Cyclosporine Sandoz - instructions for use, dose, side effects, contraindications

Excipients: d-alpha-tocopherol macrogol 1000 succinate - 300 mg, macrogol 400 - 200 mg, absolute ethanol - 200 mg, macrogol glyceryl hydroxy stearate (Cremophor RH 40) - 200 mg.

Description:

Transparent, colorless or yellowish viscous solution, free of foreign particles, with the smell of ethanol.

Pharmacotherapeutic group:Immunosuppressive remedy.

ATX: & nbsp

Pharmacodynamics:

Cyclosporin is a cyclic polypeptide consisting of 11 amino acids. Cyclosporin is a selective immunosuppressant that inhibits the activation of calcineurin lymphocytes and blocks the cell cycle of lymphocyte development in the G phase₀ or G₁. Thus, activation of T-lymphocytes is prevented and, at the cellular level, antigen-dependent release of lymphokines, including interleukin-2 (growth factor of T-lymphocytes). Cyclosporin acts on lymphocytes specifically and reversibly. Unlike cytostatics, it does not inhibit hemopoiesis and does not affect the function of phagocytes. Cyclosporin prolongs the lifespan of allogeneic grafts of the skin, heart, kidneys, pancreas, bone marrow, small intestine, lungs, and also inhibits the development of allograft cell responses, delayed type hypersensitivity skin reactions, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, graft versus host disease (GVHD), as well as T-lymphocyte-dependent antibody production.

Cyclosporine is successfully used in both HCV-infected and non-hepatitis C-infected patients with liver transplant.The positive effect of cyclosporine has also been confirmed for many autoimmune conditions.

Pharmacokinetics:

When taking the drug, stable absorption and almost complete absence of the effect of food intake are noted, which ensures low variability of pharmacokinetic parameters when applied in all dose ranges and provides a linear relationship between the dose and the effect of cyclosporine. Around-day biorhythms of the patient have a slight effect on the pharmacokinetic parameters of the drug.

The variability of the pharmacokinetics of cyclosporine in one and the same patient is low (10-22% in a patient with kidney transplantation), the correlation between bioavailability and concentration is more pronounced.

Suction

After oral administration of the drug, rapid absorption of cyclosporine is noted, the time to reach the maximum plasma concentration is 1.5-3.5 hours. Absorption is reduced after liver transplantation, with liver diseases or pathology of the gastrointestinal tract (diarrhea, vomiting, paralytic intestinal obstruction). Bioavailability is 30-60%, increases with increasing dose and duration of treatment.

Distribution

It is distributed mostly outside the bloodstream, with a volume distribution of 3.5 l / kg. The distribution in the blood depends on the concentration of cyclosporine: an average of 33-47% of cyclosporine is in plasma, 4-9% in lymphocytes, 5-12% in granulocytes and 41-58% in erythrocytes. With a high concentration of the drug increases the content of cyclosporine in leukocytes and erythrocytes. Relationship with plasma proteins 90%. Excreted in breast milk.

Metabolism

Cyclosporine is largely biotransformed in the liver by the cytochrome P-450 ZA system (isoenzyme CYP3A4), to a lesser extent in the gastrointestinal tract and kidneys, with the formation of approximately 15 metabolites. The main ways of metabolism are mono- and dihydroxylation and N-demethylation. The activity of these metabolites is not more than 10% of the activity of the starting material.

Excretion

The drug is excreted mainly with bile. 6% of the dose taken internally is excreted in the urine, 0.1% unchanged.

The values of the final half-life of cyclosporine are very variable, depend on the method used and the patient population. The final half-life is about 6.3 hours.

Pharmacokinetics in specific patient groups

Patients with impaired renal function

Impaired renal function does not have a clinically significant effect on the pharmacokinetics of the drug. In patients with kidney transplantation, the final elimination half-life is 2-25 hours (an average of 11 hours)

Patients with impaired liver function

In patients with impaired liver function, there is a slowdown in the excretion of cyclosporine from the body. In severe disorders, the terminal elimination half-life increases to 20.4 h.

Patients over the age of 65 years

There are no data on drug absorption in elderly patients. The distribution of cyclosporine is similar to that of patients aged less than 65 years.

Patients under the age of 18 years

On average, in patients under 18 years of age, cyclosporine is more rapidly excreted from the body than in adults, so higher doses of the drug may be used to achieve the desired plasma concentration of cyclosporine in this patient population.

