Entocort CR 3mg Capsules

Addition of new indication: Maintenance microscopic colitis

Addition of new indication: Maintenance microscopic colitis

4.1 Therapeutic indications

Crohn’s disease: 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 and for long-term use, to prolong remission

Microscopic colitis: Entocort CR Capsules are indicated for the induction of remission in patients with active microscopic colitis.

4.2 ​​​​​​​Posology and method of administration

Posology

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.

 Entocort CR can be used for up to 3 months a at the dose of 6 mg administered once daily in the morning. Long-term use is not recommended.

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.

Active Microscopic colitis: The recommended dose is 9 mg once daily in the morning (corresponding to 3 capsules), for up to eight weeks.

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

In line with general corticosteroid prescribing, the lowest effective dose should be given as clinically indicated.

4.1 Therapeutic indications

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 and for long-term use, to prolong remission.

4.4  Special Warnings and precautions for use
...
Co-treatment with CYP3A inhibitors, including ketoconazole and cobicistat-containing products, is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects. Concomitamt use of ketoconazole or other potent CYP3A4-inhibitors should be avoided.  If this is not possible, the period between treatments should be as long as possible and a reduction of the budesonide dose could also be considered (see also section 4.5).

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

Section 2– Changes relating to QRD update

Section 4.2 – Changes relating to QRD update

Section 4.3 – Changes relating to QRD update

Section 4.4 – Changes relating to QRD update

Section 4.6 – Changes relating to QRD update

Section 4.7 – Changes relating to QRD update

Section 4.8 – Changes relating to QRD update

Section 5.1 – Changes relating to QRD update

Section 6.3 – Changes relating to QRD update

Section 9 – Changes relating to QRD update

Section 10 – Update to Date of Revision

Sections 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.1, & 5.2

Section 10

Date of revision changed to:   25^th April 2012

Section 4.4

Additional text:

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.

Additional text in last paragraph

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).

 

Section 4.8

Additional text in first paragraph

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).

Section 10

Revision date of text: 21 July 2010

Treatment with Entocort CR Capsules results in lower systemic steroid levels than conventional oral steroid therapy. Special care is needed when transferring from other steroid therapy as disturbances in hypothalamic-pituitary-adrenal axis can be expected in these patients.

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.

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.

GlucocCorticosteroids 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.

In patients with compromised liver function, blood levels of glucocorticosteroid may increase, as with other drugs which are metabolised via the liver.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 Interactions.

Reports of acute toxicity and/or death following overdosage of glucocorticosteroids are rare. 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 immediate gastric lavage or emesis followed by supportive and symptomatic therapy.Use supportive therapy as required.

Absorption

Budesonide has a high volume of distribution (about 3 L/kg) and a high systemic clearance (about 1.2 L/min). Plasma protein binding averages 85-90%. 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 (approximately 90%) to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6b-hydroxybudesonide and 16a-hydroxy-prednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450.

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.

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%.

Section 2

Current text

Each capsule also contains up to 295 mg sucrose

New Text

Excipients; not more than 295 mg

Section 4.5

Addition of the letter “P” in front of 450 in 4^th paragraph

Section 6.1

Current text

Methacrylic acid-ethyl acrylate copolymer (1:1)

New text

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

Section 6.4

Current text

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

New text

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

Section 9

Addition of text

Date of last renewal: 24^th September 2006

Section 10

New Date of revision 12^th January 2007