Sandimmun - instructions for use, dose, side effects, contraindications

1 ml of concentrate for infusion contains: active substance - Ciclosporin 0.050 g; Excipients: ethanol 96% - 0.278 g ,. polyoxyethylated castor oil 0.650 g.

Description:

Transparent oily liquid of a yellow-brown color.

Pharmacotherapeutic group:Immunosuppressive remedy.

ATX: & nbsp

Pharmacodynamics:

Cyclosporine is a cyclic polypeptide consisting of 11 amino acids and 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 increases the lifetime of allogeneic grafts of the skin, heart, kidneys, pancreas, bone marrow, fecal gut, lungs. Cyclosporin also inhibits the development of cellular allograft reactions, delayed-type skin reactions, experimental allergic encephalomyelitis, Freund's adjuvant-induced arthritis, graft-versus-host disease (GVHD), and T-lymphocyte-dependent antibody production. The efficacy of using the drug Sandimmun® in the process of bone marrow transplantation and solid organs in humans for prevention and treatment of rejection and BTPX, as well as in the treatment of various conditions that by their nature are autoimmune or can be considered as such. Cyclosporin is also effective in liver transplantation in HCV (hepatitis C virus) positive and HCV negative patients.

Pharmacokinetics:

Distribution

Cyclosporine is distributed mainly outside the bloodstream (the apparent volume of distribution is 3.5 l / kg). In the blood, 33-47% of cyclosporine is in plasma, 4-9% in lymphocytes, 5-12% in granulocytes and 41-58% in erythrocytes. Binding to plasma proteins (mainly lipoproteins) is approximately 90%.

Metabolism

Cyclosporine is largely biotransformed by the cytochrome P-450 system (isoenzyme CYP4503A4) to form approximately 15 metabolites. The main ways of metabolism are monohydroxylation, dihydroxylation and N-demethylation. All the metabolites identified contain the peptide structure of the unchanged drug. Some of the metabolites have a slight immunosuppressive effect (up to 10% of that for cyclosporine).

Excretion

The values of the final half-life of cyclosporine are very variable, which depends on the method used to determine and the patient population to be examined. The final half-life with unchanged liver function is approximately 6.3 hours; in patients with severe liver disease - approximately 20.4 h.The drug is excreted predominantly with bile, and only 6% of the dose taken internally is excreted by the kidneys (while in unchanged form only 0.1% is excreted).

Pharmacokinetics in specific patient groups

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 for 4 hours, the average peak concentration of cyclosporine in the blood was about 1800 ng / ml (1536 to 2331 ng / ml). The average volume of distribution was 3.49 l / kg, systemic clearance 0.369 l / h / kg, which is approximately two-thirds of the average systemic clearance (0.56 l / h / kg) in patients with normal renal function. Renal impairment does not significantly affect the elimination of cyclosporine, since ciclosporin is excreted mainly with bile through the intestine.

Patients with hepatic impairment

In patients with confirmed biopsy of liver cirrhosis and violations of liver function of severe severity, the half-life of the drug averaged 20.4 hours (from 10.8 to 48.0 hours) compared with 7.4-11.0 hours in healthy volunteers.

Indications:

Transplantation of solid organs:

prevention of rejection of allotransplant: kidney, liver, heart, combined cardiopulmonary graft, lung or pancreas (in cases when oral administration is not possible, or absorption of the drug during ingestion is impaired due to diseases of the gastrointestinal tract (GI tract));
prevention of graft rejection in patients previously receiving 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 is not possible, or absorption of the drug when ingested is impaired due to GI disease).

Contraindications:

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

Carefully:

Caution is advisable to use the drug Sandimmun® in patients aged ≥65 years; in patients with hyperlipidemia, hyperkalemia, hypomagnesemia and hyperuricemia; in patients with impaired liver function, with arterial hypertension,Behcet's disease with neurological manifestations, craniocerebral trauma or brain diseases, as well as with epilepsy and alcoholism.

Pregnancy and lactation:

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

The experience of using the drug Sandimmun® in pregnant women is limited.

In pregnant patients who underwent organ transplantation and who received immunosuppressive treatment with cyclosporine or combined therapy, including ciclosporin, there is a risk of premature birth (that occurred 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 within normal limits. However, due to the lack of sufficient reliable data on the use of the drug in pregnant women, do not use the drug Sandimmun® during pregnancy, except when the expected benefit for the mother exceeds the potential risk to the fetus.