Indications:

Transplantation

Transplantation of solid organs

- Prevention of rejection of allotransplant: kidney, liver, heart, combined cardiopulmonary graft, lung or pancreas;

- treatment of transplant rejection in patients who have previously received other immunosuppressants.

Bone marrow transplantation

- prevention of graft rejection after bone marrow transplantation;

- prevention and treatment of the disease "graft versus host" (BTGTX).

Indications, not related to transplantation

Endogenous uveitis

- Active, vision-threatening uveitis of the middle or posterior region of the eye of non-infectious etiology, when the previous therapy is not effective or leads to severe undesirable phenomena;

- uveitis of Behcet (with recurrent attacks of inflammation affecting the retina).

Psoriasis

- Psoriasis in the most severe forms, when traditional systemic therapy is not effective enough.

Nephrotic syndrome

- Steroid-dependent and steroid-resistant nephrotic syndrome in adults and children due to glomerular pathology such as minimal changes nephropathy, focal and segmental glomerulosclerosis, membranous glomerulonephritis, when previous treatment with cytostatics had no effect, or in cases of severe adverse effects, only with values of renal function not less than 50% of the norm.

- Cyclosporin Sandoz® can be used to induce and maintain remission. It can also be used to maintain remission caused by glucocorticosteroids, in order to ensure the possibility of their elimination.

Rheumatoid arthritis

- Treatment of severe forms of active rheumatoid arthritis, when the previous treatment with disease-modifying (basic) drugs had no effect or in cases of severe adverse events.

Atopic dermatitis

Severe forms of atopic dermatitis, when the previous treatment had no effect, or in cases of severe adverse events requiring systemic therapy.

Contraindications:

All indications

- Hypersensitivity to cyclosporine or any other component of the drug;

- breast-feeding.

For all indications, not related to transplantation

- impaired renal function (with the exception of nephrotic syndrome with moderate renal impairment);

uncontrolled arterial hypertension;

- infectious diseases resistant to appropriate therapy;

- malignant neoplasms, precancerous skin diseases.

Additionally for the treatment of psoriasis

- marked violation of liver function;

- treatment for a long time with methotrexate;

- simultaneous psoralen-ultraviolet therapy, ultraviolet therapy;

- simultaneous use of retinoids, methotrexate and other immunosuppressants.

Additionally for the treatment of atopic dermatitis

- psoralen-ultraviolet therapy, ultraviolet therapy.

Carefully:Caution should be used with varicella (currently or recently transferred, including recent contact with the patient), Varicella zoster (risk of generalization of the process) and other viral diseases, liver and / or kidney disease, alcoholism, epilepsy, craniocerebral trauma, brain diseases, hyperkalemia, hyperuricemia, arterial hypertension, malabsorption syndrome, in patients of children and the elderly.

Pregnancy and lactation:

In experimental studies, the toxic effect of the drug on reproductive function is shown.

Experience with the drug Cyclosporin Sandoz® in pregnant women is limited.In pregnant women who have undergone organ transplantation and are receiving immunosuppressive treatment with cyclosporine or combined therapy, including ciclosporin, there is a risk of premature delivery (with a gestation period of up to 37 weeks). There is a limited number of observations of children (until they reach the age of seven) exposed to cyclosporine during the period of intrauterine development. The kidney function and blood pressure in these children were normal. However, adequate and well-controlled studies have not been conducted in pregnant women, therefore, the drug should not be used during pregnancy, unless the expected benefit to the mother exceeds the potential risk to the fetus.

Ciclosporin penetrates into breast milk. When using the drug, you should stop breastfeeding.

Dosing and Administration:

Ciclosporin Sandoz® is used inside.

The following dosage ranges should be considered as recommendations only. To adjust the dose, the concentration of cyclosporin in the blood plasma is monitored by an enzyme immunoassay,with the use of monoclonal antibodies. Determining the concentration of cyclosporine in the blood plasma is not very important in patients receiving Cyclosporin Sandoz® according to indications other than transplantation. Exceptions are cases of sudden relapse of the disease and inefficiency of therapy, which may be associated with a decrease in the concentration of cyclosporine in the blood plasma as a result of a violation of adherence to treatment, impaired absorption in the gastrointestinal tract, or pharmacokinetic interaction.

