Budenofalk

1 hard capsule of gastro-resistant pellets contains 3 mg of budesonide.
Excipients/Inactive Ingredients: Povidone K25, lactose monohydrate, sugar spheres (containing sucrose and maize starch), talc, methacrylic acid-methyl methacrylate copolymer (1:1) (Ph.Eur.), methacrylic acid-methyl methacrylate copolymer (1:2) (Ph. Eur.), ammonio methacrylate copolymer type B, ammonio methacrylate copolymer (type A) (= Eudragit L, S, RS and RL), triethyl citrate, titanium dioxide (E171), purified water, gelatin, erythrosine (E127), iron (II,III) oxide (E172), iron (III) oxide (E172), sodium lauryl sulphate.

Pharmacology: Pharmacodynamics: The exact mechanism of action 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 budesonide is predominantly based on a local action in the intestine. Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect. At doses clinically equivalent to systemically acting glucocorticosteroids, budesonide causes significantly less suppression of the hypothalamo-pituitary-adrenal axis and has a lower impact on inflammatory markers. Budenofalk 3 mg shows a dose-dependent influence on cortisol plasma levels which, at the recommended dose of 9 mg budesonide/day, is significantly less than that of an equieffective dose of systemic glucocorticosteroids.
Clinical study on autoimmune hepatitis in adults: In a prospective, double-blind, randomised, multicentre trial, 207 patients with active autoimmune hepatitis (AIH) without cirrhosis were treated with initial daily doses of 3mg budesonide three times daily (n=102) for up to 6 months or 40 mg/day prednisone (tapered to 10mg/ day, n=105). Upon biochemical remission, the budesonide dose was reduced to 3 mg twice daily (6mg/day). Patients also received 1-2 mg/kg/day azathioprine throughout the study. The composite primary endpoint was complete biochemical remission (i.e. normal serum levels of aspartate- and alanine-aminotransferase) without occurrence of predefined steroid-specific side effects at 6 months. This primary endpoint was achieved in 47% of the patients in the budesonide group and 18% of the patients in the prednisone group (p<0.001).
Regarding secondary efficacy variables, at 6 months, complete biochemical remission occurred in 60% and 39% of the patients in the budesonide group and in the prednisone group, respectively (p=0.001). 72% and 47% of the patients in the budesonide group and in the prednisone group, respectively, did not develop steroid-specific side effects (p<0.001). The mean decrease in IgG and γ-globulin concentrations and the decrease in the rates of patients with elevated IgG and γ-globulin concentrations did not show any differences between treatment groups.
An open-label follow-up treatment of additional 6 months was offered to all patients after the controlled, double-blind phase. A total of 176 patients proceeded to this open-label phase and received budesonide 3 mg twice daily in combination with 1-2 mg/kg/day azathioprine. Rates of patients with biochemical remission and rates of patients with complete response (not statistically significant) were still higher in the original budesonide group (complete response rate 60% and biochemical remission 68% at the end of the open-label phase) than in the original prednisone group (complete response rate 49% and biochemical remission 51% at the end of the open-label phase).
Clinical study in patients with Crohn's disease: In a randomized, double-blind, double-dummy trial in patients with mild to moderate Crohn's disease (200 < CDAI < 400) affecting the terminal ileum and/or the ascending colon the efficacy of 9 mg budesonide in a single daily dose (9 mg OD) was compared to the treatment with 3 mg budesonide given three times daily (3 mg TID).
The primary efficacy endpoint was the proportion of patients in remission (CDAI<150) at week 8. A total of 471 patients were included in the study (full analysis set, FAS), 439 patients were in the per protocol (PP) analysis set. There were no relevant differences in the baseline characteristics in both treatment groups. At the confirmatory analysis, 71.3% of the patients were in remission in the 9 mg OD group and 75.1% in the 3 mg TID group (PP) (p: 0.01975) demonstrating the non-inferiority of 9 mg budesonide OD to 3 mg budesonide TID.
No drug-related serious adverse events were reported.
Clinical study on autoimmune hepatitis in paediatric patients: The safety and efficacy of budesonide in 46 paediatric patients (11 males and 35 females) aged from 9 to 18 years were studied as a subset of patients of the previously mentioned clinical study. 19 paediatric patients were treated with budesonide and 27 received the active control (prednisone) for induction of remission with a daily dose of 9 mg budesonide. After 6 months in the study, 42 paediatric patients continued for a further 6 months on open-label, follow-up treatment with budesonide.
The rate of complete responders (defined as biochemical response, i.e. normalisation of liver transaminases [AST and ALT] and lack of steroid-specific side effects) in patients aged ≤ 18 years was considerably lower compared to adult patients. There was no significant difference seen between the treatment groups. After follow-up treatment with budesonide for a further 6 months, the rate of paediatric patients with complete response was still slightly lower compared to adult patients but the difference between the age groups was much smaller. There was no significant difference in the rate of complete responders between those originally treated with prednisone and those treated continuously with budesonide. Therefore, the safety and efficacy of Budenofalk in children and adolescents have not been established, and no dosage recommendations can be given.
Pharmacokinetics: Absorption: Due to the special gastro-resistant film-coating of the pellets contained in Budenofalk 3 mg hard capsules, absorption occurs after a lag phase of 2-3 hours. In healthy volunteers as well as in patients with Crohn's disease, mean peak plasma levels of approx. 1-2 ng/ml budesonide were measured at about 5 hours after a dose of 1 capsule of Budenofalk 3 mg before meals. Maximal release occurs in the terminal ileum and caecum, the main areas of inflammation in Crohn's disease.
Release of budesonide from Budenofalk 3 mg in ileostomy patients is comparable to that in healthy subjects or patients with Crohn's disease and about 30-40% of the released budesonide was found in the ileostomy bag. This shows that a considerable amount of budesonide from Budenofalk 3 mg will be transported normally into the colon.
Concomitant intake of food can delay gastrointestinal passage by approx. 2-3 hours. The lag phase in such cases is about 4-6 hours, but this does not change the rate of absorption.
Distribution: Budesonide has a high volume of distribution (approx. 3 l/kg). Plasma protein binding averages between 85 and 90%.
Biotransformation: Budesonide undergoes extensive biotransformation in the liver (approx. 90%) to metabolites with low glucocorticoid activity. The glucocorticosteroid activity of the main 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. Oral bioavailability both in healthy volunteers and in fasting patients with Crohn's disease is approx. 9-13%. Budesonide clearance is approx. 10-15 l/min.
Specific patient groups (patients with hepatic dysfunction): Depending on the type and severity of the liver disease, the metabolism of budesonide via CYP3A in these patients can be decreased. As has been shown for patients with autoimmune hepatitis, the systemic availability of budesonide in patients with hepatic dysfunction may be increased. As soon as liver function improves, the metabolism of budesonide normalises as well. The systemic availability of budesonide is significantly higher in patients with late stage primary biliary cirrhosis (PBC Stage IV) than in those in the early stages of the disease (PBC Stage I/II); the areas under the plasma concentration-time curves were on average three times higher after repeated doses of 3 x 3 mg budesonide daily.
Toxicology: Preclinical safety data: Acute toxicity: Acute toxicity of budesonide has been studied in rats and mice.
The following values were determined: (See Table 1.)