Cyclosporine is excreted in breast milk. Since the use of the drug Sandimmun® during breastfeeding can cause serious adverse reactions in children of such patients, you should stop breastfeeding or stop taking the medication, based on the importance of therapy for the patient.

You should also take into account the presence of ethanol in the composition of the drug Sandimmun®.

Dosing and Administration:

The drug is administered intravenously (IV) dropwise.

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

Adults with bone marrow transplantation On the day preceding the transplantation, the drug Sandimmun® is administered IV drip in a dose of 3-5 mg / kg / day. Intravenous infusions of the drug at this dose continue for 2 weeks after transplantation, until the transition to maintenance therapy with oral forms of cyclosporine. Supportive therapy is continued for at least 3 months (preferably 6 months), after which the dose is gradually reduced to a complete withdrawal after 1 year after transplantation.In cases where the absorption of the drug is impaired, it may be necessary to continue the intravenous administration. In some patients, after the abolition of cyclosporine therapy, it is possible to develop a tuberculosis regurgitation, which usually regresses after the resumption of therapy. In such cases, the drug should be used at the initial loading dose of 10 to 12.5 mg / kg body weight, followed by its reduction to a maintenance dose previously regarded as satisfactory. To treat this condition in its chronic course in a mild form, use the drug Sandimmun® in low doses.

When transplantation of solid organs the drug Sandimmun® is administered once / IV dropwise at a dose of 3-5 mg / kg body weight 12 hours prior to transplantation. Within 1-2 weeks after transplantation the drug is used daily in 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 of body weight in 2 divided doses.

In the case of using the drug Sandimmun® as part of combined therapy with other immunosuppressive drugs (glucocorticosteroids or as part of triple or quadruple immunosuppressive therapy), its dose can be reduced (1 - 2 mg / kg body weight in 2 doses for initial therapy).The recommended dose of the drug Sandimmun® for IV administration is one third of the corresponding oral dose. As early as possible, patients should be transferred to oral therapy.

Use in special patient groups

Use in patients with impaired renal function

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

Use in patients with impaired liver function

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

Use in children

Experience with children is limited. When using the drug Sandimmun® at recommended doses in children aged more than 1 year, the profile of drug safety was similar to that of adult patients.A number of studies have established that in this category of patients, higher doses of the drug (in terms of body weight) may be used to achieve the desired concentration of cyclosporine in the blood plasma.

Application in elderly patients (≥ 65 years)

The experience of using the drug Sandimmun® in this category of patients is limited, when using the drug in recommended doses, there are no violations deserving special attention.

In clinical studies in patients with rheumatoid arthritis aged ≥65 years with cyclosporine for 3-4 months, systolic hypertension and an increase in serum creatinine concentrations> 50% more than the baseline value were more common.

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

It is necessary to carefully select a dose of cyclosporine for patients of this age group, starting with the lowest, due to the greater frequency of concurrent liver, kidney or heart function disorders, as well as the presence of concomitant diseases or simultaneous use of other medications.

Rules for the preparation and administration of an infusion solution

Concentrate should be diluted 1:20 - 1: 100 with a 0.9% solution of sodium chloride or 5% glucose solution and administered intravenously slowly, for 2-6 hours. The contents of the ampoule should be used immediately after its opening. Unused prepared mortar should be disposed of after 24 hours.

For the preparation of an infusion solution, it is desirable to use glass containers. Plastic bottles should only be used if they meet the requirements for the "plastic blood containers" of the European Pharmacopoeia. Polyoxyethylated castor oil contained in the concentrate can cause phthalate to be isolated from polyvinyl chloride. Containers and their plugs should not contain silicone oil and fatty components.

Side effects:

The main adverse events (AEs) associated with taking the drug and observed in clinical studies are renal dysfunction, tremor, hirsutism, increased blood pressure, diarrhea, anorexia, nausea and vomiting.

Many of the side effects associated with the use of cyclosporine are dose-dependent and reversible with decreasing dose.The spectrum of side effects is generally the same for different indications, although the frequency and severity of side effects may vary. In patients after transplantation due to higher doses and longer duration of maintenance treatment side effects are more frequent and usually more severe than in other patients.

With intravenous administration of cyclosporine, cases of anaphylactoid reactions were noted.

In patients receiving immunosuppressive treatment with cyclosporine or combination therapy, including ciclosporin, Increased risk of local and generalized infections (viral, bacterial, fungal etiologies) and parasitic infestations. It is also possible to previously available exacerbation of infectious diseases or reactivation of latent infection poliomavirusnoy condition leading to the development of nephropathy poliomavirusnoy, particularly associated with BK virus, or multifocal leukoencephalopathy, JC-associated virus. It was reported on the development of severe infectious lesions, in some cases with a fatal outcome.

