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Instruction for use: Sandimmun Neoral

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Dosage form: Soft gelatine capsules; Soft capsules; Oral solution

Active substance: Cyclosporinum

ATX

L04AD01 Ciclosporin

Pharmacological group:

Immunodepressants

The nosological classification (ICD-10)

H20.9 Iridocyclitis, unspecified: Iridocyclitis; Diffusive posterior uveitis; Keratouveit; Uveitis of the middle or posterior portion of the eye; Vision-threatening uveitis of the middle or posterior portion of the eye; Keratouwites; Anterior uveitis; Sluggish anterior uveitis; Endogenous uveitis; Inflammation of the ciliary body; Uveitis of the anterior portion of the eyeball; Sympathetic uveitis

L20 Atopic dermatitis: Allergic diseases of the skin; Allergic skin disease noninfectious etiology; Allergic skin disease etiology nemikrobnoy; Allergic skin diseases; Allergic skin lesions; Allergic reactions on the skin; atopic dermatitis; Allergic dermatosis; Allergic diathesis; Allergic itching dermatosis; Allergic skin disease; Allergic skin irritation; allergic Dermatitis; atopic Dermatitis; allergic dermatoses; exudative diathesis; Itchy atopic eczema Itchy allergic dermatosis; Allergic skin disease; Cutaneous allergic reaction to drugs and chemicals; Cutaneous reactions to medications; Skin and allergic disease; Acute eczema; common neurodermatitis; Chronic atopic dermatitis; Exudative diathesis

L40 Psoriasis: Chronic plaque psoriasis with diffuse; generalized psoriasis; Psoriasis of the scalp; hairy parts of the skin; A generalized form of psoriasis; Psoriazoformny dermatitis; Psoriasis complicated with erythroderma; disabling psoriasis; Isolated psoriatic plaque; Eksfolliativny psoriasis; psoriatic erythroderma; Psoriasis with eczematization; Hyperkeratosis in psoriasis; Inverse psoriasis; Psoriasis ekzemopodobnye; dermatoses psoriazoformny; Psoriasis genitals; Psoriasis lesions with hairy areas of the skin; erythrodermic psoriasis; Chronic psoriasis of the scalp; Chronic psoriasis; ordinary psoriasis; refractory psoriasis; Koebner phenomenon; psoriasis

M06.9 Rheumatoid arthritis, unspecified: Rheumatoid arthritis; Pain syndrome in rheumatic diseases; Pain in rheumatoid arthritis; Inflammation in rheumatoid arthritis; Degenerative forms of rheumatoid arthritis; Children's rheumatoid arthritis; Exacerbation of rheumatoid arthritis; Acute articular rheumatism; Rheumatic arthritis; Rheumatic polyarthritis; Rheumatoid arthritis; Rheumatic polyarthritis; Rheumatoid arthritis; Rheumatoid arthritis; Rheumatoid arthritis of active course; Rheumatoid periarthritis; Rheumatoid polyarthritis; Acute rheumatoid arthritis; Acute rheumatism

M35.2 Behcet's disease: Arthritis in Behcet's disease; Uveitis Behcet; Behcet's syndrome; Turena is a big aphthous; Skin rashes with Behcet's syndrome

N05 Unspecified nephritic syndrome: Kidney infections; Glomerulonephritis; Glomerulosclerosis; Idiopathic nephritis; Immune kidney disease; Immune kidney diseases cytotoxic; Immune glomerulopathies; Mesangial proliferative glomerulonephritis; Membrane-proliferative glomerulonephritis; Membranous glomerulonephritis; Nephritis; Jade; Postinfectious glomerulonephritis; Post-streptococcal glomerulonephritis; Segmental glomerulosclerosis

N14 Tubulo-interstitial and tubular lesions caused by drugs and heavy metals

T86.0 Bone marrow transplant rejection: Rejection during bone marrow transplantation

T86.1 Kidney transplant death and rejection: Reaction of acute rejection of a transplanted kidney; Refractory tissue rejection in patients after allogeneic kidney transplantation

T86.2 Dying and rejection of a heart transplant

T86.3 Dying and rejection of the cardiopulmonary graft: The rejection of the combined cardiopulmonary graft

