Consumer medicine information

Budenofalk Enteric Capsules

Budesonide

BRAND INFORMATION

Brand name

Budenofalk

Active ingredient

Budesonide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Budenofalk Enteric Capsules.

What is in this leaflet

This leaflet answers some common questions about BUDENOFALK enteric capsules. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking BUDENOFALK enteric capsules against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

What BUDENOFALK is used for

BUDENOFALK enteric capsules contain the active ingredient, budesonide. Budesonide belongs to a group of medications called corticosteroids. BUDENOFALK enteric capsules are used to treat Crohn’s disease affecting the ileum and/or the ascending colon (inflammation of the last section of the small bowel and/or the first section of the large bowel) for 8 weeks.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

This medicine is not expected to affect your ability to drive a car or operate machinery.

BUDENOFALK is only available on a doctor’s prescription.

There is not enough information to recommend the use of this medicine for children or adolescents.

Before you take it

When you must not take it

Do not take BUDENOFALK if you have an allergy to:

  • any medicine containing budesonide
  • any of the ingredients listed at the end of this leaflet.

Some symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

BUDENOFALK enteric capsules contain lactose and sucrose. This may cause a problem if you have intolerance to some sugars.

Do not take BUDENOFALK if you suffer from a severe liver disease (liver cirrhosis).

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have any allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding or wish to breastfeed. Your doctor will discuss the risks and benefits of taking BUDENOFALK if you are pregnant or breastfeeding.

Tell your doctor if you have or have had any medical conditions, especially the following:

  • liver disease
  • lung disease (tuberculosis)
  • high blood pressure
  • diabetes, when the level of sugar in the blood is too high
  • disease which causes bones to become less dense, gradually making them weaker, more brittle and likely to break (osteoporosis)
  • ulcer in stomach or duodenum
  • glaucoma (high pressure in the eye)
  • cataracts
  • family history of diabetes or glaucoma
  • any infections
  • any stresses
  • intolerance to sugars
  • any other disease where use of steroids may have unwanted effects.

If you have not told your doctor about any of the above, tell him/her before you start taking BUDENOFALK enteric capsules.

Contact your doctor if you have been exposed to chicken pox, measles and shingles infections. They may become more severe when you take BUDENOFALK.

Tell your doctor if you have not yet had measles.

If you know that you need to be vaccinated please speak to your doctor first.

If you know that you are due to have an operation please tell your doctor that you are taking BUDENOFALK.

If you have been treated with a stronger cortisone preparation before starting treatment with BUDENOFALK, your symptoms may reappear when the medicine is changed.

If this happens, contact your doctor.

Contact your doctor if you experience blurred vision or other visual disturbances.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and BUDENOFALK may interfere with each other. These include:

  • cardiac glycosides such as digoxin, medicines used to treat heart conditions
  • diuretics, medicines used to treat excess fluid in your body
  • ketoconazole and itraconazole, medicines used to treat fungal infections
  • antibiotics such as clarithromycin, medicines used to treat infections
  • ritonavir and cobicistat medicines used to treat HIV infections
  • carbamazepine, medicine used to treat epilepsy
  • rifampicin, medicine used to treat tuberculosis
  • contraceptive pill
  • cholestyramine, medicine used to reduce cholesterol level
  • cimetidine, medicine used to reduce stomach acid.

These medicines may be affected by BUDENOFALK or may affect how well it works. You may need different amounts of your medicines or you may need to take different medicines.

Avoid drinking grapefruit juice while you are taking BUDENOFALK as this can alter its effects.

Your doctor or pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take it

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

How much to take

Adults and the elderly:
One BUDENOFALK 3 mg enteric capsule three times a day (morning, midday and evening), or three BUDENOFALK 3 mg enteric capsules once daily in the morning.

BUDENOFALK treatment should be terminated by gradual reduction of your dose over the last two weeks. The dosage should be reduced to two capsules daily (one in the morning and one in the evening) for one week. In the last week, only one capsule should be taken in the morning.

Once you have started taking BUDENOFALK, do not stop taking it abruptly.

How to take it

Swallow the capsules whole with a glass of water. Do not chew or crush the capsules.

If you have difficulty swallowing the capsules, open the capsule and take the granules with plenty of liquid. Do not chew or crush the granules.

