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.

Sandimmune (cyclosporine) concentrate for solution for infusion

Instructions for use:

SANDYMMUN®

Registration number:
P N008552 dated 06/29/2010.

Tradename:

Sandimmune®.

International Nonproprietary Name (INN):

cyclosporine.

Dosage form:

concentrate for the preparation of solution for infusion.

Compound.

1 ml of concentrate for infusion contains: active substance

- cyclosporine 50 mg,
excipients:
polyoxyethylene castor oil, ethanol 96%.

Description.

Transparent oily liquid of yellow-brown color (Note: “yellow-brown” means that the concentrate is no more intensely colored than the European Pharmacopoeia standard solution).

Pharmacotherapeutic group.

Immunosuppressive drug.

ATX Code:

L04AA01.

Pharmacological properties.
Pharmacodynamics.
Cyclosporine is a cyclic polypeptide consisting of 11 amino acids. Cyclosporine is a selective immunosuppressant that inhibits calcium neuron activation of lymphocytes in the G0 or G1 phase of the cell cycle. Thus, T-lymphocyte activation and, at the cellular level, antigen-dependent release of lymphokines, including interleukin 2 (T-lymphocyte growth factor), are prevented. Cyclosporine acts specifically and reversibly on lymphocytes. Unlike cytostatics, it does not suppress hematopoiesis and does not affect the function of phagocytes.

Cyclosporine increases the lifespan of allogeneic transplants of skin, heart, kidneys, pancreas, bone marrow, small intestine, and lungs. Cyclosporine also inhibits the development of cellular reactions against the allograft, delayed-type hypersensitivity skin reactions, experimental allergic encephalomyelitis, arthritis due to Freund's adjuvant, graft-versus-host disease (GVHD), and T-lymphocyte-dependent antibody formation. Sandimmune has been shown to be effective in human bone marrow and solid organ transplantation for the prevention and treatment of rejection and GVHD, as well as in the treatment of various conditions that are or may be considered autoimmune in nature.

Pharmacokinetics

. Cyclosporine is distributed mainly outside the bloodstream. In the blood, 33-47% of cyclosporine is found in plasma, 4-9% in lymphocytes, 5-12% in granulocytes and 41-58% in erythrocytes. Binding to plasma proteins (mainly lipoproteins) is approximately 90%.

Cyclosporine undergoes significant biotransformation in the liver by hydroxylation, resulting in the formation of approximately 15 metabolites. There is no one main metabolic pathway. The drug is excreted primarily in bile and only 6% of the administered oral dose is excreted in the urine (less than 1% is excreted unchanged).

The terminal half-life of cyclosporine is highly variable, depending on the determination method used and the patient population studied. The terminal half-life with unchanged liver function is approximately 6.3 hours; in patients with severe liver disease - approximately 20.4 hours.

Pharmacokinetics in special groups of patients.

Patients with impaired renal function. In patients with end-stage renal failure, after intravenous administration of the drug at a dose of 3.5 mg/kg over 4 hours, mean peak blood concentrations of cyclosporine were approximately 1800 ng/ml (range 1536 to 2331 ng/ml). The mean volume of distribution was 3.49 L/kg and systemic clearance was 0.369 L/h/kg, which is approximately two-thirds of the mean systemic clearance (0.56 L/h/kg) in patients with normal renal function. Impaired renal function does not have a significant effect on the elimination of cyclosporine, since cyclosporine is excreted mainly in bile through the intestines.

Patients with impaired liver function.

In patients with biopsy-proven cirrhosis and severe liver dysfunction, the half-life of the drug averaged 20.4 hours (range 10.8 to 48.0 hours) compared with 7.4 to 11.0 hours in healthy subjects.

Indications for use.

Solid organ transplantation:

• prevention of rejection of allografts: kidney, liver, heart, combined cardiopulmonary transplant, lungs or pancreas (in cases where oral administration of the drug is impossible, or absorption of the drug when administered orally is impaired due to diseases of the gastrointestinal tract (GIT));

• prevention of transplant rejection in patients who have previously received other immunosuppressive therapy.

Bone marrow transplantation:

• prevention of graft rejection after bone marrow transplantation;

• prevention and treatment of graft-versus-host disease (GVHD) (in cases where oral administration of the drug is impossible, or absorption of the drug when taken orally is impaired due to gastrointestinal diseases).