T86.4 Dying and rejection of liver transplant

T86.8 Dying and rejection of other transplanted organs and tissues

Composition

Capsules soft gelatinous - 1 caps.

active substance: Cyclosporine 10 mg; 25 mg; 50 mg; 100 mg

Auxiliary substances: DL-a-tocopherol - 0,1 / 0,25 / 0,5 / 1 mg, ethanol - 10/25/50/100 mg, propylene glycol 10/25/50/100 mg, mono-di- Triglycerides of corn oil - 34.4 / 86/172/344 mg, polyoxyl 40 hydrogenated castor oil - 40.5 / 101.25 / 202.5 / 405 mg

Sheath: titanium dioxide (E171), glycerol 85%, propylene glycol, gelatin, residual solvents (consisting of ethanol and water). In addition, for capsules 25 and 100 mg - iron oxide black (E172)

Solution for oral administration 1 ml

active substance: Cyclosporine 100 mg

Auxiliary substances: DL-a-tocopherol - 1.05 mg, absolute ethanol - 94.7 mg, propylene glycol - 94.7 mg, corn oil mono-di-triglycerides - 318.85 mg, polyoxyl 40 hydrogenated castor oil - 383.7 mg , Nitrogen

Description of dosage form

Capsule 10 mg: oval, soft, gelatinous, yellowish white with a red marking: "NVR 10 mg".

Capsule 25 mg: oval, soft, gelatin, gray-blue with a red marking in the form: "NVR 25 mg".

Capsule 50 mg: oblong soft gelatinous, yellowish white with a red marking in the form: "NVR 50 mg".

Capsule 100 mg: oblong soft gelatinous, gray-blue color, marked red in the form: "NVR 100 mg".

Solution for oral administration: clear liquid from yellow to light yellow or from brownish-yellow to light-brownish-yellow color.

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 dosage with a pipette.

Odor: Specific smell of oil and ethanol.

Pharmachologic effect

Mode of action - Immunosuppressive.

Pharmacodynamics

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

Cyclosporin increases the life time of allogeneic grafts of the skin, heart, kidneys, pancreas, bone marrow, small intestine, lungs. Cyclosporine also inhibits the development of cellular allograft reactions, delayed-type skin reactions, experimental allergic encephalomyelitis, Freund's adjuvant-mediated arthritis, graft-versus-host disease (TPH), and T-lymphocyte-dependent antibody production. The efficacy of using the drug Sandimmun® in the transplantation of bone marrow and solid organs in humans has been shown to prevent and treat the rejection and disease of TPH, as well as in the treatment of various conditions that are inherently autoimmune or can be considered as such.

Medicinal forms of the drug Sandimmun® Neoral® (solution for oral administration and soft gelatin capsules, which also contain a solution) have the following feature. The solution is a microemulsion preconcentrate which forms a microemulsion in the presence of a liquid (a liquid with which the oral solution is mixed before intake or liquid in the stomach when taking the drug in capsule form). This reduces the variability of pharmacokinetic parameters and provides a linear relationship between the dose and the effect of cyclosporine with a more uniform absorption profile and a lesser dependence on simultaneous eating. In the study of microemulsion preconcentrate, it was shown that the correlation between the basal concentration of cyclosporine and its action is more pronounced when using the drug Sandimmun® Neoral® than the preparation Sandimmun®.

Pharmacokinetics

When taking the drug Sandimmun® Neoral®, a clearer linear relationship between the dose and the effect of cyclosporine (AUCB), a more consistent absorption profile and a lesser dependence on simultaneous eating and daily rhythm that is characteristic of the drug Sandimmun® is provided. These properties together result in a low variability in the pharmacokinetics of cyclosporine in the same patient and a more pronounced correlation between basal and bioavailability (AUCB). Due to these additional benefits in the dosage regimen of the drug Sandimmun® Neoral®, there is no longer any need to take into account the meal time. In addition, the use of the drug Sandimmun® Neoral® provides a more even exposure to cyclosporine both during the day and during the course of maintenance therapy.

Soft gelatin capsules and solution for oral administration are bioequivalent.

Absolute bioavailability of cyclosporine varies in different populations of patients.

Tmax is 1.5-2 hours, the absorption of the drug Sandimmun® Neoral® is rapid, the average Cmax is greater by 59% and the bioavailability is higher by 29% compared to the preparation of Sandimmun®.

