SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Budenofalk 3 mg gastro-resistant capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 3mg budesonide

Excipients with known effect: Each capsule contains 240mg sucrose and 12mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Gastro-resistant capsules, hard (gastro-resistant capsules)

Capsule, hard, pink containing white gastro-resistant granules

4    CLINICAL PARTICULARS

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.

Please note:

Treatment with Budenofalk 3mg does not appear useful in patients with Crohn's disease affecting the upper gastro-intestinal tract. Extraintestinal symptoms, e.g. involving the skin, eyes or joints, are unlikely to respond to Budenofalk 3mg because of its local action.

•    Collagenous colitis.

•    Autoimmune hepatitis.

4.2 Posology and method of administration Posology:

Crohn’s disease

Adults aged > 18 years:

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.

Collagenous colitis

Adults aged > 18 years:

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

Autoimmune hepatitis

Induction of remission (adults aged > 18 years):

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 (adults aged > 18 years):

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.

All indications

Children

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:

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 AIH 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).

Duration of Administration:

Crohn’s disease, collagenous colitis

The duration of treatment in active Crohn’s Disease and in collagenous colitis should be limited to 8 weeks.

Autoimmune hepatitis

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). In the first week, the dosage should be reduced to two capsules daily, one in the morning, one in the evening. In the second week, only one capsule should be taken in the morning. Afterwards treatment can be stopped.

4.3 Contraindications

Budenofalk 3mg must not be used in patients with:

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

-    hepatic cirrhosis

4.4. Special warnings and special precautions for use

Treatment with Budenofalk 3mg results in lower systemic steroid levels than conventional oral steroid therapy. Transfer from other steroid therapy may result in symptoms relating to the change in systemic steroid levels. When patients are switched from systemically acting steroids to locally acting budesonide it should be considered that Budenofalk 3mg is not indicated for the treatment of esophageal Crohn’s disease.

Caution is required in patients with tuberculosis, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma, cataracts, family history of diabetes, family history of glaucoma.

Systemic effects of corticosteroids 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.).

If in patients with Crohn’s disease treatment is changed from systemically acting corticosteroids to budesonide it should be kept in mind that budesonide is not indicated for the treatment of esophageal Crohn’s disease. This applies particularly to the treatment of adolescent patients.

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 glucocorticoid 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 corticosteroids 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. Corticosteroids 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 immunglobulin as soon as possible after exposure.

Live vaccines: Live vaccines should not be given to individuals with impaired immune responsiveness. The antibody response to other vaccines may be diminished.

In patients with severe liver function disorders, the elimination of glucocorticosteroids including Budenofalk will be reduced, and their systemic bioavailability will be increased.

Corticosteroids 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.

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, the Lapp lactase deficiency or the congenital 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 inhibitors:

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, and clarithromycin are also likely to give a marked increase of the plasma concentrations of budesonide. In addition, concomitant intake of grapefruit juice should be avoided.

-    CYP3A4 inducers:

Compounds 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 substrates:

Compounds 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 corticosteroids 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 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 cholestyramine, and with antacids cannot be ruled out. If given at the same time as Budenofalk 3 mg, 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

Administration during pregnancy should be avoided unless there are compelling reasons for Budenofalk 3mg therapy. In pregnant animals, budesonide, like other glucocorticosteroids, has been shown to cause abnormalities of foetal development. The relevance of this to man has not been established.

Lactation

Since it is not known if budesonide passes into breast milk, the infant should not be breast-fed during treatment with Budenofalk 3mg.

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 effects are known.

4.8 Undesirable effects

The following undesirable effects and frequencies of Budenofalk 3mg have been spontaneously reported:

Very rare (< 1/10,000), including isolated reports:

•    Metabolism and nutritional disorders: oedema of legs, Cushing’s syndrome

•    Nervous system disorders: Pseudotumor cerebri (including papilloedema) in adolescents

•    Gastrointestinal disorders: Constipation

•    Musculoskeletal, connective tissue and bone disorders: diffuse muscle pain and weakness, osteoporosis

•    General disorders: tiredness, malaise

Some of the undesired effects were reported after long-term use.

