Sandimmun^® Neoral (Capsules, Solution) Instructions for Use

ATC Code

L04AD01 (Ciclosporin)

Active Substance

Ciclosporin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Immunosuppressive drug

Pharmacotherapeutic Group

Immunosuppressive agent – calcineurin inhibitor

Pharmacological Action

Ciclosporin is a cyclic polypeptide consisting of 11 amino acids and is a selective immunosuppressant that suppresses the activation of lymphocyte calcineurin and blocks the cell cycle development of lymphocytes in the G₀ or G₁ phase.

This prevents the activation of T-lymphocytes and, at the cellular level, antigen-dependent release of lymphokines, including interleukin 2 (T-lymphocyte growth factor).

Ciclosporin acts on lymphocytes specifically and reversibly.

Unlike cytostatics, it suppresses hematopoiesis to a lesser extent and does not affect the function of phagocytes.

Ciclosporin increases the survival time of allogeneic skin, heart, kidney, pancreas, bone marrow, small intestine, and lung transplants.

Ciclosporin also suppresses the development of cellular reactions against the allograft, delayed-type hypersensitivity skin reactions, experimental allergic encephalomyelitis, Freund’s adjuvant-induced arthritis, graft-versus-host disease (GVHD), and T-lymphocyte-dependent antibody formation.

The efficacy of ciclosporin has been shown in bone marrow and solid organ transplantation in humans for the prevention and treatment of rejection and GVHD, as well as in the treatment of various conditions that are autoimmune in nature or can be considered as such.

Ciclosporin is also effective in liver transplantation in HCV (hepatitis C virus) positive and HCV negative patients.

Pharmacokinetics

The solution contained in soft gelatin capsules is a concentrated microemulsion that is diluted with fluid in the stomach when the drug is taken.

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 ciclosporin (AUC – area under the concentration-time curve) with more uniform absorption and less dependence on concomitant food intake and bile secretion.

Concomitant food intake and the patient’s circadian biorhythms have a minor effect on the pharmacokinetic parameters of the drug.

These properties collectively result in low variability of ciclosporin pharmacokinetics in the same patient (10-22% in kidney transplant patients), a more pronounced correlation between concentration and bioavailability (AUC), and no need to account for meal times.

Furthermore, more uniform bioavailability of the drug is observed, both during the day and over a longer period of time during long-term use at a maintenance dose.

Data from various studies have shown that monitoring the ciclosporin AUC in the first 4 hours after administration (AUC_0-4) allows for a more accurate determination of the drug’s bioavailability compared to determining its residual plasma concentration immediately before the next dose (C₀ monitoring).

A number of other studies have demonstrated that in post-transplant patients, single monitoring 2 hours after drug administration (C₂ monitoring) correlates with AUC_0-4.

Absorption

After drug administration in solid organ transplant patients, rapid absorption of ciclosporin is noted, with the time to reach maximum concentration (T_max) being 1-2 hours.

The absolute bioavailability is 30-60%.

In stable kidney transplant patients receiving maintenance therapy with ciclosporin, the mean C_max and AUC at steady state (with the drug used at an average dose of 100 mg/day) are 793 ng/ml and 2741 h×ng/ml, respectively.

Distribution

Ciclosporin is distributed mostly outside the bloodstream (apparent volume of distribution is 3.5 L/kg).

Distribution in blood depends on the concentration of ciclosporin: on average, 33-47% of ciclosporin is in plasma, 4-9% in lymphocytes, 5-12% in granulocytes, and 41-58% in erythrocytes.

At high drug concentrations, the concentration of ciclosporin in leukocytes and erythrocytes increases.

In blood, binding to plasma proteins (mainly lipoproteins) is approximately 90%.

Metabolism

Ciclosporin is extensively biotransformed by the cytochrome P-450 system (isoenzyme CYP450 3A4), forming approximately 15 metabolites.

The main pathways of metabolism are monohydroxylation, dihydroxylation, and N-demethylation.

All identified metabolites contain the peptide structure of the unchanged drug.

Some of the metabolites have a slight immunosuppressive effect (up to 10% of that of ciclosporin).

Excretion

The value of the terminal elimination half-life (T_1/2) of ciclosporin is highly variable, depending on the determination method used and the patient population studied.

The terminal half-life is approximately 6.3 hours in healthy volunteers, 7-16 hours in kidney transplant patients, and 20.4 hours in patients with severe liver disease.

The drug is excreted mainly in the bile, and only 6% of the orally administered dose is excreted in the urine (only 0.1% is excreted unchanged).

Pharmacokinetics in special clinical cases

Patients aged ≥ 65 years

There are no data on drug absorption in elderly patients.

However, when the drug is used in this category of patients, the distribution of ciclosporin is similar to that in patients under 65 years of age.

Patients aged ≤ 18 years

Since on average, patients aged ≤ 18 years have faster elimination of ciclosporin compared to adults, higher doses of the drug (calculated per body weight) may be required in this category of patients to achieve the required plasma concentration of ciclosporin.

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 in the bile through the intestine.

Patients with impaired liver function

In patients with impaired liver function, the elimination of ciclosporin is slowed.

Indications

Transplantation

Solid organ transplantation

• Prevention of rejection of kidney, liver, heart, lung, pancreas allografts, as well as combined heart-lung transplant;
• Treatment of transplant rejection in patients previously treated with other immunosuppressants.

Bone marrow transplantation

• Prevention of transplant rejection after bone marrow transplantation;
• Prevention and treatment of graft-versus-host disease (GVHD).

Non-transplant indications

Endogenous uveitis

• Active vision-threatening intermediate or posterior uveitis of non-infectious etiology when previous treatment is ineffective or intolerable;
• Behçet’s uveitis with recurrent attacks of inflammation involving the retina.

Nephrotic syndrome

• Steroid-dependent and steroid-resistant nephrotic syndrome in adults and children caused by glomerular pathology such as minimal change nephropathy, focal and segmental glomerulosclerosis, membranous glomerulonephritis. Maintenance of remission induced by glucocorticosteroids with the possibility of their withdrawal.

