Budenofalk

Budesonide.

Each actuation contains 2.0 mg of budesonide.
Excipients/Inactive Ingredients: Cetyl alcohol (Ph.Eur.), Cetostearyl alcohol (Ph.Eur.), Polysorbate 60, Purified water, Disodium edetate (Ph.Eur.), Emulsifying wax, Macrogol stearyl ether (Ph.Eur.) (10), Propylene glycol, Citric acid monohydrate.
Propellant: n-butane, Isobutane, Propane.

Pharmacotherapeutic group: Intestinal anti-inflammatory agent, corticosteroids acting locally. ATC code: A07EA06.
Pharmacology: Pharmacodynamics: The exact mechanism of action of budesonide in the treatment of ulcerative colitis/proctosigmoiditis is not fully understood. Data from clinical pharmacology 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, which is clinically equieffective with systemically acting glucocorticoids, budesonide leads to practically no suppression of the HPA axis.
Budenofalk 2mg rectal foam investigated up to the daily dosage of 4 mg budesonide showed virtually no influence on the plasma cortisol level.
Pharmacokinetics: General aspects of budesonide: 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, 6β-hydroxybudesonide and 16α-hydroxyprednisolone - both of which are formed via CYP3A - is less than 1% of that of budesonide.
Elimination: The average elimination half-life after oral administration 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 rectal foam in patients with ulcerative colitis showed that the foam spreads out over the entire sigmoid.
Special patient groups (liver disease): Dependent on the type and severity of liver disease the metabolism of budesonide might be decreased.
Toxicology: 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 Use in Pregnancy & Lactation).

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

Posology: Adults aged > 18 years: One actuation of 2 mg budesonide daily.
Children and adolescents: Budenofalk rectal foam should not be used by children and adolescents due to insufficient experience in this age group.
Method of administration: For rectal use: Budenofalk rectal foam can be applied in the morning or evening.
Budenofalk rectal foam should be used at room temperature. 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 rectal foam, the pump dome is fully pushed down and very slowly released. Following the actuation 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 rectal foam.
Duration of treatment: The attending physician determines the duration of use. An acute episode generally subsides after 6 to 8 weeks. Budenofalk rectal foam should not be used after this time.

To date, no cases of overdosage with budesonide are known.

Budenofalk rectal foam must not be used in: hypersensitivity to budesonide or any of the excipients; hepatic cirrhosis.

Treatment with Budenofalk rectal foam results in lower systemic steroid levels than conventional oral glucocorticosteroid therapy with systemically acting corticoids. Transfer from another glucocorticosteroid therapy may result in reappearance or recurrence of symptoms relating to the change in systemic steroid levels.
Caution is required in patients suffering from one or several of the following diseases: tuberculosis, hypertension, diabetes mellitus, osteoporosis, peptic ulcer (gastric or duodenal ulcer), glaucoma, cataracts, family history of diabetes, family history of glaucoma, or any other condition in which glucocorticosteroids may have undesirable effects.
Systemic effects of glucocorticosteroids 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 Adverse Reactions).
Infections: 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 glucocorticosteroid 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 is of particular concern since this normally minor illness may be serious or fatal in immunosuppressed patients. Patients without a definite history of chickenpox should be advised to avoid close personal contact with persons suffering from chickenpox or shingles (herpes zoster) and, if exposed, they should seek urgent medical attention. If the patient is a child, parents must be given the previously mentioned advice. Passive immunization with varicella zoster immunoglobulin (VZIG) is needed by exposed non-immune patients who are receiving systemic glucocorticosteroids or who have used them within the previous 3 months. Immunisation 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. Glucocorticosteroids 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.
Vaccines: Live vaccines should not be given to individuals with chronic glucocorticosteroid use and impaired immune responsiveness. The antibody response to other (inactivated) 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 oral 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.
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 rectal foam may cause suppression of the hypothalamic-pituitary-adrenal (HPA) axis and reduce the stress response. When patients are subject to surgery or other stresses, supplementary systemic glucocorticosteroid treatment is recommended.
Concomitant treatment with ketoconazole or other CYP3A inhibitors should be avoided because inhibition of the oxidative biotransformation of budesonide can result in elevated plasma levels of budesonide (see Interactions).
It should also be noted that systemic glucocorticoid-like side effects can occur with doses that are higher than recommended (see Adverse Reactions).
Cetyl alcohol can cause local skin irritation (e.g. contact dermatitis). Propylene glycol can cause skin irritation. Budenofalk rectal foam does not contain preservatives.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.
Use in Children: Due to insufficient experience, Budenofalk rectal foam should not be used in children and adolescents.