Occasionally side effects may occur which are typical for systemic glucocorticosteroids. These side effects 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 side effects is lower with Budenofalk 3mg (approx. by half) than with oral treatment of equivalent dosages of prednisolone.

Immune system disorders:

Interference with the immune response (e.g. increase in risk of infections).

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

Metabolism and nutrition disorders:

Cushing’s syndrome: moon-face, truncal obesity, reduced glucose tolerance, diabetes mellitus, sodium retention with oedema formation, increased excretion of potassium, inactivity or atrophy of the adrenal cortex, growth retardation in children, disturbance of sex hormone secretion (e.g. amenorrhoea, hirsutism, impotence)

Psychiatric disorders:

Depression, irritability, euphoria

In addition very rarely a wide range of psychiatric/behavioural effects may occur.

Eyes disorders:

Glaucoma, cataract

Vascular disorders:

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

Gastro intestinal disorders:

Stomach complaints, gastroduodenal ulcer, pancreatitis

Skin and subcutaneous tissue disorders:

Allergic exanthema, red striae, petechiae, ecchymosis, steroid acne, delayed wound healing, contact dermatitis

Musculoskeletal, connective tissue and bone disorders:

Aseptic necrosis of bone (femur and head of the humerus)

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 steroids 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

4.9. Overdose

To date, no cases of overdosage with budesonide are known. In view of the properties of budesonide contained in Budenofalk 3 mg, an overdose resulting in toxic damage is extremely unlikely.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Glucocorticosteroid ATC code: A07EA06

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 Budenofalk 3mg capsules is predominantly based on a local action in the gut. Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect. At doses clinically equivalent to systemically acting glucocorticosteroids, budesonide gives significantly less HPA axis suppression and has a lower impact on inflammatory markers.

Budenofalk 3mg capsules show a dose-dependent influence on cortisol plasma levels which is at the recommended dose of 3 x 3 mg budesonide/day significantly smaller than that of clinically equivalent effective doses of systemic glucocorticosteroids.

Clinical efficacy and safety

Clinical study in patients with Crohn’s disease

In a randomized, double-blind, double-dummy trial in patients with mild to moderate Crohn’s disease (200 < CDAI < 400) affecting the terminal ileum and/or the ascending colon the efficacy of 9 mg budesonide in a single daily dose (9 mg OD) was compared to the treatment with 3 mg budesonide given three times daily (3 mg TID).

The primary efficacy endpoint was the proportion of patients in remission (CDAI<150) at week 8.

A total of 471 patients were included in the study (full analysis set, FAS), 439 patients were in the per protocol (PP) analysis set. There were no relevant differences in the baseline characteristics in both treatment groups. At the confirmatory analysis, 71.3% of the patients were in remission in the 9 mg OD group and 75.1% in the 3 mg TID group (PP) (p: 0.01975) demonstrating the non-inferiority of 9 mg budesonide OD to 3 mg budesonide TID.

No drug-related serious adverse events were reported.

Clinical study in patients with autoimmune hepatitis

In a prospective, double-blind, randomised, multicentre trial, 207 patients with autoimmune hepatitis (AIH) without cirrhosis were treated with initial daily doses of 9 mg/d budesonide (n=102) for up to 6 months or 40 mg/d prednisone (tapered to 10 mg/d, n=105). Upon biochemical remission, the budesonide dose was reduced to 6 mg/d. Patients also received 1-2 mg/kg/d azathioprine throughout the study. The composite primary endpoint was complete biochemical remission (i.e. normal serum levels of aspartate- and alanine-aminotransferase) without occurrence of predefined steroid-specific side effects at 6 months. This primary endpoint was achieved in 47% of the patients in the budesonide group and 18% of the patients in the prednisone group (p<.001).

Regarding secondary efficacy variables, at 6 months, complete biochemical remission occurred in 60% and 39% of the patients in the budesonide group and in the prednisone group, respectively (p=.001). 72% and 47% of the patients in the budesonide group and in the prednisone group, respectively, did not develop steroid-specific side-effects (p<.001). The mean decrease in IgG and y-globulin concentrations and the decrease in the rates of patients with elevated IgG and y-globulin concentrations did not show any differences between treatment groups.

