Instructions for use CICLOSPORIN HEXAL

Pharmacological properties of the drug Cyclosporine

Immunosuppressive agent; a cyclic polypeptide consisting of 11 amino acids. Suppresses the development of cell-type reactions, including immunity to the allograft, delayed-type skin allergic reaction, graft-versus-host reaction, allergic encephalomyelitis, arthritis caused by Freund's adjuvant, as well as T-lymphocyte-dependent antibody formation. At the cellular level, it blocks resting lymphocytes that are in the G0 or G1 phases of the cell cycle and suppresses the antigen-induced production and secretion of lymphokines (including interleukin-2 - T-lymphocyte growth factor) by activated T-lymphocytes. Cyclosporine appears to have a reversible effect on lymphocytes. Unlike cytostatics, it does not suppress hematopoiesis and does not affect the function of phagocytes. After oral administration, maximum plasma concentrations are achieved within 1–5 hours. Cyclosporine is distributed mainly outside the bloodstream; blood plasma contains 33-47%, lymphocytes - 4-9%, granulocytes - 5-12% and erythrocytes - 41-58%. In blood plasma, approximately 90% of cyclosporine is bound to proteins, mainly lipoproteins. Cyclosporine undergoes biotransformation, including various reactions, resulting in the formation of about 15 metabolites. Excretion from the body occurs mainly in bile and only 6% of the dose in urine (mainly in the form of metabolites). The half-life ranges from 6.3 hours in healthy individuals to 20.4 hours in patients with severe liver disease.

Indications for use of the drug Cyclosporine

In transplantology:

• prevention of rejection after solid organ transplantation: kidney, liver, heart, combined cardiopulmonary transplant, lung or pancreas;
• therapy for transplant rejection in patients who have previously received other immunosuppressants;
• prevention of graft rejection after bone marrow transplantation;
• prevention and treatment of graft-versus-host disease.

For autoimmune diseases:

• endogenous uveitis (active, sight-threatening uveitis of the middle or posterior part of the eye of non-infectious etiology, if conventional therapy is ineffective or leads to the development of severe adverse reactions; Behcet's uveitis with recurrent attacks of inflammation affecting the retina);
• nephrotic syndrome in adults and children, dependent on GCS and resistant to them, caused by pathology of the choroid glomerulus (in diseases such as minimal change nephropathy, focal and segmental glomerulosclerosis, membranous glomerulonephritis) - for induction of remission and its maintenance, as well as for maintaining remission induced by GCS and their subsequent withdrawal;
• severe rheumatoid arthritis in the active phase (in cases where the use of traditional antirheumatic drugs is ineffective or impossible);
• psoriasis (indicated for patients with severe psoriasis, when conventional therapy is ineffective or impossible);
• atopic dermatitis in severe form, in cases where systemic therapy is indicated.

References

1. Drug monitoring and interchangeability of original and generic immunosuppressants with a narrow therapeutic index. National clinical guidelines, 2014. - 23 p.
2. Immunosuppression in solid organ transplantation / ed. S.V. Gautier. - T.: Triada Publishing House LLC, 2011. - 382 p.
3. Stolyarevich, E.S. “Sandimmune-Neoral and generic preparations of cyclosporine; the problem of interchangeability." Nephrology and dialysis, 2006. - T. 8. - No. 2. — P. 141−147.
4. Stolyarevich, E.S., Sukhanov, A.V., Bagdasaryan, A.R. and others. On the issue of optimizing monitoring of therapy with cyclosporine drugs in the late stages after kidney allotransplantation. Nephrology and dialysis, 2004. - T. 6. - No. 2. — P. 145 – 154.
5. Barama, A., Yilmaz, S., Gough, J. et al Lower cyclosporine exposure increases the risk for sub-clinical rejection in renal transplant recipients. Transplantation, 2000. - Vol. 69. - P. 225.