Transplantation of solid organs

Treatment in adults should be started 12 hours before the operation at a dose of 10-14 mg / kg, divided into 2 doses. Within 1-2 weeks after the operation, the drug is prescribed daily, at the same dose, after which the dose is gradually reduced (weekly by 5%) under the control of the concentration of cyclosporine in the blood plasma to a maintenance dose of 2-6 mg / kg / day divided by 2 reception.

When cyclosporine is used in combination with other immunosuppressants or glucocorticosteroids, even in patients at high risk of developing rejection, the dose of cyclosporine can be reduced already at the initial stage(3-6 mg / kg per day in 2 divided doses) or adjusted during treatment, taking into account the concentration of cyclosporine in the blood plasma and the dynamics of safety indices (concentration of urea, creatinine in blood plasma, arterial pressure). The minimum concentration of cyclosporine in the blood plasma should be 100-400 ng / ml. The minimum dose of cyclosporine for kidney transplantation is 3-4 mg / kg day. At plasma concentrations below 100 ng / ml, the risk of rejection is higher.

In some patients, when combined with glucocorticosteroids, a month after the transplant operation, it is possible to use Cyclosporin Sandoz® in a maintenance dose of less than 5 mg / kg per day.

Bone marrow transplantation

Typically, a short-term combination of cyclosporine and methotrexate is recommended. Cyclosporin 1 to 2 days before transplantation intravenously at a dose of 2.5 to 5 mg / kg per day, then switch to oral maintenance therapy with cyclosporine at a daily dose of about 12.5 mg / kg divided into 2 divided doses. Supportive treatment continues for at least 3-6 months, after which the dose is gradually reduced until the drug is completely discontinued.Alternatively, cyclosporine monotherapy can be administered 1 to 3 days intravenously at a dose of 5 mg / kg per day, and then from 4 to 14 days 3 mg / kg per day or a combination of cyclosporine intravenously 3-5 mg / kg per day with glucocorticosteroids. As soon as the patient can take the medicine inside, it should be transferred to the oral administration of cyclosporine. In the presence of diseases of the gastrointestinal tract, leading to a reduction in absorption, higher doses may be required for oral administration of the drug or for switching to intravenous administration.

Graft-versus-host disease (GVHD)

Initial dose in adults is 12.5-15 mg / kg per day for 50 days. Then the dose of cyclosporine is gradually reduced (weekly by 5%) until the drug is completely discontinued within 20 weeks. In some patients, after the cessation of treatment, a relapse of the disease may occur, in which case the treatment should be resumed.

With endogenous uveitis for remission induction, the drug is used in doses of 5-10 mg / kg in 2 divided doses, until the signs of active inflammation disappear and visual acuity is improved. Duration of treatment is from 3 to 16 months. If treatment with cyclosporineis not effective enough to achieve a more rapid remission or in the acute phase, it is possible to combine with the systemic use of glucocorticosteroids in a dose: prednisolone 0.2-0.6 mg / kg / day or equivalent doses of other glucocorticosteroids. The recommended concentration of cyclosporine in the blood plasma is 100-150 ng / ml. There are single data on the use of cyclosporine in children older than 5 years, the experience of using the drug according to the indications in children under 5 years is absent.

Nephrotic syndrome

To remove symptoms of nephrotic syndrome, the recommended daily dose of cyclosporine in adults is 5 mg / kg for adults and 6 mg / kg for children over the age of 3 years (in 2 divided doses) with normal kidney function, except for cases of proteinuria. For patients with impaired renal function (creatinine concentration in plasma above 200 μmol / L in adults and 140 μmol / L in children), the initial daily dose of cyclosporine should not exceed 2.5 mg / kg.

If cyclosporine alone fails to achieve a satisfactory effect, especially in steroid-resistant patients, it is recommended that it be combined with small doses of oral glucocorticosteroids.If after 3 months of treatment no positive effect is observed, therapy with cyclosporine should be discontinued.

For maintenance treatment, the dose should be slowly reduced to the minimum effective. The recommended concentration of cyclosporine in blood plasma is 60-160 ng / ml, it is desirable to monitor it daily at the beginning of maintenance therapy, then every 2 weeks.