Rheumatoid arthritis in adults

• Treatment of severe forms of active rheumatoid arthritis.

Psoriasis

• Treatment of severe forms of psoriasis when conventional therapy is ineffective or cannot be used.

Atopic dermatitis

• Severe forms of atopic dermatitis when systemic therapy is required.

ICD codes

Dosage Regimen

Solution

Transplantation

For adults, Ciclosporin is usually prescribed together with other immunosuppressive agents.

The initial dose is 10-14 mg/kg/day in 2 divided doses at 12-hour intervals for 1-2 weeks after surgery.

Then, the concentration of ciclosporin in the blood plasma is monitored and the dose is gradually reduced to 2-6 mg/kg/day, also in 2 divided doses.

The therapeutic range of ciclosporin plasma concentrations during subsequent use is from 100 to 400 ng/ml.

In kidney transplantation, when using ciclosporin in doses less than 3-4 mg/kg and with a ciclosporin plasma concentration of about 100 ng/ml, there is a risk of developing rejection reactions.

For some patients one month after transplantation, when taking corticosteroids concomitantly, a dose of less than 5 mg/kg is recommended.

In bone marrow transplantation, short-term use of ciclosporin in combination with methotrexate is usually recommended.

The dose of ciclosporin is selected individually (1-2 days before surgery, intravenous administration of ciclosporin at a dose of 2.5-5 mg/kg/day is recommended).

After surgery, as soon as oral administration becomes possible, switch to oral administration at a dose of 12.5 mg/kg/day (in 2 divided doses) for 3-6 months.

Then the dose is gradually reduced until the course of treatment is completely finished.

When conducting therapy for acute graft-versus-host reaction, the initial dose of ciclosporin is 12.5-15 mg/kg/day in 2 divided doses.

After 50 days, the dose is reduced by 5% each time per week and therapy is discontinued after approximately 20 weeks.

If acute reaction recurs after discontinuation of ciclosporin, therapy should be restarted.

If transient gastrointestinal complaints are observed when taking ciclosporin for organ transplantation, bone marrow transplantation, and acute graft-versus-host reaction, one-third of the recommended daily dose can be administered once intravenously (in the appropriate dosage form).

The duration of use of ciclosporin in organ transplantation (except for therapy of acute graft-versus-host reaction) is determined individually.

Other diseases

For severe endogenous uveitis, the initial dose of ciclosporin is 5-10 mg/kg/day in 2 divided doses until inflammation decreases and visual acuity improves.

In acute cases, prednisolone at a dose of 200-600 mcg/kg/day or another similar corticosteroid can be additionally prescribed.

During maintenance therapy, the dose should be gradually reduced to achieve the minimum effective dose.

The therapeutic level of ciclosporin blood concentration is from 100 to 150 ng/ml.

The duration of use is from 3 to 16 months.

For severe forms of psoriasis, the drug is recommended to be prescribed at a dose of 2.5 mg/kg/day in 2 divided doses.

If no improvement in skin condition is observed after 1 month of therapy, the dose can be gradually increased by 1 mg/kg, up to a maximum of 5 mg/kg/day in 2 divided doses.

When repeating treatment, Ciclosporin should be used at the minimum effective dose.

If significant improvement does not occur after 6 weeks of using ciclosporin at a dose of 5 mg/kg/day, the drug should be discontinued.

The duration of use is generally 12 weeks.

For nephrotic syndrome with normal renal function, it is recommended to prescribe the drug to adults at a daily dose not exceeding 5 mg/kg, and to children – not exceeding 6 mg/kg, in 2 divided doses.

For patients with impaired renal function, the initial dose of ciclosporin should not exceed 2.5 mg/kg.

If serum creatinine levels in adults are above 200 µmol/L and in children – above 140 µmol/L, the use of ciclosporin is contraindicated.

In cases of severe liver dysfunction, the initial dose of ciclosporin should be reduced by 25-50%.

For patients with corticosteroid-resistant nephrotic syndrome, in case of insufficient effectiveness of ciclosporin alone, its combination with low doses of corticosteroids is recommended.

If symptoms of nephrotic syndrome persist after 3 months of treatment with ciclosporin, the drug should be discontinued.

For severe rheumatoid arthritis, during the first 6 weeks of therapy, the recommended daily dose of ciclosporin is 2.5 mg/kg in 2 divided doses.

If the drug is poorly tolerated, the dose can be reduced.

Then the dose is set individually, depending on the clinical manifestations of the disease and tolerability; the drug should be used at the minimum effective dose.

The daily dose should not exceed 4 mg/kg.

In emergency cases, it is possible to increase the dose of ciclosporin to 5 mg/kg/day.

Ciclosporin can be prescribed in combination with low doses of corticosteroids and/or NSAIDs.

If there is no therapeutic effect after 3 months of treatment, the drug should be discontinued.

For severe forms of atopic dermatitis, to relieve acute symptoms of the disease, the drug is used at a daily dose of 2.5 mg/kg in 2 divided doses.

If no significant improvement is observed after 2 weeks of treatment, it is necessary to increase the dose of ciclosporin to a maximum of 5 mg/kg/day.

In isolated, most severe cases, the use of ciclosporin at an initial dose of 5 mg/kg is required.

Upon improvement, the daily dose should be gradually reduced.

If no significant improvement is observed after 6 weeks of treatment, or if effective doses do not correspond to those recommended above, the drug must be discontinued.

As a rule, therapy for 6-8 weeks is sufficient for the disappearance of clinical symptoms of the disease.

Capsules

The drug is taken orally, regardless of meals.

The daily dose of Sandimmun^® Neoral^® should always be divided into 2 doses: in the morning and in the evening.

The oral dose ranges provided below should be considered as recommendations only.

Standard monitoring of ciclosporin blood concentration should be performed, possibly using a radioimmunoassay method based on the use of monoclonal antibodies.

Based on the results obtained, the dose required to achieve the desired ciclosporin plasma concentration in different patients is determined.