Use of the drug Cyclosporine

The dose is set individually. The choice of the initial dose and correction of the dosage regimen during treatment is carried out depending on the data of clinical and laboratory studies, as well as on the level of cyclosporine concentration in the blood plasma, which is determined daily. For adults undergoing solid organ transplantation, treatment with cyclosporine should begin at a dose of 10–15 mg/kg (divided into 2 doses) 12 hours before surgery. For 1–2 weeks after surgery, the same dose is prescribed daily, after which the dose is gradually reduced (under the control of the concentration of cyclosporine in the blood) until a maintenance dose of 2–6 mg/kg/day is reached. When cyclosporine is prescribed in combination with GCS or other immunosuppressants at the beginning of treatment, its dose can be reduced to 3-6 mg/kg. When undergoing a bone marrow transplant, cyclosporine is prescribed on the day before the transplant and during the transplantation period for at least 2 weeks orally at a daily dose of 12.5–15 mg/kg, then switch to maintenance therapy at a dose of about 12.5 mg/kg/ day Cyclosporine can be administered intravenously at a dose of 3–5 mg/kg/day. Administration of this dose is continued immediately during the post-transplant period (up to 2 weeks), then they switch to maintenance therapy with oral forms of the drug. Maintenance treatment is continued for at least 3–6 months, after which the dose is gradually reduced so that treatment is discontinued 1 year after transplantation. In some patients, after stopping treatment with the drug, graft-versus-host disease may develop. In this case, treatment should be resumed. In case of chronic mild graft-versus-host disease, low doses of cyclosporine should be used. Children over 1 year of age are prescribed in the same doses as adults (per 1 kg of body weight). For endogenous uveitis, to induce remission, an initial daily dose of 5 mg/kg orally in 1 or several doses is prescribed until the severity of inflammation decreases and visual acuity improves. In severe cases, the dose can be increased to 7 mg/kg/day for a limited period (if the desired effect cannot be achieved, systemic prednisolone can be additionally prescribed at a daily dose of 200–600 mcg/kg). During maintenance therapy, the dose should be slowly reduced until the minimum effective dose is reached, which during the period of remission of the disease should not exceed 5 mg/kg/day. In nephrotic syndrome, to induce remission, cyclosporine is prescribed in a daily dose of 5 mg/kg for adults and 6 mg/kg for children (in 2 doses) with normal renal function (except in cases of proteinuria). For patients with impaired renal function, the initial daily dose should not exceed 2.5 mg/kg. If monotherapy with cyclosporine fails to achieve the desired effect, especially in patients with resistance to GCS, it is possible to combine cyclosporine with oral GCS in low doses. If after 3 months of treatment a positive effect cannot be achieved, therapy should be discontinued. For maintenance treatment, the dose should be slowly reduced to the minimum effective dose. For rheumatoid arthritis, during the first 6 weeks of treatment, the daily dose is 3 mg/kg in 2 divided doses. In case of insufficient effect, the daily dose can be gradually increased subject to satisfactory tolerability, but it should not exceed 5 mg/kg/day. The course of treatment is up to 12 weeks. For psoriasis, to induce remission, the daily dose is 2.5 mg/kg in 2 divided doses. In severe cases of the disease, when it is necessary to achieve a rapid effect, the initial daily dose may be 5 mg/kg. If after 1 month of treatment the desired result is not observed, the daily dose can be gradually increased, but it should not exceed 5 mg/kg. If it is not possible to achieve an adequate clinical effect when using cyclosporine at a daily dose of 5 mg/kg for 6 weeks, treatment should be discontinued. The dose for maintenance treatment of patients with psoriasis should be minimally effective (not higher than 5 mg/kg/day). For atopic dermatitis, an initial dose of 2.5 mg/kg/day is recommended. In severe cases, the dose can be increased to 5 mg/kg/day. When a positive clinical result is achieved, the dose should be gradually reduced until completely discontinued.

Detailed description of the study

Cyclosporin (English: Cyclosporin, or Ciclosporin) belongs to the pharmacological group of immunosuppressants, that is, drugs that suppress the immune system.

Immunosuppressants are presented:

1. Non-selective drugs that suppress all parts of the immune system;
2. Selective, which provide selective immunosuppression;
3. Agents that additionally demonstrate anti-inflammatory activity (glucocorticosteroid hormones).

The demand for cyclosporine in clinical practice is due to its ability to selectively suppress the production and activity of T-lymphocytes. This ensures the preservation of the antibacterial, antitumor and viral immune response. The effect of the immunosuppressant is reversible: some time after completion of therapy, the immune system is completely restored.

T-lymphocytes are responsible for implementing the “friend or foe” mechanism, recognize and destroy microorganisms and the proteins they produce, and ensure the production of information cytokines responsible for signal transmission between immune cells. In a number of situations, their activity worsens the patient’s condition and provokes the development of diseases.

Inhibition of cellular immunity for therapeutic purposes is relevant in the following cases:

1. Organ transplantation (prevention of rejection);
2. Neutralization of already developed graft-versus-host reactions;
3. Autoimmune diseases;
4. Severe inflammatory processes with a high degree of activity.