An open-label, follow-up treatment of additional 6 months was offered to all patients after the controlled, double-blind phase. A total of 176 patients proceeded to this open-label phase and received 6mg/d budesonide in combination with 1-2 mg/kg/d azathioprine. Rates of patients with biochemical remission and rates of patients with complete response (not statistically significant) were still higher in the original budesonide group (complete response rate 60% and biochemical remission 68.2% at the end of the open label phase) than in the original prednisone group (complete response rate 49% and biochemical remission 50.6% at the end of the open label phase).

Paediatric population

Clinical study in autoimmune hepatitis

The safety and efficacy of budesonide in 46 paediatric patients (11 males and 35 females) aged 9 to 18 years were studied as a subset of patients of the above mentioned clinical study. 19 paediatric patients were treated with budesonide and 27 received the active control (prednisone) for induction of remission with a daily dose of 9 mg budesonide. After 6 months in the study, 42 paediatric patients continued for a further 6 months on open label, follow up treatment with budesonide.

The rate of complete responders (defined as biochemical response, i.e. normalisation of liver transaminases (ASAT, ALAT) and lack of steroid-specific side-effects) in patients aged < 18 years was considerably lower compared to adult patients. There was no significant difference seen between the treatment groups. After follow up treatment with budesonide for a further 6 months, the rate of paediatric patients with complete response was still slightly lower compared to adult patients but the difference between the age groups was much smaller. There was no significant difference in the rate of complete responders between those originally treated with prednisone and those treated continuously with budesonide.

Clinical studies in Crohn’s disease

Two randomised controlled studies with Budenofalk 3 mg capsules included patients in the age range of 8 to 19 years with mildly to moderately active Crohn’s disease (PCDAI [paediatric CD activity index] 12.5 - 40) with ileal, ileocolonic or isolated colonic inflammation.

In one study a total of 33 patients were treated with 9 mg budesonide (3 mg TID) daily for 8 weeks followed by 6 mg budesonide daily during week 9 and 3 mg budesonide daily in week 10 or with prednisone (40 mg/d for two weeks, tapered to zero in steps of 5 mg/week). Remission (PCDAI < 10) was achieved in 9/19 (47.3%) of the patients in the budesonide group (both at week 4 and 12) and 8/14 (57.1 %, at week 4) and 7/14 (50%, at week 12) of the patients in the prednisone group.

A second study including 70 children with CD compared two dosing schedules of budesonide: Patients in group 1 were treated for 7 weeks with 9 mg /day budesonide (3 mg TID) followed by 6 mg/day budesonide (3 mg BID) for additional 3 weeks. In group 2, patients were treated for 4 weeks with 12 mg/day budesonide (3 mg TID and 3 mg OD) and thereafter for each of 3 weeks with 9 mg/day budesonide (3 mg TID) and 6 mg/day budesonide (3 mg BID), respectively. Mean decrease of PCDAI at week 7 was defined as primary efficacy end point. There was a relevant decrease in the PCDAI in both treatment groups. The decrease was more pronounced in group 2 but the difference between the groups did not reach statistical significance (n.s.). Secondary efficacy endpoints: Improvement (defined as a decrease of PCDAI>10 points) was seen in 51.4% of the patients in group 1 and 74.3% of the patients in group 2 (n.s.); remission (PCDAI<12.5) was found in 42.9% of the patients in the first group versus 65.7% in the second group (n.s.).

5.2. Pharmacokinetic properties

Absorption:

Budenofalk 3mg capsules, which contain gastric juice resistant granules, have - due to the specific coating of the granules - a lag phase of 2 - 3 hours. In healthy volunteers, as well as in patients with Crohn’s disease, mean maximal budesonide plasma concentrations of 1-2 ng/ml were seen at about 5 hours following an oral dose of Budenofalk 3mg capsules at a single dose of 3 mg, taken before meals. The maximal release therefore occurs in the terminal ileum and caecum, the main area of inflammation in Crohn’s disease.

