Pharmacological properties
Pharmacodynamics. The immunosuppressive effect of cyclosporine is due to its ability to block the early activation of T-lymphocytes and inhibit the synthesis of cytokines, especially interleukin (IL)-2 or the activation of their genes at the transcriptional level. As a result of the study of the mechanism of action, it was proven that cyclosporine acts as an inactive precursor of the drug. By combining with an intracellular binding protein (cyclophilin), it forms a complex that binds and inhibits the activity of intracellular phosphatase (calcineurin), which is necessary for the activation of the cytoplasmic subunit of the nuclear factor of activated T-lymphocytes (NFAT). The non-activated cellular component of NFAT cannot penetrate the cell nucleus, as a result of which the maturation of NFAT and transcription of the gene for IL-2 are blocked.
Ekvoral is a potent immunosuppressive agent specific for T lymphocytes. Ekvoral inhibits immune responses to allografts, delayed-type hypersensitivity reactions, graft-versus-host disease (GVHD), and T-cell-dependent antibody production. Cyclosporine acts specifically and reversibly on lymphocytes. Unlike cytostatic agents, it does not adversely affect hematopoiesis and phagocyte function. Patients receiving cyclosporine therapy are less susceptible to infections than patients receiving other immunosuppressive drugs.
Equoral promotes the adhesion of transplanted tissues, especially skin, heart, kidneys, pancreas, bone marrow, and lungs.
The effectiveness of the therapy has also been proven in the treatment of various conditions with a proven or suspected autoimmune origin.
Pharmacokinetics. Cyclosporine after oral administration is absorbed in the duodenum and small intestine, after which absorption occurs in the ileum and colon. The average bioavailability in healthy volunteers was about 30%. The concentration of cyclosporine in the blood plasma after oral administration reaches a maximum after 1-6 hours. In some patients, a two-peak curve may persist, which occurs due to accelerated absorption after eating or as a result of enterohepatic circulation. The presence of cytochrome CYP 3A in the intestinal wall causes a decrease in availability due to presystemic metabolism of cyclosporine. The absorption of cyclosporine is reduced by diarrhea and increases with an increase in the rate of gastric emptying. The absorption of cyclosporine is significantly affected by the length of the small intestine. Children reduce the dose necessary to maintain therapeutic concentrations, since their small intestine lengthens with age. Absorption of cyclosporine is reduced due to impaired intestinal function in jejunoileal anastomosis, Crohn's disease, insufficient bile secretion, enteritis caused by chemo- and radiotherapy of the intestine, in GVHD. The level of absorbed cyclosporine is lower in representatives of the Negroid race (about 30%) compared with representatives of the Caucasian race (about 39%). With an increased level of TG in the blood plasma, bioavailability increases, and with an increased level of hemoglobin - decreases. Food with a high fat content promotes the induction of liver lipase, as a result of which the concentration of cyclosporine in the blood increases. In children, the bioavailability of the drug when taken orally is significantly increased when used simultaneously with alpha-tocopheryl polyethylene glycol 100 (TRGS), a water-soluble form of vitamin E.
Cyclosporine in the human body is completely metabolized by the enzyme system monooxygenases, which is catalyzed by cytochrome CYP 3A with the formation of a large number of primary metabolites. Enzymes involved in the biotransformation of cyclosporine are contained mainly in the EPR of liver cells, as well as in the digestive tract. The immunosuppressive activity of cyclosporine metabolites is significantly lower compared to the main substance. The most active metabolite AM1 retains 10-20% of the primary activity, with increasing polarity of metabolites their immunosuppressive activity decreases accordingly. The distribution of cyclosporine metabolites in tissues is uneven. Compared to blood plasma, higher concentrations are noted in adipose tissue and pancreas (40 times higher), and the highest - in the liver and kidneys (190 times higher). Although the toxicity of cyclosporine metabolites, which has been identified in animal studies, is low, it determines the hepato- and nephrotoxicity of cyclosporine.