A feature of therapy is the need for precise dose selection. Initially, the bioavailability of the drug (the proportion of the dose that reaches the point of action unchanged) is relatively low, in most cases no more than 30%. At the same time, increasing the duration of treatment and increasing the dosage contribute to its significant increase.

Cyclosporine is a critical dose medicinal product. This means that to achieve an effect without causing adverse reactions in the body, a certain concentration in the blood is required. When going beyond its limits, either the effectiveness of therapy significantly decreases, which is critical, in particular, for patients after organ transplantation, or toxic complications develop. Regular monitoring of the concentration of immunosuppressant in the blood plasma can prevent deterioration in health and a decrease in the quality of treatment.

The study of reactions to therapy in various patients made it possible to identify a separate group that needs careful monitoring of the concentration of cyclosporine in the blood. These are persons who receive not the original drug, but a generic or generic drug - a “copy” drug, the main ingredient of which is a substance previously patented by the developer. These drugs are usually cheaper and more accessible, since their manufacturer did not finance preliminary research, but used a ready-made active component as a basis. Since the chemical formula of such a drug is not completely identical to the original one, their pharmacokinetic properties may differ, sometimes quite significantly. If you switch from an original drug to a generic, the concentration of the drug in the blood may change.

Systematic assessment of the concentration of cyclosporine in the blood helps to effectively monitor treatment, avoid side effects and drug overdose.

Side effects of the drug Cyclosporine

On the part of the kidneys , renal dysfunction often develops, manifested by an increase in the concentration of creatinine and urea in the blood serum (usually these effects are observed during the first weeks of treatment, are dose-dependent and decrease with decreasing dose). With long-term treatment, some patients may develop structural changes in the kidneys (for example, interstitial fibrosis), which in patients with renal transplants should be differentiated from changes due to the development of a chronic rejection reaction. From the digestive tract and liver - anorexia, nausea, vomiting, diarrhea, abdominal pain, pancreatitis. Reversible liver function disorders are possible, manifested by an increase in the concentration of bilirubin and the activity of liver enzymes in the blood serum (the severity of these disorders is dose-dependent). From the cardiovascular system - hypertension (arterial hypertension) (especially in patients after heart transplantation). From the nervous system and skeletal muscles - possible headache, paresthesia, convulsions; rarely - muscle spasm, muscle weakness, myopathy, tremor. In patients after liver transplantation, signs of encephalopathy, impairment of vision, consciousness, and motor function have been described (however, it has not been conclusively established whether these changes are caused by the use of cyclosporine, the underlying disease, or other factors). From the endocrine system - reversible dysmenorrhea and amenorrhea. From the blood system - mild anemia. In rare cases, thrombocytopenia has developed due to microangiopathic hemolytic anemia and renal failure (hemolytic uremic syndrome). Allergic reactions - skin rash. Changes in laboratory parameters - hyperkalemia, hypomagnesemia, increased concentration of uric acid in the blood. Others - hypertrichosis, increased fatigue, gum hypertrophy; swelling, weight gain; rarely - reversible minor hyperlipidemia. There are isolated reports of the development of malignant and lymphoproliferative diseases during treatment with cyclosporine (as well as other drugs with an immunosuppressive effect), including in patients with nephrotic syndrome. There are reports of the development of malignant tumors (particularly of the skin) in patients with psoriasis.

Chronic induced urticaria: treatment algorithm

Chronic urticaria is a skin disease characterized by the appearance of recurrent blisters and/or angioedema for > 6 weeks and a significant decrease in the quality of life of patients. Chronic urticaria is classified as spontaneous and induced (CIU). Symptoms of the latter are caused by the action of external, primarily physical, factors on the skin: cold, heat, water, pressure, mechanical irritation, etc. Thus, there are several subtypes of CHINK: cold and thermal urticaria, delayed urticaria due to pressure, symptomatic dermographism (dermographic or mechanical urticaria), aquagenic urticaria, solar urticaria, vibration angioedema, cholinergic and contact urticaria. It is known that chronic urticaria affects 0.5–1% of people in the general population, with CHIU accounting for 6–30% of all cases. Silpa-Archa et al. found that the most common types of induced urticaria are dermographic urticaria (40.7%), cold urticaria (23.3%) and delayed pressure urticaria (12.8%), and the rarest are cholinergic (5–7%) solar (4.7%) and aquagenic (1.2%) urticaria. Moreover, in 13.9% of people, CLIN occurs along with chronic spontaneous urticaria.