Contraindications

. Hypersensitivity to cyclosporine or any other component of the drug, including polyoxyethylene castor oil.

Carefully.

Sandimmun® should be prescribed with caution to patients aged > 65 years, patients with hyperlipidemia, hyperkalemia, hypomagnesemia and hyperuricemia, impaired liver function, arterial hypertension, as well as epilepsy, alcoholism.

Use during pregnancy, breastfeeding and in women of childbearing age.

No special recommendations have been developed for women of childbearing age. The amount of data on the effect of the drug on fertility is limited. In experimental studies of the pathological effects of the drug

no effect on fertility was detected. Experimental studies have shown the toxic effect of the drug on reproductive function. There is little data on the use of Sandimmune® in pregnant women. Pregnant women who have undergone organ transplantation and are receiving immunosuppressive treatment with cyclosporine or combination therapy that includes cyclosporine are at risk of preterm birth (occurring before 37 weeks' gestation). There is a limited number of observations of children (up to the age of 7 years) exposed to cyclosporine during fetal development. Kidney function and blood pressure were normal in these children. However, since there is not enough reliable data on the use of the drug in pregnant women, Sandimmun® should not be used during pregnancy, unless the expected benefit to the mother justifies the potential risk to the fetus. In pregnant women, it is also necessary to take into account the ethanol content of the drug.

Cyclosporine passes into breast milk. Mothers receiving Sandimmune® should not breastfeed. Due to the risk of severe adverse reactions in newborns whose mothers are taking Sandimmun®, it is necessary to either refrain from breastfeeding or from taking the drug, taking into account how important drug therapy is for the mother. It is also necessary to remember the ethanol content in the preparation.

Method of administration and dose.

The drug is administered intravenously (IV) by drip.

The dosage regimen is set individually. The choice of the initial dose, as well as the correction of the dosage regimen during treatment, is carried out taking into account clinical and laboratory parameters, as well as the values ​​of the concentration of cyclosporine in the blood plasma, determined daily.

For adults undergoing a bone marrow transplant on the day before the transplant, Sandimmune is administered intravenously at a dose of 3-5 mg/kg/day. Administration of this dose is continued during the immediate post-transplant period for up to 2 weeks; then switch to maintenance therapy with oral forms of cyclosporine. In cases where drug absorption is impaired, it may be necessary to continue intravenous administration. Some patients may develop GVHD after discontinuation of cyclosporine therapy, the manifestations of which are usually well controlled when the drug is resumed. In such cases, an initial loading dose of the drug taken orally equal to 10-12.5 mg/kg body weight is prescribed, followed by its subsequent reduction to a maintenance, previously effective dose. Low doses of cyclosporine should be used to treat moderate manifestations of chronic GVHD. For solid organ transplantation, Sandimmune® concentrate for intravenous infusion is prescribed 12 hours before surgery, in a single dose of 3-5 mg/kg body weight. For 1-2 weeks after surgery, the drug is prescribed daily at the same dose, after which the dose is gradually reduced, under the control of the concentration of cyclosporine in the blood, to a maintenance dose of 0.7-2 mg/kg body weight in 2 doses.

When Sandimmune is prescribed in combination with glucocorticosteroids or other immunosuppressants, smaller doses of Sandimmune can be used.

Use in special groups of patients. Use in patients with impaired renal function.

The drug is almost not excreted by the kidneys and its pharmacokinetics does not depend on renal function. However, given the nephrotoxicity of cyclosporine, renal function should be monitored.

Use in patients with impaired liver function.

The drug is actively metabolized in the liver. The half-life ranges from 6.3 hours in healthy volunteers to 12.4 hours in patients with severe liver disease. To maintain the recommended blood concentration of cyclosporine in patients with severe liver dysfunction, a dose reduction may be required.

Use in children

.

Experience in children is limited. Children over 1 year of age who received standard doses of the drug tolerated the therapy well. According to several studies, children tolerated well even higher doses of mg/kg/day than those indicated for adults. In pediatric practice, Sandimmune is used at a dose of 3-5 mg/kg/day; The dosage regimen is the same as for adult patients.

Use in elderly patients

(>65 years). Experience with the use of Sandimmune in elderly patients is limited. elderly patients is limited, however, the use of standard adult doses of the drug is usually well tolerated.

