Budenofalk 3 mg gastro-resistant capsules

Each capsule contains 3 mg budesonide

Excipients: Each capsule contains 240mg Sucrose and 12mg Lactose Monohydrate.

For a full list of excipients, see 6.1.

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

Capsule, hard, pink containing white gastro-resistant granules

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

– Symptomatic relief of chronic diarrhoea due to collagenous colitis

Please note:

Treatment with Budenofalk 3 mg 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 3 mg because of its local action.

Posology:

Adults aged> 18 years:

The recommended daily dose is one capsule (containing 3 mg budesonide) three times daily (morning, midday and evening) about a half hour before meals.

Children:

Budenofalk 3 mg should not be taken by children due to insufficient experience in this age group.

Method of Administration:

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

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

The treatment with Budenofalk 3 mg should not be stopped abruptly, but withdrawn gradually (tapering doses).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.

Budenofalk 3 mg must not be used in:

– hypersensitivity to budesonide or any of the ingredients

– hepatic cirrhosis with signs of portal hypertension, e.g. late-stage primary biliary cirrhosis

Treatment with Budenofalk 3 mg 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. 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.)

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.

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:

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.

Administration during pregnancy should be avoided unless there are compelling reasons for Budenofalk 3 mg 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.

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

No effects are known.

The following undesirable effects and frequencies of Budenofalk 3 mg 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 3 mg (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 psychatric/behavioural effects may occur.

Eyes disorders:

Glaucoma, cataract

Vascular disorders:

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

Gastrointestinal 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)

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.

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 3 mg 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 3 mg 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.

Absorption:

Budenofalk 3 mg 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 12 ng/ml were seen at about 5 hours following an oral dose of Budenofalk 3 mg 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 3 mg 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 3 mg will be transferred normally into the colon.

Concomitant intake of food may delay release of granules from stomach by 2–3 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, 6β-hydroxybudesonide and 16α-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):

Dependent on the type and severity of liver diseases and due to the fact that budesonide is metabolised by CYP3A4, the metabolization of budesonide might be decreased. Therefore, the systemic exposure of budesonide might be increased in patients with impaired hepatic functions, as has been shown for patients with autoimmune hepatitis (AIH). With improving the liver function and disease, metabolization of budesonide will normalize.

The bioavailability of budesonide has been found to be significantly higher in patients in the late stage of primary biliary cirrhosis (PBC Stage IV) than in patients in the early stages of primary biliary cirrhosis (PBC Stage I/II); on average, the areas under the plasma concentration-time curves were threefold greater in patients with late-stage PBC, following repeated administration of budesonide 3 x 3 mg daily, than in patients with early-stage PBC.

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.)

Capsules contents:

Lactose monohydrate

Maize starch

Methacrylic acid, methylmethacrylate copolymer (1:1) (Eudragit L 100)

Methacrylic acid, methylmethacrylate copolymer (1:2) (Eudragit S 100)

Poly(ethylacrylate, methylmethacrylate, trimethylammonium ethylmethacrylate chloride) (1:2:0.2) (solution with 12.5 percent Eudragit RL 12.5)

Poly(ethylacrylic acid, methylmethacrylate, trimethylammonium ethylmethacrylate chloride) (1:2:0.1) (dispersion with 12.5 percent Eudragit RS 12.5)

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)

Not applicable

3 years.

Do not store above 25 °C.

Al/PVC/PVDC blister strips.

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

No special requirements.

Dr. Falk Pharma GmbH

Leinenweberstr. 5

79108 Freiburg

Postfach 6529

79041 Freiburg

PL08637/0002

4/1/2009

4/1/2009