Budesonide

Pharmacological properties

the exact mechanism of action of budesonide (inn - budesonidum) in the treatment of Crohns disease has not been elucidated. Clinical-pharmacological studies and other controlled clinical studies clearly indicate that the mechanism of influence of budesonide is based mainly on local action in the intestine. budesonide is a corticosteroids with a high local anti-inflammatory effect. in doses clinically equivalent to doses of systemic glucocorticosteroids, budesonide causes significantly less inhibition of the hypothalamic-pituitary-adrenal system and has less effect on markers of inflammation.

Budenofalk exerts a dose-dependent effect on the level of plasma cortisol, which at the recommended dose of 3 mg of budesonide 3 times a day is probably lower than the equally effective doses of systemic corticosteroids.

Clinical Efficiency and Safety

Adults Clinical study in patients with Crohns disease. In a randomized, double-blind, double-simulated study in individuals with mild to moderate Crohns disease (200 CDAI 400), involving the ileum and / or ascending colon, the efficacy of 9 mg budesonide in a single daily dose (9 mg OD) was compared with 3 mg budesonide 3 times a day (3 mg TID).

The primary endpoint for efficacy was the proportion of patients in remission (CDAI 150) at week 8.

A total of 471 patients were included in the study (complete analysis kit, FAS), 439 patients were in accordance with the protocol (PP) of the analysis kit. There were no significant differences in the baseline characteristics of the two treatment groups. In support of the analysis, 71.3% of patients were in remission in the 9 mg OD group and 75.1% in the 3 mg TID group (P: 0.01975), which showed no less efficacy of 9 mg of budesonide OD to 3 mg of budesonide TID.

Serious side effects have not been reported with the drug.

Children. Clinical studies of autoimmune hepatitis. The safety and efficacy of budesonide was studied for 6 months in 46 pediatric patients aged 9 to 18 years. In order to induce remission, 19 participants took budesonide (9 mg) and 27 patients took prednisone (initial dose 40 mg). Then patients were changed to open budesonide therapy for 6 months.

The proportion of patients with a complete response (namely, normalization of the level of AcAT and AlAT without steroid-specific adverse events) was significantly less in the group of patients ≤18 years old compared with the group of adults. However, after a further 6-month treatment with budesonide, the differences between age groups became significantly smaller. Significant differences between patients who initially took prednisone and budesonide, relative to the proportion of patients who achieved a complete response, were not observed.

Pharmacokinetics

General properties of budesonide

Suction. The oral bioavailability of both volunteers and patients with fasting Crohns disease is about 9–13%.

Distribution. Budesonide has a high volume of distribution (about 3 l / kg body weight). Binding to plasma proteins is 85–90%.

Biotransformation. Budesonide undergoes intensive biotransformation in the liver (≈90%) to metabolites with low glucocorticoid activity. GCS activity of the main metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, which are formed due to CYP 3A, is 1% of that of budesonide.

Average T_½ after oral administration, it is about 3-4 hours. The average clearance is about 10 l / min.

Specific groups of patients (patients with impaired liver function). Depending on the type and severity of the disease, the metabolism of budesonide due to CYP 3A in these patients may be reduced.

Features of budesonide

Absorption. Due to the special enteric-soluble coating of granules contained in 3 mg Budenofalk hard capsules, absorption occurs with a delay of 2-3 hours.In healthy volunteers, as in individuals with Crohns disease, C_max budesonide in plasma, which is 1–2 ng / ml, is observed on average 5 hours after taking 1 capsule of Budenofalk 3 mg before meals. The maximum release occurs in the terminal ileum and cecum, the main areas of inflammation in Crohns disease.

The release of budesonide from Budenofalk in patients with an ileostomy is the same as in healthy volunteers or patients with Crohns disease, and accounts for 30–40% of the released budesonide that is in the ileostomy bag. This indicates that a significant amount of budesonide from Budenofalk is normally transported to the colon.

Simultaneous ingestion of food can delay passage through the gastrointestinal tract by about 2-3 hours. In such cases, the lag phase is about 6-8 hours, but this does not change the rate of absorption.

Specific patient groups (patients with impaired liver function)

As shown for patients with autoimmune hepatitis, systemic availability of budesonide may increase in patients with impaired liver function. As soon as liver function improves, the metabolism of budesonide is normalized.

The systemic bioavailability of budesonide is significantly higher in patients with the last stage of primary biliary cirrhosis (stage IV) than in the early stages of this disease (stage I / II), AUC was on average 3 times greater after repeated administration of 3 mg of budesonide 3 times a day.

Indications

• Crohns disease of mild or moderate severity with localization in the ileum (part of the small intestine) and / or the ascending colon (part of the large intestine); collagenous colitis; autoimmune hepatitis.

Treatment with Budenofalk is ineffective in patients with Crohns disease, which extends to the upper gastrointestinal tract.

Given the local action of the drug, Budenofalk is unlikely to be effective for extraintestinal symptoms of the disease, for example, appearing on the skin, eyes or joints.

Application

Crohns disease

Adults (over 18 years): the recommended daily dose is 3 capsules 1 time in the morning or 1 capsule (containing 3 mg of budesonide) 3 times a day (morning, afternoon and evening), if it is more convenient for the patient.

Collagenous colitis

Adults (over 18 years): the recommended daily dose is 3 capsules 1 time in the morning before breakfast (corresponds to a daily dose of 9 mg of budesonide).

Autoimmune hepatitis

Adults

Induction of remission. For the induction of remission (that is, to normalize the elevated level of liver enzymes), the recommended daily dose corresponds to 1 hard capsule 3 times a day (morning, afternoon and evening, which is equivalent to a total daily dose of 9 mg of budesonide).

Maintenance of remission. After achieving remission, the recommended daily dose corresponds to 1 hard capsule 2 times a day (morning and evening, which is equivalent to a total daily dose of 6 mg of budesonide). If against the background of this treatment there is an increase in the level of transaminases AlAT and / or AsAT, the dose should be increased to 3 capsules per day, as for the 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 in order to maintain remission.

Patients with impaired renal function. There are no specific dosage recommendations for people with kidney failure.

Patients with impaired liver function. Caution should be exercised in relation to persons with impaired liver function of mild to moderate degree.

Capsules should be taken before meals, swallowing them whole, drinking plenty of fluids (such as a glass of water).

Patients who have difficulty swallowing capsules can open them and take only enteric granules with a sufficient amount of liquid. This will not affect the effectiveness of Budenofalk.

The duration of treatment is usually 8 weeks.

As a rule, the desired effect is achieved after 2–4 weeks.

Taking Budenofalk 3 mg can not be stopped immediately, but only gradually reducing the dose. During the first week, the dose should be reduced to 2 capsules per day (morning and evening). During the second week, only 1 capsule should be taken in the morning. After this, treatment can be stopped.

Duration of use. Crohns disease and collagenous colitis. The typical duration of treatment is 8 weeks. The full effect is usually achieved after 2–4 weeks of administration.

Autoimmune hepatitis. After achieving remission, treatment of autoimmune hepatitis should be continued for at least 24 months. If the biochemical remission is stable and there are no signs of acute inflammation on the liver biopsy, treatment can be completed.

Reception Budenofalk 3 mg should not be stopped suddenly. The drug must be discontinued gradually (slowly reducing the dose). During the first week, the dose should be reduced to 2 hard capsules per day (1 hard capsule in the morning and evening). During the second week, the patient should take 1 hard capsule per day, only in the morning. Then treatment can be stopped.

Contraindications

Hypersensitivity to budesonide or other components of the drug, local intestinal infections (bacterial, fungal, amoebic, viral), cirrhosis and signs of portal hypertension, for example, in the late stage of primary biliary cirrhosis.

Side effects

Assessment of the frequency of adverse reactions is based on the following parameters: very often (≥1 / 10); often (≥1 / 100, 1/10); infrequently (≥1 / 1000, 1/100); rarely (≥1 / 10,000, 1/1000); very rarely (1/10 000), including single messages.

There have been spontaneous reports of the following adverse reactions of budenofalk at a dose of 3 mg.

Very rarely, including single messages (1/10 000):

• metabolic disorder: leg swelling, Cushings syndrome;
• from the central nervous system and peripheral nervous system: pseudotumor of the brain, sometimes with edema of the optical disk in adolescents;
• musculoskeletal disorders: diffuse muscle pain and weakness, osteoporosis.

Some of these adverse reactions have been noted after prolonged use.

Side effects typical for systemic corticosteroids are rarely possible. These adverse reactions depend on the dose, duration of treatment, combined or prior treatment with other corticosteroids, and on individual sensitivity.

Clinical trials involving patients with Crohns disease have shown that the frequency of side effects associated with corticosteroids 3 mg Budenofalk is almost half that observed when administered orally with equal doses of prednisolone.

On the part of the skin and subcutaneous tissues: allergic rash, red striae, petechiae, ecchymosis, steroid acne, delayed wound healing, contact dermatitis.

From the musculoskeletal system, connective tissue and bones: aseptic necrosis of the bones (femur and head of the humerus).

Visual impairment: glaucoma, cataract.

Mental disorders: depression, irritability, euphoria, feeling tired, weakness, dizziness.

Gastrointestinal disorders: discomfort in the stomach, stomach and duodenal ulcer, pancreatitis, constipation, nausea, vomiting.

Metabolism disorder: Cushings syndrome, moon-shaped face, obesity, decreased glucose tolerance, diabetes mellitus, sodium retention due to the formation of edema, increased potassium excretion, inaction and / or atrophy of the adrenal cortex, growth retardation in children, impaired secretion of sex hormones (e.g. amenorrhea, hirsutism, impotence).

Vascular disorders: AH, increased risk of thrombosis, vasculitis (withdrawal symptoms after prolonged therapy), headache.

Immune system disorders: interaction with the immune response (e.g. increased risk of infections).

Adverse reactions in clinical trials in patients with autoimmune hepatitis.In clinical trials involving patients with autoimmune hepatitis, adverse events were noted in 57% of 102 patients treated with budesonide (compared with 79% of 105 patients treated with prednisone). The most common side effects observed in patients taking budesonide were skin changes (in particular acne) [23% treated], endocrine disorders such as Cushings syndrome [16% treated], gastrointestinal upsets [14% received treatment], mental disorders (mainly mood swings) [14% of those receiving treatment] and pain [12% of receiving treatment]. With the exception of headache, these adverse events were less likely to occur with budesonide than with prednisone.

The type and frequency of side effects in the subgroup of pediatric patients were comparable to those in adult patients (see PHARMACOLOGICAL PROPERTIES).

special instructions

Treatment with budenofalk leads to a more significant decrease in the systemic level of steroids than conventional therapy with oral steroids. switching to other steroid therapy may cause symptoms associated with changes in systemic steroid levels.

Particularly careful medical supervision is required by patients with one or more of the following diseases: tuberculosis, hypertension, diabetes mellitus, osteoporosis, peptic ulcer (stomach or duodenal ulcer), glaucoma, cataracts, cases of diabetes or glaucoma in a family history.

Systemic effects of corticosteroids may occur, especially when using the drug in high doses and for a long period. Similar effects may include Cushings syndrome, inhibition of adrenal function, stunted growth, decreased bone mineral density, cataracts, glaucoma, and very rarely a wide range of mental / behavioral disorders.

Infections Inhibition of the response to inflammation and the immune system increases the susceptibility to infection and the severity of its course. The risk of complications of bacterial, fungal, amoebic, and viral infections during treatment with glucocorticoids should be carefully assessed. Clinical manifestations can be atypical, and serious infections, such as sepsis and tuberculosis, can mask and reach a developed stage before they are recognized.

Chickenpox. Chickenpox deserves special attention, since this disease can be severe, and sometimes fatal, in immunocompromised patients. Patients who did not have this disease should avoid close personal contact with patients with chickenpox or shingles (herpes zoster). If a patient develops chickenpox, seek medical attention immediately. Similar recommendations should be provided to the parents of the patient-child. For non-immunized patients using systemic corticosteroids or taking them for the last 3 months, passive immunization with herpes zoster herpes virus (VZIG) should be carried out after contact with sick herpes zoster. Passive immunization should be carried out within 10 days after exposure to chickenpox. If chickenpox is confirmed, immediate special treatment is required.

Corticosteroids should not be discontinued; their dose may even be required.

Measles. In case of contact with a measles patient, patients with impaired immunity should, if possible, receive an injection of normal immunoglobulin as soon as possible after contact.

Live vaccines. Patients taking corticosteroids for a long time should not be given live vaccines. Antibody production in response to other vaccines may be reduced.

Patients with impaired liver function.Based on the experience obtained in patients with primary biliary cirrhosis of the late stage, with cirrhosis of the liver, one should expect increased systemic bioavailability of budesonide in all patients with seriously impaired liver function. However, in patients with liver disease without cirrhosis, budesonide in a daily dose of 9 mg was safe and well tolerated. There is no evidence of the need for specific dosage recommendations for patients with non-cirrhotic liver disease or with minor impaired liver function.

Others. GCS can suppress the reaction of the hypothalamic-pituitary-adrenal system to stress. For this reason, patients who have had surgery or other stresses should be prescribed additional systemic corticosteroids.

Concomitant use of ketoconazole or other CYP 3A inhibitors should be avoided.

The drug should not be taken in patients with rare hereditary diseases of galactose or fructose intolerance, sucrose-isomaltase deficiency or glucose-galactose malabsorption, as well as with Lapp-lactase deficiency or congenital lactase deficiency.

Patients with autoimmune hepatitis should regularly monitor the level of transaminases (AlAT, AsAT) in the blood plasma (every 2 weeks during the first month of treatment and at least every 3 months thereafter) in order to possible dose adjustment of budesonide.

Taking Budenofalk 3 mg may lead to positive doping test results.

Use during pregnancy or lactation. There is no experience with Budenofalk during pregnancy. Animal studies have demonstrated reproductive toxicity. The drug should not be used during pregnancy, unless it is absolutely necessary. In women of reproductive age, pregnancy should be excluded before starting treatment and appropriate contraceptives should be used during treatment.

It is not known whether budesonide, like other corticosteroids, passes into breast milk. Therefore, when treating Budenofalk 3 mg, breast-feeding should be discontinued.

Children. Due to the current lack of sufficient experience with the use of budenofalk in pediatrics, the drug should not be used in children under the age of 12 years. The safety and effectiveness of the use of Budenofalk 3 mg in adolescents aged 12 to 18 years have not been established. The currently available data from adolescents (12–18 years old) with autoimmune hepatitis are described in the SIDE EFFECTS and PHARMACOLOGICAL PROPERTIES sections. However, there are no dosage recommendations.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Budenofalk does not affect the ability to drive vehicles and work with mechanisms. But since some side effects may occur, you should be careful and evaluate your condition before driving vehicles or working with mechanisms.

Interactions

Pharmacodynamic interactions

Cardiac glycosides. The action of glycosides can be potentiated by potassium deficiency.

Saluretics. Potassium excretion may be enhanced.

Pharmacokinetic interactions

Cytochrome P450 3A (CYP 3A)

CYP 3A inhibitors such as ketoconazole, ritonavir, troleandomycin, erythromycin, cyclosporine, grapefruit juice. The effect of GCS may be enhanced.

Inducers of CYP 3A, such as carbamazepine and rifampicin, can reduce the severity of both the systemic and local effects of budesonide on the intestinal mucosa. The dose of budesonide must be corrected.

CYP 3A substrates, such as ethinyl estradiol, compete with budesonide for metabolism. If the kinship of a compound competing for CYP 3A is higher, this may cause an increase in plasma concentration of budesonide.If budesonide has a high binding capacity for CYP 3A, levels of competing compounds may increase in blood plasma. In such cases, the dose of budesonide or a competing substance requires adjustment.

In women taking estrogens or oral contraceptives, an increase in plasma concentration and an increase in the action of GCS have been reported. These interactions have not been observed with combined low-dose oral contraceptives.

The simultaneous use of cimetidine and budesonide can cause a slight, but clinically insignificant, increase in the level of budesonide in the blood plasma. The use of omeprazole does not affect the pharmacokinetics of budesonide.

Potential interactions with steroid-binding resins such as colestyramine and antacids cannot be ruled out. With simultaneous administration with budenofalk, such interactions can lead to a decrease in the severity of the effect of budesonide. Therefore, these drugs must be taken separately with an interval of at least 2 hours.

Overdose

To date, cases of overdose are not described. Given the properties of budesonide, an overdose with the development of toxic manifestations is unlikely.

Storage conditions

At temperatures up to 25 ° c.

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Supplier: Alpen Pharma AG (Switzerland).