Avoiding skin contact with the causative factor is an effective way to prevent CLI symptoms. For example, remission of cold urticaria can be achieved by stopping the skin from contacting cold water. However, in some patients, exclusion of triggers does not lead to complete disappearance of symptoms and normalization of quality of life and they require drug treatment. The International Consensus Document on Urticaria, revised at the end of 2021, proposes a 4-step approach to the treatment of CLI (Figure). First-line drugs are non-sedating 2nd generation H1-antihistamines (AGPs) in standard daily doses (usually 1 tablet per day). If symptoms persist after 2–4 weeks of treatment or earlier, if the symptoms are significantly severe, it is possible to increase the dose of 2nd generation antihypertensive drugs up to 4 times. Third-line therapy includes omalizumab, monoclonal anti-IgE antibodies, and fourth-line therapy includes cyclosporine A. One of these drugs is added to antihypertensive drugs if the latter are insufficiently effective within 2–6 weeks or earlier if symptoms are intolerable. At the same time, both omalizumab and cyclosporine, as well as increasing the dose of antihypertensive drugs, are used “off label” for the treatment of CLI, i.e., they require the informed consent of the patient and the approval of the consultation. Symptomatic treatment of HINK is aimed at mast cells, a key link in the pathogenesis of urticaria. In this case, the activation of mast cells is inhibited (for example, omalizumab, cyclosporine) or the action of mast cell mediators is blocked (for example, AGP, montelukast).

In this review, we consider the existing scientific evidence of the effectiveness of each of the listed types of treatment, as well as alternative therapy for CLI.

Antihistamines

2nd generation antihypertensive drugs are the first choice for the treatment of any type of chronic urticaria and CINK, in particular, according to the clinical recommendations of the European Academy of Allergy and Clinical Immunology (EAACI), the Global Allergy and Asthma Network (GA2LEN) ), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) and the recommendations of the American Academy of Allergy Asthma and Immunology (AAAI). The American consensus document allows the use of 1st generation antihypertensive drugs at night if the patient is bothered by severe nighttime itching and insomnia. In this case, possible side effects, such as sedation, must be taken into account.

Increasing the dose of 2nd generation antihypertensive drugs is at the second stage of the algorithm (Fig.), despite the fact that for some forms of CLI there is no published evidence of the effectiveness of such treatment yet (Table). Taking high doses of antihypertensives is considered safer than using steroid hormones or some other treatments and can reduce the frequency of their use. The sedative effect is not typical for 2nd generation antihypertensive drugs, although in some patients it may appear at high doses.

Thus, on the one hand, 2nd generation antihypertensives are a safe and affordable type of treatment, and on the other hand, they require daily use, the effect disappears after their withdrawal, and they are effective even in high doses in <50% of patients.

Omalizumab

The mechanism of action of omalizumab is binding to IgE and reducing free IgE in the blood serum, thereby reducing the density of high-affinity FcεRI receptors on mast cells and basophils. Omalizumab is currently approved for use in patients with severe atopic asthma not controlled by inhaled corticosteroids and in patients with chronic idiopathic urticaria. The use of the drug in patients with CINK is possible “off label” or when combining CICI with idiopathic urticaria. The recommended dose of the drug in patients over 12 years of age is 300 mg subcutaneously every 4 weeks.

Omalizumab was effective and safe for the treatment of most types of CLI as a third-line therapy (Fig., Table). The most significant evidence of effectiveness is described for dermographic, cold and solar urticaria. Most cases have a rapid onset of action, i.e. early control of symptoms, sometimes within 24 hours. The incidence of side effects is low, including in children.

Thus, omalizumab is a convenient, highly effective and safe treatment for patients with CLIN that is resistant to treatment with antihypertensive drugs. However, the high cost still limits its widespread use in Russia.

Cyclosporine

The immunosuppressive effect of cyclosporine is based on the inhibition of cell-mediated immune responses by regulating T-cell-dependent antibody production by B lymphocytes, as well as on the inhibition of IgE-induced histamine release from basophils and mast cells and granule proteins from eosinophils.