When to take it

Take BUDENOFALK enteric capsules about 30 minutes before a meal.

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it

BUDENOFALK enteric capsules may be used for up to 8 weeks for each episode of Crohn’s disease.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much BUDENOFALK. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking it

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking BUDENOFALK enteric capsules.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

Things that you must not do

Do not take BUDENOFALK enteric capsules to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking BUDENOFALK or change the dosage without checking with your doctor.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking BUDENOFALK.

Like all medicines, BUDENOFALK may have some side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist immediately if you notice any of the following:

  • signs or symptoms of an infection
  • headache
  • changes in behaviour such as depression, irritability, euphoria, restlessness, anxiety or aggression.

Tell your doctor or pharmacist if you notice any of the following that are troublesome or ongoing:

  • abdominal pain
  • pain in the upper middle part of the abdomen
  • diarrhoea / soft stools
  • high blood pressure
  • acne
  • tiredness, general feeling of being ill.

When BUDENOFALK is taken, side effects may occur which are typical of the more active cortisone preparations (Cushing-like properties). The side effects listed below depend on the dose, the period of treatment, whether there has been prior or accompanying treatment with other cortisone preparations and on the individual sensitivity.

  • Cushing Syndrome: roundness of the face, weight gain, increased risk of high blood sugar, fluid retention, reduced growth
  • increased risk of infection
  • irregular periods in women, male hair growth patterns in women, impotence
  • mood changes such as depression, irritation or euphoria
  • blurred vision (e.g. glaucoma and cataract)
  • increased risk of blood clotting, disease of the blood vessels (associated with stopping steroid use after long term therapy)
  • stomach complaints, gastric ulcers, pancreatitis and constipation
  • muscle pain and bone weakness (osteoporosis), loss of bone and cartilage (aseptic bone necrosis)
  • rash from hypersensitivity reactions (allergic exanthema), formation of red stripes (striations) and bleeding in the skin, delayed wound healing, local skin reactions (such as contact dermatitis)
  • isolated cases: increased brain pressure with possible additional swelling of the optic disk in adolescents.

If any of the following happens, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • allergic reaction including swelling of limbs, face, lips, mouth or throat which may cause difficulty swallowing or breathing.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some patients.

After taking it

Storage

Keep BUDENOFALK enteric capsules in their original packaging until it is time to take them.

Keep your capsules in a cool dry place where the temperature stays below 30°C.

Do not store it or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking BUDENOFALK or the expiry date has passed, ask your pharmacist what to do with any capsules that are left over.

Product description

What it looks like

BUDENOFALK 3 mg enteric capsules are pink opaque capsules containing round white pellets. BUDENOFALK capsules are approved in blister packs of 9 and 10 (starter packs), 50 and 90.

Not all pack sizes may be available.

Ingredients

Each BUDENOFALK enteric capsule contains 3 mg of the active ingredient, budesonide.

Each BUDENOFALK enteric capsule also contains lactose monohydrate, sugar spheres (sucrose), triethyl citrate, purified talc, povidone, methacrylic acid copolymer, ammonio methacrylate copolymer, gelatin, sodium lauryl sulphate, as well as the colourings titanium dioxide, iron oxide red, iron oxide black and erythrosine.

Sponsor

Dr. Falk Pharma Australia Pty Ltd,
815 Pacific Highway,
Chatswood NSW 2067

Australian Registration Number:

AUST R 179566

BUDENOFALK® is a registered trademark of Dr. Falk Pharma GmbH, Germany.

This leaflet was revised in October 2023.

Published by MIMS March 2024

BRAND INFORMATION

Brand name

Budenofalk

Active ingredient

Budesonide

Schedule

S4

 

1 Name of Medicine

Budesonide.

2 Qualitative and Quantitative Composition

Budenofalk enteric capsules contain the active ingredient budesonide.

Excipients of known effect.

Sugars (as lactose monohydrate and sucrose).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Budenofalk 3 mg enteric capsules are presented as pink opaque, oblong hard gelatin capsules. Each enteric capsule contains 3 mg of budesonide.

4 Clinical Particulars

4.1 Therapeutic Indications

Budenofalk enteric capsules are indicated for:
Induction of remission in patients with mild to moderately active Crohn's disease affecting the ileum and/or the ascending colon (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Adults and the elderly.