In patients receiving immunosuppressive treatment with cyclosporine or combination therapy, including ciclosporin, the risk of developing lymphomas, lymphoproliferative diseases and malignant neoplasms, especially of the skin, increases. The frequency of malignant neoplasms increases with increasing intensity and duration of immunosuppressive therapy.

The incidence of adverse events was estimated as follows: "very often" (≥1 / 10); "often" (≥1 / 100, <1/10); "infrequently" (≥1 / 1000, <1/100); "rarely" (≥1 / 10000, <1/1000); "very rarely" (<1/10000), including individual messages. Within each group allocated according to the frequency of occurrence, the HA are listed in decreasing order, starting with the most common.

Violations from the blood and lymphatic system: often - leukopenia.

Disorders from the metabolism and nutrition: very often - anorexia, hyperglycemia.

Impaired nervous system: very often - a tremor, a headache; often - cramps, paresthesia.

Vascular disorders: very often - increased blood pressure; often - congestion.

Disorders from the digestive system: very often - nausea, vomiting, abdominal discomfort, diarrhea, gingival hyperplasia; often a stomach and duodenal ulcer.

Disorders from the liver and bile ducts: often - hepatotoxicity.Disturbances from the skin and subcutaneous tissues: very often - hirsutism; often - acne, rash.

Disorders from the kidneys and urinary tract: very often - a violation of kidney function (see "Special instructions").

Disorders from the reproductive system and mammary glands: rarely - violation of the menstrual cycle.

General disorders: often - fever, swelling.

Undesirable phenomena according to postmarketing observations (frequency unknown)

In the postmarketing period, the following undesirable reactions were noted (since reports of AE data were obtained voluntarily from a population of undetermined size, the frequency of their occurrence can not be reliably determined, and therefore the frequency was estimated as "unknown").

Within each group, undesirable events are distributed in order of decreasing importance.

Violations from the blood and lymphatic system: Thrombotic microangiopathy, hemolytic-uremic syndrome, thrombocytopenic purpura, anemia, thrombocytopenia.

Disorders from the metabolism and nutrition: hyperlipidemia, hyperuricemia, hyperkalemia, hypomagnesemia.

Impaired nervous system: encephalopathy, including the syndrome of reverse reversible encephalopathy, and such signs as seizures, inhibition, disorientation, delayed reactions, agitation, insomnia, visual disturbances, cortical blindness, coma, paresis, cerebellar ataxia, edema of the optic nerve, including the nipple of the optic nerve, secondary to benign intracranial hypertension, peripheral polyneuropathy, migraine.

Disorders from the digestive system: acute pancreatitis.

Disturbances from the liver and bile ducts: hepatotoxicity and liver damage, including cholestasis, jaundice, hepatitis and liver dysfunction, sometimes fatal.

Disturbances from the skin and subcutaneous tissues: hypertrichosis.

Disturbances from the musculoskeletal system and connective tissue: myopathy, muscle spasms, myalgia, muscle weakness, pain in the lower extremities.

Violations of the genitals and breast: gynecomastia.

General disorders and disorders at the site of administration: fatigue, weight gain.

Description of some undesirable phenomena

Hepatotoxicity

In post-marketing observations, separate reports were received on cases of hepatotoxic effects of cyclosporine and liver damage with the development of cholestasis, jaundice, hepatitis and liver failure. In most cases, the reports relate to patients with severe concomitant diseases and other predisposing factors, such as infectious complications, simultaneous use of drugs with a hepatotoxic effect. In some cases, predominantly in patients after transplantation, these side effects have led to fatal outcomes.

Acute and chronic nephrotoxicity

In patients receiving treatment with calcineurin (TCC) inhibitors, including cyclosporine, and combination therapy, including ciclosporin, increased risk of acute or chronic nephrotoxicity. Clinical studies and data from post-marketing observations indicate that cases of acute nephrotoxicity were accompanied by hyperkalemia, hypomagnesemia, and hyperuricemia. In cases of reporting chronic nephrotoxicity, morphologicalsigns of arteriolar hyalinosis, tubular atrophy and interstitial fibrosis.

Pain in lower limbs

With the use of cyclosporin, isolated reports of cases of lower limb pain have been obtained, which is one of the components of the pain syndrome associated with the use of calcineurin-inhibitor-induced pain syndrome (CIPS) described in the literature.