Literature data on the use of cyclosporine in CLI are scarce and partly contradictory. The effectiveness of the drug has been most studied for dermographic and solar urticaria. For example, Toda et al. (2011) provide data on six cases of cyclosporine use in patients with AGP-resistant dermographic urticaria. In four of these cases the effect was positive, although complete remission was observed in only one patient. The drug was prescribed for 8, 21, 16 and 32 months. At the same time, a number of authors indicate insufficient or no effect when using cyclosporine. In particular, Hurabielle et al (2015) saw no benefit from the drug in 82% of 11 patients with solar urticaria when administered at a dose of 2.5–5 mg/kg/day for 14 weeks. The remaining patients (3 of 11) showed only a partial effect, although in one of them increasing the dose to 5 mg/kg/day led to complete clinical remission.

Adverse reactions during treatment with cyclosporine are observed in 45–75% of patients, but severe reactions requiring discontinuation of the drug occur in only 9% of patients. Seth and Khan emphasize the importance of regular clinical monitoring (blood chemistry and other studies) to optimize cyclosporine treatment and prevent the development of side effects.

Thus, cyclosporine may be an effective treatment for some types of CLI, but its use is limited by possible side effects, although the risk/benefit ratio is better compared with a long course of glucocorticosteroids.

Other treatments

In case of ineffectiveness of the already discussed types of treatment, individual patients with severe urticaria should select an alternative treatment (Table). Steroid hormones, in particular prednisolone, are highly effective for the treatment of various types of urticaria, but they are not recommended for long-term use as the basic therapy for CINC due to the likelihood of developing serious side effects. However, drugs from this group may be indicated for a short course during exacerbation of urticaria.

Dapsone is an antibacterial sulfonamide drug that is approved for use in Dühring's dermatitis herpetiformis, leprosy, malaria, and Pneumocystis pneumonia. However, dapsone may be effective for pressure-induced urticaria. The disadvantage of this method of therapy is the possible development of side effects such as anemia and peripheral neuropathy.

The effectiveness of phototherapy, including PUVA therapy, has been noted in some patients with dermographic and aquagenic urticaria, anti-TNF in patients with cold urticaria and delayed pressure urticaria, and danazol in cholinergic CINK. Plasmapheresis and intravenous immunoglobulin were effective for the treatment of solar urticaria.

Some patients with solar, cold and generalized heat urticaria may benefit from desensitization (tolerance induction). The procedure involves repeated exposure of the patient's skin to a causative stimulus until complete refractoriness is achieved. For example, in patients with cold urticaria, tolerance induction is achieved using cold water baths. In this case, the temperature of the initial bath should be significantly higher than the previously determined threshold temperature tolerated by the individual, and then the stimulus temperature is gradually reduced over several days. After this, the patient takes cold baths/showers at home daily to maintain cold tolerance. It has been suggested that a possible mechanism of action for tolerance induction is the gradual deactivation of metabolic processes in mast cells, through repeated exposure to cold, or the depletion of an as yet unknown skin antigen, which is formed after exposure to cold and is responsible for degranulation of mast cells. Tolerance induction can be used as a standalone treatment method or in addition to other types of therapy. However, the effect of this type of treatment disappears when the stimulus ceases, which requires the patient’s adherence to treatment, which is not always feasible due to the discomfort caused by subjective sensations. When using this method, the treatment protocol should be strictly followed to reduce the likelihood of side effects, including anaphylaxis.

Conclusion

Despite the fact that CLI is prone to a long-term chronic course, spontaneous remission occurs in some patients. Drug treatment is prescribed if it is impossible to completely exclude the causative factor and/or if urticaria leads to a significant decrease in quality of life. The drugs of choice for the treatment of CLI are 2nd generation antihistamines. If necessary, it is possible to increase their dose or add omalizumab or cyclosporine. Alternative treatments (eg, tolerance induction, phototherapy, etc.) should be used only in carefully selected patients in whom primary treatment has failed.

