Cyclosporin

Pharmacological properties

the immunosuppressive effect of cyclosporin lies in 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 transcription level. As a result of the study of the mechanism of action, it was proved that cyclosporine acts as an inactive precursor of the drug. When combined with an intracellular binding protein (cyclophylline), it forms a complex that binds and inhibits the activity of intracellular phosphatase (calcineurin), which is necessary for activation of the cytoplasmic subunit of the nuclear factor of activated t-lymphocytes (nfat). the inactive cellular component of nfat cannot penetrate the cell nucleus, as a result of which the maturation of nfat and the transcription of the gene for IL-2 are blocked.

Equoral is a powerful immunosuppressive drug specific for T-lymphocytes. Equoral inhibits immune responses to an allograft, delayed-type hypersensitivity reactions, graft versus host GVHD, and T-cell-dependent antibody production. Cyclosporin acts on lymphocytes specifically and reversibly. Unlike cytostatic agents, it does not adversely affect hematopoiesis and phagocyte function. Patients receiving cyclosporine therapy are less prone to infections compared with patients receiving other immunosuppressive drugs.

Equoral promotes the engraftment of transplanted tissues, especially the skin, heart, kidneys, pancreas, bone marrow, and lungs.

The effectiveness of therapy has also been proven in the treatment of various conditions of proven or suspected autoimmune origin.

Pharmacokinetics After oral administration, cyclosporin 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 blood plasma after ingestion reaches a maximum after 1-6 hours. In some patients, a curve with two peaks may occur, which occurs due to accelerated absorption after eating or as a result of enterohepatic circulation. The presence of cytochrome CUR 3A in the intestinal wall causes a decrease in bioavailability due to the presystemic metabolism of cyclosporine. Cyclosporin absorption decreases due to diarrhea and increases with an increase in the rate of gastric emptying. The absorption of cyclosporine is largely affected by the length of the small intestine. Children reduce the dose necessary to maintain therapeutic concentration, as their small intestine lengthens with age. Cyclosporine absorption is reduced due to impaired intestinal function in the case of ileo-iliac anastomosis, Crohns disease, insufficient secretion of bile, enteritis caused by chemo- and radiation therapy of the intestine, with GVHD. The level of absorbed cyclosporine is lower among representatives of the Negroid race (about 30%) compared with representatives of the Caucasian race (about 39%). With an increased level of TG in blood plasma, bioavailability increases, and with an increased level of hemoglobin it decreases. Foods high in fat contribute to the induction of liver lipase, which increases the concentration of cyclosporin in the blood. In children, the bioavailability of the drug when taken orally increases significantly with the simultaneous use of alpha-tocopheryl-polyethylene glycol 100 (TRGS), a water-soluble form of vitamin E.

Approximately 33–37% of cyclosporine is contained in blood plasma, of which about 90% are associated with plasma proteins, primarily lipoproteins. 4–9% of cyclosporine is found in lymphocytes, 5–12% in granulocytes, and 41–58% in red blood cells. Cyclosporin belongs to lipophilic substances, so it accumulates in fats.In the liver, pancreas and kidneys, a greater amount of cyclosporine is detected than in blood plasma. Cyclosporin is also found in the reticuloendothelial and endocrine systems, is distributed in many organs and tissues of a person and passes into breast milk. The maximum concentration of cyclosporine is determined in adipose tissue and pancreas, a large amount of it is also found in the kidneys, liver, spleen, bone marrow, heart, aorta, skin, eye tissues and in the synovial fluid. The volume of distribution ranges from 3.5–13 l / kg body weight. In women, the volume of distribution is slightly higher than in men, due to the higher fat content in the body. In patients after kidney transplantation, the distribution volume is 4.5 l / kg, in patients with liver disease - 3.9 l / kg and in children with heart failure - 0.9 l / kg. The volume of distribution in children with diabetes is high - about 15 l / kg. The volume of distribution of cyclosporine in patients after bone marrow transplantation changes during treatment. At the beginning of therapy, its average value is 27.2 l / kg; after 3 weeks of treatment, its decrease to 21.8 l / kg is noted.