For acute Crohn's disease (for 8 weeks):
9 mg budesonide once daily in the morning, or
3 mg budesonide 3 times daily (morning, midday and evening).
Safety and efficacy of Budenofalk enteric capsules have been assessed for up to 8 weeks in adults. Continuous treatment beyond 8 weeks is not recommended. Patients may receive episodic treatment.

At discontinuation.

At the end of treatment, the dosage should be tapered gradually, to avoid the possibility of insufficient function of the cortex of the suprarenal gland.
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. After two weeks of gradual dose reduction, treatment can be discontinued.

Method of administration.

The enteric capsules may be taken whole, without chewing or crushing, about 30 minutes before meals with sufficient water. Patients with difficulty swallowing the capsules may open the capsule and administer the granules without chewing or crushing and with plenty of liquid.

4.3 Contraindications

Budenofalk enteric capsules are contraindicated in patients with the following:
hypersensitivity to budesonide or any of the ingredients;
hepatic cirrhosis.

4.4 Special Warnings and Precautions for Use

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.
Treatment with Budenofalk enteric capsules results in lower systemic steroid levels than conventional oral steroid therapy. Particular care is needed in patients who are transferred from systemic glucocorticosteroid treatment with higher systemic effect to Budenofalk enteric capsules. These patients may have adrenocortical suppression. Therefore, monitoring of adrenocortical function may be considered in these patients and their dose of systemic steroid should be reduced cautiously.
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 a wide range of psychiatric/ behavioural effects (see Section 4.8 Adverse Effects (Undesirable Effects)).
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.
As with all glucocorticosteroids, some degree of adrenal suppression may occur in particularly sensitive patients, therefore, monitoring of haematological and adrenal function is strongly advised.

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.

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.

Budenofalk enteric 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.
Concomitant treatment with ketoconazole or other CYP3A4 inhibitors should be avoided (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in hepatic impairment.

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 3 mg TID 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.

Use in the elderly.

The experience in elderly with Budenofalk enteric capsules is limited.

Paediatric use.

Budenofalk is not recommended for use in children or adolescents. Long term effects, including on height and bone density have not been assessed.

Effects on laboratory tests.

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

4.5 Interactions with Other Medicines and Other Forms of Interactions

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.

Co-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 orally once daily 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 3 mg 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 cholestyramine, and with antacids cannot be ruled out. If given at the same time as Budenofalk enteric capsules, 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

Effects on fertility.

There are no data on the effect of budesonide on human fertility. Subcutaneous administration of budesonide to rats at doses up to 20 microgram/kg/day did not affect fertility.
(Category B3)
Administration during pregnancy should be avoided unless there are compelling reasons for therapy with Budenofalk capsules.
There are few data on 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 effects, the maximal concentration of budesonide in plasma is expected to be higher with oral budesonide compared to inhaled budesonide.
In pregnant animals, administration of budesonide, like other glucocorticoids, has been shown to cause fetal death and abnormalities of fetal development (reductions in fetal/ pup growth and litter size, skeletal and visceral abnormalities). The relevance of these findings to humans has not been established.
 Budesonide is excreted in human milk. However, only minor effects on the breast-fed infant are anticipated after Budenofalk intake within the therapeutic range. A decision should be made whether to discontinue breastfeeding or to discontinue Budenofalk taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Budenofalk is generally well tolerated. In clinical studies most adverse events were of mild to moderate intensity and of a nonserious character.
In two clinical trials involving 256 patients with acute Crohn's disease, budesonide was well tolerated. Table 1 shows the adverse events that occurred in at least 10% of patients in any of the two clinical trials included.

Post-marketing adverse effects.

The following undesirable effects and frequencies of Budenofalk 3 mg enteric capsules have been spontaneously reported.
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) and very rare: (< 1/10,000), not known (cannot be estimated from the available data).
Common (≥ 1/100 to < 1/10). Depression, irritability, euphoria;
Muscle and joint pain, muscle weakness and twitching, osteoporosis;
Dyspepsia.
Uncommon (≥ 1/1,000 to < 1/100). Psychomotor hyperactivity, anxiety;
Duodenal or gastric ulcer.
Rare (≥ 1/10,000 to < 1/1,000). Aggression;
Glaucoma, cataract, blurred vision;
Pancreatitis;
Osteonecrosis;
Ecchymosis.
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.