Concomitant use of drugs that interact with the cytochrome P450 system may affect the metabolism of cyclosporine. Cytochrome P450 inducers reduce the plasma concentration of cyclosporine, while cytochrome P450 inhibitors increase it. Grapefruit juice also affects the metabolism of cyclosporine, so its use is not recommended for patients.
The clearance of cyclosporine varies in the range of 0.28-3 l / h / kg. Cyclosporine is excreted mainly with bile. Part of cyclosporine, which is excreted with bile, is reabsorbed. The elimination of cyclosporine from the blood is biphasic. The final T ½ of the drug Ekvoral varies in the range of 8-18 h (average 8.4 h).
Cyclosporine is excreted in breast milk. Concentrations of cyclosporine in breast milk ranged from 16 to 263 ng/ml. A small amount of unchanged cyclosporine is excreted by the kidneys (0.1 to 6% of the dose). In patients with severe burns, T½ is 1 to 2 hours. A shorter T½ is observed in patients with impaired liver and kidney function, children, the elderly, and patients with diabetes mellitus. Hemodialysis has no significant effect on cyclosporine clearance. Less than 1% of the cyclosporine dose is detected in the dialysate. Plasmapheresis has a minor effect on cyclosporine clearance.
Indication
transplantation
Parenchymal organ transplantation
Prevention and treatment of tissue rejection after kidney, liver, heart, lung, pancreas transplantation or after combined heart and lung transplantation.
Bone marrow transplant
Prevention of rejection after bone marrow transplantation.
Prevention or treatment of disease caused by GVHD.
Indications not related to transplantation
endogenous uveitis
Active middle or posterior uveitis of non-infectious etiology, threatening vision, in cases where conventional therapy is ineffective or there is a risk of developing severe adverse reactions. Behçet's uveitis with recurrent retinal inflammation.
nephrotic syndrome
Steroid-resistant and steroid-dependent nephrotic syndrome in adults and children as a result of minimal change glomerular nephropathy, focal and segmental glomerulosclerosis, or membranous glomerulonephritis.
The drug Ekvoral can be used to achieve and maintain remission, as well as to maintain remission achieved by taking steroids, allowing them to be discontinued.
Rheumatoid arthritis
Treatment of severe, highly active rheumatoid arthritis in patients when traditional therapy with slow-acting antirheumatic drugs is ineffective or inappropriate.
psoriasis
Treatment of patients with severe psoriasis in whom conventional therapy has been ineffective or inappropriate.
Atopic dermatitis
Short-term treatment (8 weeks) of patients with severe atopic dermatitis in whom conventional therapy has been ineffective or inappropriate.
Application
The daily dose of Ekvoral should be divided into two separate doses, which should be taken with an interval of 12 hours (morning and evening). It is necessary to regularly monitor the level of cyclosporine in the blood to determine the optimal dosage regimen and achieve the required target concentration. Given the differences in the bioavailability of different forms of cyclosporine for oral administration, patients should not be transferred from one form of the drug to another without adequate monitoring of the level of cyclosporine and creatinine in the blood plasma and the liver.
Parenchymal organ transplantation
The use of Ekvoral should be started no later than 12 hours before surgery; the drug should be used at a dose of 10-15 mg/kg/day, divided into 2 doses (morning and evening). This daily dose should be used for 1-2 weeks from the moment of surgery, then gradually reduced depending on the level of cyclosporine in the blood until a maintenance dose of 2-6 mg/kg/day is reached, which should also be divided into 2 doses (morning and evening). Dose adjustment should be carried out under the control of the level of cyclosporine in the blood and kidney function.
If Ekvoral is used in combination with other immunosuppressants (e.g. with corticosteroids or other combinations), Ekvoral can be taken in lower doses at the beginning of treatment (3-6 mg/kg/day, divided into 2 doses (morning and evening)).
In most cases, intravenous infusion of cyclosporine is preferred; the recommended dose is 3-5 mg/kg/day. This dose is administered immediately after transplantation for 2 weeks, and only then should an oral maintenance dose of about 12.5 mg/kg/day be initiated. In cases of gastrointestinal disorders that may reduce absorption, oral administration in higher doses or intravenous administration of cyclosporine is indicated.