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

Cyclosporine is largely biotransformed by the enzymatic system of cytochrome P4503A, and, to a lesser extent, in the gastrointestinal tract and kidneys, forming about 15 metabolites. There is no single main pathway of metabolism. The drug is excreted primarily with bile and only 6% of the dose taken internally is excreted in the urine (and in unchanged form only 0.1% is excreted). The values of the final T1 / 2 cyclosporine are highly variable, which depends on the method used to determine and the patient population under study. The final T1 / 2 with unchanged liver function is approximately 6.3 hours; In patients with severe liver disease - approximately 20.4 h.

Indication of the drug Sandimmun Neoral

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;

Prevention 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 in cases where traditional treatment has no effect or in cases of severe adverse effects;

Uveitis of 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. The drug Sandimmun® 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.

Contraindications

Hypersensitivity to cyclosporine or any other component of the drug.

For indications not related to transplantation

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

Uncontrolled arterial hypertension;

Infectious diseases that cannot be adequately treated;

Malignant neoplasms.

Carefully:

pregnancy;

Period of lactation.

Application in pregnancy and breastfeeding

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 are receiving immunosuppressive treatment with cyclosporine or a combination therapy containing cyclosporine, there is a risk of premature birth (which occurred with a gestation period of up to 37 weeks). There is a limited number of observations of children (up to the age of 7 years) exposed to cyclosporine during fetal development. The kidney function and blood pressure in these children were normal. However, adequate and well-controlled studies have not been conducted in pregnant women, so do not use the drug in pregnancy, except when the expected benefit for the mother justifies the potential risk to the fetus.

Ciclosporin penetrates into breast milk. Mothers receiving the drug Sandimmun® Neoral® should not breast-feed.

Side effects

Many of the side effects associated with the use of cyclosporine are dose-dependent and reversible with decreasing dose. The spectrum of side effects is generally the same for different indications, although the frequency and severity of side effects may vary. In patients who undergone transplantation, because of a higher dose and longer duration of treatment, side effects are more frequent and usually more pronounced than in patients with other indications. With intravenous administration of cyclosporine, cases of anaphylactoid reactions were noted. In patients receiving immunosuppressive treatment with cyclosporine or combination therapy involving cyclosporine, the risk of developing local and generalized infections (viral, bacterial, fungal etiology) and parasitic infestations is increased. It is also possible to exacerbate existing infectious diseases. Cases of development of infectious lesions with a lethal outcome have been reported. In patients receiving immunosuppressive treatment with cyclosporine or combination therapy involving cyclosporine, the risk of developing lymphomas, lymphoproliferative diseases and malignant tumors, especially skin, is increased. The frequency of malignant neoplasms increases with increasing intensity and duration of immunosuppressive therapy. The incidence of adverse events was estimated as follows: very often (≥1/10), often (≥1 / 100; <1/10), sometimes (≥1 / 1000; <1/100), rarely (≥1 / 10000 ; <1/1000), very rarely (<1/10000), including individual messages.

From the side of the urinary system: very often - a violation of kidney 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, inhibition, disorientation, delayed reactions, agitation, sleep disturbance, visual disorders, cortical blindness, coma, paresis, cerebellar ataxia; Rarely - motor polyneuropathy; Very rarely - edema of the optic disc, including the nipple of the optic nerve, secondary to benign intracranial hypertension.

On the part of the digestive system: often - anorexia, nausea, vomiting, abdominal pain, diarrhea, gingival hyperplasia, impaired liver function; Rarely - pancreatitis.

From the side of 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.

On the part of the body as a whole: often fatigue; Sometimes swelling, weight gain.

On the part of the endocrine system: rarely - a violation of the menstrual cycle, gynecomastia.

Interaction

Listed below are drugs for which interaction with cyclosporine is confirmed and clinically significant. Various drugs can increase or decrease the concentrations of cyclosporine in plasma or whole blood, usually by suppressing or inducing enzymes involved in the metabolism of cyclosporin, in particular cytochrome CYP3A4 isoenzymes. Since cyclosporine is an inhibitor of cytochrome CYP3A4 and a membrane transporter of P-glycoprotein molecules, simultaneous use with the preparation of Sandimmun® Neoral® may increase the concentration of drugs that are substrates of cytochrome CYP3A4 and / or the membrane carrier of P-glycoprotein.

