SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Budenofalk® 2mg/dose rectal foam

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each dose of 1.2 g foam contains 2 mg of budesonide Excipients: cetyl alcohol, propylene glycol For the full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Rectal foam, pressurised container White to pale white, creamy firm foam

4.    CLINICAL PARTICULARS

4.1.    Therapeutic indications

For the treatment of active ulcerative colitis that is limited to the rectum and the sigmoid colon.

4.2.    Posology and method of administration

Posology:

Adults aged > 18 years:

One actuation of 2 mg budesonide daily.

Children and adolescents:

Budenofalk^® 2mg rectal foam should not be taken by children due to insufficient experience in this age group.

Method of Administration:

Budenofalk® 2mg rectal foam can be applied in the morning or evening.

The canister is first fitted with an applicator and then shaken for about 15 seconds before the applicator is inserted into the rectum as far as comfortable. Note that the dose is only sufficiently accurate when the pump dome is held downwards as vertically as possible. To administer a dose of Budenofalk® 2mg rectal foam, the pump dome is fully pushed down and very slowly released. Following the activation the applicator should be held in position for 10-15 seconds before being withdrawn from the rectum.

The best results are obtained when the intestine is evacuated prior to administration of Budenofalk® 2mg rectal foam.

The attending physician determines the duration of use. An acute episode generally subsides after 6 to 8 weeks. Budenofalk® 2mg rectal foam should not be used after this time.

4.3 Contraindications

Budenofalk 2mg rectal foam must not be used in:

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

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

4.4 Special warnings and precautions for use

Treatment with Budenofalk 2mg rectal foam results in lower systemic steroid levels than oral therapy with systemically acting corticoids. If a patient is transferred from systemic corticoids to Budenofalk, the theoretical risk of recurrence of symptoms due to differences in the pharmacokinetics has to be taken into account.

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

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 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. In some cases 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 impaired immune responsiveness. The antibody response to other vaccines may be diminished.

In patients with severe liver function disorders, the elimination of glucocorticoids including Budenofalk 2mg rectal foam will be reduced, and their systemic bioavailability will be increased.

Caution should be exercised in patients with slight to moderate hepatic impairment.

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).

This medicine contains cetyl alcohol and propylene glycol which can cause local skin reactions (e.g. contact dermatitis).

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-adaptation/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.

4.6 Fertility, pregnancy and lactation

Pregnancy

Administration during pregnancy should be avoided unless there are compelling reasons for Budenofalk 2mg rectal foam 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.

Breast-feeding

It is not known if budesonide passes into breastmilk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Budenofalk 2mg rectal foam should be made taking into account the benefit of breastfeeding to the child and the benefit of the therapy to 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

Budenofalk Rectal Foam has no or negligible influence on the ability to drive and use machines.

The assessment of undesirable effects is based on the following frequencies.

Very common: (> 1/10)

Common: (> 1/100 to <1/10)

Uncommon: (> 1/1000 to <1/100)

Rare: (> 1/10,000 to < 1/1000)

Very rare: (<1/10,000), not known (cannot be estimated from the available data).

Undesirable effects were reported in 8% of patients in clinical trials with Budenofalk rectal foam. Burning in the rectum or pain were common and nausea, headache, increase in liver enzymes were uncommon.

The details of the side effects observed during clinical trials are as follows: Infections and parasitic diseases Uncommon: urinary tract infections

Blood and lymphatic system disorders

Uncommon: anaemia, increase in erythrocyte sedimentation rate, leucocytosis

Metabolism and nutrition disorders Uncommon: increased appetite

Psychiatric disorders Uncommon: insomnia

Nervous system disorders

Uncommon: headache, dizziness, disturbances of smell

Vascular disorders Uncommon: hypertension

Gastrointestinal disorders

Uncommon: nausea, abdominal pain, dyspepsia, flatulence, paraesthesias in the abdominal region, anal fissure, aphthous stomatitis, frequent urge to defecate, haemorrhoids, rectal bleeding

Hepatobiliary disorders

Uncommon: increase in transaminases (GOT, GPT), increase in parameters of cholestasis (GGT, AP)

Skin and subcutaneous tissue disorders Uncommon: acne, increased sweating

Investigations

Uncommon: increase in amylase, change in cortisol

General disorders and administration site conditions

Common: burning in the rectum and pain Uncommon: asthenia, increase in body weight

Occasionally side effects may occur which are typical for systemically acting glucocorticosteroids. The side effects listed below depend on the dosage, the period of treatment, concomitant or previous treatment with other glucocorticosteroids and the individual sensitivity.