If the drug is taken orally at the beginning of treatment, the recommended dose of Ekvoral is 12.5-15 mg/kg/day; the dose is started 1 day before transplantation and continued to take a maintenance dose for 3-6 months. After that, the dose is gradually reduced within 1 year from the moment of transplantation and only then the drug is stopped.
Some patients develop GVHD after stopping Ekvoral. The body's response to resuming treatment is usually positive. For the treatment of moderately severe chronic disease caused by GVHD, the drug is used in low doses.
endogenous uveitis
The recommended initial dose is 5 mg/kg/day, divided into 2 doses, until remission of active uveitis and improvement in visual acuity is achieved. In refractory cases, the dose may be temporarily increased to a maximum of 7 mg/kg/day.
If cyclosporine monotherapy is not sufficient to achieve remission or eliminate the acute inflammatory process, systemic corticosteroids can be additionally used, for example, prednisone at a daily dose of 0.2-0.6 mg/kg of body weight.
For maintenance treatment, the dose of the drug should be reduced to the minimum effective dose, not exceeding 5 mg/kg/day, and used until remission is achieved.
nephrotic syndrome
If the patient's renal function, excluding the presence of proteinuria, is normal, to achieve remission, it is recommended to use 5 and 6 mg/kg/day for adult patients and children over 6 years of age, respectively. In case of impaired renal function, the initial dose should not exceed 2.5 mg/kg/day. In case of insufficient effectiveness of cyclosporine monotherapy, especially in steroid-resistant patients, it is recommended to use the drug simultaneously with oral GCS in low doses. If after 3 months of treatment a satisfactory therapeutic effect has not been achieved in patients with glomerulonephritis with minimal changes and focal segmental glomerulosclerosis, cyclosporine treatment should be discontinued.
The oral dose should be individualized for each patient based on efficacy (proteinuria control) and safety (primarily based on plasma creatinine levels) to determine the minimum effective maintenance dose. However, the dose should not exceed 5 and 6 mg/kg/day in adults and children, respectively.
Rheumatoid arthritis
It is recommended that the initial therapy lasts 12 weeks. A dose of 2.5 mg/kg/day, divided into 2 doses (morning and evening), is recommended for the first 6 weeks. If the clinical effect of the treatment is insufficient, the daily dose can be gradually increased according to the individual sensitivity of the patient; however, the dose should not exceed 4 mg/kg/day. The dose for maintenance treatment should be determined individually, depending on the tolerability of the drug.
psoriasis
To achieve remission, an initial dose of 2.5 mg/kg/day, divided into 2 doses (morning and evening), is recommended. If no improvement is observed within 1 month of treatment, the daily dose can be gradually increased; however, the dose should not exceed 5 mg/kg/day. In patients without signs of clinical improvement within 6 weeks of therapy at a dose of 5 mg/kg/day, Ekvoral treatment should be discontinued. In patients whose condition requires rapid improvement, an initial dose of 5 mg/kg/day should be used. When a satisfactory therapeutic effect is achieved, treatment with the drug can be discontinued.
In case of relapse of the disease, it is necessary to start treatment with Equoral using the already determined effective dose.
However, some patients require continuous therapy. For maintenance therapy, the dose should be determined individually, adhering to the lowest effective dose, which should not exceed 5 mg/kg/day.
Atopic dermatitis
It is recommended to use the drug in a daily dose of 2.5-5 mg/kg/day, divided into 2 doses per day for 8 weeks. If after use in the initial dose of 2.5 mg/kg/day a positive clinical effect is not observed within 2 weeks, the dose can be quickly increased to the maximum - 5 mg/kg/day. In especially severe cases, a rapid therapeutic effect can be achieved by starting treatment with a dose of 5 mg/kg/day. After achieving a positive clinical effect, the dose of the drug should be gradually reduced and, depending on the patient's condition, completely discontinue the use of Ekvoral. In case of probable relapse, a new course of treatment should be carried out.
children
The doses for children are the same as for adults. The capsules can be used in children over 6 years of age.