If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose:

Symptoms: experience of acute overdose of cyclosporine is limited. When ingested cyclosporine in a dose of up to 10 g (about 150 mg / kg), in most cases, markedly expressed clinical manifestations, such as vomiting, dizziness, headache, tachycardia. In some cases reversible violations of the kidney function of moderate severity were observed. In case of accidental parenteral overdose with cyclosporin, preterm infants in the neonatal period reported the development of severe toxic complications.

Treatment: symptomatic therapy, there is no specific antidote.

During the first 2 hours after ingestion, the drug can be removed from the body, causing vomiting, or by rinsing the stomach. Cyclosporin is practically not excreted in hemodialysis and hemoperfusion with the use of activated charcoal.

Interaction:

Listed below are drugs for which interaction with cyclosporine is confirmed and clinically relevant

Combinations with cyclosporine not recommended for use

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

Combinations with cyclosporin requiring caution

Caution should be exercised when using cyclosporine with potassium-preserving drugs (potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists) or potassium-containing preparations, since simultaneous application with cyclosporine may result in the development of severe hyperkalemia.

With the simultaneous use of cyclosporine and lercanidipine, the increase in AUC of lercanidipine is 3-fold and the increase in AUC of cyclosporine is 21%.Caution should be exercised when cyclosporine and lercanidipine are used concomitantly.

Drugs that reduce or increase the concentration of cyclosporine

Various drugs can increase or decrease the concentration of cyclosporine in blood plasma or whole blood, usually by suppressing or inducing liver enzymes involved in the metabolism of cyclosporin, in particular the isoenzyme CYP3A4.

When cyclosporine is used with drugs that decrease or increase its bioavailability in patients after transplantation, it is necessary to frequently determine the concentration of cyclosporine in the blood plasma and, if necessary, adjust its dose, especially at the initial stage of simultaneous therapy or during its cancellation.

Drugs that reduce the concentration of cyclosporine: barbiturates, carbamazepine, oxcarbazepine, phenytoin; nafcillin, sulfadimidine with its iv introduction; rifampicin; octreotide, probucol, orlistat, preparations containing St. John's wort (Hypericum perforatum), ticlopidine, terbinafine, sulfinpyrazone, bosentan.

Drugs that increase the concentration of cyclosporine: antibiotics macrolides (for example, 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; nefazadon.

Other Significant Interactions

Food interaction

There are reports that grapefruit juice increases the bioavailability of cyclosporine.

Interactions leading to potential enhancement of nephrotoxicity

When used simultaneously with drugs that enhance the nephrotoxicity of cyclosporine, regular monitoring of kidney function is required (especially creatinine concentration in the blood plasma). If there is a significant violation of kidney function, it is necessary to adjust the dose of the drug used simultaneously with cyclosporine or apply alternative therapy.

Caution should be exercised while using the drug Sandimmun® and drugs that have nephrotoxic effects (to avoid synergism): aminoglycosides (incl. gentamicin, tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+ sulfamethoxazole); Non-steroidal anti-inflammatory drugs (NSAIDs) (incl. diclofenac, naproxen, sulindac); melphalan, antagonists of H1-histamine receptors (for example, cimetidine, ranitidine), methotrexate.

Simultaneous use of cyclosporine with tacrolimus should be avoided, since this can lead to an increased risk of developing nephrotoxicity.

With the simultaneous use of diclofenac and cyclosporin, the bioavailability of the first, with the possible development of reversible renal dysfunction, increases. 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 with cyclosporine NSAIDs with a less pronounced "first pass" effect (for example, acetylsalicylic acid) increase in their bioavailability is not expected. NSAIDs with a pronounced "first pass" effect through the liver (for example, diclofenac) should be used in smaller doses than in patients who do not receive ciclosporin. Separate reports were received on the development oftransient renal dysfunction in patients after transplantation with simultaneous use of fibrolic acid derivatives (eg, fenofibrates, fibrate-free) with cyclosporine. These patients need constant monitoring of kidney function. In case of significant deterioration, simultaneous application should be canceled.

Interactions leading to gingival hyperplasia

Simultaneous use of nifedipine and cyclosporine can lead to more pronounced gingival hyperplasia than with cyclosporine monotherapy. The use of nifedipine should be avoided in those patients in whom gingival hyperplasia has developed as a side effect of cyclosporine therapy.