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 glucocorticoids. These side effects depend on the dosage, the period of treatment, concomitant or previous treatment with other glucocorticoids and the individual sensitivity.
Clinical studies showed that the frequency of glucocorticosteroid associated side effects is lower with Budenofalk enteric capsules (approx. by half) than with oral treatment of equivalent dosages of oral prednisolone.

Systemically acting glucocorticoids.

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 systemically acting glucocorticoids 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, a wide range of other psychiatric/ 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).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reportingproblems.

4.9 Overdose

Acute overdose with Budenofalk enteric capsules is unlikely to result in clinical problems. For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The exact mechanism of action of budesonide in the treatment of Crohn's disease is not fully understood. The anti-inflammatory effects of budesonide, such as inhibition of the release of inflammatory mediators and suppression of the cellular immunological response, may be important. The intrinsic potency of budesonide, measured by its affinity to the glucocorticoid receptor, is about 15 times higher than the potency of prednisolone.
Data from clinical pharmacology studies and other controlled clinical trials strongly indicate that the mode of action of orally administered budesonide is predominantly based on a local action in the mucosa of the intestine and the colon due to its metabolism (by cytochrome P450 3A4) to pharmaceutically nearly inactive metabolites in the intestinal mucosa and in the liver. Doses of comparable clinical efficacy show that compared to prednisolone, Budenofalk has a significantly lower influence on the hypothalamo-pituitary-adrenal (HPA) axis. At the recommended dosages, Budenofalk has significantly less effects on morning cortisol plasma levels, 24-hour cortisol plasma levels (AUC0-24) and 24-hour cortisol urine levels, than 20-40 mg prednisolone daily.

Clinical trials.

In a multicentre, randomised, controlled study (BUC-23/ CDA) the efficacy and safety of Budenofalk enteric capsules given at a dose of 3 mg TID was compared with a decreasing dose of prednisone (from 40 mg daily, reducing to 5 mg daily) over 8 weeks.
The Crohn's Disease Activity Index (CDAI) was the main clinical assessment for determining efficacy. The CDAI is a validated index based on subjective aspects rated by the patient (frequency of liquid or very soft stools, abdominal pain rating and general well-being) and objective observations (number of extra-intestinal symptoms, need for anti-diarrhoeal drugs, presence of abdominal mass, body weight and haematocrit).
The primary analysis was of a composite of selected steroid-related side effects and CDAI score.
Three types of responder were assessed. These were defined as:
"R1" responder - response without the occurrence of either "moon face" or "acne" (considered to be the main steroid-induced ADRs);
"R2" responder - response associated with the occurrence of at least one steroid-induced ADR;
"R0" responder - overall response (R1 or R2 response).
The overall response rate (R0) did not take differences in steroid side effects into consideration and included all patients with a CDAI < 150 at end of study and, in patients with a baseline CDAI < 210, a decrease in CDAI of ≥ 60. See Table 2.
In a double-blind, randomised, multicentre study (BUC-52/ CDA) the efficacy and safety of a 8 weeks treatment with Budenofalk enteric capsules 9 mg/day (3 mg capsules three times daily or 3 x 3 mg capsules once daily) was compared to Salofalk tablets 4.5 g/day (3 x 500 mg tablets three times daily) in the therapy of active Crohn's disease.
The primary efficacy variable was clinical remission of Crohn's disease defined as CDAI score of ≤ 150 from baseline at the final visit (week 8) or at the withdrawal visit. Results showed that Budenofalk 3 mg enteric capsules are non-inferior to mesalazine in the treatment of active Crohn's disease (non-inferiority margin -10%). No significant difference in remission rate was observed for the 2 budesonide dosage regimens (budesonide 3 mg three times daily compared to budesonide 9 mg once daily). See Tables 3 and 4.
Results of the studies show that Budenofalk enteric capsules are well tolerated in patients with active Crohn's disease (see Section 4.8 Adverse Effects (Undesirable Effects)).

5.2 Pharmacokinetic Properties

Absorption.

