Instructions for use SANDIMMUN NEORAL® capsules

Sandimmun® neoral®

The drug is prescribed orally, regardless of food intake.

The daily dose of Sandimmune Neoral should always be divided into 2 doses.

Switching from Sandimmune® to Sandimmune® Neoral®

Available data show that when switching from taking Sandimmune to taking Sandimmune Neoral, while maintaining a 1:1 dose ratio, the values ​​of basal concentrations of cyclosporine determined in whole blood are comparable. Many patients, however, may experience higher maximum concentrations and increased duration of drug exposure (AUC). In a small percentage of patients, these changes are more noticeable and may be clinically significant. Their magnitude depends largely on individual differences in the absorption of cyclosporine from the initially used Sandimmune, the bioavailability of which is characterized by high variability. In patients with variable basal concentrations or receiving Sandimmune® in very high doses (including patients with cystic fibrosis, liver transplant patients with concomitant cholestasis or poor bile secretion, children or some kidney transplant patients), the absorption of cyclosporine may be low or inconsistent, however, when switching to Sandimmune® Neoral®, absorption may improve. As a result, in this patient population, after switching from Sandimmune to Sandimmune Neoral, while maintaining a 1:1 dose ratio, the increase in cyclosporine bioavailability may be more pronounced than is usually observed. Taking this into account, the dose of Sandimmune Neoral should be reduced by individual selection depending on the range of basal concentrations and the corresponding indications.

Absorption of cyclosporine from Sandimmune Neoral is less variable and the correlation between basal concentration and bioavailability (as measured by AUC values) is much greater than with Sandimmune. This makes the basal blood concentration of cyclosporine a clearer and more reliable parameter for therapeutic drug monitoring.

Because switching from Sandimmune to Sandimmune® Neoral® may lead to an increase in drug exposure; the following rules should be observed.

In patients after transplantation

treatment with Sandimmune Neoral should be started with the same daily dose as with the previous use of Sandimmune. The basal concentration of cyclosporine in whole blood should be monitored for 4-7 days after switching to Sandimmun® Neoral®. In addition, clinical safety parameters such as serum creatinine and blood pressure should be monitored during the first 2 months after switching. If the basal blood concentration of cyclosporine is outside the therapeutic range and/or deterioration in clinical safety parameters is observed, the dose should be adjusted accordingly.

In patients treated for non-transplant indications,

treatment with Sandimmune Neoral should be started with the same dose as when using Sandimmune. Serum creatinine concentrations and blood pressure should be monitored at 2, 4, and 8 weeks after transition. If serum creatinine concentrations or blood pressure levels increase markedly compared to those before switching, or if creatinine concentrations increase by more than 30% compared to pre-Sandimmun treatment values ​​in more than one dimension, then the dose should be reduced by 25-50 %. If serum concentration increases by more than 50%, then reduce the dose by 50%. In case of toxic effects or if the drug is ineffective, basal concentrations of cyclosporine in the blood should also be monitored.

The following oral dosage ranges should be considered guidelines only. Conventional monitoring of the concentration of cyclosporine in the blood should be carried out, for which a radioimmunological method based on the use of monoclonal antibodies can be used. Based on the results obtained, the dose required to achieve the desired concentration of cyclosporine in various patients is determined.

Transplantation

For solid organ transplantation

treatment with Sandimmune Neoral should be started 12 hours before surgery at a dose of 10 to 15 mg/kg body weight, divided into 2 doses. For 1-2 weeks after surgery, the drug is prescribed daily at the same dose, after which the dose is gradually reduced (under the control of the concentration of cyclosporine in the blood) until a maintenance dose of 2-6 mg/kg/day is reached (in 2 doses).

Sandimmun® Neoral® is prescribed in combination with other immunosuppressants, incl. with GCS, as well as as part of a combined three-component (Sandimmune® Neoral® + GCS + azathioprine) or four-component (Sandimmune® Neoral® + GCS + azathioprine + mono- or polyclonal antibody preparations) therapy. The four-component regimen is used in patients at high risk of developing rejection. If Sandimmune Neoral is used as part of combination therapy regimens, its dose can be reduced already at the initial stage of therapy (3-6 mg/kg/day in 2 doses) or adjusted during treatment taking into account the concentration of cyclosporine in the blood plasma and the dynamics of safety indicators ( concentration of urea, serum creatinine, blood pressure).

