Entocort_Capsules (Budesonide)

ENTOCORT® Capsules



Glucocorticosteroid for the Treatment of Crohn’s Disease Affecting the Ileum and/or Ascending Colon

Action And Clinical Pharmacology: The active ingredient of Entocort capsules, budesonide, is a potent nonhalogenated synthetic glucocorticosteroid with high topical potency and weak systemic effects.

The exact mechanism of action of glucocorticosteroids in the treatment of Crohn’s disease is not fully understood. Anti-inflammatory actions, such as the inhibition of inflammatory mediator release and inhibition of immunological cellular responses, are probably important.

Data from clinical pharmacology studies and controlled clinical trials indicate that Entocort capsules, at least partly, act topically. Budesonide 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 by the liver with a short half-life. A glucocorticosteroid with such a profile is of particular importance for the local treatment of inflammatory bowel diseases such as Crohn’s disease. With regard to treatment of this disease with glucocorticosteroids, it is essential to achieve a high local anti-inflammatory activity in the bowel wall with systemic side effects, e.g., on the hypothalamic pituitary adrenal (HPA) axis function, as low as possible.

Indications And Clinical Uses: For the induction and maintenance of remission in patients with mild to moderate Crohn’s disease affecting the ileum and/or ascending colon.

Contra-Indications: Systemic or local bacterial, fungal or viral infections. Known hypersensitivity to any of the ingredients. Active tuberculosis.

Manufacturers’ Warnings In Clinical States: Glucocorticosteroids can reduce the response of the HPA-axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a conventional glucocorticosteroid is recommended.

Special care is demanded in treatment of patients transferred from conventional systemic steroids to budesonide capsules, as disturbances in the HPA-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 glucocorticosteroid therapy. Viral infections such as chickenpox and measles can have a more serious or fatal course in patients on immunosuppressant glucocorticosteroids. 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.

Although treatment with budesonide capsules causes significantly less lowering of plasma cortisol compared to conventional glucocorticosteroids, the knowledge with regard to treatment during the following conditions is limited and therefore cautioned: active 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 an oral glucocorticosteroid must be weighed against the risks.

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

Particular care is needed in patients who are transferred from systemic glucocorticosteroid treatment with higher systemic effect to budesonide capsules. These patients may have adrenal cortical suppression. Therefore, monitoring of adrenocortical function may be considered in these patients. 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.

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

Glucocorticosteroids should be used with caution in patients if there is a probability of bowel perforation as well as the probability of obstruction, abscess or other pyogenic infection and fresh intestinal anastomoses.

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

There may be an enhanced systemic effect of budesonide in patients with liver cirrhosis since the metabolism of budesonide may be impaired 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 glucocorticosteroids in hypoprothrombinemia.

Glucocorticosteroids should be used with caution in patients with cataracts, and 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 glucocorticosteroids 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: In clinical trials, most adverse events experienced by patients or healthy volunteers receiving budesonide capsules were of mild to moderate intensity and were classified as nonserious. A total of 530 patients with Crohn’s disease were treated with budesonide capsules for induction and maintenance of remission, in controlled clinical trials.

Adverse events reported in patients during induction of remission (n=399) with budesonide capsules included dyspepsia (9%), muscle cramps (4%), palpitations (2%), blurred vision (3%), skin reactions including rash and urticaria (6%), and menstrual disorders (2%).

A similar adverse event profile was reported in patients during maintenance treatment (n=131) with budesonide capsules. The incidence of adverse events was the same or less than observed during treatment for induction of remission.

Side effects typical of systemic glucocorticosteroid (such as Cushingoid features) may occur. The systemic effects of budesonide on the HPA-axis were found to be dose- dependent.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Acute overdosage with budesonide capsules, even in excessive doses, is not expected to be a clinical problem.

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 HPA-suppression. Decreasing the dose or stopping the therapy, with the accepted procedures for discontinuing prolonged oral therapy with systemic steroids, 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 conventional systemic steroids.

Dosage And Administration: Active Disease: The recommended daily dose for induction of remission is 9 mg, administered once daily in the morning, for up to 8 weeks. The dose should be taken before meals.

Maintenance of Remission: The recommended daily starting dose for the maintenance of remission is 6 mg, administered once daily in the morning before breakfast. The maintenance dose should be kept as low as necessary for control of disease symptoms.

During prolonged treatment, dosing may have to be adjusted depending on the disease activity.

Treatment with budesonide capsules should be tapered before cessation. It is recommended that the dose be reduced for the last 2 to 4 weeks of therapy. The rate of tapering should be patient-specific and the patient should be monitored by the treating physician during this period.

The capsules should be swallowed whole with water, and not chewed, broken or crushed before being swallowed.

Availability And Storage: Each controlled ileal release, 2-piece hard gelatin capsule, with an opaque light grey body and an opaque pink cap printed CIR 3 mg in radial black ink, contains: micronized budesonide 3 mg. Nonmedicinal ingredients: acetyltributyl citrate, dimethicone, ethylcellulose, gelatin, iron oxide, methacrylic acid copolymer, polysorbate 80, sodium lauryl sulfate, sucrose, talc, titanium dioxide and triethylcitrate. High density polyethylene bottles of 100 with a polypropylene screw cap.

There is a desiccant pellet in the cap. The capsules should be dispensed and stored in the original container. The patient should be advised to keep the bottle tightly capped. Store at controlled room temperature (15 to 30°C).

ENTOCORT® Capsules Astra Budesonide Glucocorticosteroid for the Treatment of Crohn’s Disease Affecting the Ileum and/or Ascending Colon

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