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

- Autoimmune hepatitis

4.2. Posology and method of administration

Posology

Crohn's disease

Induction of remission

The recommended daily dose is three capsules once daily in the morning or one capsule (containing 3 mg budesonide) three times daily (morning, midday and evening; corresponding to a total daily dose of 9 mg budesonide) if this is more convenient to the patient.

Duration of treatment

The duration of treatment in active Crohn's Disease should be limited to 8 weeks.

Microscopic colitis

Induction of remission

The recommended dose is three capsules once daily in the morning (corresponding to a daily dose of 9 mg budesonide).

Maintenance of remission

Maintenance therapy should only be initiated in patients with frequently recurring symptoms of microscopic colitis after successful induction treatment. A dosage regimen of two capsules once daily in the morning (6 mg budesonide) or of two capsules once daily in the morning alternating with one capsule daily in the morning (corresponding to an average daily dose of 4.5 mg budesonide) can be applied, according to the individual requirements of the patient. The lowest effective dose should be used.

Duration of treatment

The duration of treatment in active microscopic colitis should be limited to 8 weeks.

In maintenance therapy, the treatment effect should be evaluated regularly to assess if continued treatment is necessary, not later than 12 months after the initiation of maintenance treatment. Maintenance treatment should only be extended beyond a duration of 12 months if the benefits for the individual patient are considered to outweigh the risks.

Autoimmune hepatitis

Induction of remission

For the induction of remission (i.e. normalisation of elevated laboratory parameters) the recommended daily dose is one capsule (containing 3 mg budesonide) three times daily (morning, midday and evening; corresponding to a total daily dose of 9 mg budesonide).

Maintenance of remission

After achievement of remission the recommended daily dose is one capsule (containing 3 mg budesonide) twice daily (one capsule in the morning and one capsule in the evening; corresponding to a total daily dose of 6 mg budesonide).

If the transaminases ALAT and/or ASAT increase during maintenance treatment, the dose should be increased to 3 capsules per day (corresponding to a total daily dose of 9 mg budesonide) as described for induction of remission.

In patients tolerant to azathioprine, treatment for induction and maintenance of remission with budesonide should be combined with azathioprine.

Duration of treatment

For the induction of remission a total daily dose of 9 mg should be given until remission is achieved. Thereafter, for maintenance of remission a total daily dose of 6 mg budesonide should be given. Treatment for maintenance of remission in autoimmune hepatitis should be continued at least for 24 months. It might be terminated only if biochemical remission is constantly maintained and if no signs of inflammation are present in a liver biopsy.

Termination of treatment

The treatment with Budenofalk 3mg should not be stopped abruptly, but withdrawn gradually (tapering doses). Gradual dose reduction over 2 weeks is recommended.

Paediatric population

Children under the age of 12

Budenofalk 3mg should not be taken by children younger than 12 years due to insufficient experience and possibly increased risk of adrenal suppression in this age group.

Adolescent patients aged 12 to 18 years

The safety and efficacy of Budenofalk 3mg in children aged 12 to 18 years have not yet been established. Currently available data in adolescent patients (12-18 years) with Crohn's disease or autoimmune hepatitis are described in sections 4.8 and 5.1 but no recommendation on a posology can be made.

Method of administration

The capsules containing the gastro-resistant granules should be taken about half an hour before meals, swallowed whole with plenty of fluid (e.g. a glass of water).

4.3. Contraindications

Budenofalk 3mg must not be used in patients with:

- hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- hepatic cirrhosis

4.4. Special warnings and precautions for use

Treatment with Budenofalk 3mg results in lower systemic steroid levels than conventional oral glucocorticosteroid therapy. Transfer from other glucocorticosteroid therapy may result in symptoms relating to the change in systemic steroid levels.

Caution is required in patients with tuberculosis, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma, cataracts, family history of diabetes, family history of glaucoma, or any other condition in which glucocorticosteroids may have undesirable effects.

This medicine is not appropriate for patients suffering from Crohn's disease of the upper gastrointestinal tract.

Due to the preferential local mode of action of the compound beneficial effects for patients suffering from extraintestinal symptoms (e.g. of the eyes, skin, joints) cannot be expected.

