Skin reactions (rash, urticaria) occurred in 5 patients (2%).

Systemic effects of budesonide on the HPA-axis function were found to be dose-dependent. In rare cases, signs or symptoms of systemic glucocorticosteroid effects, including hypofunction of the adrenal gland, may occur with rectally administered glucocorticosteroids, probably depending on dose, treatment time, concomitant and previous glucocorticosteroid intake, and individual sensitivity. Rectal administration of high concentrations of budesonide (10 mg/dose) resulted in significant suppression of endogenous cortisol concentrations as measured by plasma and urinary cortisol levels.

In patients in whom systemic steroids are reduced or stopped, withdrawal symptoms due to decreased systemic activity may occur.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Acute overdosage with budesonide, even in excessive doses, is not expected to be a clinical problem. When used chronically at excessive doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of budesonide should be discontinued consistent with accepted procedures for discontinuing prolonged oral steroid therapy. However, the dosage form, enema, and the route of administration make any prolonged overdosage unlikely.

Occasional overdosing will not give any obvious symptoms in most cases but it will decrease the plasma cortisol level and increase the number and percentage of circulating neutrophils. The number and percentage of eosinophils will decrease concurrently. Stopping the treatment or decreasing the dose will abolish the induced effects.

Habitual overdosing may cause hypercorticism and hypothalamic-pituitary-adrenal suppression. Decreasing the dose or stopping the therapy will abolish these effects, although the restitution of the HPA-axis may be a slow process and during periods with pronounced physical stress (severe infections, trauma, surgical operations, etc.) it may be advisable to supplement with systemic steroids.

Dosage And Administration: 1 retention enema is given nightly to the patient for 4 weeks. If the patient is not in remission after 4 weeks, the treatment period may be prolonged to 8 weeks.

The enema is reconstituted by adding 1 dispersible tablet into the enema bottle, whereafter the bottle is vigorously shaken for at least 10 seconds or until the tablet is completely dissolved. The tablet will disintegrate rapidly and the suspension will turn slightly yellowish.



Availability And Storage: Each retention enema contains: budesonide 0.02 mg/mL and consists of 2 components, a dispersible tablet and a vehicle. The enema is reconstituted before use. The volume of the reconstituted enema is 115 mL. Since the residual volume is about 15 mL, the dose administered to the patient is about 2 mg budesonide. The tablets are provided in an aluminum blister package and the vehicle is in a polyethylene bottle equipped with a rectular nozzle. Nonmedicinal ingredients: tablet: colloidal silicon dioxide, cross-linked polyvidone, lactose, lactose anhydrous, magnesium stearate and riboflavin-5-phosphate sodium; vehicle: methyl parahydroxybenzoate, propyl parahydroxybenzoate, purified water and sodium chloride. Cartons of 7 dispersible tablets and vehicle solutions. Store at 15 to 30°C. After preparation of the enema, the solution is intended for immediate use. (Shown in Product Recognition Section)