Literature

1. Zuberbier T. et al. The EAACI/GA (2)LEN/EDF/WAO Guideline for the Definition, Classification, Diagnosis and Management of Urticaria. The 2021 Revision and Update // Allergy. 2021.
2. Magerl M. et al. The definition, diagnostic testing, and management of chronic inducible urticarias — The EAACI/GA (2) LEN/EDF/UNEV consensus recommendations 2021 update and revision // Allergy. 2021. 71 (6): p. 780–802.
3. Dressler C. et al. Chronic inducible urticaria: a systematic review of treatment options // J Allergy Clin Immunol. 2021.
4. Maurer M. et al. Unmet clinical needs in chronic spontaneous urticaria. A GA (2)LEN task force report // Allergy. 2011. 66 (3): p. 317–330.
5. Trevisonno J. et al. Physical urticaria: Review on classification, triggers and management with special focus on prevalence including a meta-analysis // Postgrad Med. 2015. 127 (6): p. 565–570.
6. Silpa-archa N., Kulthanan K., Pinkaew S. Physical urticaria: prevalence, type and natural course in a tropical country // J Eur Acad Dermatol Venereol. 2011. 25 (10): p. 1194–1199.
7. Bernstein JA et al. The diagnosis and management of acute and chronic urticaria: 2014 update // J Allergy Clin Immunol. 2014. 133 (5): p. 1270–1277.
8. Kocaturk E. et al. Management of chronic inducible urticaria according to the guidelines: A prospective controlled study // J Dermatol Sci. 2021. 87 (1): p. 60–69.
9. Staevska M. et al. The effectiveness of levocetirizine and desloratadine in up to 4 times conventional doses in difficult-to-treat urticaria // J Allergy Clin Immunol. 2010. 125 (3): p. 676–682.
10. Chang TW et al. The potential pharmacologic mechanisms of omalizumab in patients with chronic spontaneous urticaria // J Allergy Clin Immunol. 2015. 135 (2): p. 337–342.
11. Maurer M. et al. Omalizumab treatment in patients with chronic inducible urticaria: A systematic review of published evidence // J Allergy Clin Immunol. 2021. 141 (2): p. 638–649.
12. Hurabielle C. et al. No major effect of cyclosporin A in patients with severe solar urticaria: a French retrospective case series // Acta Derm Venereol. 2015. 95 (8): p. 1030–1031.
13. Toda S. et al. Six cases of antihistamine-resistant dermographic urticaria treated with oral ciclosporin // Allergol Int. 2011. 60 (4): p. 547–550.
14. Seth S., Khan DA The Comparative Safety of Multiple Alternative Agents in Refractory Chronic Urticaria Patients // J Allergy Clin Immunol Pract. 2021. 5 (1): p. 165–170 e2.
15. Vestergaard C. et al. Treatment of chronic spontaneous urticaria with an inadequate response to H1-antihistamines: an expert opinion // Eur J Dermatol. 2021. 27 (1): p. 10–19.
16. Zuberbier T. et al. The EAACI/GA (2) LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update // Allergy. 2014. 69 (7): p. 868–887.
17. Leenutaphong V. et al. Plasmapheresis in solar urticaria. Dermatologica, 1991. 182 (1): p. 35–8.
18. Aubin, F. et al., Severe and refractory solar urticaria treated with intravenous immunoglobulins: a phase II multicenter study // J Am Acad Dermatol. 2014. 71 (5): p. 948–953 e1.
19. Ramsay CA Solar urticaria treatment by inducing tolerance to artificial radiation and natural light // Arch Dermatol. 1977. 113 (9): p. 1222–1225.
20. Black AK, Sibbald RG, Greaves MW Cold urticaria treated by induction of tolerance // Lancet. 1979. 2 (8149): p. 964.
21. Leigh IM, Ramsay CA Localized heat urticaria treated by inducing tolerance to heat // Br J Dermatol. 1975. 92(2): p. 191–194.
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D. M. Skander A. S. Allenova P. V. Kolhir1, Doctor of Medical Sciences

Federal State Autonomous Educational Institution of Higher Education First Moscow State Medical University named after. I. M. Sechenova Ministry of Health of the Russian Federation, Moscow

1 Contact information

Chronic induced urticaria: treatment algorithm / D. M. Skander, A. S. Allenova, P. V. Kolkhir For citation: Attending physician No. 7/2018; Page numbers in the issue: 68-71 Tags: skin, diseases, blisters, angioedema