During the first six weeks of treatment, the recommended daily dose in adults is 2.5 mg / kg in 2 divided doses. In case of insufficient effect, the daily dose can be gradually increased under the condition of satisfactory tolerability, but it should not exceed 5 mg / kg per day. Cyclosporin can be administered in combination with small doses of glucocorticosteroid preparations and / or non-steroidal anti-inflammatory drugs. If there is no effect within 3 months, treatment should be discontinued.

For maintenance therapy, the dose should be selected individually and, depending on the tolerability of the drug, the dose of cyclosporine should be minimally effective.

Psoriasis

The dosage regimen should be selected individually.

For induction of remission, the recommended initial daily dose in adults is 2.5 mg / kg in 2 divided doses. If there is no improvement after 1 month of therapy, the daily dose may be gradually increased, but should not exceed 5 mg / kg. The drug should be discontinued if within 6 weeks it was not possible to achieve a satisfactory response from the manifestations of psoriasis with cyclosporine administration at a daily dose of 5 mg / kg.

In severe cases, when rapid effect is required, the initial daily dose of cyclosporine may be 5 mg / kg. If a satisfactory answer is reached, the drug can be withdrawn and the subsequent relapse treated with the repeated administration of cyclosporine at the previous effective dose.

The dose of cyclosporine for maintenance treatment of psoriasis should be minimally effective and should not exceed 5 mg / kg per day. Usually the duration of treatment is 12 weeks. In clinical studies, satisfactory results with the use of the drug for 24 weeks.

Atopic dermatitis

The dosage regimen should be selected individually. Initial dose in adults is 2.5 - 5 mg / kg per day in 2 divided doses.

If the initial daily dose of 2.5 mg / kg does not allow a satisfactory response within two weeks, it can be increased to 5 mg / kg.When a positive result is achieved, the dose of cyclosporine should be gradually reduced to a complete cancellation.

In case of relapse, a second course of cyclosporine therapy may be performed.

Although a course of treatment lasting 6-8 weeks may be sufficient for remission, therapy with a duration of up to 1 year is effective in adults and is well tolerated, provided that all necessary indications are mandatory. However, the drug Cyclosporin Sandoz® should be discontinued if no clinical effect is observed after 6 weeks.

Application in selected categories of patients

Impaired renal function

All indications

Ciclosporin is minimally excreted by the kidneys, and renal dysfunction does not affect its pharmacokinetics. However, given its possible nephrotoxicity, careful monitoring of renal function is recommended.

Impaired liver function

Dose reduction may be required in patients with severe impairment of the function of the liver to maintain plasma concentrations of the drug in the recommended range.

Patients aged <18 years

Experience with the drug Cyclosporin Sandoz® in children under the age of 1 year is absent. With the administration of cyclosporine in recommended doses to children, the safety profile of the drug was similar to that of adult patients. A number of studies have found that in this category of patients to achieve the required concentration of cyclosporine in the blood plasma can use higher doses of the drug (based on body weight).

Correction of the dosing regimen in the development of renal dysfunction in patients with endogenous uveitis, psoriasis, atopic dermatitis and rheumatoid arthritis.

Because the ciclosporin may violate the function of the kidney, then a reliable initial serum creatinine concentration must be established before the treatment begins (measurement should be performed at least two times). The concentration of creatinine should be monitored at two weekly intervals during the first three months of therapy and thereafter monthly. After 6 months of therapy, serum creatinine should be determined every 4-8 weeks, depending on the severity of the underlying disease, concomitant therapy and concomitant diseases.More frequent monitoring is necessary with an increase in the dose of cyclosporine, with the addition of concomitant therapy with non-steroidal anti-inflammatory drugs or an increase in their dose.

If during the treatment with cyclosporin the serum creatinine concentration increases by more than 30% of the baseline values (measurement should be performed at least twice), then it is necessary to reduce the dose of cyclosporin by 25-30%. If the serum creatinine concentration is increased by more than 50%, the dose of cyclosporine should be reduced by 50%.

These recommendations should be followed even if the creatinine concentration remains within the laboratory standard. If dose reduction does not lead to a decrease in creatinine concentration within one month, treatment with cyclosporine should be discontinued. Termination of treatment is necessary in the case when during treatment with cyclosporine there is an uncontrolled increase in blood pressure.