In clinical studies studying the use of the drug Sandimmune® in patients with rheumatoid arthritis, it was noted that patients over 65 years of age were more likely to experience episodes of systolic arterial hypertension, in addition, they were more likely to have an increase in plasma creatinine concentration (>50%) after 3 -4 months of taking the drug.

According to other studies, the tolerability of cyclosporine does not differ between older and younger patients.

In elderly patients, it is recommended to use Sandimmune® with caution, choosing the lower limit of the dosage range, taking into account the higher risk of developing liver, kidney, and heart failure in these patients, as well as the higher likelihood of concomitant diseases and corresponding concomitant therapy.

Rules for the preparation and administration of infusion solution.

The concentrate should be diluted in a ratio of 1:20-1:100 with a 0.9% sodium chloride solution or a 5% dextrose solution and administered over approximately 2-6 hours. The unused prepared solution should be discarded after 24 hours. It is advisable to use glass containers to prepare the infusion solution. Plastic vials may only be used if they comply with the requirements for “plastic blood containers” of the European Pharmacopoeia. Polyoxyethylene castor oil contained in the concentrate may cause phthalate release from the polyvinyl chloride. Containers and their stoppers must not contain silicone oil or fatty components.

Side effect

.

The main adverse events associated with the drug and observed in clinical studies are impaired renal function, tremor, hirsutism, increased blood pressure, diarrhea, anorexia, nausea and vomiting. Many side effects associated with cyclosporine are dose-dependent and reversible with dose reduction. The spectrum of side effects is generally the same across different indications, although the frequency and severity of side effects may vary. In transplant patients, due to the higher dose and longer duration of treatment, side effects are more common and usually more severe than in patients with other indications.

Cases of anaphylactoid reactions have been reported with intravenous administration of cyclosporine.

In patients receiving immunosuppressive treatment with cyclosporine or combination therapy including cyclosporine, the risk of developing local and generalized infections (viral, bacterial, fungal etiology) and parasitic infestations increases. It is also possible to exacerbate pre-existing infectious diseases and reactivate a polyomavirus infection, leading to the development of polyomavirus nephropathy or JCvirus, which contributes to the development of multifocal leukoencephalopathy. Severe and/or fatal outcomes have been reported.

Patients receiving immunosuppressive treatment with cyclosporine or combination therapy that includes cyclosporine have an increased risk of developing lymphomas, lymphoproliferative diseases and malignancies, especially of the skin. The incidence of malignant neoplasms increases with increasing intensity and duration of immunosuppressive therapy.

The incidence of adverse events was assessed as follows: occurring “very often” (≥1/10), “often” (≥1/100; <1/10), “occasionally” (≥1/1000; <1/100), "rarely"; (≥1/10000; <1/1000), “very rare”; (<1/10000), including individual messages.

Within each group, identified by frequency of occurrence, adverse events are distributed in decreasing order, starting with the most common. Blood and lymphatic system disorders:

often - leukopenia.

Metabolic and nutritional disorders:

very often - anorexia, hyperglycemia.

Nervous system disorders: very often - tremor, headache; often - convulsions, paresthesia.

Vascular disorders:

very often - increased blood pressure, often - hyperemia.
Disorders of the digestive system:
very often - nausea, vomiting, abdominal discomfort, diarrhea, gum hyperplasia, often - gastric and duodenal ulcers.

Disorders of the hepato-biliary system:

often - hepatotoxicity.

Disorders of the skin and subcutaneous tissues:

very often - hirsutism, often - acne, rash.
Renal and urinary tract disorders:
very often - renal dysfunction (see "Special Instructions").

Disorders of the reproductive system and mammary glands:

rarely - menstrual irregularities.
General disorders:
often - fever, swelling.

Adverse events based on post-marketing observations (frequency unknown)

The following adverse events were identified during post-marketing surveillance through spontaneous reports and publications.
Since the reports were received voluntarily and the size of the population in which they were recorded is unknown, it is impossible to estimate the frequency of their occurrence. Within each group, adverse events are distributed in order of decreasing importance. Blood and lymphatic system disorders:
thrombotic microangiopathy, hemolytic-uremic syndrome, thrombocytopenic purpura, anemia, thrombocytopenia.

Metabolic and nutritional disorders:

hyperlipidemia, hyperuricemia, hyperkalemia, hypomagnesemia.