In ileostomy patients release of budesonide from Budenofalk 3mg is comparable to healthy subjects or Crohn’s disease patients. In ileostomy patients it was demonstrated that about 30 - 40 % of released budesonide is still found in the ileostomy bag, indicating that a substantial amount of budesonide from Budenofalk 3mg will be transferred normally into the colon.

Concomitant intake of food may delay release of granules from stomach by 23 hours, prolonging the lag phase to about 4-6 hours, without change in absorption rates.

Distribution:

Budesonide has a high volume of distribution (about 3 l/kg). Plasma protein binding averages 85-90 %.

Biotransformation:

Budesonide undergoes extensive biotransformation in the liver (approximately 90 %) to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6^-hydroxybudesonide and 16a-hydroxyprednisolone, is less than 1 % of that of budesonide.

Elimination:

The average elimination half-life is about 3-4 hours. The systemic availability in healthy volunteers as well as in fasting patients with Crohn’s disease is about 9-13 %. The clearance rate is about 10-15 l/min for budesonide, determined by HPLC-based methods.

Specific patient populations

Liver diseases:

A relevant proportion of budesonide is metabolised in the liver. The systemic exposure of budesonide might be increased in patients with impaired hepatic functions due to a decrease in budesonide metabolism by CYP3A4. This is dependent on the type and severity of liver disease.

Paediatric patients:

Pharmacokinetics of budesonide were evaluated in 12 paediatric patients with Crohn’s disease (age: 5 to 15 years). Following multiple dose administration of budesonide (3 x 3 mg of budesonide for one week) mean AUC of budesonide during the dosing interval was about 7 ng h/ml, and C_max about 2 ng/ml. Disposition of oral budesonide (3 mg, single dose) in paediatric patients was similar to that in adults.

5.3. Preclinical safety data

Preclinical data in acute, subchronic and chronic toxicological studies with budesonide showed atrophies of the thymus gland and adrenal cortex and a reduction especially of lymphocytes. These effects were less pronounced or at the same magnitude as observed with other glucocorticosteroids. Like with other glucocorticosteroids, and in dependence of the dose and duration and in dependence of the diseases these steroid effects might also be of relevance in man.

Budesonide had no mutagenic effects in a number of in vitro and in vivo tests.

A slightly increased number of basophilic hepatic foci were observed in chronic rat studies with budesonide, and in carcinogenicity studies was an increased incidence of primary hepatocellular neoplasms, astrocytomas (in male rats) and mammary tumors (female rats) observed. These tumors are probably due to the specific steroid receptor action, increased metabolic burden on the liver and anabolic effects, effects which are also known from other glucocorticosteroids in rat studies and therefore represent a class effect. No similar effects have ever been observed in man for budesonide, neither in clinical trials nor from spontaneous reports.

In general, preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.

In pregnant animals, budesonide, like other glucocorticosteroids, has been shown to cause abnormalities of foetal development. But the relevance to man has not been established (see also section 4.6)

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Capsules contents:

Ammonio methacrylate copolymer (type A) (Eudragit RL), ammonio methacrylate copolymer (type B) (Eudragit RS), lactose monohydrate, maize starch,

methacrylic acid-methyl methacrylate copolymer (1:1) (Eudragit L 100), methacrylic acid-methyl methacrylate copolymer (1:2) (Eudragit S 100), povidone K25, purified water*, sucrose,

talc,

triethyl citrate

* intermediate excipient

Capsule shell:

Black iron oxide (E 172)

Erythrosine (E 127)

Gelatin

Purified water

Red iron oxide (E 172)

Sodium Laurilsulphate

Titanium dioxide (E 171)

6.2.    Incompatibilities

Not applicable

6.3.    Shelf life

3 years.

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions

6.5.    Nature and contents of container

Al/PVC/PVDC blister strips.

Pack sizes: 10, 50, 90, 100 or 120 capsules. Not all pack sizes may be marketed.

6.6.    Instructions for use/handling

No special requirements.

7.    MARKETING AUTHORISATION HOLDER

Dr. Falk Pharma GmbH

Leinenweberstr. 5 79108 Freiburg Germany

8.    MARKETING AUTHORISATION NUMBER

PL 08637/0002

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

04/01/2009

10    DATE OF REVISION OF THE TEXT

01/07/2016