Mode of application

Solution for oral administration Cyclosporin Sandoz® should always be taken at the same time of the day when eating. The daily dose of cyclosporine should always be divided into 2 divided doses (morning and evening).

You can not drink the drug grapefruit juice.

The drug should be taken with the attached measuring syringe with a graduation of 0.5 to 4 ml with an interval of 0.1 ml (pay attention to the attached drawing of the selection of solution). The selected solution is recommended to be diluted with drinking water immediately before use (but not in a plastic cup). Added drink and Cyclosporin Sandoz®, solution for oral administration should be well mixed. Do not wash the syringe with water or any other liquid.

At initial use for the selection of Ciclosporin Sandoz® solution it is necessary

remove the plastic cover (figure 1),
release the bottle from the aluminum crimp cap (Figure 2),
remove the black plug from the vial (Figure 3).
tightly insert the rod with a hole in a bottle of dark glass (Figure 4). The stem will be in the vial permanently.
insert the graduated syringe into the rod (Figure 5)
select the volume of the solution corresponding to the prescribed dose in a graduated syringe (Figure 6). If there are a lot of air bubbles in the vial, it is necessary to merge the selected contents into a vial and recruit the solution anew (Fig. 7).
the solution selected by syringe is poured into a beaker with pre-prepared drinking water. The syringe should not come in contact with the solution in the glass.
to clean the syringe do not rinse, it is best to wipe it with a dry cloth outside and place it in a protective plastic test tube (Figure 8).
After taking the solution, the bottle must be closed with the attached screw cap.

For subsequent use, begin with step 5.

Side effects:

According to the World Health Organization (WHO), undesirable effects are classified according to their frequency of development as follows: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely (> 1/10000, <1/1000) and very rarely (<1/10000), including individual messages.

From the genitourinary system

Often: impaired renal function (see "Special instructions"); rarely: violation of the menstrual cycle; frequency not known: gynecomastia, with prolonged use in some patients may develop structural changes in the kidneys: for example, interstitial fibrosis with glomerular atrophy, arteriolar hyalinosis.

From the side of the cardiovascular system

Often: increased blood pressure; often: "tides" of blood to the face; rarely:cardiac ischemia.

From the nervous system

Often: tremor, headache; often: fatigue, paresthesia, convulsions; frequency not known: motor polyneuropathy, hyperesthesia, peripheral neuropathy, encephalopathy (including reversible rear encephalopathy syndrome), inhibition, disorientation, psychomotor agitation, restlessness, sleep disturbance, visual impairment, impaired consciousness, paresis, impaired coordination of movements, cerebellar ataxia, edema of the optic nerve nipple of the optic nerve, secondary to benign intracranial hypertension, cortical blindness, coma, migraine.

From the digestive system

Often: nausea, vomiting, abdominal pain, diarrhea, gingival hyperplasia; often: decreased appetite, impaired liver function (increased activity of "liver" transaminases and bilirubin concentration in blood plasma), stomach ulcer; frequency not known: acute pancreatitis, cholestasis, jaundice, hepatitis and hepatic insufficiency (including death).

From the side of the musculoskeletal system

frequency not known: muscle spasms, myalgia, muscle weakness, myopathy.

On the part of the organs of hematopoiesis

often: leukopenia; frequency not known: thrombocytopenia, thrombotic microangiopathy, hemolytic-uremic syndrome, thrombocytopenic purpura, anemia.

From the skin

Often: hirsutism; often: a rash, acne; frequency not known: hypertrichosis.

Laboratory indicators

frequency not known: hyperlipidemia, hyperuricemia, hyperkalemia, hypomagnesemia;

From the immune system

rarely: lymphoproliferative diseases after lymphoma transplantation, malignant diseases (especially skin).

Other

frequency is not known (or can not be calculated from available data): fatigue, weight gain, local and generalized infection (viral, bacterial, fungal etiology) and parasitic infestations (possibly exacerbation of previously existing infectious diseases or reactivation of polyomavirus infection from the latent state leading to the development of polyomavirus nephropathy, especially associated with VC virus, or multifocal leukoencephalopathy associated with JC virus, in some cases with a fatal outcome).

Many of the side effects associated with the use of cyclosporine, dose-dependent, and reversible with a decrease in dose.

Overdose:

Information about drug overdose is limited.

