Entocort^® CR 3 mg Gastro-Resistant Prolonged-Release Hard Capsules

Each capsule contains budesonide 3 mg.

Excipients: not more than 295 mg sucrose.

For full list of excipients, see section 6.1.

Gastro-resistant, prolonged-release capsules, hard.

Hard gelatin capsules with an opaque, light grey body and opaque, pink cap, marked

CIR

3 mg

in black radial print.

Entocort CR Capsules are indicated for the induction of remission in patients with mild to moderate Crohn's disease affecting the ileum and/or the ascending colon. The full effect is usually achieved within 2–4 weeks.

Adults

Active Crohn's disease: The recommended daily dose for induction of remission is 9 mg once daily in the morning, for up to eight weeks. The full effect is usually achieved within 2–4 weeks.

When treatment is to be discontinued, the dose should normally be reduced for the last 2 to 4 weeks of therapy.

For long-term use, to prolong remission, the recommended dose is 6 mg, administered once daily in the morning.

To replace prednisolone in steroid dependent patients, the recommended dose is 6 mg, administered once daily in the morning. When treatment with Entocort CR Capsules is initiated the prednisolone dose should be tapered.

To prevent recurrence after surgery in patients with high disease activity, the recommended dose is 6 mg, administered once daily in the morning. No benefit of Entocort has been shown in post surgical patients with obstructive fibrostenotic Crohn's disease.

Children

There is presently no experience with Entocort CR Capsules in children. Entocort is not recommended for use in children.

Elderly

No special dose adjustment is recommended. However, experience with Entocort CR Capsules in the elderly is limited.

The capsules should be swallowed whole with water. The capsules must not be chewed.

Known hypersensitivity to any of the ingredients.

Use with caution in patients with bacterial, fungal or viral infections, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts or with a family history of diabetes or glaucoma or with any other condition where the use of glucocorticosteroids may have unwanted effects.

This product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis.

Treatment with Entocort CR Capsules results in lower systemic steroid levels than conventional oral glucocorticosteroid therapy. When patients are transferred from systemic glucocorticosteroid treatment with higher systemic effect to Entocort CR Capsules, they may have adrenocortical suppression. Therefore, monitoring of adrenocortical function may be considered in these patients and their dose of systemic steroid should be reduced cautiously.

Replacement of systemic glucocorticosteroid treatment with higher systemic effect with Entocort CR Capsules, sometimes unmasks allergies, e.g. rhinitis and eczema, which were previously controlled by the systemic drug.

Chicken pox and measles may follow a more serious course in patients on oral glucocorticosteroids. Particular care should be taken to avoid exposure in patients who have not previously had these diseases. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If chicken pox develops, treatment with antiviral agents may be considered.

Glucocorticosteroids may cause suppression of the HPA axis and reduce the stress response. Where patients are subject to surgery or other stresses, supplementary systemic glucocorticoid treatment is recommended.

As with all glucocorticosteroids the possibility of local or systemic infections should be borne in mind when using this product, particularly in view of the possible absence of systemic response thereto.

Reduced liver function may affect the elimination of glucocorticosteroids. The pharmacokinetics after oral ingestion of budesonide was affected by compromised liver function as evidenced by increased systemic availability. The intravenous pharmacokinetics of budesonide however was similar in cirrhotic patients and in healthy subjects.

When treatment is to be discontinued, the dose should normally be reduced for the last 2 to 4 weeks of therapy. Some patients may feel unwell in a non-specific way during the withdrawal phase, e.g. pain in muscles and joints. In some instances withdrawal symptoms may involve or resemble a clinical relapse of the disease for which the patient has been undergoing treatment. 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.

In vivo studies have shown that oral administration of ketoconazole (a known inhibitor of CYP3A activity in the liver and in the intestinal mucosa), caused a several fold increase of the systemic exposure to oral budesonide. If treatment with ketoconazole together with budesonide is indicated, reduction of the budesonide dose should be considered if side effects typical of systemic glucocorticosteroids occur.

After extensive intake of grapefruit juice (which inhibits CYP3A activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times. As with other drugs primarily being metabolised through CYP3A, regular ingestion of grapefruit or juice of it, should be avoided in connection with budesonide administration (other juices such as orange juice or apple juice do not inhibit CYP3A). See also section 4.5.

When Entocort CR Capsules are used chronically in excessive doses, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may appear, and very rarely a wide range of psychiatric/behavioural effects may also occur (see section 4.8).

Although not studied, concomitant administration of colestyramine may reduce Entocort uptake, in common with other drugs.

Elevated plasma levels and enhanced effects of corticosteroids have been reported in women also receiving oestrogens or oral contraceptives. However, a low-dose combination oral contraceptive that more than doubled the plasma concentration of oral prednisolone, had no significant effect on the plasma concentration of oral budesonide.

At recommended doses, omeprazole was without effect on the pharmacokinetics of oral budesonide whereas cimetidine had a slight but clinically insignificant effect.

The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450. Inhibition of this enzyme by e.g. ketoconazole and grapefruit juice can therefore increase the systemic exposure to budesonide. See section 4.4 Special warnings and special precautions for use.