Nervous system disorders:

encephalopathy, including posterior reversible encephalopathy syndrome, and its symptoms such as convulsions, lethargy, disorientation, slow reactions, agitation, insomnia, visual disturbances, cortical blindness, coma, paresis, cerebellar ataxia, papilledema, including the optic nipple, secondary to benign intracranial hypertension, peripheral polyneuropathy, migraine.

Digestive system disorders:

acute pancreatitis.

Disorders of the hepato-biliary system:

hepatotoxicity and liver damage, including cholestasis, jaundice, hepatitis and liver dysfunction, sometimes fatal.

Disorders of the skin and subcutaneous tissues:

hypertrichosis.

Musculoskeletal and connective tissue disorders:

myopathy muscle spasms, myalgia, muscle weakness.

Disorders of the reproductive system and mammary glands:

gynecomastia.

Common disorders:

fatigue, weight gain.

Description of some adverse events.

Hepatotoxicity and liver damage.

In post-marketing surveillance, there have been isolated case reports of cyclosporine hepatotoxicity and liver injury resulting in cholestasis, jaundice, hepatitis and liver failure. In most cases, reports concerned patients with severe concomitant diseases and other predisposing factors, such as infectious complications, concomitant use of drugs that have a hepatotoxic effect. In some cases, mainly in transplant patients, these side effects have been fatal.

Acute and chronic nephrotoxicity.

Patients treated with calcineurin inhibitors (CNIs), including cyclosporine, and treatment regimens containing cyclosporine are at increased risk of acute or chronic nephrotoxicity. Clinical studies and post-marketing surveillance data indicate that cases of acute nephrotoxicity were associated with hyperkalemia, hypomagnesemia and hyperuricemia. In cases of chronic nephrotoxicity reported, morphological signs of arteriolar hyalinosis, tubular atrophy and interstitial fibrosis were noted.

If any of the side effects indicated in the instructions get worse, or you notice any other side effects not listed in the instructions, tell your doctor.

Overdose.
Symptoms:
Available experience with acute overdoses of cyclosporine is limited.
When cyclosporine was taken orally at a dose of up to 10 g (about 150 mg/kg), in most cases mild clinical manifestations were observed, such as vomiting, dizziness, headache, and tachycardia. In some cases, reversible impairment of moderate renal function was observed. However, with accidental parenteral overdose of cyclosporine in premature infants in the neonatal period, the development of severe toxic complications has been reported. Treatment:
symptomatic therapy, there is no specific antidote. During the first 2 hours after oral administration, the drug can be removed from the body by inducing vomiting or by gastric lavage. Cyclosporine is practically not excreted during hemodialysis and hemoperfusion using activated charcoal.

Drug interactions and other forms of interaction.
Interaction with drugs
. Listed below are drugs for which interaction with cyclosporine is confirmed and clinically significant.

Combinations with cyclosporine not recommended for use.

Vaccinations may be less effective during treatment with cyclosporine. The use of live attenuated vaccines should be avoided.

Combinations with cyclosporine requiring caution.

Caution should be exercised when using cyclosporine together with potassium-sparing drugs (potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists) or drugs containing potassium, as when used simultaneously with cyclosporine, severe hyperkalemia may develop.

With simultaneous use of cyclosporine and lercanidipine, there is an increase in lercanidipine AUC by 3 times and an increase in cyclosporine AUC by 21%. Caution should be exercised when using cyclosporine and lercanidipine in combination. Cyclosporine is a highly active P-glycoprotein (Pgp) inhibitor. As a result, when administered concomitantly, it may increase the serum concentrations of drugs that are Pgp substrates, such as aliskiren. When iclosporin and aliskiren are taken together, the Cmax of aliskiren increases by approximately 2.5 times, and the aAUC of aliskiren increases by 5 times. However, the pharmacokinetics of cyclosporine does not change significantly. Therefore, caution should be exercised when cyclosporine and aliskiren are used in combination.

Drugs that reduce or increase the concentration of cyclosporine.

Various agents are known to decrease and increase cyclosporine plasma or whole blood levels by inhibiting or inducing isoenzymes involved in cyclosporine metabolism, particularly CYP3A4. If such interactions in post-transplant patients cannot be avoided, frequent regular monitoring of cyclosporine concentrations and, if necessary, correction are necessary, which is especially important when prescribing or discontinuing a drug that interacts with cyclosporine.