If therapy with Sandimmun^® Neoral^® in capsule form in 2 divided doses in equal doses in the morning and evening is ineffective (especially in patients with low body weight), the following is possible

• Use of different doses of the drug in the morning and evening;
• Use of the oral solution.

In patients receiving Ciclosporin for non-transplant indications, monitoring of ciclosporin plasma concentration is not of significant importance.

Exceptions are cases of disease recurrence during ciclosporin therapy, which may be associated with a decrease in ciclosporin plasma concentration due to non-adherence to treatment, impaired gastrointestinal absorption, or pharmacokinetic interaction.

Transplantation

Solid organ transplantation

Treatment with Sandimmun^® Neoral^® should be started 12 hours before transplantation at a dose of 10 to 15 mg/kg/day, divided into 2 doses.

For 1-2 weeks after surgery, the drug is used daily at the same dose, after which the dose is gradually reduced under the control of ciclosporin blood concentration until a maintenance dose of 2-6 mg/kg/day, divided into 2 doses, is reached.

If Sandimmun^® Neoral^® is used as part of combination therapy regimens with other immunosuppressants (e.g., with glucocorticosteroids as part of triple or quadruple therapy), its dose may be reduced (e.g., 3-6 mg/kg/day in 2 divided doses).

Bone marrow transplantation

The initial dose should be taken on the day preceding transplantation.

It is recommended to start therapy with the drug at a dose of 12.5-15 mg/kg/day in 2 divided doses.

Maintenance therapy is carried out for at least 3 months (preferably 6 months), after which the dose is gradually reduced until complete withdrawal of the drug within 1 year after transplantation.

Patients with digestive system diseases accompanied by reduced absorption may require higher doses of Sandimmun^® Neoral^® or the use of ciclosporin as intravenous infusions.

After discontinuation of Sandimmun^® Neoral^®, some patients may develop graft-versus-host disease (GVHD), which usually regresses after resumption of therapy.

In such cases, the drug should be used at an initial loading dose of 10-12.5 mg/kg/day and then continue therapy with the drug at a maintenance dose previously considered satisfactory.

For the treatment of this condition in its chronic, mild form, Sandimmun^® Neoral^® should be used in low doses.

Non-transplant indications

When using Sandimmun^® Neoral^® for any of the non-transplant indications, the following general rules should be observed.

• Before starting therapy, the baseline plasma creatinine concentration must be determined at least twice, and renal function must be regularly monitored.
• The total daily dose should not exceed 5 mg/kg, except for the total daily dose in patients with vision-threatening endogenous uveitis and in children with nephrotic syndrome.
• For maintenance therapy, the smallest effective and well-tolerated dose of the drug should be individually selected.
• In cases where clinical efficacy cannot be achieved with the drug therapy within a certain period (depending on the indication), or achieving an effective dose is not compatible with safety, treatment with Sandimmun^® Neoral^® should be discontinued.

Endogenous Uveitis

Achieving Remission

To achieve remission, the drug is used at an initial dose of 5 mg/kg/day, divided into 2 doses, until the signs of active inflammation disappear and visual acuity improves. If the initial dose is insufficiently effective, therapy with the drug can be carried out at a dose of up to 7 mg/kg/day, divided into 2 doses, for a short period.

To achieve remission more quickly (to reduce the severity of inflammatory reactions) and/or in cases where monotherapy with Sandimmun^® Neoral^® is not sufficiently effective, additional therapy with glucocorticosteroids, for example, prednisolone at a dose of 0.2-0.6 mg/kg/day or another glucocorticoid drug at an equivalent dose, is possible.

Treatment with Sandimmun^® Neoral^® should be discontinued if there is no improvement in the patient’s condition 3 months after the start of therapy.

Maintaining Remission

During maintenance therapy, the dose of the drug should be slowly reduced until the lowest effective dose is reached, which during the disease remission period should not exceed 5 mg/kg/day, divided into 2 doses.

Psoriasis

Achieving Remission

Psoriasis therapy should be individualized due to the different variants of the disease course. 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 Sandimmun^® Neoral^® should be discontinued if, after 6 weeks of using the maximum dose of 5 mg/kg/day, divided into 2 doses, sufficient clinical effect is not observed or if the effective dose of the drug does not meet established safety parameters.

Maintaining Remission

For maintenance therapy, the drug is used at 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 Sandimmun^® Neoral^® until its complete discontinuation.

Atopic Dermatitis

Achieving Remission

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

Maintaining Remission

Upon achieving a satisfactory response to therapy, the dose of the drug should be gradually reduced until, if possible, complete discontinuation. If a disease relapse occurs, repeated treatment with the drug in a subsequent course is possible.

Although an 8-week course of treatment may be sufficient to clear the skin, therapy lasting up to 1 year has been shown to be effective and well-tolerated, provided that all necessary parameters are monitored.

Treatment with Sandimmun^® Neoral^® should be discontinued if, after 4 weeks of using the maximum dose of 5 mg/kg/day, divided into 2 doses, a satisfactory clinical effect is not observed.

Rheumatoid Arthritis

Achieving Remission

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

Maintaining Remission

For maintenance therapy, the dose should be selected individually depending on the drug tolerance; the dose of the drug for maintenance therapy should be the minimum effective.

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

Nephrotic Syndrome

Achieving 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 renal function, excluding proteinuria. In patients with moderate renal impairment (plasma creatinine concentration 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 doses. The dose must be selected individually, taking into account efficacy (proteinuria) and safety (plasma creatinine concentration) indicators, but should not exceed 5 mg/kg/day, divided into 2 doses for adults and 6 mg/kg/day, divided into 2 doses for children.

Maintaining Remission

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

Since in patients of this category, the use of Sandimmun^® Neoral^® may lead to the development or progression of renal function impairment, renal function should be carefully monitored during the use of the drug. If the plasma creatinine concentration increases by more than 30% compared to baseline values, the dose of Sandimmun^® Neoral^® should be reduced by 25-50%. Careful monitoring of these patients is necessary.