Cyclosporin in the human body is completely metabolized by the monooxygenase enzyme system, which is catalyzed by the cytochrome CYP 3A with the formation of a large number of primary metabolites. Enzymes involved in the biotransformation of cyclosporine are found mainly in the endoplasmic reticulum 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 its primary activity; with an increase in the polarity of metabolites, their immunosuppressive activity decreases accordingly. The distribution of cyclosporin metabolites in the tissues is uneven. Compared with blood plasma, higher concentrations are observed in adipose tissue and pancreas (40 times higher), and the highest - in the liver and kidneys (190 times higher). Although the toxicity of cyclosporin metabolites, which was detected during animal studies, is low, it determines the hepato- and nephrotoxicity of cyclosporin.

The simultaneous use of drugs that interact with the cytochrome P450 system can affect cyclosporin metabolism. Inducers of cytochrome P450 reduce the concentration of cyclosporine in blood plasma, while inhibitors of cytochrome P450 increase it. Grapefruit juice also affects the metabolism of cyclosporine, so its use is not recommended for patients.

Cyclosporine clearance ranges from 0.28-3 l / h / kg. Cyclosporin is excreted mainly with bile. The portion of cyclosporin that is excreted in the bile is reabsorbed. The elimination of cyclosporine from the blood is biphasic. Final t_½ Equoral drug ranges from 8-18 hours (an average of 8.4 hours).

Cyclosporine passes into breast milk. The concentrations of cyclosporine in breast milk were detected in the range of 16–263 ng / ml. A small amount of unchanged cyclosporine is excreted by the kidneys (0.1-6% of the dose). In patients with severe T burns_½ 1-2 hours. Smaller T_½ detected in patients with impaired liver and kidney function, children, the elderly and in patients with diabetes mellitus. Hemodialysis does not significantly affect cyclosporine clearance. In the dialysate, less than 1% of the dose of cyclosporine was detected. Plasmapheresis has a negligible effect on the cyclosporin clearance.

Indications

Transplantation

Transplantation of parenchymal organs

Prevention and treatment of tissue rejection after transplantation of a kidney, liver, heart, lung, pancreas, or after combined heart and lung transplantation.

Bone marrow transplantation

Prevention of rejection after bone marrow transplantation.

Prevention or treatment of a disease caused by GVHD.

Non-transplant indications

Endogenous uveitis

Active middle or posterior uveitis of non-infectious etiology, threatening vision, in cases where traditional therapy is ineffective or there is a risk of serious adverse reactions. Uveitis Behcet with repeated inflammation of the retina.

Nephrotic syndrome

Steroid-resistant and steroid-dependent nephrotic syndrome in adults and children as a result of glomerular nephropathy with minimal changes, focal and segmental glomerulosclerosis or membranous glomerulonephritis.

The drug Equoral can be used to achieve and maintain remission, as well as to maintain remission achieved by taking steroids, which allows you to stop taking them.

Rheumatoid arthritis

Treatment of severe highly active rheumatoid arthritis in patients if traditional therapy with slowly acting antirheumatic drugs is ineffective or impractical.

Psoriasis

Treatment of patients with severe psoriasis in whom conventional therapy has been ineffective or inappropriate.

Atopic dermatitis

Short-term treatment (8 weeks) for patients with severe atopic dermatitis, in whom conventional therapy was ineffective or inappropriate.

Application

The daily dose of equoral should be divided into two separate doses, which must be taken at intervals 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 desired target concentration. given the differences in bioavailability of different forms of cyclosporine for oral use, patients cannot be transferred from one form of the drug to another without proper control of the level of cyclosporin and creatinine in blood plasma and hell.

Transplantation of parenchymal organs

The use of Equoral should be started no later than 12 hours before surgery; the drug should be used in a dose of 10-15 mg / kg / day, divided into 2 doses (morning and evening). The indicated daily dose should be used for 1–2 weeks from the moment of surgery, then gradually reduce it 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 renal function.