Click on icon to see table/diagram/image

Subacute and chronic toxicity: After repeated oral administration of budesonide to rats (in doses comparable to those used in man), reduced numbers of leucocytes (especially lymphocytes) and regression of the thymus gland were observed. There were also signs of atrophy-induced adrenal inactivity. Increased milk duct proliferation and secretory activity were found in the mammary glands. In a long-term study (104 weeks) in female rats, haematocrit, haemoglobin and erythrocytes were reduced. In the same dose groups, neutrophil counts tended to be increased and lymphocytes, eosinophils and normocytes decreased. Only in male rats were the number of lymphocytes significantly reduced (immunosuppressant effect) and alkaline phosphatase slightly increased.
In dogs, packed cell volume was reduced and concentrations of alkaline phosphatase and alanine aminotransferase increased. Atrophy of the adrenal cortex and lymphatic system, increased myocardial content and elevated hepatic glycogen content (hepatomegaly) were also demonstrated.
Mutagenic potential: Budesonide had no mutagenic effects in a series of in vitro and in vivo tests.
Carcinogenic potential: A slightly increased number of basophilic hepatic foci were observed in male rats treated with budesonide for up to 104 weeks compared to control animals. In carcinogenicity studies, the incidence of primary hepatocellular neoplasms (0.025 and 0.05 mg/kg/day), astrocytomas (male rats, 0.05 mg/kg/day) and mammary tumours (female rats, 0.05 mg/kg/day) was significantly increased. The hepatic tumours are probably due to anabolic effects and the increased metabolic burden on the liver. The results represent a class effect in which glucocorticoid receptors are probably involved.
Reproduction toxicity: Budesonide impaired fertility in rats, increased postimplantation losses and prolonged gestation. Embryotoxicity studies in rats and rabbits have produced evidence of dose-dependent embryotoxic effects (visceral and skeletal anomalies).