Combinations that increase the concentration of other drugs

Because the ciclosporin is an inhibitor of the CYP3A4 isoenzyme and a membrane transporter of P-glycoprotein molecules, while simultaneously increasing the concentration of preparations that are substrates of the CYP3A4 isoenzyme and / or the P-glycoprotein membrane transporter.

Cyclosporine can reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins), etoposide, aliskiren, bosentan or dabigatran.Several cases of severe glycoside intoxication were reported within a few days after starting treatment with cyclosporine in patients receiving digoxin. There are also reports that ciclosporin can 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 simultaneously with digoxin or colchicine, careful clinical observation is necessary to timely detect the toxic effects of these drugs and to address the issue of dose reduction or withdrawal of treatment.

The use of cyclosporine in clinical practice, as well as in literature, reported cases of muscle toxicity, including muscle pain, weakness, myositis and rhabdomyolysis, when simultaneous cyclosporine was used with lovastatin, simvastatin, atorvastatin, iravastatin and, in rare cases, fluvastatin . If it is necessary to simultaneously use the above drugs with cyclosporin, a reduction in their dose is necessary. Therapy with statins should be temporarily discontinued or canceled in patientswith symptoms of myopathy, as well as in patients with an increased risk of developing severe renal dysfunction, including renal failure secondary to rhabdomyolysis. If simultaneous use of cyclosporine and digoxin, colchicine, or HMG-CoA reductase inhibitors is necessary, patients should be closely monitored in order to diagnose as early as possible the toxic effects of these drugs, with a subsequent reduction in their dose or complete withdrawal of therapy.

An increase in creatinine concentration was observed in studies in which the simultaneous use of everolimus or sirolimus with high doses of cyclosporin in the form of a microemulsion was studied. This effect is often reversible after lowering the dose of cyclosporine. Everolimus and sirolimus have little effect on the pharmacokinetic parameters of cyclosporine. Simultaneous use of cyclosporine with everolimus or sirolimus leads to a significant increase in the concentration of the latter in the blood plasma.

Simultaneous use of cyclosporin and bosentan in healthy volunteers led to a twofold increase in exposurebosentan and a 35% decrease in the exposure of cyclosporine.

With the simultaneous use of cyclosporine and aliskiren C_max and the AUC of aliskiren increases approximately 2.5 and 5 times, respectively. The pharmacokinetics of cyclosporine does not change significantly. Therefore, care must be taken when using cyclosporine and aliskiren at the same time.

With the simultaneous use of dabigatran and cyclosporin, the concentration of the first in blood plasma increases as a result of the ability of cyclosporine to exert an inhibitory effect on P-glycoprotein. Since dabigatran has a narrow therapeutic index, an increase in its concentration in the blood plasma can lead to an increased risk of bleeding.

With the simultaneous use of cyclosporine and repaglinide, it is possible to increase the concentration of the latter in blood plasma with an increased risk of developing hypoglycemia. Long-term simultaneous use of ambrisent and cyclosporine in healthy volunteers caused a double increase in ambrisent exposure, while exposure to cyclosporine increased insignificantly (by 10%).

A significant increase in the exposure of anthracycline antibiotics (eg, doxorubicin, mitoxantrone, daunorubicin) has been observed in patients with oncological diseases receiving intravenous anthracycline antibiotics and very high doses of cyclosporine.

Special instructions:

Medical surveillance

The drug Sandimmun® should be used only by physicians with experience of immunosuppressive therapy and have the ability to provide adequate monitoring of the patient, including regular complete physical examination, measurement of blood pressure (BP), and monitoring of laboratory safety safety measures. Follow-up of patients after transplantation receiving therapy with the drug should be performed only in institutions with the availability of trained medical personnel and adequate laboratory resources.

Lymphoproliferative diseases and other malignant neoplasms

It should be borne in mind that when using cyclosporine, as well as other immunosuppressants, the risk of developing lymphomas and other malignant neoplasms, more often of the skin, is increased.The increased risk of developing this complication is more associated with the intensity and duration of immunosuppression than with the use of a particular drug. Therefore, care should be taken when using combined regimens of immunosuppressive therapy, remembering the likelihood of developing lymphoproliferative diseases and solid tumors, sometimes leading to fatal outcomes.