Drugs that reduce the concentration of cyclosporine: barbiturates, carbamazepine, oxcarbazepine, phenytoin; nafcillin, sulfadimidine when administered intravenously; rifampicin; octreotide; probucol; orlistat; preparations containing St. John's wort (Hypericumperforatum); ticlopidine, terbinafine, sulfinpyrazone, bosentan.

Drugs that increase the concentration of cyclosporine:

macrolide antibiotics (eg, erythromycin, azithromycin and clarithromycin); ketoconazole, fluconazole, itraconazole, voriconazole; diltiazem, nicardipine, verapamil; metoclopramide; oral contraceptives; danazol; methylprednisolone (high doses); allopurinol; amiodarone; cholic acid and its derivatives; protease inhibitors, imatinib, colchicine, nefadazone.

Other significant interactions.

Food interactions.

There are reports that grapefruit juice increases the bioavailability of cyclosporine.
Interactions leading to potential increased nephrotoxicity.
When used simultaneously with drugs that increase the nephrotoxicity of cyclosporine, regular monitoring of renal function (especially plasma creatinine concentrations) is necessary. If significant renal impairment is detected, it is necessary to adjust the dose of the drug combined with cyclosporine or prescribe alternative therapy. Nonsteroidal anti-inflammatory drugs with a pronounced first-pass effect through the liver (for example, diclofenac) should be prescribed in lower doses than in patients not receiving cyclosporine. There are isolated reports that post-transplant patients experienced severe but transient renal dysfunction (with increased plasma creatinine concentrations) when fibric acid derivatives (eg, fenofibrates, bezofibrates) were used concomitantly with cyclosporine. In these patients, constant monitoring of renal function is necessary. In case of significant deterioration, combined use should be discontinued.

Interactions leading to gingival hyperplasia.

The combined use of nifedipine and cyclosporine may lead to more severe gingival hyperplasia than with cyclosporine monotherapy. Nifedipine should be avoided in patients who have developed gingival hyperplasia as a side effect of cyclosporine therapy.

Combinations that increase the concentration of other drugs.

Since cyclosporine is an inhibitor of the CYP3A4 isoenzyme and the membrane transporter of P-glycoprotein molecules, when used simultaneously with it, it is possible to increase the concentration of drugs that are substrates of the CYP3A4 isoenzyme and/or the membrane transporter of P-glycoprotein. Cyclosporine may reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins) and etoposide.

Several cases of severe glycoside toxicity have been reported within a few days of starting cyclosporine treatment in patients receiving digoxin. There are also reports that cyclosporine may enhance the toxic effects of colchicine, such as the development of myopathy or neuropathy, especially in patients with impaired renal function. When cyclosporine is used concomitantly with digoxin or colchicine, careful clinical monitoring is necessary to promptly identify the toxic effects of these drugs and to decide whether to reduce the dose or discontinue treatment.

When using cyclosporine in clinical practice, as well as according to the literature, cases of muscle toxicity, including muscle pain, weakness, myositis and rhabdomyolysis, have been reported during the simultaneous use of cyclosporine with lovastatin, simvastatin, atorvastatin, pravastatin and, in rare cases, with fluvastatin . If it is necessary to use the above drugs simultaneously with cyclosporine, it is necessary to reduce their dose. Statin therapy should be temporarily discontinued or discontinued in patients with symptoms of myopathy, as well as in patients with predisposition factors for severe renal impairment, including renal failure secondary to rhabdomyolysis. If digoxin, colchicine, HMG-CoA reductase inhibitors (statins) must be taken together with cyclosporine, patients should be carefully examined for the earliest possible detection of toxic effects of the drugs, which will require a dose reduction or discontinuation of the drugs.

An increase in creatinine concentrations was observed in studies that examined the coadministration of everolimus or sirolimus with high-dose cyclosporine microemulsion. This effect is often reversible after reducing the dose of cyclosporine. Everolimus and sirolimus have little effect on the pharmacokinetic parameters of cyclosporine. The combined use of cyclosporine with everolimus or sirolimus leads to a significant increase in the concentration of the latter in the blood plasma.

Concomitant use of cyclosporine and bosentan in healthy volunteers resulted in a twofold increase in bosentan exposure and a 35% decrease in cyclosporine exposure. Long-term concomitant use of ambrisentan and cyclosporine in healthy volunteers caused a twofold increase in ambrisentan exposure, while cyclosporine exposure increased slightly (by 10%). Significantly increased exposure to anthracycline antibiotics (eg, doxorubicin, mitoxantrone, daunorubicin) in patients with cancer receiving intravenous anthracycline antibiotics and very high doses of cyclosporine.