Mild to moderate active Crohn's disease affecting the ileum and/or the ascending colon (part of the large intestine).
Non-cirrhotic active autoimmune hepatitis.
Induction of remission in patients with active collagenous colitis.

Crohn's disease: Adults: The recommended daily dose is three capsules once daily in the morning or one capsule (containing 3 mg budesonide) three times daily (morning, midday and evening).
Collagenous colitis: Adults (over 18 years): The recommended daily dose is three capsules once daily in the morning (corresponding to a daily dose of 9mg budesonide).
Autoimmune hepatitis: Adults (over 18 years): Induction of remission: For the induction of remission (i.e. for the normalisation of elevated liver enzymes), the recommended daily dose is 1 hard capsule 3 times daily (morning, midday and evening, equivalent to a total daily dose of 9 mg budesonide).
Maintenance of remission: Once remission has been achieved, a daily dose of 1 hard capsule twice daily (morning and evening, equivalent to a total daily dose of 6 mg budesonide) is recommended. If the transaminases ALT and/or AST increase during this treatment, the dose should be increased to 3 hard capsules daily, as for induction of remission (equivalent to a total daily dose of 9 mg budesonide).
In patients who tolerate azathioprine, budesonide should be combined with this drug for the induction and maintenance of remission.
Autoimmune liver cirrhosis: There is limited information on the efficacy of budesonide in cirrhosis patients, and such patients have higher frequency of steroid specific side effects. Budesonide should not be used in cirrhosis patients.
Children: Budenofalk 3 mg should not be given to children due to insufficient experience in this age group.
Adolescents: The safety and efficacy of Budenofalk 3 mg in children aged 12 to 18 years have not been established. Currently available data on adolescent patients (12 to 18 years of age) with autoimmune hepatitis are described in Adverse Reactions and Pharmacology: Pharmacodynamics under Actions. No dosage recommendations can be given, however.
Method of administration: The capsules should be taken before meals, swallowed whole with plenty of fluid (e.g. a glass of water).
Patients who have difficulty in swallowing capsules may open them and just take the gastro-resistant pellets whole with plenty of fluid. This will not impair the effectiveness of Budenofalk 3 mg.
Crohn's disease and collagenous colitis: The duration of treatment is generally 8 weeks.
As a rule, the full effect is achieved after 2-4 weeks.
Autoimmune hepatitis: After remission has been achieved, treatment of autoimmune hepatitis should be continued for at least 12 months. Beyond 12 months, if the biochemical remission is stable and liver biopsy does not reveal any signs of acute inflammation, decisions to continue budesonide or to stop therapy should be made on a case by case basis.
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.

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

Budenofalk 3 mg must not be used in patients with: hypersensitivity to budesonide or any of the other ingredients, hepatic cirrhosis.