If Equoral is used in combination with other immunosuppressants (for example, with GCS or other combinations), you can take Equoral in lower doses at the beginning of treatment (3-6 mg / kg / day, divided into 2 doses (morning and evening)).

Bone marrow transplantation

In most cases, iv infusion of cyclosporine is preferred; the recommended dose is 3-5 mg / kg / day. The specified dose is used immediately after transplantation for 2 weeks, and only after this should you start taking an oral maintenance dose of about 12.5 mg / kg / day. In case of gastrointestinal disorders, which may lead to a decrease in absorption, oral administration in higher doses or in / in the introduction of cyclosporine is indicated.

If the drug is taken orally at the beginning of treatment, the recommended dose of Equoral is 12.5-15 mg / kg / day; reception begins 1 day before transplantation and continues to be taken in a maintenance dose for 3-6 months. After this, the dose is gradually reduced for 1 year from the moment of transplantation and only after that the drug is stopped.

In some patients, after stopping the use of Equoral, GVHD occurs. The bodys response to repeated treatment is usually positive.To treat a mild chronic disease caused by GVHD, a low-dose drug is used.

Endogenous uveitis

The recommended initial dose is 5 mg / kg / day, which is divided into 2 doses and is used to achieve remission of active uveitis and increase visual acuity. In refractory cases, the dose can be temporarily increased to a maximum of 7 mg / kg / day.

If cyclosporine monotherapy is not enough to achieve remission or eliminate the acute inflammatory process, systemic corticosteroids can be used, for example, prednisone in a daily dose of 0.2-0.6 mg / kg body weight.

For maintenance treatment, the dose should be reduced to the minimum effective, not exceeding 5 mg / kg / day and applied until remission is achieved.

Nephrotic syndrome

If the patients kidney function, excluding the presence of proteinuria, is normal, it is recommended to use doses of 5 and 6 mg / kg / day, respectively, for achieving remission for adult patients and children over 6 years old. In case of impaired renal function, the initial dose should not exceed 2.5 mg / kg / day. In the case of insufficient effectiveness of cyclosporine monotherapy, especially in patients who are resistant to steroids, it is recommended to use the drug simultaneously with oral corticosteroids 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, treatment with cyclosporine should be discontinued.

The dose per os must be selected individually for each patient depending on the effectiveness of the drug (control of proteinuria) and its safety (primarily depending on the level of creatinine in blood plasma) in order to determine the minimum effective maintenance dose. However, the dose should not exceed 5 and 6 mg / kg / day in adult patients and children, respectively.

Rheumatoid arthritis

Initial therapy is recommended for 12 weeks. A dose of 2.5 mg / kg / day, divided into 2 doses (morning and evening), is recommended for use during the first 6 weeks. If the clinical effect of treatment is insufficient, the daily dose can be gradually increased in accordance with 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 is recommended, divided into 2 doses (morning and evening). If as a result of treatment for 1 month there is no improvement in the patients condition, the daily dose can be gradually increased; however, the dose should not exceed 5 mg / kg / day. In patients without signs of clinical improvement during 6 weeks of therapy, when taken at a dose of 5 mg / kg / day, treatment with Equoral should be discontinued. In patients whose condition requires rapid improvement, it is necessary to use 5 mg / kg / day as an initial dose. When a satisfactory therapeutic effect is achieved, drug treatment can be discontinued.

In case of recurrence of the disease, it is necessary to begin treatment with Equoral using an already determined effective dose.

However, some patients require ongoing 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, distributed in 2 doses for 8 weeks. If after application in an initial dose of 2.5 mg / kg / day, a positive clinical effect is not observed for 2 weeks, the dose can be quickly increased to a maximum of 5 mg / kg / day.In especially severe cases, a quick 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 patients condition, stop using Equoral. With a likely relapse, a new course of treatment is necessary.

Children

Doses for children correspond to doses for adult patients. Capsules can be used for children over 6 years old.