Special instructions.

Sandimmune should only be used by physicians experienced in administering immunosuppressive therapy and able to provide adequate patient monitoring, including regular complete physical examination, blood pressure measurement, and serum creatinine concentration monitoring. Monitoring of transplant patients receiving the drug should be carried out only in institutions that have trained medical personnel and adequate laboratory resources.

It should be borne in mind that when using cyclosporine, as well as other immunosuppressants, the risk of developing lymphomas and other malignant neoplasms, most often of the skin, increases. The increased risk of developing this complication is related more to the strength and duration of immunosuppression than to the use of a specific drug. Therefore, caution should be exercised when using combination immunosuppressive regimens, keeping in mind the potential for the development of lymphoproliferative diseases and solid organ tumors, sometimes leading to death.

Given the potential risk of developing skin malignancies, patients receiving cyclosporine treatment should avoid excessive exposure to direct sunlight.

The use of cyclosporine, like other immunosuppressants, predisposes to the development of various bacterial, fungal, parasitic and viral infections, often involving opportunistic pathogens. In patients treated with cyclosporine, reactivation of polyomavirus infection from a latent state was observed, leading to the development of polyomavirus nephropathy (especially associated with BK virus) or multifocal leukoencephalopathy caused by JC virus. These conditions are caused by a high overall load of immunosuppressive drugs. The development of such conditions should be taken into account in the differential diagnosis of the causes of renal and nervous system dysfunction in patients receiving immunosuppressive therapy.

Considering the potential danger of these infections for the patient’s life, an effective system of preventive and therapeutic measures should be used, especially in cases of long-term use of combined immunosuppressive treatment.

During the first few weeks of Sandimmune therapy, a common and potentially dangerous complication may occur: increased serum creatinine and urea levels. These functional changes are reversible and dose-dependent, normalizing with dose reduction. 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 chronic rejection.

Sandimmune may also cause a dose-dependent, reversible increase in serum bilirubin and, rarely, liver enzymes. In these cases, careful monitoring of renal and liver function parameters is required. If these indicators deviate from the norm, a dose reduction may be required.

In elderly patients, renal function should be especially carefully monitored.

Measuring the concentration of cyclosporine in the blood.

Routine monitoring of cyclosporine blood levels is an important safety monitoring mechanism. To monitor the concentration of cyclosporine in whole blood, it is preferable to use specific monoclonal antibodies (measurement of the amount of unchanged drug).

A high-performance liquid chromatography (HPLC) method can be used, which also measures the unchanged substance content. If plasma or serum is used, standard separation procedures (time and temperature) should be followed. For initial monitoring of cyclosporine concentrations in liver transplant patients, both specific monoclonal antibodies and parallel determinations using specific and nonspecific monoclonal antibodies should be used to achieve a dose that provides adequate immunosuppression.

It should be remembered that the concentration of cyclosporine in whole blood plasma or serum is only one of many factors characterizing the clinical condition of the patient. The results of determining the concentration of cyclosporine are only one of the factors determining the dosage regimen, and are considered in relation to various clinical and laboratory indicators. Blood pressure (BP) control.

During treatment with Sandimmune, regular blood pressure monitoring is indicated; if blood pressure increases, adequate antihypertensive therapy should be prescribed. Preference should be given to antihypertensive drugs that do not affect the pharmacokinetics of cyclosporine, such as isradipine.

Since in rare cases Sandimmune causes minor reversible hyperlipidemia, it is recommended to determine blood lipid concentrations before treatment and one month after the start of therapy. If lipid concentrations increase, consideration should be given to limiting dietary fat intake and, if necessary, reducing the dose of Sandimmune.

Cyclosporine increases the risk of hyperkalemia, especially in patients with impaired renal function. Caution should also be exercised when cyclosporine is used concomitantly with potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists and potassium-containing drugs, as well as when using a potassium-enriched diet. In these cases, monitoring the concentration of potassium in the blood is recommended.

Cyclosporine increases the excretion of magnesium from the body, which can lead to clinically significant hypomagnesemia, especially in the peritransplant period. In this regard, it is recommended to monitor the concentration of magnesium in the blood during the peritransplantation period, especially when neurological symptoms appear. If necessary, magnesium supplements are prescribed.

It is recommended to monitor serum uric acid concentrations, especially in patients with pre-existing hyperuricemia.

Live attenuated vaccines.

During treatment with Sandimmune®, vaccination may be less effective. The use of live attenuated vaccines should be avoided.

Ethanol.

When using the drug Sandimmune® in pregnant and lactating women, in patients with liver diseases, epilepsy, alcoholism, as well as in children, it is necessary to remember the ethanol content of the drug.

Impact on the ability to perform potentially hazardous activities that require increased attention and quick reactions (driving a car, working with moving mechanisms, etc.)

Some side effects of Sandimmun®, including dizziness or visual disturbances, may adversely affect the ability to drive vehicles and perform potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Release forms.

Concentrate for the preparation of solution for infusion 50 mg/ml in ampoules of 1 ml. 10 ampoules along with instructions for use are packed in a cardboard box.

Storage conditions.

At a temperature not higher than 30°C. Keep out of the reach of children. List B.

Shelf life.

4 years. Do not use after the expiration date indicated on the package.

Conditions for dispensing from pharmacies.

On prescription.

, Switzerland.

www.novartis.ru

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.

Not everything is so simple: possible problems when using monoclonal antibodies

Monoclonal antibody preparations have been used in rheumatological practice for quite some time. However, they are not prescribed to everyone - not to every first or even every second patient. The main limitation that doctors and patients face is the truly “exorbitant” cost of drugs in this group. Rheumatic diseases cannot be cured in a week or a month - they require many years (or even lifelong) use of therapy. Therefore, when selecting a drug, not only its effectiveness is important, but also its price.

For example, one pack of methotrexate costs approximately 200 rubles. The price of a package of infliximab is about 43 thousand rubles. The difference is obvious. For a year of treatment with methotrexate, even at the maximum dosage, the patient will spend 1–2 thousand rubles on the medicine (depending on the manufacturer, treatment regimen and the cost of the drug in local pharmacies). The price of annual therapy with infliximab is approximately 700 thousand rubles. It is clear that only a very limited group of patients will be able to provide themselves with this medicine.

Therefore, treatment of rheumatic diseases is carried out according to strict algorithms. If a pathology is detected, the patient is prescribed a basic drug. For example, for rheumatoid arthritis, methotrexate will most likely be the main drug. Doctors will add monoclonal antibodies to the standard treatment regimen only in exceptional cases. In Russia, they are considered reserve drugs—additional drugs that should be “left for later,” even despite their high effectiveness. So, if the severity of symptoms does not decrease for a long time (at least 6 months!), a biological drug can be added to methotrexate. Basic therapy is not canceled.

If the disease is initially highly active, progresses rapidly and is accompanied by extra-articular complications, then the patient can immediately be prescribed a combination treatment with basic drugs and monoclonal antibodies. This is due to the fact that biological drugs work best in the “acute period”, when the severity of symptoms is maximum. In addition, the effect of their use is observed faster. Treatment with infliximab produces results within 2–4 weeks, while methotrexate “starts working” only after several months.

The use of biological drugs is permissible in cases where the patient develops intolerance to basic drugs. Patients experience severe side effects from the medication, which further worsens their condition. The use of drugs with a different mechanism of action, including monoclonal antibodies, allows minimizing side effects [18].

The prescription and sale of biological drugs is controlled by the state. Many drugs from the group of monoclonal antibodies (infliximab, etanercept, tocilizumab, golimumab) are included in the “List of Vital and Essential Medicines”. In accordance with it, a list of medications is formed that are supplied to hospitals throughout Russia. Of course, biological drugs are not available in every hospital today. They are usually used in regional centers or specialized hospitals.

If they are unable to provide themselves with medications, patients receive disability and undergo therapy at state expense. This right is enshrined in the current “Program of State Guarantees for the Provision of Free Medical Care.” Treatment with biological drugs is provided for rheumatoid arthritis, ankylosing spondylitis, SLE, dermatopolymyositis, juvenile arthritis and other diseases. At the same time, doctors must determine clear indications for prescribing this or that drug. Getting expensive treatment is quite difficult - you need to undergo a full examination and collect documents. However, the provision of a state quota for many patients is the last chance for a full life.