If there is no improvement in the patient’s condition after 3 months of treatment, Sandimmun^® Neoral^® should be discontinued.

If satisfactory effect cannot be achieved with Sandimmun^® Neoral^® monotherapy, especially in steroid-resistant patients, its combination with low doses of oral glucocorticosteroids is recommended.

In some cases, in patients with nephrotic syndrome receiving Sandimmun^® Neoral^®, it was difficult to identify the causes of renal function impairment (since the cause could be either the drug treatment or the underlying disease). In rare cases, patients with nephrotic syndrome showed changes in renal tissue structure caused by the use of the drug and not accompanied by a pronounced increase in plasma creatinine concentration. Thus, in patients with steroid-dependent nephropathy with minimal changes receiving treatment with the drug for more than a year, the possibility of a kidney biopsy should be considered.

Use in Specific Patient Groups

Patients with Renal Impairment

All Indications

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

Non-transplant Indications

The use of ciclosporin in patients with renal impairment, except for nephrotic syndrome, is contraindicated. In patients with nephrotic syndrome and renal impairment, the initial dose of the drug should not exceed 2.5 mg/kg/day. If the plasma creatinine concentration increases by more than 50% compared to the baseline value, it is necessary to reduce the ciclosporin dose by more than 50%.

Patients with Hepatic Impairment

A dose reduction may be required in patients with severe hepatic impairment to maintain the drug concentration in the plasma within the recommended range.

Patients Aged ≤ 18 Years

There is no experience with the use of Sandimmun^® Neoral^® in children under 1 year of age. When using Sandimmun^® Neoral^® in recommended doses in children over 1 year of age, the safety profile of the drug was similar to that in adult patients. A number of studies have established that in this category of patients, higher doses of the drug (calculated per body weight) may be used to achieve the required ciclosporin concentration in plasma.

In children, Sandimmun^® Neoral^® should not be used for non-transplant indications, except for nephrotic syndrome.

Patients Aged ≥ 65 Years

Experience with the use of Sandimmun^® Neoral^® in this category of patients is limited; when using the drug in recommended doses, no disorders of particular concern were identified. In patients with rheumatoid arthritis aged ≥65 years, systolic arterial hypertension and an increase in plasma creatinine concentration by ≥ 50% above the baseline value developed more frequently during ciclosporin therapy for 3-4 months.

The ciclosporin dose for patients in this age group must be carefully selected, starting with the lowest, due to the higher frequency of hepatic, renal, or cardiac impairment, as well as the development of pathological conditions due to the presence of concomitant diseases and simultaneous use of other medications.

Adjustment of the Dosing Regimen in Case of Renal Function Impairment in Patients with Endogenous Uveitis, Psoriasis, Atopic Dermatitis, and Rheumatoid Arthritis

Since the use of Sandimmun^® Neoral^® may lead to renal function impairment, the baseline plasma creatinine concentration must be determined before starting the drug, in at least two measurements. Plasma creatinine concentration should be determined at weekly intervals for the first 2 months after the start of therapy. Subsequently, if the plasma creatinine concentration remains stable, determination should be performed monthly. More frequent monitoring is necessary when increasing the dose of Sandimmun^® Neoral^® and when using concomitant therapy with non-steroidal anti-inflammatory drugs or when increasing their dose.

If the plasma creatinine concentration increases by more than 30% compared to baseline values in two or more measurements (even if the creatinine concentration remains within the normal range), the dose of Sandimmun^® Neoral^® should be reduced by 25-50%. If the creatinine concentration increases by more than 50% compared to the baseline value, the possibility of a further dose reduction should be considered.

If the dose reduction does not lead to a decrease in plasma creatinine concentration within one month, treatment with Sandimmun^® Neoral^® must be discontinued.

Adverse Reactions

The most common adverse events (AEs) during therapy with Sandimmun^® Neoral^®, identified in clinical studies, include renal function impairment, tremor, hirsutism, arterial hypertension, diarrhea, anorexia, nausea, vomiting, microangiopathic hemolytic anemia, and post-transplant distal limb syndrome.

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

Cases of anaphylactoid reactions have been noted with intravenous administration of ciclosporin.

Infections

In patients receiving immunosuppressive treatment with ciclosporin or combination therapy including Ciclosporin, the risk of developing local and generalized infections (of viral, bacterial, fungal etiology) and parasitic infestations increases. Exacerbation of pre-existing infectious diseases or reactivation of polyomavirus infection from a latent state, leading to the development of polyomavirus nephropathy, especially associated with BK virus, or multifocal leukoencephalopathy associated with JC virus, is also possible. The development of severe infectious lesions, in some cases with fatal outcome, has been reported.

Lymphoproliferative Disorders and Malignancies

In patients receiving immunosuppressive treatment with ciclosporin or combination therapy including Ciclosporin, the risk of developing lymphomas, lymphoproliferative disorders, and malignancies, especially of the skin, increases. The frequency of malignancy development increases with the intensity and duration of immunosuppressive therapy.

The data below summarize information on AEs registered during clinical studies, as well as data on the drug’s safety profile obtained during its use in clinical practice. AEs are grouped according to the MedDRA classification of organ systems and are listed in order of decreasing significance. Criteria for assessing the frequency of adverse reactions: very common (≥1/10), common (≥1/100; <1/10), uncommon (≥1/1000; <1/100), rare (≥1/10,000; <1/1000), very rare (<1/10,000), including isolated reports. Since reports of AEs in the post-marketing period are received voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency of occurrence, therefore for these AEs the frequency is stated as “frequency unknown”.

Blood and Lymphatic System Disorders common – leukopenia; uncommon – anemia, thrombocytopenia; rare – thrombotic microangiopathy (including thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome).

Metabolism and Nutrition Disorders: very common – hyperlipidemia; common – anorexia, hyperuricemia, hyperkalemia, hypomagnesemia; rare – hyperglycemia.

Nervous System Disorders very common – tremor, headache, including migraine; common – paresthesia; uncommon – signs of encephalopathy, including the development of posterior reversible encephalopathy syndrome (PRES) with manifestations such as seizures, confusion, disorientation, slowed reactions, agitation, insomnia, visual impairment, cortical blindness, coma, paresis, cerebellar ataxia; rare – motor polyneuropathy; very rare – optic disc edema (including papilledema) with possible visual impairment due to benign intracranial hypertension.

Vascular Disorders very common – increased blood pressure (15-40%); common – flushing.

Gastrointestinal Disorders very common – decreased appetite, nausea, vomiting, abdominal discomfort, diarrhea, gingival hyperplasia; common – peptic ulcer.

Hepatobiliary Disorders very common – hepatotoxicity; rare – pancreatitis.

Skin and Subcutaneous Tissue Disorders very common – hypertrichosis; common – acne, rash; uncommon – skin allergic reactions.

Musculoskeletal and Connective Tissue Disorders common – muscle spasms, myalgia; rare – muscle weakness, myopathy; frequency unknown – lower limb pain.

Renal and Urinary Disorders very common – renal function impairment (the frequency of this AE is 10-50% depending on the indication).

Reproductive System and Breast Disorders rare – menstrual pain, gynecomastia.

General Disorders and Administration Site Conditions common – fatigue, fever, edema; uncommon – increased body weight.

In the post-marketing period, cases of hepatotoxic effects of ciclosporin have been noted, including cholestasis, jaundice, hepatitis, and liver failure. As a rule, these patients had concomitant diseases, predisposing conditions, other risk factors, including infectious complications, or received Ciclosporin simultaneously with other drugs with hepatotoxic effects. Some cases, mainly in transplant patients, had a fatal outcome.

Lower Limb Pain

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

Contraindications

For All Indications

• Hypersensitivity to ciclosporin or any other component of the drug;
• Children under 3 years of age (for this dosage form).

For Non-transplant Indications

• Renal impairment (except for patients with nephrotic syndrome and plasma creatinine concentration not more than 200 μmol/L in adults and 140 μmol/L in children);
• Uncontrolled arterial hypertension;
• Infectious diseases not amenable to adequate therapy;
• Malignant neoplasms;
• Children under 18 years of age for all non-transplant indications, except for nephrotic syndrome.

With Caution

Sandimmun^® Neoral^® should be used with caution in patients aged ≥ 65 years, patients with hyperkalemia and hyperuricemia, liver diseases, Behçet’s disease with neurological manifestations, traumatic brain injury or brain diseases, epilepsy, alcoholism.

Use in Pregnancy and Lactation

Adequate or well-controlled clinical studies in pregnant women taking Ciclosporin have not been conducted.

Experience with the use of ciclosporin in pregnant women is limited to post-registration data, including scientific publications.

In pregnant women who have undergone organ transplantation and are receiving immunosuppressive treatment with ciclosporin or combination therapy including the use of ciclosporin, there is a risk of premature birth (at a gestational age of less than 37 weeks).

Available data have not demonstrated an increase in the frequency of miscarriage, serious congenital malformations, or events in the pregnant woman compared to the general population.

Studies of the toxic effects of ciclosporin on embryo-fetal development in rats and rabbits showed embryofetal toxicity at a dose below the maximum recommended for human use, based on body surface area.

Data from the National Transplantation Pregnancy Registry have been published, describing pregnancy outcomes in women receiving Ciclosporin after kidney (482), liver (97), and heart (43) transplantation. Successful pregnancy with a live birth rate was noted in 76%, 76.9%, and 64% of women after kidney, liver, and heart transplantation, respectively. Preterm delivery (before 37 weeks of gestation) was recorded in 52%, 35%, and 35% of women after kidney, liver, and heart transplantation, respectively.

This rate of pregnancy loss and serious congenital malformations is comparable to that in the general population. Given the limitations inherent in registries and post-marketing safety reports, it is not possible to directly establish the influence of ciclosporin on the frequency of hypertension, pre-eclampsia, infections, or maternal diabetes mellitus.

There is a limited number of observations of children (up to the age of seven years) exposed to ciclosporin during intrauterine development. No deviations from the norm in renal function parameters and blood pressure were noted in these children.

The drug should not be used during pregnancy, except in cases where the expected benefit to the mother outweighs the potential risk to the fetus.

Ciclosporin passes into breast milk. The presence of ethanol in the capsule composition should be taken into account. Since Sandimmun^® Neoral^® can cause serious adverse reactions in children of such patients, breastfeeding should be discontinued or drug administration stopped, based on the benefit of breastfeeding for the child or the importance of therapy for the patient.

The ratio of ciclosporin concentration in breast milk relative to its concentration in maternal blood ranged from 0.17 to 1.4. Based on breast milk intake, the highest estimated dose of ciclosporin ingested by a fully breastfed infant was approximately 2% of the mother’s weight-adjusted dose.

There are no specific recommendations for women with preserved reproductive potential.

There are limited data on the effect of Sandimmun^® Neoral^® on human fertility.

No reduction in fertility was established in rats of both sexes at a ciclosporin dose of up to 5 mg/kg/day (below the maximum recommended human dose based on body surface area).

Use in Hepatic Impairment

A dose reduction may be required in patients with severe hepatic impairment to maintain the drug plasma concentration within the recommended range.

Use in Renal Impairment

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

The use of ciclosporin in patients with impaired renal function for non-transplant indications, except for 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. If the plasma creatinine concentration increases by more than 50% compared to the baseline value, it is necessary to reduce the ciclosporin dose by more than 50%.

Pediatric Use

There is no experience with the use of Sandimmun^® Neoral^® in children under 1 year of age. When Sandimmun^® Neoral^® was used at recommended doses in children over 1 year of age, the safety profile of the drug was similar to that in adult patients. A number of studies have established that in this category of patients, higher doses of the drug (calculated per body weight) may be used to achieve the required plasma ciclosporin concentration.

Soft capsules are not prescribed to children under 3 years of age.

Sandimmun^® Neoral^® should not be used in children under 18 years of age for non-transplant indications, except for nephrotic syndrome.