Special instructions for the use of the drug Cyclosporine

Treatment with cyclosporine should only be administered by a physician experienced in immunosuppressive therapy and the management of patients after organ or bone marrow transplantation. Treatment is carried out only in specialized medical institutions. Caution should be exercised when prescribing cyclosporine to patients with impaired renal and/or liver function, hyperuricemia, and a tendency to develop hyperkalemia. Patients receiving treatment with cyclosporine are less susceptible to infections compared to those patients receiving other immunosuppressive therapy. Determination of the concentration of cyclosporine in the blood is carried out by radioimmunoassay using monoclonal antibodies or by high-performance liquid chromatography. In patients after liver transplantation, specific monoclonal antibodies should be used to determine the concentration of cyclosporine or parallel determination should be carried out using both specific and nonspecific monoclonal antibodies. During treatment with cyclosporine, systematic monitoring of blood pressure, the functional state of the kidneys and liver is indicated; determining the concentration of potassium in the blood plasma (especially in patients with impaired renal function), as well as determining the level of lipids in the blood serum (before the start of treatment and after the 1st month of treatment). If the increase in the concentration of urea, creatinine, bilirubin, and liver enzymes in the blood is persistent, the dose of cyclosporine should be reduced. In case of development of hypertension (arterial hypertension), it is necessary to begin antihypertensive treatment. If serum lipids increase, it is necessary to consider reducing the dose of the drug and/or prescribing an appropriate diet. Before prescribing cyclosporine for the treatment of autoimmune diseases, it is necessary to determine the initial level of creatinine in the blood serum (at least 2 studies). During treatment, systematic monitoring of serum creatinine concentration is necessary (preferably at intervals of 2 weeks during the first 3 months of treatment; thereafter - once every 1 or 2 months). The dose is adjusted taking into account changes in serum creatinine concentration. If there is an increase in serum creatinine concentration by more than 30% relative to the initial level, then a dose reduction of 25–50% is required. If the serum creatinine level increases by more than 50%, the dose should be reduced by 50%. These recommendations should be followed even if serum creatinine levels remain within the normal range. If dose reduction does not result in a decrease in serum creatinine concentration within a month, treatment with cyclosporine should be discontinued. Further use of cyclosporine is not indicated if hypertension (arterial hypertension) that developed during treatment remains refractory to adequate antihypertensive therapy. Cyclosporine can be prescribed to patients with endogenous uveitis only if renal function is initially normal. People with steroid-dependent minimal change nephropathy who have been treated for more than 1 year are advised to undergo a kidney biopsy. In patients with psoriasis, skin lesions that are not typical for psoriasis and if they are suspected of being malignant or precancerous should be biopsied before starting treatment with cyclosporine. Patients with cancerous or precancerous skin changes should receive treatment with cyclosporine only after appropriate treatment of such changes, unless alternative effective therapy exists. Experimental studies have not revealed the teratogenic effect of cyclosporine. Experience with the use of cyclosporine in pregnant women is limited. Data obtained from patients who have undergone organ transplantation indicate that, in comparison with traditional methods, treatment with cyclosporine does not have a negative effect on the course and outcome of pregnancy. Cyclosporine passes into breast milk. If it is necessary to prescribe cyclosporine during breastfeeding, breastfeeding should be discontinued.

Cyclosporine is a drug, an immunosuppressant that inhibits the function of the cellular component of immunity and prevents rejection of a transplanted organ or tissue.

Synonyms Russian

Consupren, Orgasporin, Panimune Bioral, Sandimmune, Sandimmune Neoral, Cycloprene, Cycloral-FS, Ecoral.

English synonyms

Cyclosporine, CSA Level, Gengraf, Neoral, Sandimmune.

Research method

Chemiluminescent immunoassay.

Units

ng/ml (nanograms per milliliter).

What biomaterial can be used for research?

Venous blood.

How to properly prepare for research?

• Do not eat for 2-3 hours before the test; you can drink clean still water.
• Do not smoke for 30 minutes before the test.

General information about the study

Cyclosporine is a strong immunosuppressant used to prevent organ and tissue transplant rejection. It selectively affects T-lymphocytes and inhibits the cellular component of the immune system. In addition to transplantation, cyclosporine is used to treat autoimmune diseases: endogenous uveitis, rheumatoid arthritis, severe psoriasis and atopic dermatitis, glomerulonephritis, chronic, treatment-resistant urticaria. Unlike cytostatics, cyclosporine does not inhibit hematopoiesis and phagocytosis.

Pharmacokinetic parameters of absorption and half-life of the drug vary depending on the dosage form, individual characteristics of the patient, and drug interactions. In the liver, cyclosporine is actively transformed by the enzyme CYP3A4 to 30 less active metabolites. The drug is excreted primarily in bile and only in small amounts in urine.

Cyclosporine interacts with many drugs, increases the neuro- and nephrotoxicity of antibiotics and antifungals, and other immunosuppressants. It has a narrow therapeutic window with frequent development of adverse events, which indicates the need for regular monitoring of its concentration in the blood.

Most side effects of cyclosporine are dose dependent. While taking the drug, increased blood pressure, headache, muscle pain, paresthesia, tremor, convulsions, nausea, vomiting, diarrhea, excess hair growth, gum hyperplasia, impaired liver function, pancreatitis, increased cholesterol levels in the blood, changes in electrolyte levels may occur. , bacterial, fungal, parasitic and viral infections, renal dysfunction.