Systemic effects of glucocorticosteroids 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 a wide range of psychiatric/behavioural effects (see section 4.8).

Infection

Suppression of the inflammatory response and immune function increases the susceptibility to infections and their severity. The risk of deterioration of bacterial, fungal, amoebic and viral infections during glucocorticosteroid treatment should be carefully considered. The clinical presentation may often be atypical and serious infections such as septicaemia and tuberculosis may be masked, and therefore may reach an advanced stage before being recognised.

Chickenpox

Chickenpox is of particular concern since this normally minor illness may be fatal in immunosuppressed patients. Patients without a definite history of chickenpox should be advised to avoid close personal contact with chickenpox or herpes zoster and if exposed they should seek urgent medical attention. If the patient is a child, parents must be given the above advice. Passive immunisation with varicella zoster immunoglobulin (VZIG) is needed by exposed non-immune patients who are receiving systemic glucocorticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Glucocorticosteroids should not be stopped and the dose may need to be increased.

Measles

Patients with compromised immunity who have come into contact with measles should, wherever possible, receive normal immunoglobulin as soon as possible after exposure.

Vaccines

Live vaccines should not be given to individuals with chronic glucocorticosteroid use. The antibody response to other vaccines may be diminished.

Patients with liver function disorders

Based on the experience with patients suffering from late stage primary biliary cirrhosis (PBC) with hepatic cirrhosis an increased systemic availability of budesonide in all patients with severely impaired hepatic function is to be expected.

However, in patients with liver disease without hepatic cirrhosis budesonide in daily doses of 9 mg was safe and well tolerated. There is no evidence that a specific dose recommendation for patients with non-cirrhotic liver diseases or only slightly impaired liver function is necessary.

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.

Others

Glucocorticosteroids may cause suppression of the hypothalamic-pituitary-adrenal (HPA) axis and reduce the stress response. When patients are subject to surgery or other stresses, supplementary systemic glucocorticosteroid treatment is recommended.

Concomitant treatment with ketoconazole or other CYP3A4 inhibitors should be avoided (see section 4.5).

Budenofalk 3mg capsules contain lactose and sucrose. Patients with rare hereditary problems of galactose or fructose intolerance, glucose-galactose malabsorption, sucrase-isomaltase insufficiency or total lactase deficiency should not take this medicine.

In patients with autoimmune hepatitis serum levels of transaminases (ALAT, ASAT) should be evaluated at regular intervals to adapt the dose of budesonide adequately. During the first month of treatment, transaminase levels should be evaluated every two weeks, thereafter at least every 3 months.

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

Pharmacodynamic interactions

Cardiac glycosides

The action of the glycoside can be potentiated by potassium deficiency.

Saluretics

Potassium excretion can be enhanced.

Pharmacokinetic interactions

Cytochrome P450

– CYP3A4 inhibitorsCo-treatment with CYP3A inhibitors, including 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.

Ketoconazole 200 mg once daily p.o. increased the plasma concentrations of budesonide (3 mg single dose) approximately 6-fold during concomitant administration. When ketoconazole was administered 12 hours after budesonide, the concentrations increased approximately 3-fold. As there are not enough data to give dose recommendations, the combination should be avoided.Other potent inhibitors of CYP3A4 such as ritonavir, itraconazole, clarithromycin, and grapefruit juice are also likely to cause a marked increase of the plasma concentrations of budesonide. Therefore concomitant intake of budesonide should be avoided.

– CYP3A4 inducersCompounds or drugs such as carbamazepine and rifampicin, which induce CYP3A4, might reduce the systemic but also the local exposure of budesonide at the gut mucosa. An adjustment of the budesonide dose might be necessary.

– CYP3A4 substratesCompounds or drugs which are metabolized by CYP3A4 might be in competition with budesonide. This might lead to an increased budesonide plasma concentration if the competing substance has a stronger affinity to CYP3A4, or – if budesonide binds stronger to CYP3A4 – the competing substance might be increased in plasma and a dose-adaption/reduction of this drug might be required.

Elevated plasma concentrations and enhanced effects of glucocorticosteroids have been reported in women also receiving oestrogens or oral contraceptives, but this has not been observed with oral low dose combination contraceptives.