Geriatric Use

Experience with the use of Sandimmun^® Neoral^® in elderly patients is limited; no abnormalities requiring special attention were identified when the drug was used at recommended doses. In patients with rheumatoid arthritis aged ≥65 years, systolic arterial hypertension and an increase in plasma creatinine concentration by ≥ 50% above the baseline value developed more frequently during therapy with ciclosporin for 3-4 months.

The dose of ciclosporin for patients in this age category should be carefully selected, starting with the lowest dose, due to the higher frequency of impaired liver, kidney, or heart function, as well as the development of pathological conditions due to concomitant diseases and the simultaneous use of other drugs.

Renal function should be monitored with particular care in elderly patients.

Special Precautions

Therapy with Sandimmun^® Neoral^® should be carried out only by physicians experienced in the use of immunosuppression after transplantation.

Monitoring of ciclosporin plasma concentration

To ensure safety when using Sandimmun^® Neoral^® in post-transplant patients, it is important to monitor the blood concentration of ciclosporin.

For monitoring ciclosporin blood concentration (measuring the amount of unchanged drug), the use of specific monoclonal antibodies, as well as the high-performance liquid chromatography (HPLC) method, is preferable. When using plasma or serum, a standard separation technique (time and temperature) should be followed. The initial determination of ciclosporin concentration in patients with a liver transplant should be performed using specific monoclonal antibodies or a parallel determination using both specific and non-specific monoclonal antibodies should be performed to achieve a dose that provides adequate immunosuppression.

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

Impairments of renal and hepatic function

During the first few weeks of therapy with Sandimmun^® Neoral^®, a frequent and potentially dangerous complication may occur – an increase in plasma creatinine and urea concentrations. These functional changes are reversible and dose-dependent, normalizing when the drug dose is reduced. During long-term treatment, some patients may develop structural changes in the kidneys (e.g., arteriolar hyalinosis, tubular atrophy, and interstitial fibrosis), which in patients with a kidney transplant should be differentiated from changes in chronic rejection. Careful monitoring of renal function should be carried out. If impaired renal function is detected, a dose reduction of the drug may be required.

Sandimmun^® Neoral^® can also cause a dose-dependent reversible increase in plasma bilirubin concentration and liver enzyme activity.

Post-marketing reports have been received of cases of hepatotoxicity with the development of cholestasis, jaundice, hepatitis, and liver failure in patients receiving Ciclosporin. Some cases were fatal, mainly in post-transplant patients. Typically, such patients had comorbidities, predisposing conditions, other risk factors, or were receiving Ciclosporin concomitantly with other hepatotoxic drugs. In these cases, careful monitoring of liver function parameters is required. If these parameters deviate from the norm, a dose reduction of Sandimmun^® Neoral^® may be required.

Elderly patients

Renal function should be monitored with particular care in elderly patients.

Blood pressure (BP) monitoring

Regular blood pressure monitoring is required during treatment with Sandimmun^® Neoral^®. If BP increases, appropriate antihypertensive therapy should be applied. Preference should be given to antihypertensive drugs that do not affect the pharmacokinetics of ciclosporin.

Changes in blood biochemical composition

Since there are rare reports of the development of mild reversible hyperlipidemia during ciclosporin therapy, it is recommended to determine plasma lipid concentrations before starting and 1 month after starting treatment. If hyperlipidemia is detected, a fat-restricted diet should be recommended and, if necessary, the drug dose should be reduced.

Ciclosporin increases the risk of hyperkalemia, especially in patients with impaired renal function. Caution should be exercised when using ciclosporin concomitantly with potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, and potassium-containing drugs, as well as in cases of using a potassium-enriched diet. In these cases, blood potassium levels should be monitored.

Ciclosporin increases magnesium excretion, which can lead to symptomatic hypomagnesemia, especially in the peritransplant period. In this regard, blood magnesium levels should be monitored during this period, especially if neurological symptoms appear. Magnesium preparations are used if necessary.

Treatment with the drug should be carried out with caution in patients with hyperuricemia, with monitoring of plasma uric acid concentration, especially in patients with pre-existing hyperuricemia.

Additional instructions for use in endogenous uveitis

Sandimmun^® Neoral^® should be used with caution in patients with neurological manifestations of Behçet’s disease. Neurological status should be carefully monitored in this category of patients.

Experience with the use of Sandimmun^® Neoral^® in children with endogenous uveitis is limited.

Additional instructions for use in nephrotic syndrome

In some cases, in patients with nephrotic syndrome receiving Sandimmun^® Neoral^®, it was difficult to identify the causes of impaired renal function (since the cause could be either treatment with the drug or the underlying disease). In rare cases, patients with nephrotic syndrome observed changes in renal tissue structure caused by the use of the drug and not accompanied by a pronounced increase in plasma creatinine concentration. Thus, in patients with steroid-dependent minimal change nephropathy receiving treatment with the drug for longer than one year, the possibility of performing a kidney biopsy should be considered.

In rare cases, patients with nephrotic syndrome treated with immunosuppressants (including ciclosporin) experienced the development of malignant neoplasms (including Hodgkin’s lymphoma).

Additional instructions for use in psoriasis

In patients treated with ciclosporin, as in patients treated with other immunosuppressive drugs, cases of lymphoma and other malignant neoplasms, particularly of the skin, have been reported. A skin biopsy should be performed for lesions suspected of malignancy.

The drug should be used in patients of this category only after adequate therapy has been carried out, and only in the absence of the possibility of successful alternative therapy.

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

Additional instructions for use in atopic dermatitis

Benign lymphadenopathy is often associated with periods of exacerbation of atopic dermatitis and usually resolves spontaneously or with a decrease in disease activity.

Patients with lymphadenopathy receiving treatment with ciclosporin should be carefully monitored. If there is no reduction in signs of lymphadenopathy despite a decrease in disease activity, a biopsy of the affected lymph nodes should be performed to rule out the development of lymphoma.

Active herpes simplex virus infection should be treated before starting ciclosporin. Exacerbation of this disease, however, is not a reason to discontinue ciclosporin treatment if it has already been started, except in cases of severe infection.