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

Infections

The use of cyclosporine, like other immunosuppressants, predisposes to the development of various bacterial, fungal, parasitic and viral infections, often associated with opportunistic pathogens. Patients treated with cyclosporine showed a reactivation of poliomavirus infection from the latent state leading to the development of polyomavirus nephropathy (especially associated with BV virus) or multifocal leukoencephalopathy due to JC virus.These conditions are caused by a high total load of immunosuppressive drugs. The risk of developing such conditions should be taken into account in the differential diagnosis of the causes of renal and nervous system dysfunction in patients who are immunosuppressive.

Given the potential risk of these infections for the life of the patient, an effective system of preventive and curative interventions should be applied, especially in cases of prolonged use of combined immunosuppressive treatment.

Acute and chronic nephrotoxicity

During the first few weeks of therapy with the drug Sandimmun®, a frequent and potentially dangerous complication may occur - an increase in the concentration of creatinine and urea in the blood serum. These functional changes are reversible and dose-dependent, normalized with a reduced dose. With prolonged treatment, some patients may develop structural changes in the kidneys (eg, arteriolar hyalinosis, tubular atrophy and interstitial fibrosis), which in patients with kidney transplants should be differentiated with changes in chronic rejection.Regular monitoring of kidney function is necessary. If a deviation is detected, a dose reduction may be required.

Hepatotoxicity

The drug Sandimmun® can also cause a dose-dependent reversible increase in serum bilirubin concentration and, rarely, an increase in the activity of liver enzymes. In the postmarketing period, reports of cases of hepatotoxicity of cyclosporine with the development of cholestasis, jaundice, hepatitis and liver failure in patients receiving ciclosporin. Some cases ended in a fatal outcome, mainly in patients after transplantation. As a rule, these patients had concomitant diseases, predisposing states, other risk factors or received ciclosporin simultaneously with other drugs that have a hepatotoxic effect. In these cases, careful monitoring of kidney and liver function is required. In case of deviations of these parameters from the norm, a dose reduction may be required.

Elderly patients (≥65 years)

In elderly patients, monitoring of kidney function should be particularly careful.

Measurement of the concentration of cyclosporine in the blood

Routine monitoring of the concentration of cyclosporine in the blood is an important safety monitoring mechanism. To control the concentration of cyclosporine in whole blood, it is preferable to use specific monoclonal antibodies (measurement of the amount of unchanged drug), as well as the method of high-performance liquid chromatography (HPLC). When using plasma or serum, the standard separation procedure (time and temperature) should be followed. For initial monitoring of the concentration of cyclosporine in patients with liver transplant, both specific monoclonal antibodies and a concurrent determination 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 one of many factors characterizing the clinical state of the patient. Correction of the dosing regimen should be based on the concentration of cyclosporine, taking into account other indicators of clinical and laboratory studies.

Control of blood pressure (BP)

In the process of treatment with the drug Sandimmun®, blood pressure should be regularly monitored; with an increase in blood pressure should be used adequate antihypertensive therapy. Preference should be given to such antihypertensive drugs that do not affect the pharmacokinetics of cyclosporine, for example, isradipine.

Hyperlipidemia

Since the drug Sandimmun® promotes the development of minor hyperlipidemia, it is necessary to determine the concentration of lipids in the blood before and one month after the initiation of therapy. In case of detection of hyperlipidemia, a diet with restriction of fats should be recommended and, if necessary, the dose of the drug should be reduced.

Hyperkalemia

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

Hypomagnesemia

Cyclosporine increases the excretion of magnesium from the body, which can lead to clinically significant hypomagnesemia, especially in the peri-transplant period.In this regard, in this period it is recommended to monitor the magnesium content in the blood, especially when neurologic symptoms appear. If necessary, magnesium preparations are used.

Hyperuricemia

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

Live attenuated vaccines

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

Ethanol

When using the drug Sandimmun® in pregnant and lactating women, patients with liver disease, epilepsy, alcoholism, as well as children should remember the content of the drug ethanol.

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

Some side effects of the drug Sandimmun®, including dizziness or visual disturbances, can adversely affect the ability to drive vehicles and carry out potentially dangerous activities that require increased concentration and speed of psychomotor reactions.

Form release / dosage:

Concentrate for the preparation of a solution for infusions of 50 mg / ml, 1 ml in ampoules.

Packaging:

10 ampoules together with instructions for use in a cardboard box.

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

Shelf life 4 years.

Do not use the drug at the end of the period indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:P N008552

Date of registration:29.06.2010

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

NOVARTIS PHARMA, AG Switzerland

Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC

Information update date: & nbsp12.10.2015

Illustrated instructions

Instructions

Sandimmun® (Sandimmun®)