Administration during pregnancy should be avoided unless there are compelling reasons for Entocort therapy. In pregnant animals, budesonide, like other glucocorticosteroids, has been shown to cause abnormalities of foetal development. The relevance of this to man has not been established.

Budesonide is excreted in breast milk. However, based on data from inhaled budesonide, at therapeutic doses of Entocort exposure to the suckling child is anticipated to be low.

No effects are known.

Clinical studies showed the frequency of steroid associated side effects for Entocort CR Capsules to be approximately half that of conventional prednisolone treatment, at equipotent doses. Very rarely a wide range of psychiatric/behavioural effects may occur, when systemic steroids are prescribed at high doses and for prolonged periods (see section 4.4).

Table of undesirable effects

Acute overdosage with Entocort CR Capsules, even at very high doses, is not expected to lead to an acute clinical crisis. In the event of acute overdosage, no specific antidote is available. Treatment consists of supportive and symptomatic therapy.

Chronic overdosage may lead to systemic corticosteroid effects, such as Cushingoid features. If such changes occur, the dose of Entocort CR Capsules should be gradually reduced until treatment is discontinued, in accordance with normal procedures for the discontinuation of prolonged oral glucocorticosteroid therapy.

Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect.

ATC Code: A07E A06.

The exact mechanism of budesonide in the treatment of Crohn's disease is not fully understood. Data from clinical pharmacology studies and controlled clinical trials strongly indicate that the mode of action of Entocort CR Capsules is based, at least partly, on a local action in the gut. At doses clinically equivalent to prednisolone, budesonide gives significantly less HPA axis suppression and has a lower impact on inflammatory markers.

At recommended doses, Entocort CR Capsules caused significantly less effect than prednisolone 20–40 mg daily on: morning plasma cortisols; 24 hour plasma cortisol (AUC 0-24h) and 24 hour urine cortisol levels.

ACTH tests have shown Entocort CR Capsules to have significantly less effect than prednisolone on adrenal functions.

In a study investigating bone mineral density during treatment with Entocort CR Capsules or prednisolone for up to two years, treatment with Entocort capsules resulted in significantly less bone loss than prednisolone treatment in steroid naïve patients.

Absorption

After oral dosing of plain micronised compound, absorption is rapid and seems to be complete. A large proportion of the drug is absorbed from the ileum and ascending colon. Systemic availability in healthy subjects is approximately 9–12% for Entocort CR Capsules, similar to the systemic availability of plain micronised budesonide, indicating complete absorption. In patients with active Crohn's disease systemic availability is approximately 12–20%.

Distribution

Budesonide has a high volume of distribution (about 3 L/kg). Plasma protein binding averages 85–90%. In healthy volunteers mean maximal plasma concentrations of 5–10 nmol/L were seen at 3–5 hours following a single oral dose of Entocort CR Capsules 9 mg.

Biotransformation

Budesonide then undergoes extensive biotransformation in the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxy-prednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450.

Elimination

Elimination is rate-limited by absorption. The average terminal half-life is 4 hours. Budesonide has a high systemic clearance (about 1.2 L/min).

Results from acute, subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe or similar to those observed after administration of other glucocorticosteroids, e.g. decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex.

Budesonide, eva luated in six different test systems, did not show any mutagenic or clastogenic effects.

An increased incidence of brain gliomas in male rats in a carcinogenicity study could not be verified in a repeat study, in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups.

Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide as well as the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect.

Available clinical experience shows that there are no indications that budesonide or other glucocorticosteroids induce brain gliomas or primary hepatocellular neoplasms in man.

The toxicity of Entocort CR Capsules, with focus on the gastrointestinal tract, has been studied in cynomolgus monkeys in doses up to 5 mg/kg after repeated oral administration for up to 6 months. No effects were observed in the gastrointestinal tract, neither at gross pathology nor in the histopathological examination.

Ethylcellulose

Tributyl acetylcitrate

Methacrylic acid-ethyl acrylate copolymer (1:1) dispersion 30 per cent

Triethylcitrate

Simeticone (Antifoam M)

Polysorbate 80

Talc

Sugar spheres (consisting of sucrose and maize starch)

Capsule shell:

Black Iron oxide (E172)

Titanium dioxide (E171)

Gelatin

Sodium laurilsulfate

Colloidal anhydrous silica

Liquid Paraffin

Red iron oxide (E172)

Yellow iron oxide (E172)

Shellac

Soya lecithin

Silicon antifoam

Ammonium hydroxide

Potassium hydroxide

Not applicable.

3 years.

Do not store above 30°C. Store in the original package. Keep the container tightly closed.

White polyethylene bottles of 100 capsules, having a tamper evident, child proof polypropylene screw cap, with an integral desiccant.

No special requirements.

AstraZeneca UK Ltd.,

600 Capability Green,

Luton, LU1 3LU, UK.

PA 970/39/2

Date of first authorisation: 24^th September 1996

Date of last renewal: 24^th September 2006

21^st July 2010