Pregnancy: Administration during pregnancy should be avoided unless there are compelling reasons for therapy with Budenofalk. 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 compared to inhaled budesonide. In pregnant animals, budesonide, like other glucocorticosteroids, has been shown to cause abnormalities of fetal development (see Pharmacology: Toxicology: Preclinical safety data under Actions). The relevance of this to man has not been established.
Breast-feeding: 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 intake/application of Budenofalk 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 Pharmacology: Toxicology: Preclinical safety data under Actions).

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

Click on icon to see table/diagram/image

The following adverse reactions were additionally reported in clinical studies with Budenofalk rectal foam (frequency: uncommon): increased appetite, increase in erythrocyte sedimentation rate, leucocytosis, nausea, abdominal pain, flatulence, paraesthesias in the abdominal region, anal fissure, aphthous stomatitis, frequent urge to defecate, rectal bleeding, increase in transaminases (GOT, GPT), increase in parameters of cholestasis (GGT,AP), increase in amylase, change in cortisol, urinary tract infection, dizziness, disturbances of smell, insomnia, increased sweating, asthenia, increase in body weight.
Most of the adverse events mentioned can also be expected for treatments with other glucocorticosteroids.
Occasionally, adverse events may occur which are typical for systemic glucocorticosteroids. These adverse events depend on the dosage, the period of treatment, concomitant or previous treatment with other glucocorticosteroids and the individual sensitivity.
Some of these undesired effects were reported after long-term use of orally administered budesonide.
Due to its local action, the risk of undesired effects of Budenofalk rectal foam is generally lower than with systemically acting glucocorticoids.
An exacerbation or the reappearance of extra intestinal manifestations (especially affecting skin and joints) can occur on switching a patient from systemically acting glucocorticosteroids to the locally acting budesonide.
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 according to the guidelines issued by the local health authority.

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 3A (CYP3A): 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 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 administration of budesonide should be avoided.
CYP3A4 inducers: Compounds or drugs such as carbamazepine and rifampicin can reduce both the systemic as well as the local exposure of budesonide at the gut mucosa. An adjustment of the budesonide dose might be necessary.
CYP3A4 substrates: Compounds or drugs such as ethinyl estradiol compete in the metabolism of budesonide. If the affinity of the competing substance for CYP3A is greater, this can lead to higher plasma concentrations of budesonide. If budesonide binds stronger to CYP3A, this can result in higher plasma levels of the competing substance. It may then be necessary to adjust the dose of budesonide or of the competing substance.
Elevated plasma concentrations and increased effects of glucocorticosteroids have been reported in women also receiving oestrogens or oral contraceptives, but this has not been observed with oral low-dose combination contraceptives.
Because adrenal function may be suppressed by treatment with budesonide, an ACTH stimulation test for diagnosing pituitary insufficiency might show false results (low values).

Special precautions for disposal and other handling: No special requirements.
Incompatibilities: Not applicable.

Do not store above 25°C.
Do not refrigerate or freeze.
This is a pressurised container, containing inflammable propellant. It should be kept away from any flames or sparks, including cigarettes. It should be protected from direct sunlight and must not be forced open, pierced or burned even when empty. Do not spray near a flame or incandescent material.
Shelf life: 2 years.
After first actuation: 4 weeks.

GIT Regulators, Antiflatulents & Anti-Inflammatories

A07EA06 - budesonide ; Belongs to the class of corticosteroids acting locally. Used in the treatment of intestinal inflammation.

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