Another difficulty that can be encountered when using biological drugs is adverse reactions. In parallel with the accumulation of data on the effectiveness of the use of drugs, new undesirable effects from their use are being identified. Most of these reactions are associated with the process of immunosuppression. By suppressing the activity of immune cells, monoclonal antibodies reduce the body's protective function. Anti-infective and anti-tumor immunity are primarily affected [18], [24].

Paradoxically, the use of new drugs against autoimmunity can cause acute autoimmune reactions. All biological drugs are protein molecules that are foreign to the body to one degree or another. Therefore, when therapeutic agents penetrate the patient’s body, the immune system can recognize them as antigens. An active immune response appears - antibodies are produced against the components of the drug.

Autoimmune syndromes provoked by drug administration are usually represented by vasculitis, SLE, antiphospholipid syndrome, and psoriasis [25]. Infliximab, which contains foreign murine fragments, is highly immunogenic. Fully “human” drugs provoke immunity less actively. But even with their use, there is a high risk of developing adverse autoimmune reactions. To eliminate these disorders, it is necessary to adjust the patient’s treatment regimen. It includes additional immunosuppressants that will suppress complications. This may be why combinations of biological drugs with disease-modifying drugs are often more effective than isolated therapy, even with the newest drugs [24].

Despite all possible difficulties, monoclonal antibodies have firmly entered the register of drugs used in rheumatology. The future of biologics and their place in rheumatology will depend on the results of many years of research that remain to be done. But even now we can say that the development of therapeutic monoclonal antibodies is an important step towards defeating autoimmune inflammation.

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.

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.

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Systemic rheumatic diseases are pathologies that arise due to the aggressive effects of the immune system on one’s own tissues. Their development is based on an error of the immune system, which incorrectly recognizes the normal components of the human body - autoantigens . Immune cells mistake them for foreign agents, which they see as a threat to the body. The protective function is activated, and healthy cells are “bombarded” by factors of the immune system - autoantibodies (Fig. 1).

The basics of normal immunity and the autoimmune process are presented in an accessible form on “Biomolecule” in the article “Immunity: the fight against strangers and... our own” [1].

Figure 1. Diagram of the structure of antibodies. Antibodies are immunoglobulin proteins that have two H chains (heavy) and two L chains (light). Each protein molecule contains specific Fab fragments . These regions are responsible for binding to the antigen , the “target” that the antibody acts on. The structure of the Fab fragment is very variable, which allows it to adapt to the active centers of the antigen - epitopes . Chemical bonds (ionic, hydrogen, hydrophobic) are formed between the antibody and antigen. The other end of the molecule, the Fc fragment , is responsible for binding the resulting immune complexes to the Fc receptor located on the membranes of immune cells (neutrophils, macrophages, mast cells). Activation of immune components triggers a “killing reaction” against a foreign antigen. Antibody-dependent cytotoxicity occurs in this way.

“Antibodies, structure and functions of immunoglobulins”

The theory of autoimmunity was formulated a century ago by the German researcher Paul Ehrlich. Over the following years, many autoimmune diseases have been described. These include rheumatoid arthritis, systemic lupus erythematosus (SLE), systemic scleroderma, myopathies, vasculitis and other pathologies.

You can read more about the mechanisms of development of some rheumatic diseases in the articles: “Systemic lupus erythematosus: a disease with a thousand faces” [2] and “Rheumatoid arthritis: change the composition of joints” [3].

Diseases associated with an autoimmune component are a serious problem in modern society. Their prevalence in the world population is approximately 5%. Diseases quickly become chronic, which reduces the quality of life of patients. Autoimmune pathologies often lead to disability in patients [1], [4].

In 2021, Biomolecule published a special project dedicated to autoimmune diseases.

Despite many years of searching for new ways of pharmacotherapy, modern medicine cannot offer treatment methods that directly affect the cause of autoimmunity. Doctors can only slow down the progression of the pathology and reduce the severity of the clinic - carry out pathogenetic and symptomatic treatment. For this purpose, basic therapy has been developed and has been used for many years. However, proven drugs do not always work as they should.

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.

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** The Drug Directory is intended for informational purposes only. For more complete information, please refer to the manufacturer's instructions. Do not self-medicate; Before starting to use Cyclosporine, you should consult a doctor. EUROLAB is not responsible for the consequences caused by the use of information posted on the portal. Any information on the site does not replace medical advice and cannot serve as a guarantee of the positive effect of the drug.

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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