During initial therapy with cyclosporine (the first 2 months after transplantation), it is recommended to maintain the drug concentration in the blood within the range of 150-400 ng/ml.

The target concentration of the drug in the blood depends on the clinical protocol for patient management, type of transplant, risk of rejection, and concomitantly taken immunosuppressants. 2 months after transplantation, the target dose and blood level of the drug are usually reduced to 75-300 ng/ml. Most patients have an optimal response to cyclosporine at a blood concentration of 100-400 ng/ml.

The material for analysis is taken immediately before the planned dose is administered. Whole blood is taken for the study, since up to 80% of the drug penetrates into red blood cells. Blood taken at other times has higher values. The level of cyclosporine in the blood can also be analyzed 2 hours after administration of the drug (C2 monitoring), but in this case it is impossible to rely on the therapeutic concentration of this immunosuppressant.

What is the research used for?

• Monitoring the concentration of cyclosporine in the blood, especially when co-prescribing drugs with the properties of inducers or inhibitors of the CYP3A4 enzyme;
• selection and correction of the optimal dose for immunosuppression with minimal toxicity;
• identification of toxic levels of the drug;
• assessment of drug interactions;
• monitoring the regularity of taking the drug.

When is the study scheduled?

• Immediately after prescribing cyclosporine 2-3 times a week, then periodically (once every 1-2 months) after achieving a stable or maintenance dose;
• if there is a suspected violation of the dosage of the drug;
• when adjusting the dose or changing the prescription of other drugs taken simultaneously;
• when side effects occur.

What do the results mean?

The therapeutic range of cyclosporine concentrations is indicated by the attending physician according to the clinical situation (maintenance/induction therapy). Toxic concentration: values ​​above 400 ng/ml.

The results of the study are analyzed only taking into account the clinical picture of the disease, treatment regimen, and drug interactions.

What can influence the result?

• Drugs that reduce the concentration of cyclosporine: barbiturates, carbamazepine, phenytoin; nafcillin, sulfadimidine when administered; rifampicin; octreotide; probucol; orlistat; preparations containing St. John's wort; troglitazone;
• drugs that increase the concentration of cyclosporine: some macrolide antibiotics (mainly erythromycin and clarithromycin); ketoconazole, fluconazole, itraconazole; diltiazem, nicardipine, verapamil; metoclopramide; oral contraceptives; danazol; methylprednisolone (high doses); allopurinol; amiodarone; cholic acid and its derivatives.

Drug interactions Cyclosporine

When cyclosporine is co-administered with potassium supplements or potassium-sparing diuretics, the risk of developing hyperkalemia increases. With the simultaneous administration of cyclosporine and drugs such as aminoglycoside antibiotics, amphotericin B, ciprofloxacin, melphalan, colchicine, trimethoprim, the risk of developing nephrotoxicity increases. The risk of side effects from the kidneys also increases when prescribed simultaneously with NSAIDs. When cyclosporine is co-administered with lovastatin or colchicine, the risk of myalgia and muscle weakness increases. Various drugs may increase or decrease plasma concentrations of cyclosporine by inhibiting or inducing liver enzymes involved in its metabolism and elimination. Drugs that increase the concentration of cyclosporine in the blood plasma: ketoconazole, some macrolide antibiotics (including erythromycin and josamycin), doxycycline, oral contraceptives, propafenone, some calcium channel blockers (including verapamil, diltiazem, nicardipine). Drugs that cause a decrease in the concentration of cyclosporine in the blood plasma: barbiturates, carbamazepine, phenytoin, metamizole sodium, rifampicin, nafcillin, as well as sulfadimidine and trimethoprim when administered intravenously. If combined use cannot be avoided, careful monitoring of cyclosporine blood concentrations and appropriate dose adjustments are necessary. Cyclosporine reduces the clearance of prednisolone, and treatment with high doses of prednisolone may increase the concentration of cyclosporine in the blood.

Overdose of the drug Cyclosporine, symptoms and treatment

Available experience with cyclosporine overdose is limited. Impaired renal function may develop, which is probably reversible. If there are appropriate indications, symptomatic treatment is carried out. Removal of cyclosporine from the body can be achieved through nonspecific measures, including gastric lavage. It should be borne in mind that cyclosporine is practically not excreted from the body during hemodialysis and hemoperfusion using activated charcoal.

List of pharmacies where you can buy Cyclosporine:

• Moscow
• Saint Petersburg