Drugs that reduce the concentration of cyclosporine: barbiturates, carbamazepine, oxcarbazepine, phenytoin; Nafcillin, sulfadimidine with its iv introduction; Rifampicin; Octreotide; Probucol; Orlistat; Preparations containing St. John's wort (Hypericum perforatum); Ticlopidine, sulfinpyrazone, terbinafine, bosentan.

Drugs that increase the concentration of cyclosporine: some antibiotics-macrolides (eg erythromycin, azithromycin and clarithromycin); Ketoconazole, fluconazole, itraconazole, voriconazole; Diltiazem, nicardipine, verapamil; Metoclopramide; Oral contraceptives; Danazol; Methylprednisolone (high doses); Allopurinol; Amiodarone; Cholic acid and its derivatives; Protease inhibitors, imatinib, colchicine; Nefazodone.

Other significant drug interactions

Caution should be exercised when using the drug Sandimmun® Neoral® and preparations with nephrotoxic effects: aminoglycosides (including gentamicin, tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+ sulfamethoxazole); NSAIDs (including diclofenac, naproxen, sulindac); Melphalan, H2-histamine receptor antagonists (eg, cimetidine, ranitidine), methotrexate. It is necessary to avoid the combined use of cyclosporine with tacrolimus, tk. This may lead to an increased risk of developing nephrotoxicity. The combined use of nifedipine and cyclosporine may lead to more pronounced gingival hyperplasia than with cyclosporine monotherapy. With the simultaneous administration of cyclosporine and lercanidipine, the increase in AUC of lercanidipine is 3-fold and AUC of cyclosporine is 21%. Caution should be exercised when combined use of cyclosporine and lercanidipine.

It was found that the combined use of diclofenac and cyclosporine can significantly increase the bioavailability of diclofenac, with the possible development of reversible renal dysfunction. An increase in the bioavailability of diclofenac is most likely due to a decrease in its metabolism upon first passage through the liver. When combined with cyclosporine NSAIDs with a less pronounced first-pass effect (eg acetylsalicylic acid), an increase in their bioavailability is not expected. Cyclosporine can reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins) and etoposide. Several cases of severe glycoside intoxication have been reported for several days after initiation of cyclosporine treatment in patients receiving digoxin. There are also reports that cyclosporine may 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.

The use of cyclosporine in clinical practice, as well as in literature, reported cases of development of muscle toxicity, including muscle pain, weakness, myositis and rhabdomyolysis, accompanied by simultaneous cyclosporine with lovastatin, simvastatin, atorvastatin, pravastatin and, in rare cases, fluvastatin . If it is necessary to use the above medicines simultaneously with cyclosporine, a reduction in their dose is necessary. Therapy with statins should be temporarily stopped or canceled altogether in patients with symptoms of myopathy, as well as in patients with predisposing factors to severe impairment of kidney function, including renal failure secondary to rhabdomyolysis. An increase in creatinine concentration was observed in studies in which the combined use of everolimus or sirolimus with high doses of cyclosporin in the form of a microemulsion was studied. This effect is often reversible after lowering the dose of cyclosporine. Everolimus and sirolimus have little effect on the pharmacokinetic parameters of cyclosporine. Joint 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 administering cyclosporine together with potassium-sparing drugs (potassium-sparing diuretics, ACE inhibitors, angiotensin II antagonists) or potassium preparations, and with the simultaneous use of cyclosporine with the above drugs, it is possible to develop 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. If you cannot avoid the simultaneous use of cyclosporine and drugs that can interact with it, the following recommendations should be observed. When cyclosporine is combined with a drug with nephrotoxic effects, careful monitoring of kidney function (in particular, plasma creatinine concentration) is necessary. If there is a pronounced impairment of kidney function, the dose of this drug should be reduced or considered for alternative treatment. There are separate reports of the development of a significant but reversible renal dysfunction (with a corresponding increase in creatinine concentration) in patients who underwent transplantation, while using cyclosporine with fibrolic acid derivatives (for example, bezafibrate, fenofibrate). