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

1 ml solution for oral administration contains: active substance - cyclosporine 100 mg; Excipients: DL-α-tocopherol 1.050 mg, ethanol absolute 94.70 mg, propylene glycol 94.70 mg, corn oil mono-di-triglycerides 318.850 mg, polyoxyl 40 hydrogenated castor oil 383.70 mg, nitrogen q.s.

Description:

Transparent liquid from yellow to light yellow or from brownish-yellow to light-brownish-yellow, respectively.

The solution contains oily components of natural origin, which tend to harden at low temperatures.At temperatures below 20 ° C, a transition to a jelly-like state is possible, which, however, again gives way to liquid at temperatures up to 30 ° C. This may leave a small residue or flakes. All this does not affect the effectiveness and safety of the drug, as well as the accuracy of its dosing with a pipette.

Odor: a specific smell of oil and ethanol.

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:

The solution contained in the soft gelatin capsules is a concentrated microemulsion diluted with liquid in the stomach when the preparation is used. This reduces the variability of pharmacokinetic parameters when used in all dose ranges and provides a linear relationship between the dose and the effect of cyclosporine (AUC is the area under the curve"concentration-time") with more uniform absorption and less dependence on simultaneous ingestion and secretion of bile.

Simultaneous food intake and circadian biorhythms of the patient have a slight effect on the pharmacokinetic parameters of the drug. These properties together result in a low variability in the pharmacokinetics of cyclosporine in the same patient (10-22% in patients with kidney transplantation), a more pronounced correlation between concentration and bioavailability (AUC) and no need to take into account meal times. In addition, there is a more uniform bioavailability of the drug, both during the day and for a longer period of time with long-term use in a maintenance dose. Data from various studies have shown that monitoring AUC of cyclosporine in the first 4 hours after admission (AUC_0-4), allows to more accurately determine the bioavailability of the drug as compared with the determination of its residual concentration in the blood plasma immediately before taking the subsequent dose (C₀monitoring). In a number of other studies, it has been demonstrated that in patients after transplantation the results of single monitoring at 2 hours after taking the drug (C₂ monitoring) correlate with AUC_0-4.

Suction

After taking the drug in patients with a solid organ transplant, there is a rapid absorption of cyclosporine, the time to reach the maximum concentration (T_max) is 1-2 hours. Absolute bioavailability is 30-60%. In patients with a kidney transplant who are in a stable state receiving maintenance therapy with cyclosporine, the mean C_max and AUC in the equilibrium state (when the drug is administered at an average dose of 100 mg / day) is 793 ng / ml and 2741 hg / ml, respectively.

Distribution

Cyclosporine is distributed mostly outside the bloodstream (the apparent volume of distribution is 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 concentration of cyclosporine in leukocytes and erythrocytes. In blood, binding to plasma proteins (mainly lipoproteins) is approximately 90%.

Metabolism

Cyclosporine is largely biotransformed by the cytochrome P-450 system (CYP450 isoenzyme ZA4), with the formation of 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 value of the final half-life of cyclosporine is very variable, which depends on the method used to determine and the patient population under study. The final half-life is approximately 6.3 hours in healthy volunteers. 7-16 hours in patients after kidney transplantation and 20.4 hours in patients with severe liver disease. The drug is excreted primarily with bile and only 6% of the dose taken internally is excreted in the urine (unchanged, only 0.1% is excreted).

Pharmacokinetics in special cases

Patients ≥65 years of age

There are no data on drug absorption in elderly patients. However, when the drug is used in patients of this category, the distribution of cyclosporine is similar to that in patients aged less than 65 years.

Patients aged ≤ 18 years

Since, on average, patients with ≤18 years of age experience a faster excretion of cyclosporine compared to adults, in patients of this category, higher doses of the drug (based on body weight) may be used to achieve the desired plasma cyclosporine concentration.

Patients with impaired renal function

Impaired renal function does not have a clinically significant effect on the pharmacokinetics of the drug, since ciclosporin is excreted mainly with bile through the intestine.

Patients with impaired hepatic function

In patients with impaired hepatic function there is a delay in excretion.

Indications:

Transplantation

Transplantation of solid organs

Prevention of rejection of allografts of the kidney, liver, heart, lung, pancreas, as well as a combined cardiopulmonary transplant.
Treatment of transplant rejection in patients who had previously received other immunosuppressants.

Bone marrow transplantation

Prevention of graft rejection after bone marrow transplantation.
Prophylaxis and treatment of "graft versus host disease" (TPH).

Indications not related to transplantation

Endogenous uveitis

Active, vision-threatening, middle or posterior uveitis of non-infectious etiology with ineffectiveness or intolerance of previous treatment.
Uveitis Behcet with repeated attacks of inflammation involving the retina.

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. Maintenance of remission caused by glucocorticosteroids with the possibility of their cancellation.

Rheumatoid arthritis of adults

Treatment of severe forms of active rheumatoid arthritis.

Psoriasis

Treatment of severe forms of psoriasis with ineffectiveness or inability to use traditional therapy.

Atopic dermisatum

Severe forms of atopic dermatitis if systemic therapy is necessary.

Contraindications:

For all indications

Hypersensitivity to cyclosporine or any other component of the drug.
Children under 3 years old for the drug Sandimmun® Neoral® (for this dosage form).

For indications not related to transplantation

Renal dysfunction (except in patients with nephrotic syndrome and creatinine concentration in blood plasma of not more than 200 μmol / l in adults and 130 μmol / l in children).
Uncontrolled hypertension.
Infectious diseases that can not be adequately treated.
Malignant neoplasms.
Children up to age 18 years for all indications not related to the transplant, with the exception of nephrotic syndrome.

Carefully:

It should be used with caution in drug Sandimmun Neoral in patients aged ≥ 65 years, patients with hyperkalemia and hyperuricemia, liver disease, Behcet's disease with neurological manifestations, brain injury or brain disease, epilepsy, alcoholism, as well as in children.

Pregnancy and lactation:

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

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

In pregnant women who have undergone organ transplantation and receiving immunosuppressive cyclosporin treatment or combination therapy comprising the use of cyclosporin,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. There was no deviation from the norm of indicators of kidney function and blood pressure in these children. 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.

Cyclosporine is excreted in breast milk. You should take into account the presence of ethanol in capsules of the drug Sandimmun® Neoral®. Because Sandimmun® Neoral® can cause serious adverse reactions in children during breastfeeding, breastfeeding should be abandoned or the drug should be discontinued based on the importance of therapy for the patient.

Dosing and Administration:

The drug is used inside, regardless of food intake. The daily dose of the drug Sandimun Neoral should always be divided into 2 receptions: morning and evening.

The following ranges of oral doses should be considered only as recommendations.Conventional monitoring of the concentration of cyclosporin in the blood should be performed, with the possible use of a radioimmunoassay method based on the use of monoclonal antibodies. Based on the results obtained, determine the dose necessary to achieve the desired concentration of cyclosporine in blood plasma in different patients.

In case of ineffectiveness of Sandimmun Neoral therapy in capsule form in 2 divided doses in the morning and evening (especially in patients with low body weight) it is possible:

use of different doses of the drug in the morning and in the evening;

use of solution for oral administration.

In patients receiving ciclosporin for indications not related to transplantation, the control of the concentration of cyclosporine in the blood plasma is not significant. Exceptions are cases of recurrence of the disease against the background of cyclosporine 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 with impaired absorption in the gastrointestinal tract or with pharmacokinetic interaction.

Transplantation

Transplantation of solid organs

Treatment with the drug Sandimmun Neoral should be started 12 hours prior to transplantation at a dose of 10 to 15 mg / kg / day, divided into 2 divided doses. 13 1-2 weeks after the operation, the drug is used daily at the same dose, 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 divided into 2 divided doses is achieved.

In the case of using the drug Sandimmun Neoral as part of combined therapy with other immunosuppressants (for example, with glucocorticosteroids in a three-component or four-component therapy), its dose can be reduced (for example, 3-6 mg / kg / day in 2 divided doses).

Bone marrow transplantation

The initial dose should be taken on the day preceding the transplant. It is recommended to start therapy with a drug at a dose of 12.5-15 mg / kg / day in 2 divided doses. Supportive therapy is performed for at least 3 months (preferably 6 months), after which the dose is gradually reduced to complete discontinuation of the drug within 1 year after transplantation. Patients with diseases of the digestive system, accompanied by a decrease in absorption, may require higher doses of the drug Sandimmun Neoral or the use of cyclosporine in the form of intravenous infusions.

After the discontinuation of the use of the drug Sandimun Neoral, some patients may develop a "graft-versus-host disease" (GVHD), which usually regresses after the resumption of therapy. In such cases, the drug should be used at the initial loading dose of 10-12.5 mg / kg / day and further continue therapy with the drug in a maintenance dose previously regarded as satisfactory. To treat this condition with its chronic course in a mild form, use the drug Sandimmun Neoral in low doses.

Indications not related to transplantation

When using the drug Sandimmun Neoral for any of the indications not related to transplantation, the following general rules should be observed.

Before the start of therapy, it is necessary to determine at least twice the initial concentration of creatinine in the blood plasma, and also regularly monitor the kidney function.

The total daily dose should not exceed 5 mg / kg. with the exception of the total daily dose in patients with endogenous uveitis, threatening vision, and in children with nephrotic syndrome.

For maintenance therapy, the lowest effective and well tolerated dose of the drug should be individually selected.

In cases where during a certain period (depending on the indication) the drug fails to achieve clinical efficacy, or the achievement of an effective dose is not compatible with safety, treatment with the drug Sandimmun Neoral should be discontinued.

Endogenous uveitis

Achievement of remission

To achieve remission, the drug is used in an initial dose of 5 mg / kg / day, divided into 2 doses, until the signs of active inflammation disappear and visual acuity improvement. If the initial dose is not effective, therapy with the drug can be carried out at a dose of up to 7 mg / kg / sug. divided into 2 receptions for a short period.

To achieve a more rapid remission (to reduce the severity of inflammatory reactions) and / or when monotherapy with the drug Sandimmun Neoral is not effective enough, additional therapy with glucocorticosteroids, for example, prednisolone in a dose of 0.2-0.6 mg / kg / day or another glucocorticosteroid drug in an equivalent dose.

It is necessary to cancel therapy with the drug Sandimmun Neoral if there is no improvement in the patient's condition 3 months after the start of therapy.

Maintaining remission

In the course of maintenance therapy, the dose of the drug should be slowly reduced to the lowest effective dose, which during the remission period of the disease should not exceed 5 mg / kg / day. divided into 2 receptions.

Psoriasis

Achievement of remission

Therapy of psoriasis should be of an individual nature in connection with various variants of the course of the disease. To achieve remission, the recommended initial dose is 2.5 mg / kg / day, divided into 2 doses. If there is no improvement after 1 month of therapy, the daily dose can be gradually increased by 0.5-1 mg / kg per month, but should not exceed 5 mg / kg / day, divided into 2 doses. Treatment with the drug Sandimmun Neoral should be discontinued if after 6 weeks of applying the maximum dose of 5 mg / kg / day, divided into 2 doses, there is no sufficient clinical effect or if the effective dose of the drug does not meet the established safety parameters.

Maintaining remission

For maintenance therapy, the drug is used in the minimum effective dose, but not more than 5 mg / kg / day.

After 6 months of maintenance therapy, it is necessary to gradually reduce the dose of the drug Sandimmun Neoral up to its complete cancellation.

Atopic dermatitis

Achievement of remission

In connection with various variants of the course of the disease, therapy should be individualized. The recommended dose is 2.5-5 mg / kg / day, divided into 2 divided doses. In case, after 2 weeks of treatment at a starting dose of 2.5 mg / kg / day, a satisfactory response to treatment is not achieved, the dose can be increased to a maximum of 5 mg / kg / day. In the case of severe disease, faster and more adequate control is achieved with a starting dose of 5 mg / kg / day.

Maintaining remission

When a satisfactory response to therapy is achieved, the dose of the drug should be gradually reduced, to the extent possible, until it is completely eliminated. With the development of recurrence of the disease, repeated treatment with the drug following the course is possible. Despite the fact that a course of treatment of 8 weeks may be sufficient to cleanse the skin, it is shown that therapy with a duration of up to 1 year is effective and well tolerated, provided that all necessary indications are mandatory.

Treatment with the drug Sandimmun Neural should be discontinued if after 4 weeks of applying a maximum dose of 5 mg / kg / day, divided into 2 doses, there is no satisfactory clinical effect.

Rheumatoid arthritis

Achievement of remission

During the first six weeks of treatment, the recommended dose is 3 mg / kg / day, divided into 2 divided doses. In case of insufficient effect, the daily dose can be gradually increased, if tolerability allows, but should not exceed 5 mg / kg / day. To achieve a satisfactory clinical response, it may take up to 12 weeks of therapy with the drug Sandimmun Neoral.

Maintaining remission

For maintenance therapy, the dose should be selected individually depending on the tolerability of the drug, the dose of the drug for maintenance therapy should be minimal effective.

The drug Sandimmun® Neural can be used in combination with low doses of glucocorticosteroids and / or non-steroidal anti-inflammatory drugs. The drug Sandimmun® Neoral can also be combined with a weekly course of methotrexate in low doses in patients with an unsatisfactory response to methotrexate ion therapy. The initial dose of the drug Sandimmun Neoral in this case is 2.5 mg / kg / day, divided into 2 doses, while the dose can be increased to a level limited by tolerability.

Nephrotic syndrome

Achievement of remission

To achieve remission, the recommended dose is up to 6 mg / kg / day, divided into 2 doses, for children and up to 5 mg / kg / day, divided into 2 doses for adult patients with normal kidney function, excluding proteinuria. In patients with impaired renal function of moderate severity (creatinine concentration in blood plasma is not more than 200 μmol / l for adults and 140 μmol / l for children), the initial dose should not exceed 2.5 mg / kg / day, divided into 2 divided doses. The dose should be selected individually, taking into account the efficacy (proteinuria) and safety (creatinine concentration in the blood plasma), but should not exceed 5 mg / kg / day divided into 2 divided doses for adults and 6 mg / kg / day divided by 2 reception for children.

Maintaining remission

For maintenance therapy, the dose should be gradually reduced to a minimum effective dose.

Since patients of this category with the use of the drug SandimmunNeural can develop or progress the violation of kidney function, with the use of the drug should closely monitor kidney function. When the concentration of creatinine in the blood plasma increases by more than 30% compared with the initial values, the dose of the drug Sandimmun Neoral should be reduced by 25-50%.It is necessary to ensure careful monitoring of the condition of these patients.

In the absence of improvement in the patient's condition after 3 months of treatment, the drug Sandimmun® Neoral should be discarded.

If monotherapy with the drug Sandimmun Neoral fails to achieve a satisfactory effect, especially in steroid-resistant patients, it is recommended that it be combined with low doses of glucocorticosteroids for oral administration.

In some cases, in patients with nephrotic syndrome receiving the drug Sandimmun® Neoral®, it was difficult to identify the causes of renal dysfunction (because the cause may be both treatment with the drug and the underlying disease). In rare cases, patients with nephrotic syndrome experienced changes in the structure of the kidney tissue caused by the drug, and not accompanied by a marked increase in the concentration of creatinine in the blood plasma. Thus, patients with a steroid-dependent form of nephropathy with minimal changes receiving treatment with the drug for longer than a year should consider the possibility of a kidney biopsy.

Use in patients of certain categories

Patients with impaired renal function

All indications

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

Indications not related to transplantation

The use of cyclosporine in patients with impaired renal function, with the exception of nephrotic syndrome, is contraindicated. In patients with nephrotic syndrome and impaired renal function, the initial dose of the drug should not exceed 2.5 mg / kg / day. When the concentration of creatinine in the blood plasma is increased by more than 50%, compared with the initial value, it is necessary to reduce the dose of cyclosporine by more than 50%.

Patients with impaired hepatic function

Dose reduction may be required in patients with severe liver dysfunction to maintain the plasma concentration of the drug in the recommended range.

Patients aged ≤ 18 years

The experience of using the drug Sandimmun Neoral in children under the age of 1 year is absent. When using the drug Sandimmun Neoral at recommended doses in children over the age of 1 year, the safety profile of the drug was similar to that of adult patients.In a number of studies, it has been established that in patients of this category, higher doses of the drug (based on body weight) may be used to achieve the desired concentration of cyclosporine in the blood plasma.

In children, the drug Sandimmun Neoral should not be used for indications other than transplantation, with the exception of nephrotic syndrome.

Patients ≥65 years of age

The experience of using the drug Sandimmun Neoral in patients of this category is limited, with the use of the drug in the recommended doses, there are no violations deserving special attention. In patients with rheumatoid arthritis aged ≥65 years with cyclosporine for 3-4 months, systolic arterial hypertension and an increase in creatinine plasma concentration> 50% higher than baseline were more likely.

It is necessary to carefully select a dose of cyclosporine for patients of this age category, starting with the lowest, due to a greater frequency of violations of the liver, kidney or heart, as well as the development of pathological conditions due to the presence of concomitant diseases and the simultaneous use of other medications.

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

Since the use of the drug Sandimmun Neural possibly development of violations of kidney function, before starting the drug should determine the initial concentration of creatinine in the blood plasma, at least in two dimensions. The concentration of creatinine in the blood plasma should be determined at weekly intervals for 2 months after the initiation of therapy. In the future, if the creatinine concentration in the blood plasma remains stable, the determination should be made monthly. More frequent control is necessary with an increase in the dose of the drug Sandimmun Neoral and with the use of concomitant therapy with non-steroidal anti-inflammatory drugs or with an increase in their dose.

When the creatinine concentration in the blood plasma is increased by more than 30% compared to the baseline values for 2 or more measurements (even if the creatinine concentration remains within normal limits), the dose of the drug Sandimmun Neoral should be reduced by 25-50%.If the creatinine concentration is increased by more than 50% compared with the baseline value, further dose reduction should be considered.

If a decrease in the dose of the drug does not lead to a decrease in the concentration of creatinine in the blood plasma for one month, treatment with the drug Sandimmun Neoral should be discontinued.

Side effects:

The most common adverse events associated with the treatment with Sandimmun Neoral, revealed in clinical studies, include renal dysfunction, tremor, hirsutism, arterial hypertension, diarrhea, anorexia, nausea, vomiting, microangiopathic hemolytic anemia, and posttransplantation distal limb syndrome.

Many of the side effects associated with the use of cyclosporine are dose-dependent and reversible with decreasing dose. The spectrum of AEs is generally the same for different indications, although the frequency and severity of side effects may vary. In patients who undergone transplantation, because of a higher dose and longer duration of treatment, side effects occur more often and are usually more pronounced,than in patients with other diseases or conditions.

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

Infections

In patients receiving immunosuppressive treatment with cyclosporine or combination therapy, including ciclosporin, the risk of developing local and generalized infections (viral, bacterial, fungal etiology) and parasitic infestations increases. 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 legal outcome.

Lymphoproliferative diseases and malignant neoplasms

In patients receiving immunosuppressive treatment with cyclosporine or combination therapy, including ciclosporin, the risk of developing lymphomas, lymphoproliferative diseases and malignant neoplasms, especially from the skin, increases.The frequency of malignant neoplasms increases with increasing intensity and duration of immunosuppressive therapy. The data below summarizes the information on IH, registered during clinical trials, as well as data on the safety profile of the drug obtained during its use in clinical practice. AEs are grouped according to the classification of organs and systems of MedDRA organs. are listed in order of decreasing importance. Criteria for assessing the incidence of adverse reactions: "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. Since in the postmarketing period reports of AEs are received voluntarily from a population of undetermined size, it is not possible to reliably estimate the frequency of their occurrence, and for this reason, "frequency is unknown".

Violations from the blood and lymphatic system: often - leukopenia; infrequently - anemia, thrombocytopenia; rarely - thrombotic microangiopathy (including thrombotic thrombocytopenic purpura, haemolytic syndrome).

Disorders from the metabolism and nutrition: very often hyperlipidemia; often - anorexia, hyperuricemia, hyperkalemia, hypomagnesemia; rarely hyperglycemia.

Impaired nervous system: very often - tremor, headache, including migraines; often paresthesia; infrequent signs of encephalopathy, including the development of the syndrome of reversible posterior encephalopathy (ZOE) with such manifestations as convulsions, confusion, disorientation, delayed reactions, agitation, insomnia, visual impairment, cortical blindness, coma, paresis, cerebellar ataxia; rarely - motor polyneuropathy: very rarely - edema of the optic disc (including the nipple of the optic nerve) with possible visual impairment as a result of benign intracranial hypertension.

Vascular disorders: very often - increased blood pressure (15-40%); often - hot flushes.

Disorders from the digestive system: very often - a decrease in appetite, nausea, vomiting, abdominal discomfort, diarrhea, gingival hyperplasia; often - peptic ulcer.

Disorders from the liver and bile ducts: very often hepatotoxicity; rarely - pancreatitis.

Disturbances from the skin and subcutaneous tissues: very often hypertrichosis; often - acne, rash; infrequently skin allergic reactions.

Disturbances from the musculoskeletal and connective tissue: often - muscle spasms, myalgia; rarely - muscle weakness, myopathy; frequency unknown - pain in the lower extremities.

Disorders from the kidneys and urinary tract: very often - a violation of kidney function (the frequency of this AE is 10-50%, depending on the indication).

Violations of the genitals and breast: rarely - menstrual pain, gynecomastia.

General disorders and disorders at the site of administration: often - fatigue, fever, swelling; infrequently - an increase in body weight.

In the postmarketing period, hepatotoxic effects of cyclosporine have been reported, including cholestasis, jaundice, hepatitis, and liver failure. Typically, these patients had co-morbidities, predisposing conditions, other risk factors, including infectious complications, or received ciclosporin simultaneously with other drugs that have a hepatotoxic effect. Some cases, mainly in patients after transplantation, had a legal outcome.

Pain in lower limbs

With the use of cyclosporine, separate reports have been received of cases of development of pain in the lower extremities, 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.

Overdose:

Symptoms: data on cases of drug overdose Sandimmun Neural are 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, there was a development of impaired renal function of moderate severity. However, 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 by inducing vomiting or by rinsing the stomach. Cyclosporin is practically not excreted in hemodialysis and hemoperfusion with the use of activated charcoal.

Interaction:

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-sparing drugs (potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists) or preparations containing potassium, so when expressed in combination with cyclosporine, pronounced hyperkalemia may develop.

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

Care should be taken when using the drug Sandimmun Neoral with methotrexate in patients with rheumatoid arthritis in connection with the risk of an increase in total nephrotoxicity.

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 inhibiting or inducing liver enzymes,participating in the metabolism of cyclosporin, in particular the isoenzyme CYP3A4.

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

In patients receiving ciclosporin on indications not related to transplantation,monitoring the concentration of cyclosporine in the blood plasma is not significant, because for patients in this category the relationship between blood concentration and clinical effects is not clearly proven. When cyclosporine is used together with drugs that increase its concentration in the blood plasma, frequent monitoring of kidney function and monitoring of side effects of cyclosporine are more important than determining the concentration of cyclosporine in the blood plasma.

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

Drugs that increase the concentration of cyclosporine in blood plasma: chloroquine, a number of antibiotics-macrolides (for example, erythromycin, azithromycin and clarithromycin), antifungal agents (including ketoconazole, and, to a lesser extent, fluconazole, itraconazole. voriconazole), diltiazem, nicardipine, verapamil, metoclopramide, oral contraceptives, danazol, methylprednisolone (high doses), allopurinol. amiodarone; Cholic acid and its derivatives, HIV protease inhibitors. imatinib, colchicine, nefazodone.

Food interaction

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

Drugs that can enhance the nephrotoxic effect of cyclosporine

With the simultaneous use of cyclosporine with drugs that can enhance its nephrotoxicity, careful monitoring of kidney function (in particular, the determination of the concentration of creatinine in the blood plasma) is necessary.

If there is a marked violation of kidney function, you should reduce the dose of the drug or change the therapy schedule.

Caution should be exercised while using the drug Sandimmun Neoral with drugs that have a nephrotoxic effect: aminoglycosides (including gentamicin, tobramycin), amphotericin B, ciprofloxacin, mannitol, melphalan, co-trimoxazole (trimethoprim + sulfamethoxazole), vancomycin, non-steroidal anti-inflammatory drugs (including diclofenac, indomethacin, naproxen, sulindac), H2-histamine receptor blockers (including cimetidine, ranitidine), methotrexate with tacrolimus, t. this can lead to an increased risk of developing nephrotoxicity. The simultaneous use of diclofenac and cyclosporine can significantly increase the bioavailability of the first, with the possible development of reversible renal dysfunction. An increase in the bioavailability of diclofenac is most likely due to the slowing of its metabolism in the "first pass" through the liver. With the simultaneous use of non-steroidal anti-inflammatory drugs with less pronounced effect of "first passage" (eg, acetylsalicylic acid) with cyclosporine, their bioavailability is not expected to increase.Non-steroidal anti-inflammatory drugs with pronounced "first pass" effect through the liver (for example, diclofenac) should be used in smaller doses than in patients who do not receive ciclosporin.

There are separate reports on the development of significant, reversible renal dysfunction (with a corresponding increase in plasma creatinine concentration) in patients after transplantation, while using cyclosporine with fibrolic acid derivatives (for example, bezafibrate, fenofibrate), so patients in this category need to monitor kidney function. In the case of development of severe renal dysfunction, simultaneous use of the above medicines should be discontinued.

Interactions leading to the development of gingival hyperplasia

The simultaneous use of nifedipine and cyclosporine may lead to the development of more pronounced gingival hyperplasia than against the background of cyclosporine monotherapy. In patients with gingival hyperplasia receiving cyclosporine therapy, simultaneous use of nifedipine should be avoided.

Combinations that increase the concentration of other drugs

Because the ciclosporin is an inhibitor of the isoenzyme CYP3A4 and the membrane carrier of the P-glycoprotein, it is possible to increase the plasma concentration of preparations that are substrates of the isoenzyme CYP3A4 and / or P-glycoprotein when they are used simultaneously with cyclosporine.

Cyclosporine can slow the clearance of digoxin, colchicine, prednisolone. inhibitors of HMG-CoA reductase (statins), etoposide, aliskiren, bosentan or dabigatran.

Several cases of severe glycoside intoxication have been reported for several days after initiation of cyclosporine treatment in patients taking digoxin. There are also reports that ciclosporin can enhance the toxic effects of colchicine, for example, the development of myopathy or neuropathy, especially in patients with impaired renal function. With the simultaneous use of cyclosporine 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.

When cyclosporine is used in clinical practice,as well as from literature sources reported cases of development of muscle toxicity, including muscle pain, weakness, myositis and rhabdomyolysis against a simultaneous application of cyclosporine with lovastatin, simvastatin. atorvastatin, pravastatin and. in rare cases, with fluvastatin. If you need to use the above drugs simultaneously with cyclosporine, you need to reduce their dose. Statin therapy should be temporarily discontinued or canceled in patients with symptoms of myopathy, as well as in patients with risk factors for severe renal dysfunction, including renal failure secondary to rhabdomyolysis.

If necessary, simultaneous application of cyclosporine and digoxin. colchicine or HMG-CoA reductase inhibitors should be carefully monitored for the purpose of early diagnosis of the toxic effects of these drugs, followed by a reduction in their dose or complete withdrawal of therapy.

An increase in creatinine concentration was observed in studies of the simultaneous use of everolimus or sirolimus with high doses of cyclosporin in the form of a microemulsion.This effect is often reversible with a decrease in 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.

Caution should be exercised when using cyclosporine with potassium-sparing drugs (potassium-sparing diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists) or potassium preparations, since concomitant use of cyclosporine with the above drugs may result in severe hyperkalemia.

With the simultaneous use of cyclosporine and repaglinide, it is possible to increase the concentration in the plasma of the latter and increase the risk of developing hypoglycemia.

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

With the simultaneous use of cyclosporine and aliskiren, there was an increase in C_maxand AUC aliskiren in 2.5 and 5 times, respectively. Changes in C_maxcyclosporine was not observed. In this regard, it is recommended to use caution while using cyclosporine and aliskiren.

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 simultaneous prolonged use of ambrisent and cyclosporine, an increase in the concentration of both drugs in the blood plasma is possible.

In patients with cancer, with the simultaneous use of the drug in high doses with antibiotics anthracycline (for example, doxorubicin, mitoxantrone, daunorubicin) there was an increase in their concentration in blood plasma with intravenous administration.

If you can not avoid the simultaneous use of cyclosporine and drugs that can interact with it, the following recommendations should be observed

With the simultaneous use of cyclosporine with a drug that has a nephrotoxic effect, careful monitoring of kidney function (in particular, the determination of the concentration of creatinine in the blood plasma) is necessary. If there is a pronounced impairment of kidney function, the dose of the drug taken together should be reduced or considered for alternative treatment.

The likelihood of developing drug interactions increases in elderly patients.

Special instructions:

Therapy with the drug Sandimmun Neoral can be performed only by physicians who have experience in the use of immunosuppression after transplantation.

Control of the concentration of cyclosporine in the blood plasma

To ensure the safety of the drug Sandimmun Neoral in patients after transplantation, it is important to monitor the concentration of cyclosporine in the blood.

To control the concentration of cyclosporin in the blood (measurement of the amount of unchanged drug), it is preferable to use specific monoclonal antibodies, as well as the high-performance liquid chromatography (HPLC) method.When using plasma or serum, the standard separation procedure (time and temperature) should be followed. Initial determination of the concentration of cyclosporine in patients with liver transplant should be performed using specific monoclonal antibodies or a parallel determination using both specific and non-specific monoclonal antibodies to achieve a dose that provides adequate immunosuppression.

In patients with cystic fibrosis, the absorption of calcineurin inhibitors may be impaired.

Impaired kidney and liver function

During the first few weeks of therapy with the drug Sandimmun Neoral, a frequent and potentially dangerous complication can occur - an increase in the concentration of creatinine and urea in the blood plasma. These functional changes are reversible and dose-dependent, normalized with a decrease in the dose of the drug. With prolonged treatment, some patients may develop structural changes in the kidneys (eg, arteriolar hyalinosis, canal atrophy and interstitial fibrosis), which in patients with kidney transplant should be differentiated with changes in chronic rejection. Careful monitoring of kidney function should be performed.If a violation of kidney function is detected, a dose reduction may be required. The drug Sandimmun Neoral can also cause a dose-dependent reversible increase in the concentration of bilirubin in the blood plasma and the activity of liver enzymes.

In the postmarketing period, reports of cases of hepatotoxicity with the development of cholestasis were received. jaundice, hepatitis and liver failure in patients receiving ciclosporin. Some cases ended in a fatal outcome, mainly in patients after transplantation. As a rule, such 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 the liver function indices is required. In the event of deviations of these values from the norm, a decrease in the dose of the drug Sandimmun® Neoral® may be required.

Elderly patients

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

Control of blood pressure (BP)

When treatment with the drug Sandimmun Neoral requires regular monitoring of blood pressure. With an increase in blood pressure, appropriate antihypertensive therapy should be used. Preference should be given to antihypertensive drugs that do not affect the pharmacokinetics of cyclosporine.

Changes in the biochemical composition of the blood

Since there are rare reports of the development of minor reversible hyperlipidemia in cyclosporine therapy, it is recommended to determine the concentration of lipids in the blood plasma before and 1 month after the start of treatment. In case of detection of hyperlipidemia, a diet with restriction of fats 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. 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, the potassium content in the blood should be monitored.

Cyclosporine increases the excretion of magnesium, which can lead to symptomatic hypomagnesemia, especially in the peri-transplant period. In this regard, in this period should monitor the magnesium content in the blood, especially when neurologic symptoms appear. If necessary, magnesium preparations are used. Care should be taken with drug treatment in patients with hyperuricemia with control of uric acid concentration in blood plasma, especially in patients with previous hyperuricemia.

Additional indications for use in endogenous uveitis

The drug Sandimmun Neoral should be used with caution in patients with neurological manifestations of Behcet's disease. Care should be taken to monitor neurological status in patients in this category.

The experience of using the drug Sandimmun Neoral in children with endogenous uveitis is limited.

Additional indications for use in nephrotic syndrome

In some cases, in patients with nephrotic syndrome receiving the drug Sandimmun Neoral, it was difficult to identify the causes of renal dysfunction (because the cause can be both treatment with the drug, and the underlying disease).In rare cases, patients with nephrotic syndrome experienced changes in the structure of the kidney tissue caused by the use of the drug and not accompanied by a marked increase in the concentration of creatinine in the blood plasma. Thus, patients with a steroid-dependent form of nephropathy with minimal changes receiving treatment with the drug for longer than a year should consider the possibility of a kidney biopsy.

In rare cases, patients with nephrotic syndrome treated with immunosuppressants (including cyclosporine), developed malignant neoplasms (including Hodgkin's lymphoma).

Additional indications for use in psoriasis

In patients treated with cyclosporine, as in patients receiving therapy with other immunosuppressive drugs, cases of lymphoma and other malignancies, in particular, from the skin, have been observed. A biopsy of skin lesions should be performed if there is a suspected malignancy. Use the drug in patients of this category should only after adequate therapy, and only if there is no possibility of alternative successful therapy.

Given the potential risk of skin cancer, patients receiving cyclosporin therapy, to avoid over-exposure to direct sunlight, ultraviolet UV-B radiation, PUVA therapy (photochemotherapy).

Additional indications for use in atopic dermatitis

Benign lymphadenopathy is often associated with periods of exacerbation of atopic dermatitis and. as a rule, is resolved independently spontaneously or with a decrease in the activity of the disease.

Patients with lymphadenopathy treated with cyclosporine should be carefully monitored. In the absence of a decrease in signs of lymphadenopathy, despite a decrease in the activity of the disease, a biopsy of the affected lymph nodes should be performed in order to exclude the development of lymphoma.

It should be treated with an active infection caused by the herpes simplex virus, before the use of cyclosporine. The aggravation of this disease, however, is not a reason to discontinue treatment with cyclosporine if it has already begun, except in cases of severe infection.

The patient has an infection of the skin caused by Staphylococcus aureus, is not an absolute contraindication for therapy with the drug Sandimmun Neoral, but requires adequate treatment with appropriate antibiotic therapy. It should avoid the simultaneous use of medicinal forms of erythromycin for ingestion and cyclosporine, in connection with an increase in the concentration in the blood of the latter. In case of impossibility of using alternative therapy, simultaneous treatment with these drugs should be carried out with careful monitoring of cyclosporine concentration in blood plasma, control of kidney function and alertness to the development of AE cyclosporine.

Substitution of the drug Sandimmun Neural other oral drugs of cyclosporine

Transition from the drug Sandimmun Neoral (in the form of soft gelatin capsules or solution for oral administration) to another oral drug cyclosporine should be performed with caution under appropriate medical supervision. It is necessary to conduct a common control of the concentration of cyclosporine in the blood plasma in order to make sure that after the transition of the concentration of cyclosporine in the blood plasma corresponds to that before the transition.Two dosage forms of the drug Sandimmun Neoral, soft gelatin capsules and solution for oral administration are bioequivalent.

Application of the drug Sandimmun Neoral with other immunosuppressants

It should be borne in mind that when using cyclosporine, as well as other immunosuppressants, the risk of developing lymphomas and other malignant tumors, more often from the skin, increases. The increased risk of developing this complication is mainly due to the duration and degree of immunosuppression. than with the use of any particular drug. Therefore, care should be taken when using combined regimens of immunosuppressive therapy, remembering the likelihood of developing lymphoproliferative diseases and solid organ tumors that rarely lead to death.

Infections

The use of cyclosporine, like other immunosuppressants, predisposes to the emergence of various bacterial, fungal, parasitic and viral infections, often associated with opportunistic pathogens. In patients treated with cyclosporine, reactivation of poliomavirus infection from the latent state was noted,leading to the development of polyomavirus nephropathy, especially associated with VC virus, or multifocal leukoencephalopathy due to JC virus. These conditions are caused by a high total 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 disorders in patients receiving immunosuppressive therapy. 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.

Lymphoproliferative diseases and solid malignant neoplasms

With prolonged immunosuppressive treatment (including cyclosporine therapy), the risk of developing lymphoproliferative diseases and solid malignant neoplasms increases. When using the drug, appropriate monitoring of patients should be provided to identify these conditions in the early stages.When detecting lymphoproliferative diseases, solid malignant neoplasms or pre-tumoral conditions, treatment with the drug should be canceled.

The effect of direct solar radiation, UV-B radiation and photochemotherapy

Given the potential risk of developing malignant skin tumors, patients treated with cyclosporine should avoid excessive exposure to direct sunlight, exposure to ultraviolet UV-B radiation. PUVA therapy (photochemotherapy).

Special components: ethanol

When cyclosporine is used in pregnant women and during breastfeeding, patients with liver disease, epilepsy, alcoholism or when used in children should take into account the presence of ethanol in the drug. The content of ethyl alcohol in the preparation is about 9.5% of the weight of the contents of the capsule, which corresponds to 0.010 g of ethanol for a dosage of 10 mg, 0.025 g for a dosage of 25 mg. 0.050 g for a dosage of 50 mg and 0.100 g for a dosage of 100 mg.

Vaccination

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

It is necessary to monitor laboratory parameters in patients with cystic fibrosis.

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

Some side effects of the drug, 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. Therefore, during the treatment period, care should be taken when driving vehicles and performing potentially hazardous activities.

When these undesirable phenomena appear, one should refrain from these activities.

Form release / dosage:Solution for oral administration, 100 mg in 1 ml.

Packaging:

50 ml of the drug in a bottle of dark glass, closed with a rubber stopper, covered with an aluminum cap with a plastic lid complete with a screw cap and a set for dosing (2 syringes measuring 1 ml and 4 ml, 2 tubes for taking the drug from the bottle).

Each syringe, together with a tube for taking the drug from the bottle, is placed in a transparent plastic cylinder, closed with a plastic stopper.

The bottle and the dosing set together with the instruction for use are placed in a cardboard box.

Storage conditions:

At a temperature of no higher than 30 ° C.

The drug should be stored out of the reach of children.

Shelf life:

3 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N012962 / 01

Date of registration:17.11.2009

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

Manufacturer: & nbsp

DELPHARM HUNINGUE, S.A.S. France

Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC

Information update date: & nbsp12.10.2015

Illustrated instructions

Instructions

Sandimmun® Neoral® (Sandimmun® Neoral®)