For bone marrow transplantation

The initial dose should be administered on the day before transplantation. In most cases, IV administration is preferred; The recommended dose is 3-5 mg/kg/day. Infusion administration at the same dose is continued for 2 weeks after transplantation, then switched to oral maintenance therapy with Sandimmune Neoral at a daily dose of about 12.5 mg/kg, divided into 2 doses. Maintenance therapy is carried out for at least 3 months (preferably 6 months), after which the dose is gradually reduced to zero within 1 year after transplantation. If Sandimmune® Neoral® is also prescribed for the initial stage of therapy, then the recommended daily dose is 12.5-15 mg/kg (in 2 divided doses) starting from the day before the transplant.

In the presence of gastrointestinal diseases leading to decreased absorption, higher doses of Sandimmune Neoral or, in some cases, the use of intravenous infusions of Sandimmune may be required.

After discontinuation of Sandimmune, some patients may develop GVHD, which usually regresses after resumption of therapy. To treat this condition in its chronic, mild form, Sandimmune® Neoral® should be used in low doses.

Indications not related to transplantation

With endogenous uveitis

to
induce remission
, the drug is prescribed at an initial daily dose of 5 mg/kg orally in 2 divided doses until signs of active inflammation disappear and visual acuity improves. In cases that are difficult to treat, the dose can be increased to 7 mg/kg/day for a short period.

If it is not possible to control the situation with Sandimmune Neoral alone, then to achieve initial remission or to stop an attack of inflammation, systemic corticosteroids can be added (prednisolone in a daily dose of 0.2-0.6 mg/kg or another glucocorticosteroid in an equivalent dose).

During maintenance therapy

the dose should be slowly reduced until the lowest effective dose is reached, which during the period of remission of the disease should not exceed 5 mg/kg/day.

For nephrotic syndrome

to
induce remission,
the recommended daily dose for
adults
is 5 mg/kg, for
children
- 6 mg/kg (in 2 divided doses) provided that renal function is normal, not counting proteinuria.
In patients with impaired renal function,
the initial dose should not exceed 2.5 mg/kg/day.

If the use of Sandimmune Neoral alone fails to achieve a satisfactory effect, especially in steroid-resistant patients, then its combination with oral corticosteroids in low doses is recommended. If after 3 months of treatment no improvement has been achieved, Sandimmun® Neoral® should be discontinued.

Doses should be individualized, taking into account efficacy (proteinuria) and safety (serum creatinine concentration), but should not exceed a dose of 5 mg/kg/day for adults and 6 mg/kg/day for children.

For maintenance therapy

the dose should be gradually reduced to the minimum effective.

For rheumatoid arthritis

during
the first 6 weeks of treatment,
the recommended dose is 3 mg/kg/day in 2 divided doses. In case of insufficient effect, the daily dose can be gradually increased if tolerated, but it should not exceed 5 mg/kg. It may take up to 12 weeks of treatment with Sandimmune Neoral to achieve full effectiveness.

For maintenance therapy

the dose should be selected individually depending on the tolerability of the drug.

Sandimmune® Neoral® can be prescribed in combination with low doses of GCS and/or NSAIDs. 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 Sandimmune Neoral is 2.5 mg/kg/day (in 2 divided doses), and the dose can be increased to a level limited by tolerability.

For psoriasis

The dosage regimen should be selected individually.
To induce remission,
the recommended initial dose is 2.5 mg/kg/day in 2 divided doses. If there is no improvement after 1 month of therapy, the daily dose can be gradually increased, but should not exceed 5 mg/kg. Treatment should be discontinued if a satisfactory response to psoriasis is not achieved after 6 weeks of treatment with a dose of 5 mg/kg/day or if the effective dose does not meet established safety parameters.

The use of a higher initial dose of 5 mg/kg/day may be justified in patients whose condition requires rapid improvement. If a satisfactory response is achieved, Sandimmun® Neoral® can be discontinued, and a subsequent relapse can be treated by re-prescribing Sandimmune Neoral at the previous effective dose. Some patients may require long-term maintenance therapy.

For maintenance therapy

Doses should be individualized to the minimum effective level and should not exceed 5 mg/kg/day.

For atopic dermatitis

The dosage regimen should be selected individually. The recommended initial dose is 2.5-5 mg/kg/day in 2 divided doses. If the initial dose of 2.5 mg/kg/day does not achieve a satisfactory response within 2 weeks, the daily dose can be quickly increased to a maximum of 5 mg/kg. In very severe cases, rapid and adequate disease control can be achieved by initially using a dose of 5 mg/kg/day. When a satisfactory response is achieved, the dose should be gradually reduced and, if possible, Sandimmun® Neoral® should be discontinued. In case of relapse, a second course of Sandimmune Neoral may be administered.