Elderly patients
Patients on dialysis
The dose of the drug should not be adjusted during and after dialysis.
Doses for some pathological conditions
Patients with cystic fibrosis of the lungs and diabetes require the use of the drug in higher doses. Cyclosporine causes neurotoxic effects in patients with hypocholesterolemia. Therefore, such patients are recommended to use the drug in lower doses (the dose should be reduced by 50% in the case of a 50% decrease in plasma cholesterol). Patients with excess body weight should be used in a dose based on ideal body weight, not actual.
The capsules should be swallowed whole, without chewing, with sufficient water; the drug should be taken regularly, every 12 hours, following the same schedule (before meals or between meals).
It is not recommended to drink grapefruit juice within 1 hour before and after taking the drug.
Monitoring cyclosporine blood levels
For monitoring cyclosporine levels in whole blood, specific monoclonal antibody methods are preferred, although high-performance liquid chromatography can also be used. Initial monitoring of patients immediately after transplantation can be performed using specific monoclonal antibodies or by simultaneous assessment with both specific and nonspecific monoclonal antibodies to ensure dosing that ensures adequate immunosuppression. In practice, cyclosporine concentrations are usually determined by RIA in whole blood samples at their lowest level, i.e. before the next dose is administered. Nonspecific monoclonal antibody RIA is used to determine the concentration of cyclosporine and its metabolites. The therapeutic range of the level has not been precisely established, the standard range is determined by the manufacturer supplying the diagnostic kits. Cyclosporine levels are determined during the first 2 weeks after transplantation 2 times a day, during 3-6 weeks - 1 time a week, during outpatient monitoring of the patient - 1 time in 2-3 months. When changing the dose, control is carried out no earlier than after 2 days. The therapeutic range in patients with autoimmune diseases is not unified, but individual. The concentration of cyclosporine in the blood is only one of many factors that determine the clinical condition of the patient, which are guided by the selection and correction of the dose of the drug.
Contraindication
Hypersensitivity to cyclosporine or other components of the drug; children under 6 years of age.
In non-transplant indications, the use of the drug is contraindicated in patients with severe renal (except nephrotic syndrome) or hepatic impairment, in patients with hypertension who show a poor response to appropriate treatment, in patients with uncontrolled infections (mainly herpes zoster with a risk of generalization of the disease and chickenpox), and in patients with malignant tumors. In rheumatoid arthritis, the drug should not be prescribed to patients under 18 years of age.
Concomitant treatment with drugs containing tacrolimus.
Side effects
Side effects, as a rule, depend on the dose, with its decrease, their severity is noted to decrease. The most common are hypertrichosis, tremor, renal dysfunction, arrhythmia (especially in patients after heart transplantation), liver dysfunction, fatigue, gingival hypertrophy, gastrointestinal disorders (lack of appetite, nausea, vomiting, abdominal pain, diarrhea), acute pain in the extremities (during the first week of treatment).
Cyclosporine nephrotoxicity can be of varying severity. It usually develops 2-3 months after transplantation and disappears after dose reduction. More pronounced nephrotoxicity with a rapid increase in blood urea and creatinine levels, which must be distinguished from tissue rejection, can be observed relatively soon after transplantation. Only in some patients can nephrotoxicity and rejection occur simultaneously, which are also eliminated by dose reduction. During cyclosporine treatment, chronic progressive nephrotoxicity may develop, manifested by significant impairment of renal function and their morphological changes (interstitial fibrosis with simultaneous tubular atrophy). Sometimes toxic tubulopathy, peritubular capillary congestion, arteriolopathy and focal interstitial fibrosis with simultaneous tubular atrophy are also detected. Symptoms of chronic nephrotoxicity occur as a result of prolonged use of the drug in high doses, as well as in the case of maintaining high levels of cyclosporine in the blood for a long time; moreover, symptoms of nephrotoxicity may become irreversible.