Elderly patients

Elderly patients are more likely to increase blood pressure and creatinine in blood plasma by more than 50% of the initial value after treatment for 3-4 months. Therefore, caution should be exercised when dosing and blood creatinine and cyclosporin levels should be monitored.

Dialysis patients

The dose of the drug should not be corrected during and after dialysis.

Doses for certain pathological conditions

Patients with cystic fibrosis of the lungs and diabetes need to use the drug in higher doses. Cyclosporin causes a neurotoxic effect in patients with hypocholesterolemia. Therefore, such patients are recommended to use the drug in reduced doses (the dose should be reduced by 50% in the case of a 50% decrease in the level of cholesterol in the blood plasma). Overweight patients should be used in a dose based on ideal body weight, not real.

Capsules must be swallowed whole, not chewed, washed down with enough water; the drug should be taken regularly, every 12 hours, adhering to one scheme (before meals or between meals).

Drinking grapefruit juice is not recommended for 1 hour before and after using the drug.

Blood Cyclosporin Control

To control cyclosporin levels in whole blood, preference is given to methods using specific monoclonal antibodies, although high performance liquid chromatography can also be used. Initial observation in patients immediately after transplantation can be carried out using specific monoclonal antibodies or by simultaneous assessment of both specific and non-specific monoclonal antibodies to ensure dosage that guarantees appropriate immunosuppression. In practice, the cyclosporin concentration is usually determined by the RIA method in samples of whole blood at its lowest level, that is, before the next dose is used. Using the RIA method using nonspecific monoclonal antibodies, the concentration of cyclosporin and its metabolites is determined. The therapeutic range of the level is not precisely established, the standard range is determined by the manufacturer who supplies the diagnostic kits. Cyclosporin levels are determined during the first 2 weeks after transplantation 2 times a day, for 3–6 weeks - 1 time per week, during outpatient monitoring of the patient - 1 time in 2-3 months. When changing the dose control is carried out no earlier than 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.

Contraindications

Hypersensitivity to cyclosporine or other components of the drug; children under the age of 6 years.

In the case of indications that are not related to transplantation, the use of the drug is contraindicated in patients with severe impaired renal function (with the exception of nephrotic syndrome) or in the liver, in patients with hypertension who have a mild reaction to the appropriate treatment, in patients with uncontrolled infections (in mainly shingles with a risk of generalization of the disease and chickenpox), as well as in patients with malignant tumors. In case of rheumatoid arthritis, the drug should not be prescribed to patients under the age of 18 years.

Concomitant treatment with drugs containing tacrolimus.

Side effects

Side effects, as a rule, depend on the dose, with its decrease, a decrease in their severity is noted.hypertrichosis, tremor, impaired renal function, ag (especially in patients after heart transplantation), impaired liver function, fatigue, gum hypertrophy, gastrointestinal disorders (lack of appetite, nausea, vomiting, abdominal pain, diarrhea), acute pain in the limbs (during the first week of treatment).

Nephrotoxicity of cyclosporine can be of varying severity. It usually develops 2–3 months after transplantation and disappears after a dose reduction. More pronounced nephrotoxicity with a rapid increase in the level of urea and creatinine in the blood, which must be distinguished from tissue rejection, can be noted after a relatively short time after transplantation. Only in some patients at the same time can nephrotoxicity and rejection be noted, which are also eliminated by lowering the dose. During treatment with cyclosporine, chronic progressive nephrotoxicity may develop, manifested by a significant impairment of renal function and their morphological changes (interstitial fibrosis with simultaneous tubular atrophy). Sometimes toxic tubulopathy, peritubular capillary stasis, arteriolopathy and focal interstitial fibrosis with simultaneous atrophy of the tubules are also detected. Symptoms of chronic nephrotoxicity occur due to prolonged use of the drug in high doses, as well as in the case of maintaining a high level of cyclosporine in the blood for a long time; and symptoms of nephrotoxicity may become irreversible.

The development of hypertension (11.2–50%) depends on many factors: the initial state of the patient’s health (state of kidney function, concomitant heart disease), concomitant use of medications (for example, steroids, etc.). Therefore, it is difficult to determine the causal relationship between the development of hypertension and cyclosporine therapy. An increase in blood pressure is noted in approximately 50% of patients after kidney transplantation and in most patients after heart transplantation.

In addition to nephrotoxicity and hypertension, the most common side effects include hypertrichosis and tremor. Tremor and hirsutism were detected in 21–55% of patients after transplantation of a kidney, liver, and heart.

Gingival hyperplasia was observed in 4–16% of patients after transplantation. After cessation of cyclosporine treatment, regression occurred or the symptoms completely disappeared after 1–2 months.

Hepatotoxicity (4%) was detected with high doses of cyclosporin. A transient increase in plasma bilirubin levels during the first months of treatment was observed in 20% of patients after kidney transplantation. An increase in the level of liver enzymes was not determined so often. An increase in the level of bilirubin and liver enzymes was noted at cyclosporine concentrations exceeding 500 ng / ml and oral doses above 17 mg / kg / day. The clinical significance of cyclosporin-induced hepatotoxicity is much less than the clinical significance of nephrotoxicity.

Headaches, acne, skin rashes of an allergic origin, impaired liver function (asymptomatic hepatotoxicity), hyperkalemia (confusion, arrhythmia, impaired sensitivity and swelling of the limbs or face (lips), shortness of breath, nervousness, fatigue and weakness, a feeling of heaviness in the lower extremities), hyperuricemia, hypomagnesemia (convulsions), gastrointestinal tract disorders (lack of appetite, nausea, vomiting, rare bowel movements), weight gain, edema, pancreatitis and malignancy (especially skin). Arrhythmia is usually the first symptom of hyperkalemia, it can be detected by ECG. Hyperkalemia can sometimes be associated with hyperchloremic metabolic acidosis.In some cases, leukopenia and thrombocytopenia can be associated with microangiopathic hemolytic anemia, hyperlipidemia, lymphoproliferative disorders, symptoms of encephalopathy (confusion, impaired vision, hearing, mobility, decreased ability to recognize objects).

The presence of malignant neoplasms and lymphoproliferative disorders (primarily lymphomas, 1–6%) was also detected, but their frequency was similar to that in patients receiving traditional therapy. In addition, during treatment with cyclosporine, a large number of skin malignancies were recorded, including basal cell carcinoma, epidermoid cancer, Kaposi’s sarcoma, keratoacanthomas, and malignant melanoma. With the development of lymphoproliferative disorders in patients with psoriasis, a rather rapid elimination of them after cessation of therapy was noted.

special instructions

In the case of taking cyclosporine with food, the concentration of cyclosporin 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, adhering to one scheme (before meals, after meals or between meals).

A high fat diet promotes the induction of liver lipase, resulting in an increase in the concentration of cyclosporin in the blood.

Flavonoids contained in grapefruit juice act on cytochrome CYP 3A, and therefore it is not recommended to drink grapefruit juice 1 hour before and after taking the drug.

Drinking large amounts of alcoholic beverages can increase blood cyclosporin levels in patients after kidney transplantation.

Use during pregnancy or lactation. Adequate and well-controlled studies regarding the use of the drug during pregnancy have not been carried out, therefore, pregnant women can use the drug only when the expected benefits of its use exceed the probable risk to the fetus.

Cyclosporine passes into breast milk, so if you take it, you should stop breast-feeding.

Children. The drug is not recommended for use in children under the age of 6 years. For patients of this age category, the drug is prescribed in a different dosage form.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Does not affect.

Interactions

Drugs that enhance cyclosporine nephrotoxicity

Aminoglycoside antibiotics, amphotericin B, ketoconazole, trimethoprim, melphalan, ciprofloxacin, colchicine, cephalosporin antibiotics, NSAIDs, ACE inhibitors, cimetidine, ranitidine, tacrolimus.

Cyclosporin-enhancing drugs

Quinidine and its derivatives, theophylline and its derivatives, sodium valproate and its derivatives.

