Dr. Falk Pharma UK Ltd

Budenofalk 9mg gastro-resistant granules

Each sachet contains 9 mg budesonide

Excipients: Each sachet contains 828 mg Sucrose, 36 mg Lactose Monohydrate and 900 mg Sorbitol (E420).

For a full list of excipients, see 6.1.

Gastro-resistant granules

white to off-white granules with smell of lemon flavour

Induction of remission in patients with active collagenous colitis

Posology:

Adults aged > 18 years:

The recommended daily dose is one sachet (containing gastro-resistant granules with 9 mg budesonide) once daily in the morning about a half hour before meals.

Paediatric patients ( 18 years):

Budenofalk 9mg gastro-resistant granules should not be taken by children and adolescents due to insufficient experience in this age group.

Patients with renal impairment:

There are no specific dosage recommendations for patients with renal insufficiency (see 5.2).

Patients with hepatic impairment:

Since the information is limited in this patient-population a specific dose recommendation cannot be made (see 4.3, 4.4 and 5.2).

Method of Administration:

Oral use

The content of one sachet should be taken before breakfast. The granules should be placed on the tongue and swallowed whole, with plenty of liquid (e.g. a glass of water). The granules should not be chewed or crushed to avoid destruction of the gastro-resistant coating of the granules. Premature disintegration will affect drug disposition in an unpredictable fashion.

The duration of treatment should be limited to 8 weeks.

The treatment with Budenofalk 9mg gastro-resistant granules should not be stopped abruptly. At the end of the treatment, Budenofalk 9mg gastro-resistant granules should be given in prolonged dosing intervals, i.e. every other day for up to two weeks. Afterwards treatment can be stopped.

Budenofalk 9mg gastro-resistant granules must not be used in patients with:

– hypersensitivity to budesonide or any of the ingredients

– hepatic cirrhosis

Treatment with Budenofalk 9mg gastro-resistant granules 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, or any other condition in which glucocorticoids may have undesirable effects.

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 immunoglobulin as soon as possible after exposure.

Live vaccines: Live vaccines should not be given to individuals with chronic corticosteroid 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.

Others:

Corticosteroids may cause suppression of the HPA axis and reduce the stress response. When 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 9mg gastro-resistant granules contain lactose, sucrose and sorbitol. 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:

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 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 (using e.g. budesonide 3mg capsules) 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 colestyramine, and with antacids cannot be ruled out. If given at the same time as Budenofalk 9mg gastro-resistant granules, 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.

Pregnancy

Administration during pregnancy should be avoided unless there are compelling reasons for therapy with Budenofalk 9mg gastro-resistant granules. 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 9 mg gastro-resistant granules compared to inhaled budesonide. In pregnant animals, budesonide, like other glucocorticosteroids, has been shown to cause abnormalities of fetal development (please refer to section 5.3). The relevance of this to man has not been established.

Lactation

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 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).

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

The following undesirable effects and frequencies of Budenofalk 9mg gastro-resistant granules 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 9mg gastro-resistant granules (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.

Eye 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.

Pharmacotherapeutic group: Corticosteroids acting locally,

ATC code: A07EA06

The exact mechanism of budesonide in the treatment of inflammatory bowel diseases is not fully understood. Data from clinical pharmacology studies and controlled clinical trials strongly indicate that the mode of action of Budenofalk gastro-resistant granules 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 gastro-resistant granules show a dose-dependent influence on cortisol plasma levels which is at the recommended dose of 9 mg budesonide/day significantly smaller than that of clinically equivalent effective doses of systemic glucocorticosteroids.

Absorption:

Due to the specific coating of the Budenofalk 9mg gastro-resistant granules there is a lag phase of 2 - 3 hours. In fasting healthy volunteers, mean peak plasma concentrations of budesonide were 2.2 ng/ml at about 6 hours following a single oral dose of 9 mg budesonide gastro-resistant granules.

In a study with a single dose of budesonide 3 mg gastro-resistant granules it was shown that concomitant intake of food may delay release of granules from stomach by about 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 inflammatory bowel diseases is about 9-13 %. Clearance of budesonide is about 10-15 l/min.

Budesonide is eliminated only in marginal if any amounts by the kidney.

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.

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 an increased incidence of primary hepatocellular neoplasms, astrocytomas (in male rats) and mammary tumours (female rats) were observed. These tumours are probably due to the specific steroid receptor action, increased metabolic burden and anabolic effects on the liver, effects which are also known from other glucocorticosteroids in rat studies and therefore represent a class effect in this species.

Budesonide had no effect on fertility in rats. In pregnant animals, budesonide, like other glucocorticosteroids, has been shown to cause fetal death and abnormalities of fetal development (smaller litter size, intrauterine growth retardation of fetuses and skeletal abnormalities). Some glucocorticoids have been reported to produce cleft palate in animals. The relevance of these findings to man has not been established (see also section 4.6.).

Ammonio methacrylate copolymer (type A) (Eudragit RL),

ammonio methacrylate copolymer (type B) (Eudragit RS),

citric acid anhydrous (for pH-adjustment),

lactose monohydrate,

lemon flavour,

magnesium stearate,

methacrylic acid-methyl methacrylate copolymer (1:1) (Eudragit L 100),

methacrylic acid-methyl methacrylate copolymer (1:2) (Eudragit S 100),

povidone K25,

sucralose,

sugar spheres (consisting of maize starch and sucrose),

sorbitol (E420),

talc,

triethyl citrate,

xanthan gum

Not applicable

2 years

This medicinal product does not require any special storage conditions.

Polyester/aluminium/polyethylene foil sachet

Pack sizes: 15, 20, 30, 50, 60 sachets. Not all pack sizes may be marketed.

No special requirements.

Dr. Falk Pharma GmbH

Leinenweberstr. 5

79108 Freiburg

Germany

Tel: +49 (0)761 1514-0

PA/573/2/3

Dec 2010