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

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.

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 Budesonide 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 Budesonide CR Capsules in older people is limited.

Method of administration

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

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.

Use with caution in patients with 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.

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.

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).

Treatment with Budesonide 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 Budesonide 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 high systemic effect glucocorticosteroid treatment with Budesonide CR Capsules, sometimes unmasks allergies, e.g. rhinitis and eczema, which were previously controlled by the systemic drug.

Chicken pox and measles can have 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 patients are infected or suspected of being infected, consider reduction or discontinuation of glucocortiocosteriods treatment and immediately consult a physician. Glucocorticosteroids may cause suppression of the hypothalamus-pituitary-adrenal (HPA) axis and reduce the stress response. Where patients are subject to surgery or other stress situations, supplementary systemic glucocorticoid treatment is recommended.

Reduced liver function may affect 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.

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

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 be as long as possible and a reduction of the budesonide dose could also be considered (see also section 4.5).

After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times. As with other drugs primarily metabolised through CYP3A4, regular ingestion of grapefruit or its juice, should be avoided in connection with Budesonide CR Capsules administration (other juices such as orange juice or apple juice do not inhibit CYP3A4). See also Section 4.5.

When Budesonide CR Capsules are used chronically in excessive doses, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may appear.

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

Paediatric population

It is recommended that the height of children receiving prolonged treatment with glucocorticosteroids is regularly monitored. If growth is slowed, therapy should be re-evaluated. The benefits of the glucocorticosteroid therapy and the possible risks of growth suppression must be carefully weighed. Long-term studies have not been performed in children treated with Budesonide CR Capsules.

4.5. Interaction with other medicinal products and other forms of interaction

Although not studied, concomitant administration of colestyramine may reduce Budesonide 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, intra- uterine 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 Budesonide 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

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

4.8. Undesirable effects

Tabulated list of adverse events

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); Not Known (cannot estimate from the available data).

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

SOC

Frequency

Reaction

Immune system disorders

Very Rare

Anaphylactic reaction

Unknown

Hypersensitivity reactions such as angioedema

Endocrine disorders

Common

Cushingoid features

Very Rare

Growth retardation

Metabolism and nutrition disorders

Common

Hypokalemia

Psychiatric disorders

Common

Behavioural changes such as nervousness, insomnia, mood swings and depression

Uncommon

Anxiety

Rare

Aggression

Nervous system disorders

Uncommon

Tremor, psychomotor hyperactivity

Eye disorders

Rare

Glaucoma, cataract including subcapsular cataract, blurred vision (see also section 4.4)

Cardiac disorders

Common

Palpitations

Gastrointestinal disorders

Common

Dyspepsia

Skin and subcutaneous tissue disorders

Common

Skin reactions (urticaria, exanthema)

Rare

Ecchymosis

Musculoskeletal and connective tissue disorders

Common

Muscle cramps

Reproductive system and breast disorders

Common

Menstrual disorders

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

Description of selected adverse events

Side effects typical of systemic corticosteroids (e.g. cushingoid features and growth retardation) may occur. These side effects are dependent on dose, treatment time, concomitant and previous corticosteroid intake, and individual sensitivity.

In clinical studies, at recommended doses, the incidence of adverse events was comparable to placebo.

Clinical studies showed the frequency of steroid associated side effects for Budesonide CR Capsules to be approximately half that of conventional prednisolone treatment, at equipotent doses. In studies of patients with active disease, receiving Budesonide 9 mg daily, the incidence of adverse events was comparable to placebo. 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: https://yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Reports of acute toxicity or death following overdosage of glucocorticosteroids are rare. Thus, acute overdosage with Budesonide 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 Budesonide CR Capsules should be gradually reduced until treatment is discontinued, in accordance with normal procedures for the discontinuation of prolonged oral glucocorticosteroid therapy.