Drugs that increase the concentration of cyclosporine in the blood due to inhibition of enzymes (mainly cytochrome CYP 3A), metabolizing and eliminating it

Oral contraceptives, corticosteroids, macrolide antibiotics (erythromycin, clarithromycin), imidazole and triazole antifungals (metronidazole, fluconazole, itraconazole, ketoconazole), N antagonists₂receptors (ranitidine, cimetidine), calcium antagonists (diltiazem, nifedipine, nimodipine, nicardipine, verapamil), fluoroquinolone, pristinamycin, doxycycline, propafenone, allopurinol, bromocriptine, danazole, metoclopramide.

With the simultaneous use of the above drugs and cyclosporine, an increase in the frequency of side effects, especially nephrotoxicity, is noted.

Drugs that reduce the concentration of cyclosporine in the blood due to the induction of enzymes, especially cytochrome CYP 3A, metabolizing and eliminating cyclosporin

Antiepileptic drugs (non-barbiturates - phenytoin, carbamazepine), barbiturates, benzodiazepines, butyrophenone and its derivatives, progestogens and estrogens, including their combinations, octreotide, ticlopidine, aminoglutethimide, phenothiazine, rifampicinimisoprimonidiazinazinazinazinazinazinazinazinazino as well as drugs containing Hypericum perforatum (Hypericum perforatum).

Caution is advised to use cyclosporine simultaneously with the aforementioned drugs. When using them, it is necessary to control the level of cyclosporin and creatinine in blood plasma more often.

Drugs that increase the risk of myopathy while using cyclosporine

With the simultaneous administration of cyclosporine with colchicine and lovastatin, the risk of developing myopathy increases. If, when using a combination of the above drugs, muscle pain or muscle weakness appears, it is necessary to determine the level of creatine kinase, since there is a risk of rhabdomyolysis and acute renal failure.

Given that nifedipine can cause gum hypertrophy, it should not be used in patients in whom the gums were affected during treatment with cyclosporine.

In the treatment of cyclosporine, vaccination efficacy may decrease, therefore, in the treatment of cyclosporine, the use of live attenuated vaccines should be avoided.

Given that the drug can sometimes cause hyperkalemia or an exacerbation of existing hyperkalemia, the use of drugs containing potassium or contributing to an increase in potassium in the blood plasma should be carefully monitored. In this regard, it is recommended to control the level of potassium in the blood plasma, especially in patients with significant impaired renal function.

With the simultaneous use of cyclosporine / imipenem / cilastatin preparations, it is necessary to take into account the increase in the concentration of cyclosporine, which is the cause of neurotoxicity symptoms (confusion, tremor, agitation). Therefore, it is necessary to more often monitor the level of cyclosporine in the blood when using the above combination of drugs, as well as to observe the general condition of the patient in order to prevent possible disorders of the central nervous system.

With the simultaneous use of cyclosporine and other immunosuppressants, the risk of developing infectious and lymphoproliferative diseases increases. Therefore, cyclosporine should not be used concurrently with the aforementioned drugs, with the exception of GCS (low doses of prednisone) and azathioprine. With the simultaneous administration of cyclosporine and the aforementioned drugs, it is necessary to accordingly reduce the dose of cyclosporin. If it is necessary to use a combination of these drugs, the patient should be monitored taking into account the above risk.

Overdose

If the dose is exceeded, there may be impaired renal function, which are transient in nature and disappear after discontinuation of the drug. taking into account the slow absorption of cyclosporine from the capsules, in case of an overdose, it is recommended to induce vomiting no later than 2 hours after taking the drug, and symptomatic treatment should be performed.

By dialysis or hemoperfusion using activated charcoal, cyclosporine cannot be removed from the body. Symptoms of nephrotoxicity or hepatotoxicity in most cases disappear after a dose reduction.

Storage conditions

In the original packaging at temperatures up to 30 ° C. do not freeze.

At temperatures above 40 ° C, softening or deformation of the capsule is possible. Relative humidity above 75% can cause softening, deformation of the capsule, etc., especially contamination of gelatin with microorganisms.