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)

Nervous system disorders: depression, irritability, euphoria

in isolated cases (< 1/10,000): pseudotumor cerebri (including papilloedema) in adolescents.

Eye disorders: glaucoma, cataract

Vascular disorders:

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

Gastro intestinal disorders:

stomach complaints, duodenal ulcer, pancreatitis, constipation Skin and subcutaneous tissue disorders:

allergic exanthema, red striae, petechiae, ecchymoses, steroid acne, delayed wound healing.

Due to the cetyl alcohol and propylene glycol content local skin reactions may occur, e.g. contact dermatitis.

Musculoskeletal, connective tissue and bone disorders :

aseptic necrosis of bone (femur and head of the humerus), diffuse muscle pain

and weakness, osteoporosis.

General disorders:

Tiredness, malaise.

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

Due to its local action, the risk of unwanted effects of Budenofalk 2mg rectal foam is generally lower than when taking systemically acting glucocorticoids.

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:

United Kingdom

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® 2mg rectal foam, an overdose resulting in toxic damage is extremely unlikely.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Intestinal antiinflammatory agents, corticosteroids

acting locally

ATC code: A07EA06

The exact mechanism of action of budesonide in the treatment of ulcerative colitis/procto-sigmoiditis is not fully understood. Data from clinical pharmacology studies and controlled clinical trials strongly indicate that the mode of action of budesonide is predominantly based on a local action in the gut. Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect. At a dosage of 2 mg budesonide, applied rectally, budesonide leads to practically no suppression of the hypothalamus-hypophysis-adrenal cortex axis.

Budenofalk 2mg rectal foam investigated up to the daily dosage of 4 mg budesonide showed virtually no influence on the plasma cortisol level.

5.2. Pharmacokinetic properties

Absorption:

After oral application the systemic availability of budesonide is about 10%. After rectal administration the areas under the concentration time curves are about 1.5-fold higher than in historical controls considering the identical oral budesonide dose. Peak levels are obtained after an average of 2-3 hours after administering Budenofalk® 2mg rectal foam.

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 mean clearance rate is about 10 -15 l/min for budesonide, determined by HPLC-based methods.

Spread:

A scintigraphic investigation with technetium-marked Budenofalk^{® 2mg} rectal foam on patients with ulcerative colitis showed that the foam spreads out over the entire sigmoid.

Specific patient populations (liver diseases):

Dependent on the type and severity of liver diseases the metabolism of budesonide might be decreased.

5.3 Preclinical safety data

Preclinical investigations on dogs have shown that Budenofalk® 2mg rectal foam is well tolerated locally.

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. 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 there was an increased incidence of primary hepatocellular neoplasms, astrocytomas (in male rats) and mammary tumours (female rats) observed. These tumours 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

Cetyl Alcohol Citric acid monohydrate Disodium edentate Emulsifying wax Macrogol stearyl ether Propylene glycol Purified water

Propellant:

n-Butane

Isobutane

Propane

6.2. Incompatibilities

Not applicable.

6.3    Shelf life

3 years

After first opening: 4 weeks.

6.4    Special precautions for storage

Do not store above 25°C.

Do not refrigerate or freeze.

This is a pressurised container, containing inflammable propellant.

Do not expose to temperature higher than 50°C, protected from direct sunlight. Do not pierce or burn even when empty.

6.5. Nature and contents of container

Aluminium pressurised container with metering valve together with 14 PVC applicators coated with white soft paraffin and liquid paraffin for administration of the foam and 14 plastic bags for hygienic disposal of the applicators.

Pack sizes:

Original pack with 1 pressurised container, contains at least 14 doses of 1.2 g rectal foam each.

Original pack with 2 pressurised containers, contains at least 2 x 14 doses of

1.2 g rectal foam each.

Hospital pack with 1 pressurised container, contains at least 14 doses of 1.2 g rectal foam each.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Dr. Falk Pharma GmbH Leinenweberstr. 5 D-79108 Freiburg Germany

8    MARKETING AUTHORISATION NUMBER(S)

PL08637/0011

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11/11/2011

10    DATE OF REVISION OF THE TEXT

28/11/2014