Cimetidine at recommended doses in combination with budesonide has a small but insignificant effect on the pharmacokinetics of budesonide. Omeprazole has no effect on the pharmacokinetics of budesonide.

Steroid-binding compounds

In theory, potential interactions with steroid-binding synthetic resins such as colestyramine, and with antacids cannot be ruled out. If given at the same time as Budenofalk 3mg, such interactions could result in a reduction in the effect of budesonide. Therefore these preparations should not be taken simultaneously, but at least two hours apart.

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

4.6. Fertility, pregnancy and lactation

Pregnancy

Administration during pregnancy should be avoided unless there are compelling reasons for therapy with Budenofalk 3mg. There are few data of pregnancy outcomes after oral administration of budesonide in humans. Although data on the use of inhaled budesonide in a large number of exposed pregnancies indicate no adverse effect, the maximal concentration of budesonide in plasma has to be expected to be higher in the treatment with Budenofalk 3mg compared to inhaled budesonide. In pregnant animals, budesonide, like other glucocorticosteroids, has been shown to cause abnormalities of fetal development (see section 5.3). The relevance of this to man has not been established.

Breast-feeding

Budesonide is excreted in human milk (data on excretion after inhalative use is available).

However, only minor effects on the breast-fed child are anticipated after Budenofalk 3mg intake within the therapeutic range. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from budesonide therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effect of budesonide on human fertility. Fertility was unaffected following budesonide treatment in animal studies (see section 5.3).

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8. Undesirable effects

The following frequency conventions are used in the evaluation 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 be estimated from the available data).

System organ class

Frequency according to MedDRA convention

Adverse reaction

Metabolism and nutrition disorders

Common

Cushing's syndrome: e.g. with moon face, truncal obesity, reduced glucose tolerance, diabetes mellitus, hypertension, sodium retention with oedema, increased potassium excretion, inactivity or atrophy of the adrenal cortex, red striae, steroid acne, disturbance of sex hormone secretion (e.g. amenorrhoea, hirsutism, impotence)

Very rare

Growth retardation in children

Eye disorders

Rare

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

Gastrointestinal disorders

Common

Dyspepsia, abdominal pain

Uncommon

Duodenal or gastric ulcer

Rare

Pancreatitis

Very rare

Constipation

Immune system disorders

Common

Increased risk of infection

Musculoskeletal and connective tissue disorders

Common

Muscle and joint pain, muscle weakness and twitching, osteoporosis

Rare

Osteonecrosis

Nervous system disorders

Common

Headache

Very rare

Pseudotumor cerebri including papilloedema in adolescents

Psychiatric disorders

Common

Depression, irritability, euphoria

Uncommon

Psychomotor hyperactivity, anxiety

Rare

Aggression

Skin and subcutaneous tissue disorders

Common

Allergic exanthema, petechiae, delayed wound healing, contact dermatitis

Rare

Ecchymosis

Vascular disorders

Very rare

Increased risk of thrombosis, vasculitis (withdrawal syndrome after long-term therapy)

General disorders and administration site conditions

Very rare

Fatigue, malaise

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

Occasionally, adverse events may occur which are typical for systemic glucocorticosteroids. These adverse events depend on the dosage, the period of treatment, concomitant or previous treatment with other glucocorticosteroids and the individual sensitivity.

Clinical studies showed that the frequency of glucocorticosteroid-associated adverse events is lower with oral Budenofalk than with oral treatment of equivalent dosages of prednisolone.

An exacerbation or the reappearance of extra-intestinal manifestations (especially affecting skin and joints) can occur on switching a patient from systemically acting glucocorticosteroids to the locally acting budesonide.

Side effects in clinical studies with paediatric patients

Crohn's disease

In clinical trials with Budenofalk 3mg capsules in 82 paediatric patients with Crohn's disease adrenal suppression and headache were the most frequent undesirable effects. Side effects which are typical for glucocorticosteroids were reported as well as other rare reactions such as dizziness, nausea, vomiting, and hyperacusis (see also section 5.1).

Autoimmune hepatitis

Safety data from the subset of a total of 42 paediatric patients in an autoimmune hepatitis clinical trial revealed that undesirable effects reported were not different and not more frequent compared to the adult population in this study (see also section 5.1).

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 national reporting system:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

To date, no cases of overdose with budesonide are known.