ENTOCORT Dispersible tablet and solution for rectal suspension Ref.[27517] Active ingredients: Budesonide

Side effects typical of systemic corticosteroids may occur. Potential systemic effects include glaucoma.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

When patients are transferred from systemic glucocorticosteroid treatment with higher systemic effect to Entocort enema, 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 high systemic effect glucocorticosteroid treatment with Entocort enema sometimes unmasks allergies, e.g. rhinitis and eczema, which were previously controlled by the systemic drug.

Reduced liver function affects the elimination of glucocorticosteroids, causing lower elimination rate and higher systemic exposure. Be aware of possible systemic side effects. The pharmacokinetics after oral ingestion of budesonide was affected by compromised liver function as evidenced by increased systemic availability in patients with moderately severe hepatic cirrhosis.

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 their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis (See section 4.8). Systemic effects of steroids may occur, particularly when prescribed at high doses and for prolonged periods. Such effects may include Cushing’s syndrome, adrenal suppression, growth retardation, decreased bone mineral density, cataract, glaucoma and very rarely a wide range of psychiatric/ behavioural effects (see Section 4.8).

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. If this is not possible, the period between treatments should as long as possible, and a reduction of the budesonide dose could also be considered (see section 4.5).

Entocort enema contains the excipients lactose and methyl-, propyl-parahydroxybenzoate, therefore caution should be taken in patients with hypersensitivity to these excipients.

Some patients may feel unwell in a non-specific 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.

When Entocort Enema is used chronically in excessive doses, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may appear. However, the dosage form and the route of administration make any prolonged overdosage unlikely.

Raised plasma concentrations of and enhanced effects of corticosteroids have been reported in women also treated with oestrogens and contraceptive steroids. However, a low-dose combination oral contraceptive that more than doubled the plasma concentration of prednisolone, had no significant effect on the plasma concentration of oral budesonide.

The metabolism of budesonide is primarily mediated by CYP3A4, one of the cytochrome P450 enzymes.

Inhibitors of this enzyme, e.g. ketoconazole, itraconazole and HIV protease inhibitors, can therefore increase systemic exposure to budesonide several times (see Sections 4.4 and 5.2). Since there is no data to support a dosage recommendation, the combination should be avoided. If this is not possible, the period between treatments should as long as possible, and a reduction of the budesonide dose could also be considered. Other potent inhibitors of CYP3A4 are also likely to markedly increase plasma levels of budesonide. Inhibition by budesonide on other drugs metabolism via CYP3A4 is unlikely, since budesonide has low affinity to the enzyme.

Concomitant treatment with CYP3A4 inducers such as carbamazepine probably reduces budesonide exposure, which may require a dose increase.

Because adrenal function may be suppressed, an ACTH stimulation test for diagnosing pituitary insufficiency might show false results (low values).

Pregnancy

The ability of corticosteroids to cross the placenta varies between individual drugs, however, in mice, budesonide and/or its metabolites have been shown to cross the placenta.

In pregnant animals, administration of budesonide, like other glucocorticosteroids, is associated with abnormalities in foetal development including cleft palate, intra-uterine growth retardation and affects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate/lip in humans. However, when administered for prolonged periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. Hypoadrenalism may, in theory, occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important. When corticosteroids are essential however, patients with normal pregnancies may be treated as though they were in the non-gravid state.

As with other drugs the administration of Entocort enema during pregnancy requires that the benefits for the mother are weighed against the risk for the foetus.

Breast-feeding

Budesonide is excreted in breast milk.

Maintenance treatment with inhaled budesonide (200 or 400 micrograms twice daily) in asthmatic nursing women results in negligible systemic exposure to budesonide in breast-fed infants.

In a pharmacokinetic study the estimated daily infant dose was 0.3% of the daily maternal dose for both dose levels, and the average plasma concentration in infants was estimated to be 1/600th of the concentrations observed in maternal plasma, assuming complete infant oral bioavailability. Budesonide concentrations in infant plasma samples were all less than the limit of quantification.

Based on data from inhaled budesonide and the fact that budesonide exhibits linear PK properties within the therapeutic dosage intervals after inhaled, oral and rectal administrations, at therapeutic doses of budesonide, exposure to the suckling child is anticipated to be low.

Infants of mothers taking higher than recommended doses of budesonide may have a degree of adrenal suppression.

These data support continued use of budesonide, oral and rectal administrations during breast-feeding.

Entocort Enema has no influence on the ability to drive and operate machinery.

The following definitions apply to the incidence of undesirable effects: Very Common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000).

Adverse drug reactions by frequency and system organ class (SOC):

Most of the adverse events mentioned in this SmPC can also be expected for other treatments with glucocorticoids.

Description of selected adverse events

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.

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)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme.

Website: yellowcard.mhra.gov.uk

Not applicable.