Treatment with Budenofalk 3 mg results in lower systemic steroid levels than conventional oral glucocorticosteroid therapy. Transfer from other glucocorticosteroid therapy may therefore result in symptoms relating to the change in systemic steroid levels.
Particularly close medical supervision is required in patients suffering from one or more of the following diseases: tuberculosis, hypertension, diabetes mellitus, osteoporosis, peptic ulcer (gastric or duodenal), glaucoma, cataract, family history of diabetes or glaucoma or any other condition in which glucocorticosteroids may have undesirable effects.
This medicine is not appropriate for patients suffering from Crohn's disease of the upper gastrointestinal tract.
Due to the preferential local mode of action of the compound beneficial effects for patients suffering from extraintestinal symptoms (e.g. of the eyes, skin, joints) cannot be expected.
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 a wide range of psychiatric/behavioural effects.
Bone mineral density measurements should be performed regularly on patients who are on budesonide for more than 6 months.
Infections: Suppression of the inflammatory response and immune system 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 can be atypical and serious infections such as sepsis and tuberculosis may be masked and may reach an advanced stage before being recognised.
Chickenpox is of particular concern because this illness may be severe or even fatal in immunosuppressed patients. Patients without a definite history of this disease should be advised to avoid close personal contact with chickenpox or shingles (herpes zoster) and, if exposed, they should seek urgent medical attention. Passive immunisation with varicella zoster immunoglobulin (VZIG) is indicated for exposed non-immune patients who are receiving systemic glucocorticosteroids or who have used them within the previous 3 months, and should be given within 10 days of exposure to chickenpox. If chickenpox is confirmed, the illness requires immediate, specialist treatment. 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 used in persons with with chronic glucocorticosteroid use. The antibody response to other vaccines (killed 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.
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: In patients with autoimmune hepatitis, serum transaminase levels (ALT, AST) should be regularly monitored (every 2 weeks for the first month of treatment and at least every 3 months thereafter), in order to facilitate dose adjustments of budesonide.
The elimination of Budenofalk 3 mg and that of other glucocorticosteroids may be reduced in patients with severe hepatic dysfunction, and systemic bioavailability increased; therefore these patients should not be treated with budesonide.
Budenofalk 3 mg can suppress the response of the hypothalamo-pituitary-adrenal axis to stress. For this reason, a supplementary systemic glucocorticoid should be given to patients undergoing surgery or other stresses.
Concomitant treatment with ketoconazole or other CYP3A inhibitors should be avoided (see Interactions).
Patients with rare hereditary problems of galactose intolerance, fructose intolerance, the Lapp lactase deficiency, sucrase isomaltase insufficiency or glucose galactose malabsorption should not take this medicine.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.

Pregnancy: Administration during pregnancy should be avoided unless there are compelling reasons for therapy with Budenofalk 3mg. 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 3mg 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.
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 3mg 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 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 2.)

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Most of the adverse events mentioned in this monograph 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.
Clinical studies showed that the frequency of glucocorticosteroid-associated adverse events is lower with oral Budenofalk than with oral treatment of equivalent dosages of prednisolone.
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.
Undesirable effects in clinical studies in patients with autoimmune hepatitis: In a clinical study involving patients with autoimmune hepatitis, undesirable effects were reported in 57% of the 102 patients treated with budesonide (by comparison: in 79% of the 105 patients on prednisone). The most common undesirable effects reported in those patients on budesonide were skin changes (particularly acne) [23% of those treated], endocrine disorders, such as Cushing's symptoms [16% of those treated], gastrointestinal disorders [14% of those treated], psychiatric disorders (mainly mood swings) [14% of those treated] and headache [12% of those treated]. With the exception of headache, these undesirable effects were observed more rarely with budesonide than with prednisone.

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): CYP3A 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 intake of budesonide should be avoided.
The effect of the corticosteroid can be potentiated.
CYP3A inductors, such as carbamazepine and rifampicin may reduce the systemic and also the local exposure of budesonide at the intestinal mucosa. The budesonide dose may require adjustment.
CYP3A substrates, such as ethinylestradiol compete for metabolism with budesonide. If the affinity of the competing substance for CYP3A is stronger, this may lead to increased budesonide plasma concentrations. If budesonide binds stronger to CYP3A, plasma levels of the competing substance may be increased. In such cases, the dose of budesonide or the competing substance may need adjustment.
Elevated plasma concentrations and enhanced effects of glucocorticosteroids have been reported in women also receiving estrogens or oral contraceptives. This interaction has not been observed with oral low dose combination contraceptives.
Concurrent administration of cimetidine and budesonide can result in a small, but clinically insignificant increase in budesonide plasma levels. Concurrent administration of omeprazole has no effect on the pharmacokinetics of budesonide.
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 3 mg, such interactions could result in a reduction in the effect of budesonide. Therefore these preparations should be taken at least 2 hours apart.
Because adrenal function may be suppressed by treatment with budesonide, an ACTH stimulation test for diagnosing pituitary insufficiency might show false results (low values).

Incompatibilities: None known to date.
Instructions for use/handling: No special instructions.

Shelf life: 3 years.
Do not store above 30 °C.

GIT Regulators, Antiflatulents & Anti-Inflammatories

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

POM