The development of hypertension (11.2-50%) depends on many factors: the patient's initial health status (kidney function, concomitant heart disease), concomitant medication (e.g. steroids, etc.). Therefore, it is difficult to determine the causal relationship between the development of hypertension and cyclosporine therapy. Increased blood pressure is observed in approximately 50% of patients after kidney transplantation and in most patients after heart transplantation.
Gingival hyperplasia has been reported in 4-16% of patients after transplantation. After discontinuation of cyclosporine treatment, regression or complete resolution of symptoms occurred within 1-2 months.
Hepatotoxicity (4%) has been reported with high doses of cyclosporine. Transient elevations of plasma bilirubin during the first months of treatment have been reported in 20% of renal transplant patients. Elevations of liver enzymes have been reported less frequently. Elevations of bilirubin and liver enzymes have been reported with cyclosporine concentrations exceeding 500 ng/mL and oral doses exceeding 17 mg/kg/day. The clinical significance of cyclosporine-induced hepatotoxicity is much less than that of nephrotoxicity.
Less commonly, headache, acne, allergic skin rashes, liver dysfunction (asymptomatic hepatotoxicity), hyperkalemia (confusion, arrhythmia, sensory disturbances and swelling of the extremities or face (lips), difficulty breathing, nervousness, fatigue and weakness, feeling of heaviness in the lower extremities), hyperuricemia, hypomagnesemia (convulsions), gastrointestinal disorders (lack of appetite, nausea, vomiting, loose stools), weight gain, edema, pancreatitis and malignancy (primarily of the skin) were noted. Arrhythmia is usually the first symptom of hyperkalemia, it can be detected by conducting an ECG examination. Hyperkalemia can sometimes be associated with hyperchloremic metabolic acidosis. In some cases, leukopenia and thrombocytopenia may be associated with microangiopathic hemolytic anemia, hyperlipidemia, lymphoproliferative disorders, and symptoms of encephalopathy (confusion, impaired vision, hearing, and mobility, decreased ability to recognize objects).
Malignancies and lymphoproliferative disorders (primarily lymphoma, 1-6%) have also been reported, but their incidence is similar to that seen in patients receiving conventional therapy. In addition, a large number of skin malignancies, including basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, and malignant melanoma, have been reported in patients treated with cyclosporine. Lymphoproliferative disorders in patients with psoriasis have been reported to resolve relatively quickly after discontinuation of therapy.
Special instructions
When cyclosporine is taken with food, the concentration of cyclosporine in the blood may change (decrease or increase) as a result of the effect on absorption. In some cases, absorption remains unchanged. To ensure a constant level of absorption during the use of cyclosporine, it is necessary to take the drug according to the same schedule (before meals, after meals or between meals).
High-fat meals induce hepatic lipase, resulting in increased blood concentrations of cyclosporine.
Flavonoids contained in grapefruit juice act on cytochrome CYP 3A, therefore it is not recommended to drink grapefruit juice 1 hour before and after taking the drug.
Drinking large amounts of alcohol may increase the blood levels of cyclosporine in kidney transplant patients.
Use during pregnancy or breastfeeding. Adequate and well-controlled studies on the use of the drug during pregnancy have not been conducted, therefore the drug can be used in pregnant women only if the expected benefit from its use outweighs the potential risk to the fetus.
Cyclosporine passes into breast milk, so breastfeeding should be discontinued when taking it.
Children. The drug is not recommended for use in children under 6 years of age. Patients in this age group are prescribed the drug in a different dosage form.
The ability to influence the reaction speed when driving vehicles or working with other mechanisms. Does not affect.
Interactions
Drugs that enhance the nephrotoxicity of cyclosporine
Aminoglycoside antibiotics, amphotericin B, ketoconazole, trimethoprim, melphalan, ciprofloxacin, colchicine, cephalosporin antibiotics, nonsteroidal anti-inflammatory drugs, ACE inhibitors, cimetidine, ranitidine, tacrolimus.