Although a course of treatment of 8 weeks may be sufficient to clear the skin, therapy for up to 1 year has been shown to be effective and well tolerated, subject to mandatory monitoring of all necessary indicators.

Experience of using Sandimmune Neoral in elderly patients

limited.

In clinical studies of cyclosporine for the treatment of rheumatoid arthritis, the proportion of patients aged 65 years and older was 17.5%. These patients have been shown to be more likely to develop systolic hypertension and also more likely to have serum creatinine concentrations greater than 50% above baseline after 3 to 4 months of cyclosporine therapy.

The number of patients aged 65 years and older included in clinical trials of Sandimmune Neoral in transplant patients and in patients with psoriasis was not sufficient to determine whether the response to treatment in this category of patients differs from the response to treatment in older patients. young patients. Based on other available information on the use of cyclosporine in clinical practice, it can be concluded that the response to treatment does not differ between older and younger patients.

Dose selection in elderly patients should be done with caution; Usually, treatment is started at the lowest dose, taking into account the greater incidence of liver, kidney or cardiac dysfunction, as well as taking into account concomitant diseases or other concomitant therapy.

Additional guidance on dosage regimen for endogenous uveitis, psoriasis and atopic dermatitis

Since Sandimmun® Neoral® may impair renal function, a reliable baseline serum creatinine concentration should be established in at least two measurements prior to treatment. Creatinine concentrations should be monitored at 2-week intervals during the first three months of therapy. Thereafter, if the creatinine concentration remains stable, measurements should be performed monthly. If the serum creatinine concentration increases and remains elevated by more than 30% of baseline values ​​in more than one measurement, then the dose should be reduced by 25-50%. These recommendations should be followed even if creatinine concentrations continue to remain within the laboratory normal range. If dose reduction does not lead to a decrease in creatinine concentration within one month, then treatment with Sandimmune Neoral should be discontinued.

Discontinuation of treatment is also necessary if an uncontrolled increase in blood pressure occurs during treatment with Sandimmune Neoral.

Additional dosing instructions for nephrotic syndrome

Since Sandimmune® Neoral® may cause renal dysfunction, it should be monitored frequently. If serum creatinine concentration remains elevated by more than 30% of baseline values ​​and in more than one dimension, then a dose reduction of Sandimmune Neoral by 25-50% is required. For patients with initially impaired renal function, the initial dose should be 2.5 mg/kg/day. It is necessary to ensure careful monitoring of the condition of these patients.

Additional dosing guidelines for rheumatoid arthritis

Since Sandimmun® Neoral® may impair renal function, a reliable baseline serum creatinine concentration should be established in at least two measurements prior to treatment. Creatinine concentrations should be monitored at 2-week intervals during the first three months of therapy and monthly thereafter. After 6 months of therapy, serum creatinine concentrations should be determined every 4-8 weeks depending on the stability of the underlying disease, concurrent therapy and concomitant diseases. More frequent monitoring is necessary when increasing the dose of Sandimmune Neoral, when adding concomitant NSAID therapy or increasing their dose.

If the serum creatinine concentration remains elevated by more than 30% of baseline values ​​and in more than one dimension, then the dose should be reduced. If the serum creatinine concentration increases by more than 50%, then the dose should be reduced by 50%. These recommendations should be followed even if creatinine concentrations continue to remain within the laboratory normal range. If dose reduction does not lead to a decrease in creatinine concentration within one month, then treatment with Sandimmune Neoral should be discontinued.

Discontinuation of treatment is also necessary if an uncontrolled increase in blood pressure occurs during treatment with Sandimmune Neoral.

Rules for the use and storage of the drug Sandimmune® Neoral®

Instructions for using the drug in the form of soft capsules

Softgels should be left in the blister pack until needed. After opening the blister pack, a characteristic odor is felt. This is normal.

Capsules should be swallowed whole.

Instructions for using the drug in the form of an oral solution

During initial use:

1. Remove the plastic cover.

2. Tear off the sealing ring completely.

3. Remove the black plug and discard it.

4. Push the tube with the white stopper firmly into the neck of the bottle.

5. Insert the measuring syringe into the white stopper.

6. Draw into a measuring syringe the volume of solution corresponding to the prescribed dose.

7. Expel any large bubbles by moving the plunger back and forth several times before separating the syringe containing the prescribed dose volume from the vial. The presence of a few very small bubbles is not significant and does not affect the dose in any way.