The use of cyclosporine in a dose of 10 g (150 mg / kg) was followed by the following symptoms: vomiting, headache, dizziness, impaired consciousness, tachycardia and, in some cases, renal dysfunction, reversible with withdrawal of the drug. However, in case of accidental parenteral overdose of cyclosporine in preterm infants in the neonatal period, the development of severe toxic complications was reported.

Treatment: There is no specific antidote, in the presence of indications, symptomatic therapy is performed.

Cyclosporine is practically not excreted from the body during hemodialysis and hemoperfusion with the use of activated charcoal. Nonspecific methods of elimination are shown, such as forced vomiting and gastric lavage in the first hours after taking the drug.

Interaction:

During treatment with Cyclosporine Sandoz®, vaccination may be less effective (use of live attenuated vaccines should be avoided).

A drug Cyclosporin Sandoz® can cause hyperkalemia and magnesium deficiency; drug use should be avoided Cyclosporin Sandoz® in combination with drugs that increase the concentration of potassium in the blood plasma, for example, with potassium-sparing diuretics,angiotensin converting enzyme inhibitors, angiotensin II antagonists, preparations containing potassium, a diet with an elevated potassium content is not recommended.

With the simultaneous use of cyclosporine and lercanidipine Increased AUC (area under the concentration-time curve) of lercanidipine by 3 times and AUC of cyclosporine by 21%. Caution should be exercised when using these medications together.

Cyclosporine is a membrane carrier of the P-glycoprotein and is able to increase the concentration in the plasma of the drug substrates of P-glycoprotein,applied together, for example, the maximum plasma concentration aliskirenincreases by 2.5 times. Changes in the concentration of cyclosporine were not observed.

When using the following drugs, the concentration of cyclosporine in the blood plasma decreases:barbiturates, carbamazepine, phenytoin, rifampicin, nafcillin, octreotide, probucol, orlistat, ticlopidine, sulfopyrazone, terbinafine, bosentan, oxcarbazepine, sulfadimidine at intravenous introduction, and also the preparations containing a grass of a St. John's wort perforated, in these cases, a dose adjustment is required Cyclosporin Sandoz®.

With the simultaneous use of the following drugs increases the concentration of cyclosporine in the blood plasma: antibiotics from the macrolide group (eg, erythromycin, azithromycin and clarithromycin), ketoconazole, fluconazole, itraconazole, voriconazole, diltiazem, nicardipine, verapamil, metoclopramide, oral contraceptives, danazol, methylprednisolone (in high doses) allopurinol, amiodarone, cholic acid and its derivatives, protease inhibitors, imatinib, colchicine, nefadozone.

Bioavailability of cyclosporine is also increased when taking fatty foods or grapefruit juice.

Risk of nephrotoxicity of the drug Cyclosporin Sandoz® increases with joint use with drugs that have nephrotoxicity, for example, methotrexate, aminoglycosides (including gentamicin and tobramycin), amphotericin B, ciprofloxacin, mannitol, vancomycin, trimethoprim (+ sulfamethoxazole), nonsteroidal anti-inflammatory drugs (diclofenac, naproxen, sulindac), melphalan, histamine H2 receptor blockers (eg, cimetidine, ranitidine).

The simultaneous use of tacrolimus and cyclosporine, due to the increased risk of developing nephrotoxicity.

There are isolated reports of severe but reversible renal dysfunction when combined derivatives of fibroic acid (e.g., bezafibrate, fenofibrate) in patients who underwent kidney transplantation.

When used simultaneously with nifedipine the risk of developing gingival hyperplasia increases. Nifedipine should be avoided in those patients in whom gingival hyperplasia develops as a side effect of cyclosporine.

It was found that simultaneous application of diclofenac and cyclosporine can significantly increase the bioavailability of diclofenac, with the possible development of reversible renal dysfunction. The increase in the bioavailability of diclofenac is most likely due to a decrease in its metabolism in the "first pass" through the liver.

When used in conjunction with cyclosporine nonsteroidal anti-inflammatory drugs with a less pronounced "first pass" effect (for example, acetylsalicylic acid) increase in their bioavailability is not expected.

Cyclosporine is an inhibitor of cytochrome CYP3A4 and a membrane transporter of P-glycoprotein molecules, while simultaneous application with it, an increase in the concentrationdrugs that are substrates of cytochrome CYP3A4 and / or a membrane transporter of P-glycoprotein.