Drugs that enhance the effects of cyclosporine
Quinidine and its derivatives, theophylline and its derivatives, sodium valproate and its derivatives.
Drugs that increase the concentration of cyclosporine in the blood by inhibiting enzymes (mainly cytochrome CYP 3A) that carry out its metabolism and excretion
Oral contraceptives, corticosteroids, macrolide antibiotics (erythromycin, clarithromycin), imidazole and triazole antifungals (metronidazole, fluconazole, itraconazole, ketoconazole), H2-receptor antagonists (ranitidine, cimetidine), calcium antagonists (diltiazem, nifedipine, nimodipine, nicardipine, verapamil), fluoroquinolone, pristinamycin, doxycycline, propafenone, allopurinol, bromocriptine, danazol, metoclopramide.
With the simultaneous use of the above-mentioned drugs and cyclosporine, an increased incidence of side effects is observed, primarily nephrotoxicity.
Antiepileptic drugs (non-barbiturates - phenytoin, carbamazepine), barbiturates, benzodiazepines, butyrophenone and its derivatives, gestagens and estrogens, including their combinations, octreotide, ticlopidine, aminoglutethimide, phenothiazine, rifampicin, isoniazid, metamizole, trimethoprim and sulfamidine when administered intravenously, as well as drugs containing Hypericum perforatum (St. John's wort).
Cyclosporine should be used with caution in combination with the above-mentioned drugs. When using them, it is necessary to monitor the level of cyclosporine and creatinine in the blood plasma more often.
Drugs that increase the risk of myopathy when used concomitantly with cyclosporine
The risk of myopathy is increased when cyclosporine is taken concomitantly with colchicine and lovastatin. If muscle pain or weakness occurs with the combination of the above-mentioned drugs, it is necessary to determine the level of creatine kinase, since there is a risk of rhabdomyolysis and acute renal failure.
Given that nifedipine may cause gingival hypertrophy, it should not be used in patients whose gums have been affected during treatment with cyclosporine.
During treatment with cyclosporine, the effectiveness of vaccination may decrease, therefore, the use of live attenuated vaccines should be avoided during cyclosporine therapy.
Given that the drug can sometimes cause hyperkalemia or exacerbation of pre-existing hyperkalemia, the use of drugs containing potassium or contributing to an increase in plasma potassium levels should be carefully monitored. In this regard, it is recommended to monitor the level of potassium in the blood plasma, especially in patients with significant renal impairment.
When using cyclosporine/imipenem/cilastatin simultaneously, it is necessary to take into account the increase in cyclosporine concentration, which causes symptoms of neurotoxicity (confusion, tremor, agitation). Therefore, it is necessary to monitor the level of cyclosporine in the blood more often when using the above combination of drugs, as well as observe the general condition of the patient in order to prevent possible disorders of the central nervous system.
The risk of developing infectious and lymphoproliferative diseases increases with the simultaneous use of cyclosporine and other immunosuppressants. Therefore, cyclosporine should not be used simultaneously with the above-mentioned drugs, with the exception of corticosteroids (low doses of prednisone) and azathioprine. When taking cyclosporine and the above-mentioned drugs simultaneously, the dose of cyclosporine should be reduced accordingly. If it is necessary to use a combination of these drugs, the patient's condition should be monitored taking into account the above-mentioned risk.
Overdose
If the dose is exceeded, renal dysfunction may occur, which are transient in nature and disappear after discontinuation of the drug. Given the slow absorption of cyclosporine from capsules, in case of overdose it is recommended to induce vomiting no later than 2 hours after taking the drug, and to carry out symptomatic treatment.
Cyclosporine cannot be removed from the body by dialysis or hemoperfusion with activated charcoal. Symptoms of nephrotoxicity or hepatotoxicity in most cases disappear after reducing the dose of the drug.
Storage conditions
In the original packaging at a temperature not exceeding 30 °C. Do not freeze.
Temperatures above 40 °C may cause softening or deformation of the capsule. Relative humidity above 75% may cause softening, deformation of the capsule, etc., especially contamination of the gelatin with microorganisms.