8. After use, wipe the outside of the measuring syringe only with a dry cloth and place it in the protective case. The white stopper and tube should remain in the bottle. Close the bottle with a lid.

When using the solution subsequently, you should start from step 5.

Immediately before taking the solution, Sandimmune Neoral should be taken from the bottle using a measuring syringe (as indicated above), transferred to a glass or cup and mixed with orange or apple juice. You can also use other non-alcoholic drinks (according to individual taste). The added drink and solution should be mixed well. Grapefruit juice should not be used for dilution, given the possibility of its interaction with the P450-dependent enzyme system. Do not allow the measuring syringe to come into contact with the mixing drink. Do not rinse the syringe with water or any other liquid.

Sandimmun® Neoral® oral solution should be used within 2 months from the moment the bottle is opened and stored at a temperature of 15° to 30°C, preferably at a temperature of at least 20°C for long periods of storage, since the drug contains oil components of natural origin , which are prone to hardening at low temperatures. At temperatures below 20°C, a transition to a jelly-like state is possible, which again changes to liquid when the temperature rises to 30°C. This may leave a small sediment or flakes. These phenomena do not affect the effectiveness and safety of the drug and the accuracy of dosing using a measuring syringe.

Nosological classification (ICD-10)

• H20.9 Iridocyclitis, unspecified
• L20 Atopic dermatitis
• L40 Psoriasis
• M06.9 Rheumatoid arthritis, unspecified
• M35.2 Behçet's disease
• N05 Nephritic syndrome, unspecified
• N14 Tubulointerstitial and tubular lesions caused by drugs and heavy metals
• T86.0 Bone marrow transplant rejection
• T86.1 Death and rejection of kidney graft
• T86.2 Heart graft death and rejection
• T86.3 Death and rejection of cardiopulmonary graft
• T86.4 Death and liver graft rejection
• T86.8 Death and rejection of other transplanted organs and tissues

Use during pregnancy and breastfeeding

Experimental studies have shown the toxic effect of the drug on reproductive function. Experience with the use of Sandimmune® Neoral® in pregnant women is limited. Pregnant women who have undergone organ transplantation and are receiving immunosuppressive treatment with cyclosporine or combination therapy that includes cyclosporine are at risk of preterm birth (occurring before 37 weeks' gestation). There is a limited number of observations of children (up to the age of 7 years) exposed to cyclosporine during fetal development. Kidney function and blood pressure were normal in these children. However, adequate and well-controlled studies have not been conducted in pregnant women, so the drug should not be used during pregnancy unless the expected benefit to the mother justifies the potential risk to the fetus.

Cyclosporine passes into breast milk. Mothers receiving Sandimmun®Neoral® should not breastfeed.

Pharmacodynamics

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

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

Dosage forms of the drug Sandimmune® Neoral® (oral solution and soft gelatin capsules, which also contain the solution) have the following feature. The solution is a microemulsion preconcentrate that forms a microemulsion in the presence of liquid (the liquid with which the oral solution is mixed before administration or the liquid in the stomach when taking the drug in capsule form). Due to this, the variability of pharmacokinetic parameters is reduced and a linear relationship between the dose and the effect of cyclosporine is ensured with a more uniform absorption profile and less dependence on simultaneous food intake. When studying a microemulsion preconcentrate, it was shown that the correlation between the basal concentration of cyclosporine and its effect is more pronounced when using the drug Sandimmune® Neoral® than with the drug Sandimmune®.

Indications of the drug Sandimmune® Neoral®

Transplantation

Solid organ transplantation:

prevention of rejection of kidney, liver, heart, lung, pancreas allografts, as well as combined cardiopulmonary transplant;

treatment of transplant rejection in patients previously treated with other immunosuppressants.

Bone marrow transplantation

prevention of graft rejection after bone marrow transplantation;

prevention and treatment of graft-versus-host disease (GVHD).

Indications not related to transplantation

Endogenous uveitis

active vision-threatening middle or posterior uveitis of non-infectious etiology in cases where traditional treatment has not had an effect or in cases of severe side effects;

Behcet's uveitis with repeated 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. The drug Sandimmune® Neoral® can be used to induce and maintain remission. It can also be used to maintain remission caused by GCS, which allows them to be canceled.

Rheumatoid arthritis

treatment of severe forms of active rheumatoid arthritis.

Psoriasis

treatment of severe forms of psoriasis, when traditional therapy is ineffective or impossible.

Atopic dermatitis

severe forms of atopic dermatitis when systemic therapy is required.