Cyclosporine may reduce clearance digoxin, colchicine, prednisolone, inhibitors of HMG-CoA reductase (statins) and etoposide.

Several cases of severe glycoside intoxication have been reported following initiation of cyclosporine treatment in patients taking digoxin, the increased toxic effects of colchicine, for example, the development of myopathy or neuropathy, especially in patients with impaired renal function. When combined use of cyclosporine and lovastatin, simvastatin, atorvastatin, pravastatin and, more rarely, fluvastatin cases of development of myotoxicity, including muscle pain and weakness, myositis and rhabdomyolysis, are described.

With simultaneous application digoxin, colchicine or statins, A thorough clinical examination of patients for early detection of toxic manifestations and, accordingly, dose reduction or drug withdrawal is required.

When used simultaneously with cyclosporine, the concentration increases everolimus, sirolimus. The plasma concentration of cyclosporin varies little.

Cyclosporine may increase concentration repaglinide, which can lead to hypoglycemia.

Orlistat inhibits the absorption of fats from food, and thus can change the bioavailability of the drug Cyclosporin Sandoz®.

In patients receiving ciclosporin together with bosentan, it is possible to increase the content of the latter in blood plasma.

With simultaneous prolonged use ambrascient and cyclosporine, it is possible to increase the content of both drugs in blood plasma.

In patients with cancer, with the simultaneous use of the drug in high doses with anthracycline antibiotics there was an increase in the concentration of the latter in blood plasma.

If combined use of cyclosporine with a drug with nephrotoxic effects is required, careful monitoring of kidney function is required (in particular, creatinine clearance in the blood plasma should be assessed). If there is a pronounced impairment of kidney function, the dose of the drug should be reduced or considered the possibility of an alternativetreatment.

Chlorokhin can increase the serum level of cyclosporine and increase the risk of developing nephrotoxicity.

Cyclosporine - when combined with furosemide, the risk of gouty arthritis is increased due to furosemide-induced hyperuricemia and cyclosporin-induced uracate excretion by the kidneys.

Special instructions:

Cyclosporine should be used only by physicians with experience of immunosuppressive therapy and are able to provide adequate follow-up of the patient, including regular full examination, blood pressure measurement and control of creatinine concentration in the blood plasma. The results of the determination of the concentration of cyclosporine are only one of the factors determining the dosage regimen and are considered in conjunction with various clinical and laboratory indicators. To monitor the concentration of cyclosporine in blood plasma, it is desirable to use an enzyme-linked immunosorbent assay using specific monoclonal antibodies. It is also possible to use the method of high-performance liquid chromatography (HPLC).

Ciclosporin treatment requires regular monitoring of blood pressure. With an increase in blood pressure, appropriate antihypertensive therapy should be prescribed. Preference should be given to antihypertensive drugs that do not affect the pharmacokinetics of cyclosporine. When a drug resistant to arterial hypertension is established, treatment with cyclosporine is stopped.

Since there are rare reports of insignificant reversible hyperlipidemia in cyclosporine therapy, it is recommended before the start of treatment and 1 month after its inception to determine the concentration of lipids in the blood plasma. In case of an increased concentration of lipids, a diet with a restriction of fat should be recommended and, if necessary, a dose of the drug should be reduced.

Cyclosporine increases the risk of hyperkalemia, especially in patients with impaired renal function, it is recommended to control the concentration of potassium in the blood plasma.

Cyclosporine increases the excretion of magnesium from the body, which can lead to symptomatic hypomagnesemia, especially in the early post-transplant period.In this regard, in the early post-transplant period it is recommended to monitor the concentration of magnesium in the blood plasma, especially when neurologic symptoms appear. If necessary, prescribe magnesium preparations.

It is recommended to monitor the concentration of uric acid in the blood plasma, especially in patients with previous hyperuricemia.

Additional indications for indications, not related to transplantation

Additional indications for use in endogenous uveitis

Cyclosporine therapy should be performed under the supervision of an ophthalmologist, as well as with a constant control of the concentration of cyclosporine in the blood plasma and kidney function. When cyclosporine is used in the case of Behcet, it is recommended to monitor the patient's neurological status on a regular basis. The experience of using cyclosporine in children older than 5 years is very insignificant.