The presence of a skin infection caused by Staphylococcus aureus in a patient is not an absolute contraindication for therapy with Sandimmun^® Neoral^®, but requires adequate treatment with appropriate antibacterial therapy. The simultaneous use of oral dosage forms of erythromycin and ciclosporin should be avoided due to an increase in the blood concentration of the latter. If alternative therapy is not possible, concomitant treatment with these drugs should be carried out with careful monitoring of ciclosporin plasma concentration, monitoring of renal function, and vigilance for the development of ciclosporin adverse reactions.

Replacement of Sandimmun^® Neoral^® with other oral ciclosporin drugs

Switching from Sandimmun^® Neoral^® to another oral ciclosporin drug should be done with caution under appropriate medical supervision. Standard monitoring of ciclosporin plasma concentration must be carried out to ensure that after the switch, the ciclosporin plasma concentrations correspond to those before the switch. The two dosage forms of Sandimmun^® Neoral^®, soft gelatin capsules and oral solution, are bioequivalent.

Use of Sandimmun^® Neoral^® with other immunosuppressants

It should be borne in mind that when using ciclosporin, as well as other immunosuppressants, the risk of developing lymphomas and other malignant neoplasms, more often of the skin, increases. The increased risk of developing this complication is associated more with the duration and degree of immunosuppression than with the use of any particular drug. Thus, caution should be exercised when using combined regimens of immunosuppressive therapy, bearing in mind the likelihood of developing lymphoproliferative disorders and solid organ tumors, which infrequently lead to fatal outcomes.

Infections

The use of ciclosporin, like other immunosuppressants, predisposes to the occurrence of various bacterial, fungal, parasitic, and viral infections, often associated with opportunistic pathogens. In patients treated with ciclosporin, reactivation of polyomavirus infection from a latent state has been reported, leading to the development of polyomavirus nephropathy, especially associated with BK virus, or multifocal leukoencephalopathy caused by JC virus. These conditions are due to a high overall burden of immunosuppressive drugs. The development of such conditions should be taken into account in the differential diagnosis of causes of renal and nervous system dysfunction in patients receiving immunosuppressive therapy. Given the potential life-threatening nature of these infections, an effective system of preventive and therapeutic measures should be applied, especially in cases of long-term use of combined immunosuppressive treatment.

Lymphoproliferative disorders and solid malignant neoplasms

During long-term immunosuppressive treatment (including therapy with ciclosporin), the risk of developing lymphoproliferative disorders and solid malignant neoplasms increases. When using the drug, appropriate monitoring of patients should be ensured to detect these conditions at an early stage. If lymphoproliferative disorders, solid malignant neoplasms, or pre-tumor conditions are detected, treatment with the drug must be discontinued.

Exposure to direct sunlight, UV-B radiation, and photochemotherapy

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

Special components: ethanol

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

Vaccination

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

Monitoring of laboratory parameters is necessary in patients with cystic fibrosis.

Effect on ability to drive vehicles and operate machinery

Some side effects of the drug, including dizziness or visual disturbances, may adversely affect the ability to drive vehicles and perform potentially hazardous activities requiring increased concentration and speed of psychomotor reactions. Caution is required when driving vehicles or operating machinery. If the described adverse events occur, one should refrain from these activities.

No studies have been conducted on the effect of Sandimmun^® Neoral^® on driving vehicles and operating machinery.

Overdose

Symptoms data on cases of overdose with Sandimmun^® Neoral^® are limited. When ciclosporin was taken orally in doses up to 10 g (about 150 mg/kg), mild clinical manifestations such as vomiting, dizziness, headache, and tachycardia were noted in most cases. In isolated cases, the development of moderate renal impairment was observed. However, in cases of accidental parenteral overdose with ciclosporin in premature infants in the neonatal period, the development of severe toxic complications has been reported.

Treatment symptomatic therapy, there is no specific antidote. Within the first 2 hours after oral intake, the drug can be removed from the body by inducing vomiting or by gastric lavage. Ciclosporin is practically not removed by hemodialysis and hemoperfusion using activated charcoal.

Drug Interactions

Combinations with ciclosporin not recommended for use

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

Combinations with ciclosporin requiring caution

Caution should be exercised when using ciclosporin together with potassium-sparing drugs (potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists) or drugs containing potassium, as their simultaneous use with ciclosporin may lead to severe hyperkalemia.

When ciclosporin and lercanidipine are used concomitantly, the AUC of lercanidipine increases 3-fold and the AUC of ciclosporin increases by 21%. Caution should be exercised when using ciclosporin and lercanidipine concomitantly.

Caution should be exercised when using Sandimmun^® Neoral^® with methotrexate in patients with rheumatoid arthritis due to the risk of increased overall nephrotoxicity.

Drugs that Decrease or Increase Cyclosporine Concentration

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

Ciclosporin is a substrate for P-glycoprotein, so inhibitors or inducers of P-glycoprotein can affect cyclosporine concentration.

When using cyclosporine with drugs that decrease or increase its bioavailability in transplant patients, frequent determination of cyclosporine concentration in plasma is necessary and, if required, the cyclosporine dose should be adjusted, especially at the initial stage of concomitant therapy or during its withdrawal.

In patients receiving Ciclosporin for indications not related to transplantation, monitoring of cyclosporine concentration in plasma is not of significant importance, since for this category of patients the relationship between blood concentration of the drug and clinical effects has not been clearly proven. When using cyclosporine together with drugs that increase its plasma concentration, frequent monitoring of renal function and observation for cyclosporine side effects are more important than determining the cyclosporine plasma concentration.

Drugs that decrease cyclosporine plasma concentration barbiturates, carbamazepine, oxcarbazepine, phenytoin, nafcillin, sulfadimidine when administered intravenously, orlistat, trimethoprim when administered intravenously, rifampicin, octreotide, probucol, preparations containing St. John’s wort (Hypericum perforatum), ticlopidine, sulfinpyrazone, terbinafine, bosentan.