Budenofalk 3 mg enteric capsules, which contain gastric juice resistant granules, have a lag phase of 2 - 3 hours due to the specific coating of the granules. In healthy volunteers, as well as in patients with Crohn's disease, mean maximal budesonide plasma concentrations of 1-2 nanogram/mL were seen about 5 hours following a single 3 mg oral dose of Budenofalk, taken before a meal. 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 enteric capsules is comparable to healthy subjects or Crohn's disease patients.
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 intestinal mucosa and in the liver (approximately 90%) to metabolites of low glucocorticoid activity. The glucocorticoid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of that of budesonide.

Metabolism.

Budesonide is mainly metabolised via cytochrome P450 3A4 in the intestinal mucosa and in the liver.

Excretion.

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 in the liver, the metabolism of budesonide may be decreased in patients with liver diseases. Therefore, the systemic exposure of budesonide may be increased in patients with impaired hepatic function. With improving liver function and disease, metabolism of budesonide will normalize.
The bioavailability of budesonide has been found to be significantly higher in patients with liver cirrhosis (PBC Stage IV) than in patients with liver diseases without cirrhosis (PBC Stage I/II). Following repeated administration of budesonide 3 x 3 mg daily the AUC, on average, was threefold greater in patients with liver cirrhosis (late-stage PBC), than in patients with early-stage PBC.

Budenofalk enteric capsules.

The mean peak plasma concentration of budesonide after a single dose of 9 mg budesonide (Budenofalk 3 x 3 mg capsules) was 1.73 ± 1.40 nanogram/mL at a median Tmax of 5.00 hours. For the metabolite 6-β-hydroxy-budesonide, the mean plasma concentration and Tmax were similar to budesonide (2.80 ± 1.26 nanogram/mL, and 5.5 hours, respectively). Higher concentrations were observed for the major metabolite 16-α-hydroxyprednisolone: the mean Cmax of 23.11 nanogram/mL occurred after a median Tmax of 5.45 hours. Of the 9 mg dose, 11.58% could be recovered in urine in form of 16-α-hydroxyprednisolone and 1.46% in form of 6-β-hydroxy-budesonide.
Pharmacokinetic data are summarised in Table 5 for Budenofalk enteric capsules (3 x 3 mg budesonide once daily) in 18 healthy subjects:
Pharmacokinetic data are summarised in Table 6 for Budenofalk enteric capsules (3 mg budesonide three times daily) in 12 healthy subjects:

5.3 Preclinical Safety Data

Genotoxicity.

Budesonide had no genotoxic effects in a battery of in vitro and in vivo tests.

Carcinogenicity.

The carcinogenic potential of budesonide has been assessed in mice and rats at respective oral doses up to 200 and 50 microgram/kg/day. No oncogenic effect was noted in mice. One study showed an increased incidence of malignant gliomas in male Sprague-Dawley rats given budesonide 50 microgram/kg/day; however this was not confirmed in further studies in male Sprague-Dawley and Fischer rats. In male rats dosed with 10, 25 and 50 microgram/kg/day, those receiving 25 and 50 microgram/kg/day showed an increased incidence of primary hepatocellular tumours; however this was also observed in rats treated with prednisolone and triamcinolone acetonide, thus indicating a class effect of corticosteroids in rats.

6 Pharmaceutical Particulars

6.1 List of Excipients

Budenofalk 3 mg enteric capsules contain the following excipients: sugar spheres (sucrose), lactose monohydrate, povidone, methacrylic acid copolymer, ammonio methacrylate copolymer, triethyl citrate, purified talc, gelatin, erythrosine, sodium lauryl sulfate, titanium dioxide, iron oxide red and iron oxide black.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Enteric capsules are supplied in blister strips with aluminum foil backing.
Cartons of 9*, 45* and 90 are available.
(*currently not marketed).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Budesonide is a white or almost white, crystalline powder. It is practically insoluble in water, freely soluble in methylene chloride, sparingly soluble in alcohol.

Chemical structure.


Budesonide.

Proper name: Budesonide.
Chemical name: 16α,17α-butylidene dioxy-11β, 21-dihydroxy-1,4-pregnadiene-3, 20-dione.
C25H34O6 = 430.5.

CAS number.

51333-22-3.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes