Budenofalk, 9 mg, enteric granules, 20 pcs.

Budenofalk, 9 mg, enteric granules, 20 pcs.

Budenofalk can suppress the function of the hypothalamic-pituitary-adrenal system. Before surgery or exposure to another stress factor, additional administration of systemic glucocorticosteroids is recommended.

Budenofalk contains lactose, sucrose and sorbitol. The drug should not be taken by patients with rare hereditary conditions of galactose or fructose intolerance, sucrose-isomaltase deficiency or glucose-galactose malabsorption, or lactase deficiency.

Suppression of the inflammatory response and immune function when taking the drug increases the susceptibility to severe infections. The risk of worsening bacterial, fungal, amoebic and viral infections should be taken into account during treatment with Budenofalk.

Patients who have not previously had chickenpox should avoid contact with people who have chickenpox or herpes zoster. If exposed to or at risk of contracting varicella, these patients should receive passive immunization using varicella immune globulin. Immunization must be carried out within 10 days after contact with the patient. You should not stop taking budesonide; the dose may need to be increased.

Immunocompromised patients exposed to measles should receive treatment with normal immunoglobulins as soon as possible.

Live vaccines should not be administered to patients chronically taking budesonide due to the possible suppression of the antibody response to such vaccines.

When prescribing high doses and long-term treatment, systemic effects of corticosteroids may occur, including Cushing's syndrome, suppression of adrenal function, decreased bone mineralization, cataracts, glaucoma and a variety of mental disorders (see section "Side effects").

The drug has a predominantly local effect, as a result of which a beneficial effect of the drug cannot be expected in patients with extraintestinal symptoms.

Treatment with Budenofalk is not indicated for patients with Crohn's disease affecting the upper gastrointestinal tract.

Treatment with Budenofalk results in a greater reduction in steroid hormone levels in the body than conventional oral steroid therapy. When switching from other treatment regimens with steroid drugs, symptoms may appear due to changes in the level of steroid hormones in the body.

When taking Budenofalk in patients with severely impaired liver function, an increase in the systemic bioavailability of budesonide can be expected. In patients with liver diseases without cirrhosis, daily doses of Budenofalk are safe; there is no need for dose adjustment in such patients.

Taking the drug Budenofalk may give a positive result in doping tests.

Experience with the use of budesonide in the treatment of autoimmune hepatitis and its variant form

Effective treatment of autoimmune hepatitis (AIH), based on a combination of prednisolone with azathioprine, was developed almost half a century ago [1] and led to a significant increase in the life expectancy of patients, which is now equal to the population [2].

At the same time, discussions continue about the use of other, alternative treatment regimens. This is due to the fact that AIH therapy is long-term: according to recent recommendations of the European Association for the Study of the Liver (EASL), it is prescribed for 3 years or for at least 2 years after complete normalization of laboratory parameters [3]. . In addition, treatment is often lifelong, since in a fairly small percentage of cases it is possible to achieve drug-free remission. At the same time, existing treatment regimens that include prednisolone lead to a large number of side effects due to its systemic action [3].

Unfortunately, probably due to the good effectiveness of existing therapy, virtually no randomized clinical trials (RCTs) have been conducted on the use of alternative immunosuppressive agents for AIH. Their effect is supported primarily by case series and open-label studies. The exception is budesonide, for the use of which there are not only observational data, but also the results of a multicenter RCT [4]. Budesonide is a 2nd generation glucocorticosteroid (GCS), whose affinity for glucocorticoid receptors is 15–20 times higher than that of prednisolone. In addition, when taken orally, 90% of it is metabolized in the liver during its first pass [4].

In a study by MP Manns et al. in 2010, in a multicenter, prospective, double-blind, actively controlled RCT, the administration of budesonide (at a dose of 9 mg/day) in combination with azathioprine was significantly more likely (60.0% versus 38.8% of cases) to achieve biochemical remission of AIH after 6 months of treatment, than standard therapy with prednisolone (40 mg followed by reduction to 10 mg) and azathioprine. At the same time, there were no systemic side effects in 72.0% of patients (compared to 46.6% of those receiving prednisolone). Subsequently, all patients took open-label budesonide. Among patients who initially received prednisolone, steroid side effects decreased from 44.8% to 26.4% [5]. Disadvantages of the work of MP Manns et al. is the lack of histological verification of remission and assessment of long-term results. But based on the data obtained, the authors concluded that budesonide is more effective than prednisolone in AIH. This thesis has been subject to some criticism from the point of view of the equivalence of the compared doses. There is contrary evidence that in some patients budesonide is less effective in achieving remission compared to prednisolone [6], this may be due to the lack of possibility of increasing the dose and malabsorption of the oral drug.

However, a study by MP Manns et al. The following has been clearly proven:

a) budesonide can be used to induce remission of AIH; b) budesonide is less likely to cause systemic side effects than prednisolone; c) patients who have achieved remission by prescribing prednisolone can be transferred to budesonide therapy to reduce the side effects of GCS while maintaining remission.

These results have led to increased prescribing of budesonide for AIH in a number of countries. Thus, according to an Israeli epidemiological study [7], 16% of patients diagnosed with AIH receive budesonide (as monotherapy or in combination with azathioprine). It has been shown that budesonide can be safely and effectively used to induce and maintain remission not only in adults, but also in children [6].

A limitation to the use of budesonide in AIH is the stage of liver cirrhosis, since in this case the presence of portacaval shunts increases the systemic concentration of the drug, and, in addition, the risk of thrombosis increases, especially in the area of ​​the portal blood flow [8–10].

The widespread use of budesonide in the treatment of AIH is hampered by the limited amount of data on long-term use of the drug (the possibility of long-term maintenance of remission) and the optimal option for dose reduction. However, in recent years, a number of hepatology associations have issued recommendations for the treatment of AIH, including the use of budesonide-containing regimens.

Russian and American recommendations for the treatment of AIH do not include budesonide, although it is noted that its advantage over prednisolone “lies in the possibility of long-term maintenance therapy in patients at the pre-cirrhotic stage with early-onset side effects of systemic steroids” [11, 12].

According to the recommendations of the British Society of Gastroenterology (BSG), budesonide, along with other immunosuppressants, can be used in case of incomplete response to standard therapy, and can also be prescribed for severe side effects of systemic glucocorticosteroids in “non-cirrhotic” patients [13].

Recent recommendations from the European Association for the Study of the Liver (2015) discuss budesonide (9 mg/day) in combination with azathioprine in previously untreated patients with early disease without cirrhosis in whom side effects from corticosteroids are expected [3]. This regimen is recommended as induction therapy for patients with concomitant diseases that may worsen with prednisolone treatment. If the response to budesonide is insufficient, it is recommended to replace it with prednisolone. In contrast, prednisolone may be substituted for budesonide in prednisolone responders with severe steroidal side effects if an adequate dose of azathioprine is insufficient to maintain remission. It is noted that the process of reducing the dose of budesonide remains unclear. Also, due to the short half-life of budesonide, it is not clear whether the dose should be reduced to twice daily (6 mg) or once daily (3 mg) or whether the three times daily dose should be continued while reducing the daily dose.

A separate problem is the treatment of so-called crossover (or variant) syndromes, the most common of which is the combination of AIH and primary biliary cirrhosis (AIH/PBC).

It should be noted that, according to some experts from the European Association for the Study of the Liver [14], uncontrolled PBC in itself is an indication for the prescription of budesonide. This thesis is repeated in domestic recommendations for the treatment of cholestatic diseases, according to which in patients at the pre-cirrhotic stages of the disease with a suboptimal biochemical response to therapy with ursodeoxycholic acid (UDCA), it is proposed to use its combination with budesonide (6–9 mg/day) [15]. The positive effect of budesonide on the course of PBC when prescribed at stages I-II of the disease was shown in a number of prospective studies, including a 3-year open RCT by H. Rautiainen et al. (2005) and a 2-year double-blind RCT by M. Leuschner et al. (1999), where its administration in combination with UDCA led to an improvement in the histological picture [16–17].

In the treatment of AIH/PBC overlap syndrome, leading associations and working groups [3, 14] suggest using a combination of UDCA and GCS. Previously, the prescription of UDCA monotherapy in these cases, followed by the addition of GCS if monotherapy is ineffective, was discussed [18]. Recent recommendations from the European Association for the Study of the Liver emphasize the mandatory use of immunosuppressive therapy, and if signs of AIH predominate, they recommend starting with immunosuppressives followed by the addition of UDCA [3]. The problem of developing clear recommendations for the treatment of AIH/PBC is also associated with the lack of well-designed clinical studies. At the same time, the use of prednisolone in PBC leads to a sharp decrease in bone mineral density, and also increases the risk of developing other adverse events [19]. In this situation, budesonide may be preferable.

In a meta-analysis by H. Zhang et al. (2015) evaluated 8 RCTs including 214 patients with AIH/PBC, of ​​whom 97 received budesonide + UDCA and the rest received UDCA monotherapy. The combination of budesonide + UDCA has been shown to improve laboratory parameters more significantly, although there is no evidence of an effect on symptoms, mortality or the need for liver transplantation, which may be explained by the heterogeneity of the compared groups [20]. According to a domestic study [21], when using the combination of UDCA + budesonide, 93.7% of patients with AIH/PBC showed laboratory improvement, and 1/4 had a decrease in necroinflammatory activity in the biopsy specimen. Work has also appeared on the possibility of combining budesonide with new bile acid derivatives (obetacholic acid) [22].

Let us present our own experience of using budesonide for AIH.

Materials and research methods

A retrospective analysis of the results of treatment with budesonide (Budenofalk) was carried out in two hepatology centers: the Department of Gastroenterology and Dietetics of Northwestern State Medical University named after. I. I. Mechnikov and the Expert polyclinic (St. Petersburg).

The study included data from 24 women treated with budesonide. In 11 cases, the diagnosis was “AIH type 1,” and in 13 cases, “primary biliary cirrhosis with signs of AIH (AIH/PBC).” The age of the patients ranged from 32 to 76 years (average age - 55.2 ± 13.4 years), the duration of the disease from the moment of appearance of the first clinical or laboratory symptoms was from 3 months to 9 years (average 3.5 ± 2.8 years) . The diagnosis of AIH was established on the basis of clinical, laboratory and histological data using the diagnostic system EM Hennes et al. [23]. The presence of AIH/PBC was determined according to the criteria of O. Chazouilleres et al. [24]. All patients did not experience severe systemic manifestations of an autoimmune disease (fever, arthritis, etc.).

Response to therapy in AIH was assessed as remission, treatment failure, or incomplete response [13]. Additionally, complete (normalization of alanine (ALT) and aspartic (AST) aminotransferases, as well as IgG) and incomplete remission (decrease in AST and ALT to a level less than 2 times higher than the upper limit of reference values, or normalization of ALT and AST without complete normalization) were distinguished IgG) [25]. Response to therapy in AIH/PBC was considered according to the response criteria for AIH, as well as the Paris and Barcelona response criteria for UDCA [26, 27].

Results and discussion

A retrospective analysis revealed the following indications for budesonide:

a) the presence of concomitant diseases and conditions, the course of which could potentially worsen during treatment with prednisolone - in 8 patients (including existing osteoporosis - in 4, diabetes mellitus - in 3, deep vein thrombosis of the lower extremities - in 1 patient); b) the occurrence of side effects during previous prednisone therapy - in 9 patients. Moreover, one patient often experienced several side effects of GCS therapy. Thus, osteoporosis developed in three cases, diabetes mellitus in two, “steroid purpura” in one, significant cosmetic changes were observed in 6 patients (severe Cushingoid syndrome, intense hypertrichosis); c) patient refusal to take systemic corticosteroids – 7 people.

In 17 cases, budesonide was prescribed to induce remission of AIH in primary patients or in patients who had a relapse of the disease due to discontinuation of therapy or reduction in doses of GCS. In 7 patients, budesonide was used to maintain remission after a standard induction course of prednisolone (with achievement of criteria for complete or incomplete laboratory remission).

For AIH, monotherapy with budesonide at a dose of 9 mg was used in 5 cases (these patients had contraindications to the administration of azathioprine - cytopenia), and in 6 cases a combination of budesonide 9 mg/day and azathioprine 50–100 mg/day was prescribed. For AIH/PBC, a combination of budesonide 9 mg/day with UDCA (13–15 mg/kg/day) was used in 9 cases, and azathioprine 50 mg/day was also prescribed to 4 patients. The mean duration of therapy at the time of analysis was 20.3 ± 11.1 months (maximum duration 36 months). The results of treatment are presented in table.

In 15 patients (88.2% of cases), budesonide therapy (in combination with and without azathioprine) ensured remission of AIH during the first year of treatment. At the same time, achievement of remission was observed on average 8.3 ± 3.4 months from the start of therapy. There were no side effects from taking budesonide in this group. Subsequently, these patients continued maintenance therapy with budesonide with stable maintenance of remission. In 10 patients, a year after the start of treatment, the dose of budesonide was reduced to 6 mg/day.

The absence of clinical and laboratory improvement was observed in one patient with AIH and one with AIH/PBC. Budesonide was replaced with prednisolone in a standard dose, which also did not lead to an improvement in laboratory parameters. In a patient with AIH/PBC, incomplete laboratory remission was later achieved with methotrexate.

For patients previously treated with prednisolone (10–15 mg/day), budesonide therapy was prescribed 6–12 months after the start of treatment in order to minimize previously developed side effects. In these cases, the replacement of prednisolone with budesonide was carried out gradually, over 2–3 weeks, to avoid “withdrawal syndrome” of the systemic action of GCS.

As a result, 4 patients maintained complete/incomplete remission throughout the observation period, including with a further reduction in the daily dose of budesonide to 6 mg, and the level of laboratory parameters corresponded to those previously observed during prednisone therapy. In 3 patients, remission was maintained when taking budesonide at a dose of 9 mg/day, and AIH relapse occurred after reduction to 3 mg/day (1 patient) and 6 mg/day (2 patients). The period of relapse after dose change ranged from 4 to 13 months.

It should be noted that when switching to budesonide, in most cases, regression of a number of phenomena that arose earlier when taking prednisolone was observed: Cushingoid syndrome, hyperglycemia, a decrease in the intensity of “steroid purpura”. In 2 patients with AIH/PBC, persistence of Cushingoid syndrome was noted.

Currently, the goal of treatment for AIH is to achieve remission and then maintain it on a minimum maintenance dose of immunosuppressive drugs [3]. Our data show the high effectiveness of budesonide in inducing and maintaining remission in AIH and its variant form and coincide with the results of other authors [4, 28–30]. At the same time, the frequency of achieving remission when inducing it with budesonide corresponded to the data given for systemic corticosteroids [3] with a minimum of side effects. In cases of ineffectiveness of budesonide, hormone resistance was also observed during treatment with prednisolone.

When treating AIH/PBC with a combination of UDCA and budesonide (+/- azathioprine), an improvement in the laboratory profile was observed in all patients, and remission of AIH was achieved in 77.8% of cases.

Budesonide was also effective in maintaining remission previously induced by prednisolone. It is important that some patients in our study received budesonide therapy for 3 years with retention of its effectiveness, which indicates the possibility of its long-term use. At the same time, when the maintenance dose was reduced, disease relapse was observed in 3 patients. It is the issues of dose reduction during budesonide therapy that are the least developed and, undoubtedly, require clinical studies to develop optimal tactics.

Currently, the use of budesonide in Russia has ceased to be classified as “off-label”, since the indication for use of the drug Budenofalk in 2015 was “autoimmune hepatitis without histological signs of liver cirrhosis” (in patients over 18 years of age). Moreover, according to the instructions, doses of 9 mg/day (in 3 divided doses) are recommended for an active process for 6–12 months and 6 mg/day (in 2 divided doses) for up to 24 months with maintenance therapy.

In our opinion, budesonide should be actively used in the treatment of AIH and its variant forms in non-cirrhotic patients without pronounced systemic manifestations of the disease, especially in groups at risk of developing steroid complications.

conclusions

Budesonide is an effective drug for inducing and maintaining remission in AIH, and it can also be successfully used in the treatment of AIH/PBC.

Literature

1. Soloway RD, Summerskill H, Baggenstoss AH et al. Clinical, biochemical, and histological remission of severe chronic active liver disease: a controlled study of treatments and early prognosis // Gastroenterol. 1972. Vol. 63, No. 5. P. 820–833.
2. Czaja AJ Current and future treatments of autoimmune hepatitis // Expert. Rev. Gastroenterol. Hepatol. 2009. Vol. 3, No. 3. P. 269–291.
3. EASL Clinical Practice Guidelines: Autoimmune hepatitis // J. Hepatol. 2015. Vol. 63, No. 4. P. 971-10-04.
4. Rautiainen H., Färkkilä M., Neuvonen M. et al. Pharmacokinetics and bone effects of budesonide in primary biliary cirrhosis // Aliment. Pharmacol. Ther. 2006. Vol. 24, No. 11. P. 1545–1552.
5. Manns MP, Woynarowski M., Kreisel W., Lurie Y. et al. European AIH-BUC Study Group: budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis // Gastroenterol. 2010. Vol. 139, no.4. P. 1198–1206.
6. Woynarowski M., Nemeth A., Baruch Y. et al. European AIH-BUC Study Group. Budesonide versus prednisone with azathioprine for the treatment of autoimmune hepatitis in children and adolescents // J. Pediatr. 2013. Vol. 163, No. 5. P. 1347–1353.
7. Delgado JS, Vodonos A, Malnick S et al. Autoimmune hepatitis in southern Israel: a 15-year multicenter study // J. Dig. Dis. 2013. Vol.14, No. 11. P. 611–618.
8. EASL Clinical Practice Guidelines. Management of cholestatic liver diseases // J. Hepatol. 2009. Vol.51, No. 2. P. 237–267.
9. Hempfling W., Grunhage F., Dilger K. et al. Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis // Hepatology. 2003. Vol. 38, No. 1. P. 196–202.
10. Mederacke I., Helfritz F., Puls F. et al. Budd-Chiari syndrome after treatment with budesonide in a cirrhotic patient with autoimmune hepatitis // Ann Hepatol. 2012. Vol. 11, No. 1. P. 143–144.
11. Ivashkin V. T., Bueverov A. O., Mayevskaya M. V., Abdulganieva D. I. Clinical guidelines for the diagnosis and treatment of autoimmune hepatitis [Electronic resource]. M., 2013. Access mode: https://www.gastro.ru/? pageId=41.
12. Manns MP, Czaja AJ, Gorham JD et al. American Association for the Study of Liver Diseases. Diagnosis and management of autoimmune hepatitis // Hepatol. 2010. Vol. 51, No. 6, pp. 2193–2213.
13. Gleeson D., Heneghan A. British Society of Gastroenterology (BSG) guidelines for management of autoimmune hepatitis // Gut. 2011. Vol. 60, No. 12. P. 1611–1629.
14. EASL Clinical Practice Guidelines. Management of cholestatic liver diseases // J. Hepatol. 2009. Vol. 51, No. 2. P. 237–267.
15. Ivashkin V. T., Shirokova E. N., Mayevskaya M. V. et al. Clinical recommendations of the Russian Gastroenterological Association and the Russian Society for the Study of the Liver for the diagnosis and treatment of cholestasis // Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2015. T. 25, No. 2. pp. 41–57.
16. Leuschner M., Maier KP, Schlichting J. et al. Oral budesonide and ursodeoxycholic acid for the treatment of primary biliary cirrhosis: results of a prospective double-blind trial // Gastroenterology. 1999. Vol. 117, No. 4. P. 918–925.
17. Rautiainen H., Karkkainen P., Karvonen AL et al. Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three year randomized trial // Hepatol. 2005. Vol. 41, No. 4. P. 747–752.
18. Boberg KM, Chapman RW, Hirschfield GM et al. On behalf of the International Autoimmune Hepatitis Group. Overlap syndromes: The International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue // J. Hepatol. 2011. Vol. 54, No. 2. P. 374–385.
19. Mitchison H. S., Bassendine MF, Malcolm AJ A pilot, double-blind, controlled 1-year trial of prednisolone treatment in primary biliary cirrhosis: hepatic improvement but greater bone loss // Hepatol. 1989. Vol. 10, No. 4. P. 420–429.
20. Zhang H., Yang J., Zhu R. et al. Combination therapy of ursodeoxycholic acid and budesonide for PBC–AIH overlap syndrome: a meta-analysis // Drug Des. Devel. Ther. 2015. Vol. 9. P. 567–574.
21. Golovanova E. V. Modern aspects of the treatment of patients with autoimmune liver diseases // Clinical perspectives in gastroenterology and hepatology. 2015. No. 3. pp. 9–15.
22. Silveira MG, Lindor KD Obeticholic acid and budesonide for the treatment of primary biliary cirrhosis // Expert. Opin. Pharmacother. 2014. Vol. 15, No. 3. P. 365–372.
23. Hennes EM, Zeniya M, Czaja AJ et al. Simplified criteria for the diagnosis of autoimmune hepatitis // Hepatol. 2008. Vol. 48, No. 1. P. 169–176.
24. Chazouilleres O. Wendum D., Serfaty L. et al. Primary biliary cirrhosis - autoimmune hepatitis overlap syndrome: clinical features and response to therapy // J. Hepatol. 1998. Vol. 28, No. 2. P. 296–301.
25. Lohse AW, Mieli-Vergani G. Autoimmune hepatitis // J. Hepatol. 2011. Vol. 55, No. 3. P. 171–182.
26. Corpechot C., Abenavoli L., Rabahi N. et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis // Hepatol. 2008. Vol. 48, No. 3. P. 871–877.
27. Pares A., Caballerial L., Rodes J. et al. Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial // J. Hepatol. 2000. Vol. 32, No. 4. P. 561–566.
28. Csepregi A., Rocken C., Treiber G. et al. Budesonide induces complete remission in autoimmune hepatitis // World J. Gastroenterol. 2006. Vol. 12, No. 9. P. 1362–1366.
29. Zandieh I., Krygier D., Wong V. et al. The use of budesonide in the treatment of autoimmune hepatitis in Canada // Can. J. Gastroenterol. 2008. Vol. 22, No. 4. P. 388–392.
30. Wiegand J., Schuler A., ​​Kanzler S. et al. Budesonide in previously untreated autoimmune hepatitis // Liver Int. 2005. Vol. 25, No. 5. P. 927–934.

K. L. Raikhelson*, 1, Doctor of Medical Sciences, Professor M. K. Prashnova* N. V. Marchenko*, Candidate of Medical Sciences S. N. Mehdiev**, Doctor of Medical Sciences, Professor E. N. Zinovyeva** *, Candidate of Medical Sciences

* State Budgetary Educational Institution of Higher Professional Education of North-Western State Medical University named after. I. I. Mechnikova Ministry of Health of the Russian Federation, St. Petersburg ** State Budgetary Educational Institution of Higher Professional Education First St. Petersburg State Medical University named after. ak. I. P. Pavlova Ministry of Health of the Russian Federation, St. Petersburg *** Polyclinic “Expert”, St. Petersburg

1 Contact information