Drugs that increase cyclosporine plasma concentration chloroquine, a number of macrolide antibiotics (e.g., erythromycin, azithromycin and clarithromycin), antifungal drugs (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 May Enhance the Nephrotoxic Effect of Cyclosporine

When cyclosporine is used concomitantly with drugs that may enhance its nephrotoxic effect, careful monitoring of renal function (in particular, determination of plasma creatinine concentration) is necessary.

In case of significant impairment of renal function, the drug dose should be reduced or the treatment regimen changed.

Caution should be exercised when using Sandimmun^® Neoral^® concomitantly with drugs possessing nephrotoxic effects: 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, as this may lead to an increased risk of nephrotoxicity.

Concomitant use of diclofenac and cyclosporine may significantly increase the bioavailability of the former, with possible development of reversible renal dysfunction. The increased bioavailability of diclofenac is most likely associated with a slowdown of its metabolism during the “first pass” through the liver. When NSAIDs with a less pronounced “first pass” effect (e.g., acetylsalicylic acid) are used concomitantly with cyclosporine, an increase in their bioavailability is not expected. NSAIDs with a pronounced “first pass” effect through the liver (e.g., diclofenac) should be used in lower doses than in patients not receiving Ciclosporin.

There are isolated reports of significant, but reversible, renal dysfunction (with a corresponding increase in plasma creatinine concentration) in transplant patients with concomitant use of cyclosporine and fibric acid derivatives (e.g., bezafibrate, fenofibrate), therefore, renal function should be monitored in these patients. In case of development of significant renal impairment, concomitant use of the aforementioned drugs should be discontinued.

Interactions Leading to Gingival Hyperplasia

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

Combinations that Increase the Concentration of Other Drugs

Since Ciclosporin is an inhibitor of the CYP3A4 isoenzyme and the membrane transporter P-glycoprotein, an increase in the plasma concentration of drugs that are substrates of the CYP3A4 isoenzyme and/or P-glycoprotein is possible when they are used concomitantly with cyclosporine.

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

Several cases of severe glycoside intoxication have been reported within a few days after starting cyclosporine treatment in patients taking digoxin. There are also reports that Ciclosporin may enhance the toxic effects of colchicine, such as the development of myopathy or neuropathy, especially in patients with impaired renal function. When cyclosporine is used concomitantly with digoxin or colchicine, careful clinical monitoring is necessary for the timely detection of toxic effects of these drugs and to decide on dose reduction or treatment discontinuation.

In clinical practice with cyclosporine, as well as from literature sources, cases of muscular toxicity have been reported, including muscle pain, weakness, myositis, and rhabdomyolysis during concomitant use of cyclosporine with lovastatin, simvastatin, atorvastatin, pravastatin and, in rare cases, fluvastatin. If it is necessary to use the aforementioned drugs concomitantly with cyclosporine, their dose should be reduced. Statin therapy should be temporarily discontinued or withdrawn in patients with symptoms of myopathy, as well as in patients with risk factors for the development of severe renal impairment, including renal failure secondary to rhabdomyolysis.

If concomitant use of cyclosporine and digoxin, colchicine, or HMG-CoA reductase inhibitors is necessary, patients should be carefully monitored for early diagnosis of toxic effects of these drugs, followed by dose reduction or complete therapy withdrawal.

An increase in creatinine concentration was observed in studies of concomitant use of everolimus or sirolimus with high doses of cyclosporine in microemulsion form. This effect is often reversible upon reduction of the cyclosporine dose. Everolimus and sirolimus have a minor impact on the pharmacokinetic parameters of cyclosporine. Concomitant use of cyclosporine with everolimus or sirolimus leads to a significant increase in the plasma concentration of the latter.

Caution should be exercised when using cyclosporine with potassium-sparing drugs (potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists) or potassium preparations, as concomitant use of cyclosporine with the aforementioned drugs may lead to the development of significant hyperkalemia.

Concomitant use of cyclosporine and repaglinide may lead to an increase in the plasma concentration of the latter and an increased risk of hypoglycemia.

In patients receiving Ciclosporin with bosentan, an increase in the plasma concentration of the latter is possible.

Concomitant use of cyclosporine and aliskiren resulted in an increase in C_max and AUC of aliskiren by 2.5 and 5 times, respectively. No changes in Cmax of cyclosporine were noted. In this regard, caution is recommended when using cyclosporine and aliskiren concomitantly.

Concomitant use of dabigatran and cyclosporine increases the plasma concentration of the former due to the ability of cyclosporine to exert an inhibitory effect on P-glycoprotein. Since dabigatran has a narrow therapeutic index, an increase in its plasma concentration may lead to an increased risk of bleeding.

With prolonged concomitant use of ambrisentan and cyclosporine, an increase in the plasma concentration of both drugs is possible.

In oncology patients, with concomitant use of the drug in high doses with anthracycline antibiotics (e.g., doxorubicin, mitoxantrone, daunorubicin), an increase in their plasma concentration upon intravenous administration was noted.

Combinations that Decrease the Concentration of Other Drugs

Concomitant use of cyclosporine and mycophenolate sodium/mycophenolate mofetil in transplant patients may reduce the average exposure to mycophenolic acid by 20-50% compared to other immunosuppressants. This information should be taken into account when prescribing these drugs together.

A single dose of cyclosporine (200 mg or 600 mg) together with a single dose of eltrombopag (50 mg) reduces the area under the pharmacokinetic curve of the latter by 18-24% and reduces the maximum plasma concentration by 25-39%. This reduction does not have a clinically significant impact.

If concomitant use of cyclosporine and drugs capable of interacting with it cannot be avoided, the following recommendations should be observed

When cyclosporine is used concomitantly with a drug possessing nephrotoxic effects, careful monitoring of renal function (in particular, determination of plasma creatinine concentration) is necessary. If significant impairment of renal function is detected, the dose of the concomitantly used drug should be reduced or the possibility of alternative treatment considered.

The likelihood of drug interactions increases in elderly patients.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years. Do not use the drug after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.