Additional indications for use in nephrotic syndrome

Due to changes in renal function due to nephrotic syndrome, it may be difficult for some patients to detect renal dysfunction caused by cyclosporine.This explains the fact that in some cases, associated with the administration of cyclosporine structural changes in the kidneys were observed without an increase in the concentration of creatinine in the blood plasma. A kidney biopsy is indicated for patients with a steroid-dependent nephropathy who received maintenance therapy with CYCLOSPORIN Sandoz® for more than 1 year. In rare cases, patients with nephrotic syndrome treated with immunosuppressants, noted the appearance of malignant neoplasms (including Hodgkin's lymphoma).

Additional indications for use in rheumatoid arthritis

When combined with non-steroidal anti-inflammatory drugs, more frequent monitoring of creatinine concentration in the blood plasma is necessary.

As with other long-term immunosuppressive treatment, one should remember about the increased risk of lymphoproliferative disorders. Particular care should be taken when using cyclosporine in combination with methotrexate.

Additional indications for use in psoriasis

The use of cyclosporine in elderly patients is possible only in cases of disabling psoriasis, with careful monitoring of kidney function.The experience with cyclosporine in patients under 18 years of age with psoriasis is limited. In patients with psoriasis, treated with cyclosporine, as with other conventional immunosuppressive treatment, the occurrence of malignant tumors, especially the skin, has been reported. In the presence of skin lesions that are not typical for psoriasis, and if there is a suspicion of their malignancy or precancerous condition, a biopsy should be performed before starting treatment with cyclosporine. Treatment of patients with malignant or premalignant skin lesions cyclosporin is possible only after appropriate treatment of these lesions in the absence of an effective alternative therapy.

Patients who are treated with cyclosporine should not simultaneously receive ultraviolet radiation or psoralen-UV treatment.

Additional indications for use in atopic dermatitis

The experience with cyclosporine in patients under 18 years of age with atopic dermatitis is still limited. Cyclosporine elderly patients is only possible in cases disabling the disease, with careful monitoring of renal function.

Benign lymphadenopathy is usually associated with sudden exacerbations of atopic dermatitis. It passes either alone or against a background of general improvement in the course of the disease. Lymphadenopathy, which appeared on the background of treatment with cyclosporine, should be monitored. With prolonged lymphadenopathy, a lymph node biopsy should be performed to exclude the presence of lymphoma.

Cases of active course of herpes simplex should be cured before starting treatment with cyclosporine, but the appearance of herpes simplex is not a reason to discontinue the drug if the treatment has already begun, except in severe cases.

Skin infectious diseases caused by Staphylococcus aureus are not an absolute contraindication for cyclosporine therapy, but should be controlled by the use of appropriate antibacterial drugs.

Due to the potential risk of skin cancer, patients with cyclosporine should be warned against direct exposure to sunlight, ultraviolet radiation, psoralen-ultraviolet therapy.

There is no need for special precautions for the destruction of unused medications.

Effect on the ability to drive transp. cf. and fur:

At present, there is no evidence of the effect of cyclosporine on the ability to drive a car and work with mechanisms. However, due to the likelihood of side effects, such headache, tremor and visual impairment, as well as the content in the ethanol preparation, care should be taken when dealing with potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Form release / dosage:Solution for oral administration 100 mg / ml.

Packaging:

To 50 or 100 ml in a bottle of dark glass, ukuporenny aluminum crimping cap with a plastic cover.

One bottle together with a ukuporennoy plastic tube containing a graduated syringe and a cannula, and a screwed plastic lid for the bottle in a plastic pallet. One pallet together with instructions for use in a cardboard box.

Storage conditions:

Store at a temperature of 20 ° C to 30 ° C.

When stored below 20 ° C, the solution may take a gelatinous consistency, which disappears when the temperature rises to 30 ° C.At the same time, an insignificant sediment can form, which does not affect the efficacy and safety of the drug and does not require adjustment of the doses.

Keep out of the reach of children.

Shelf life:

4 years.

Open vials can be used within 2 months.

Do not take the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N014330 / 02

Date of registration:31.10.2008

The owner of the registration certificate:Sandoz d.Sandoz d. Slovenia

Manufacturer: & nbsp

SALUTAS PHARMA, GmbH Germany

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp25.10.2015

Illustrated instructions

Instructions

Cyclosporine Sandoz® (Cyclosporin Sandoz®)