ENTOCORT CR 3 MG CAPSULES - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Entocort CR 3 mg Capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains budesonide 3 mg

Excipient(s) with known effect:

Sucrose

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Hard gelatin capsules for oral administration with an opaque, light grey body and opaque, pink cap marked CIR 3mg in black radial print.

Each capsule contains budesonide 3 mg as gastro-resistant, prolonged-release granules.

4.1 Therapeutic indications

Crohn’s disease – Induction of remission in patients with mild to moderate active Crohn’s disease affecting the ileum and/or the ascending colon.

Microscopic colitis – Induction of remission in patients with active microscopic colitis Maintenance of remission in patients with microscopic colitis.

4.2 Posology and method of administration

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.

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

Maintenance of Microscopic colitis: The recommended dose is 6 mg once daily in the morning (corresponding to 2 capsules), or the lowest effective dose.

Paediatric population

There are limited data on the use of Entocort CR Capsules in children (see Sections 5.1 and 5.2). The available data are insufficient to support safety and efficacy in the paediatric population, therefore such use cannot be recommended until further data become available.

Older people

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

4.3 Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

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 cobicistatcon­taining 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-, propylparahydro­xybenzoate, 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.

4.5 Interaction with other medicinal products and other forms of interaction Although not studied, concomitant administration of colestyramine may reduce Entocort uptake, in common with other drugs.

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 oral prednisolone, had no significant effect on the plasma concentration of oral budesonide.

At recommended doses, omeprazole does not affect the pharmacokinetics of oral budesonide, whereas cimetidine has a slight but clinically insignificant effect.

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

Inhibitors of this enzyme, e.g. ketoconazole, itraconazole, HIV protease inhibitors and grapefruit juice, 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 be 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 may reduce 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

4.6 Fertility, Pregnancy and lactation

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, intrauterine growth retardation and effects 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 CR Capsules 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.

4.7 Effects on ability to drive and use machines

Entocort CR Capsules have no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

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.

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 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: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Reports of acute toxicity or death following overdosage of glucocorticos­teroids are rare. Thus, acute overdosage with Entocort CR Capsules even in excessive 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Corticosteroids acting locally.

ATC code: A07EA06

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

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. Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect. 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; on 24 hour plasma cortisol (AUC 0–24 h) and on 24 hour urine cortisol levels.

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

HPA axis function. At recommended doses, Entocort CR Capsules cause significantly less effect than prednisole 20–40 mg daily on morning plasma cortisol, on 24-hour plasma cortisol (AUC 0–24 h) and on 24-hour urine cortisol. Also ACTH tests have shown that Entocort CR Capsules, compared with prednisolone, have significantly less impact on the adrenal function. Children with Crohn’s disease have a slightly higher systemic exposure and cortisol suppression than adults with Crohn’s disease.

Long-term studies have not been performed in children treated with Entocort CR Capsules. In a study evaluating the effect of Entocort CR Capsules on cortisol suppression in 8 children (range 9–14 years) and 6 adults , the oral administration of 9 mg Entocort CR Capsules for 7 days induced a mean cortisol suppression (± SD) of 64% (±18%) in children and 50% (±27%) in adults with respect to baseline values. No clinically relevant findings in terms of safety have been reported. (Study 08–3044)

A study performed in children with mild to moderate Crohn’s disease (CDAI > 200) compared the activity of Entocort CR Capsules at the dose of 9 mg once daily with that of prednisolone, administered at tapering doses, starting from 1 mg/kg. 22 patients were treated with Entocort CR Capsules and 26 patients were treated with the reference drug prednisolone. After 8 weeks of treatment, 70.8% of patients treated with prednisolone reached the endpoint (CDAI < 150), as compared to 54.5% of subjects treated with Entocort CR Capsules, the difference was not statistically significant (p = 0.13). In the course of the study, adverse events were observed in 96% of patients treated with prednisolone and 91% of patients treated with Entocort CR Capsules. The nature of these adverse events was similar in both study arms, but the incidence of glucocorticoid-related side-effects (such as acne and moon face) was lower in patients treated with Entocort CR Capsules. (Study SD-008–3037)