Pharmacokinetics

Sandimmune® Neoral® provides a clearer linear relationship between dose and effect of cyclosporine (AUCB), a more constant absorption profile and less dependence on simultaneous food intake and circadian rhythm, which is characteristic of Sandimmune®. These properties together account for the low intra-patient variability in cyclosporine pharmacokinetics and the stronger correlation between basal concentration and bioavailability (AUCB). Due to these additional advantages, the dosing regimen of Sandimmune® Neoral® no longer needs to take into account the timing of meals. In addition, when using the drug Sandimmune® Neoral®, a more uniform effect of cyclosporine is ensured both during the day and during the course of maintenance therapy.

Soft gelatin capsules and oral solution are bioequivalent.

The absolute bioavailability of cyclosporine varies among different patient populations.

Tmax is 1.5–2 hours, absorption of the drug Sandimmun® Neoral® occurs quickly, the average Cmax value is 59% higher and the bioavailability is 29% higher in comparison with the drug Sandimmun®.

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

Cyclosporine is largely biotransformed by the cytochrome P4503A enzyme system, and, to a lesser extent, in the gastrointestinal tract and kidneys, with the formation of approximately 15 metabolites. There is no one main metabolic pathway. The drug is excreted primarily in bile and only 6% of the dose taken orally is excreted in the urine (and only 0.1% is excreted unchanged). The values ​​of the final T1/2 of cyclosporine are very variable, which depends on the method of determination used and the patient population being examined. The final T1/2 with unchanged liver function is approximately 6.3 hours; in patients with severe liver disease - approximately 20.4 hours.

Contraindications

Hypersensitivity to cyclosporine or any other component of the drug.

For non-transplant indications

impaired renal function (except for patients with nephrotic syndrome with an acceptable degree of these disorders);

uncontrolled arterial hypertension;

infectious diseases that cannot be treated adequately;

malignant neoplasms.

Carefully:

pregnancy;

breastfeeding period.

Side effects

Many side effects associated with cyclosporine are dose-dependent and reversible with dose reduction. The spectrum of side effects is generally the same across different indications, although the frequency and severity of side effects may vary. In transplant patients, due to the higher dose and longer duration of treatment, side effects are more common and usually more severe than in patients with other indications. Cases of anaphylactoid reactions have been reported with intravenous administration of cyclosporine. In patients receiving immunosuppressive treatment with cyclosporine or combination therapy including cyclosporine, the risk of developing local and generalized infections (viral, bacterial, fungal etiology) and parasitic infestations increases. Exacerbation of pre-existing infectious diseases is also possible. Cases of the development of infectious lesions with a fatal outcome have been reported. In patients receiving immunosuppressive treatment with cyclosporine or combination therapy that includes cyclosporine, the risk of developing lymphomas, lymphoproliferative diseases and malignancies, especially of the skin, increases. The incidence of malignant neoplasms increases with increasing intensity and duration of immunosuppressive therapy. The incidence of adverse events was assessed as follows: occurring very often (≥1/10), often (≥1/100; <1/10), sometimes (≥1/1000; <1/100), rarely (≥1/10000 ; <1/1000), very rarely (<1/10000), including isolated reports.

From the urinary system:

very often - impaired renal function (see "Special Instructions").

From the cardiovascular system:

very often - increased blood pressure.

From the nervous system:

very often - tremor, headache; often - paresthesia; sometimes - signs of encephalopathy, such as convulsions, lethargy, disorientation, slow reactions, agitation, sleep disturbance, visual disturbances, cortical blindness, coma, paresis, cerebellar ataxia; rarely - motor polyneuropathy; very rarely - papilledema, including papilledema, secondary to benign intracranial hypertension.

From the digestive system:

often - anorexia, nausea, vomiting, abdominal pain, diarrhea, gum hyperplasia, liver dysfunction; rarely - pancreatitis.

Metabolism:

very often - hyperlipidemia; often - hyperuricemia, hyperkalemia, hypomagnesemia; rarely - hyperglycemia.

From the musculoskeletal system:

often - muscle spasms, myalgia; rarely - muscle weakness, myopathy.

From the hematopoietic system:

sometimes - anemia, thrombocytopenia; rarely - microangiopathic hemolytic anemia, hemolytic uremic syndrome.

Dermatological reactions:

often - hypertrichosis; sometimes - an allergic rash.

From the body as a whole:

often increased fatigue; sometimes - swelling, weight gain.

From the endocrine system:

rarely - menstrual irregularities, gynecomastia.

Compound