Study D9422C0001 was an open-label, uncontrolled study designed to evaluate Entocort in 108 pediatric patients (children and adolescents aged 5 to 17 years) diagnosed with mild to moderate Crohn’s disease of the ileum and/or ascending colon. The median duration of treatment exposure of Entocort of 58 days (range: 5 days to 90 days). Patients were dosed with oral Entocort once daily according to bodyweight, patients weighing <25 kg received 6 mg once daily for 8 weeks; patients weighing >25 kg received 9 mg once daily for 8 weeks. During the 8 weeks of treatment there was a reduction in the mean (±SD) PCDAI score from 19.1 (±10.1) to 9.1 (±8.5), indicating an improvement in disease activity; with an improvement in mean (±SD) IMPACT 3 score from 132.1 (±18.8) to 140.9 (±16.9). AEs were observed at a similar frequency and severity as seen in adults, and were mostly related to Crohn’s disease, puberty and possible GCS related side effects.

Study D9422C00002 was an open-label, un-comparative study designed to evaluate Entocort 6 mg once daily as maintenance treatment in 50 pediatric patients (children and adolescents aged 5 to 17 years) with a diagnosis of mild to moderate Crohn’s disease of the ileum and/or ascending colon who were in clinical remission (PCDAI <10). Treatment consisted of a 12-week maintenance treatment phase of 6 mg once daily, a 2-week taper phase to 3 mg once daily. The median duration of treatment exposure of Entocort was 98.5 days (range: 11 days to 135 days). Most patients remained in the clinical remission stage, as there were no major changes in the mean PCDAI composite score or IMPACT 3 score. Mean (SD) PCDAI was 4.85 (3.62) at baseline and 6.89 (8.08) after 12 weeks of maintenance treatment with Entocort 6 mg daily. At the same points in time the mean IMPACT3 score was 145.62 (12.43) and 146.98 (15.48), respectively. AEs were observed at a similar frequency and severity as seen in adults, and were mostly related to Crohn’s disease, puberty and possible GCS related side effects.

5.2 Pharmacokinetic properties

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. This is 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% at the start of treatment.

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 510 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, 6^-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.

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).

Paediatric population

In a study comparing the pharmacokinetics of Entocort CR Capsules in 8 children (range 9–14 years) and 6 adults,, Entocort CR Capules 9 mg for 7 days induced a systemic exposure (AUC) that was 17% higher in children than in adults, with maximum concentrations (Cmax) 50% higher in children than in adults (mean AUC ± SD: children 41.3 nmol/L ± 21.2; adults 35.0 nmol/L ± 19.8. Mean Cmax ± SD: children 5.99 nmo/L ± 3.45; adults 3.97 nmo/L ± 2.11.) (Study 08–3044).

5.3 Preclinical safety data

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, evaluated 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 gastro-intestinal 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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Ethylcellulose

Tributyl acetylcitrate

Methacrylic acid copolymer

Triethylcitrate, Antifoam M

Polysorbate 80

Talc

Sucrose

Maize starch

Gelatine

Titanium dioxide (E171)

Iron oxide (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 30°C. Store in the original container in order to protect from light/moisture. Replace cap firmly after use. Keep this medicine out of the sight and reach of children.

6.5 Nature and contents of container

White polyethylene bottles of 50 or 100 capsules, having either a tamper-evident or child-resistant polypropylene screw cap, with an integral desiccant

6.6 Special precautions for disposal

No special requirements. See section 4.2.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Tillotts Pharma UK Ltd.

Wellingore Hall, Wellingore,

Lincoln, LN5 0HX

UK

Telephone: +44 (0)1522 813500

8 MARKETING AUTHORISATION NUMBER(S)

PL 36633/0006

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

Date of first authorisation: 31st January 1996

Date of latest renewal: 4th June 2002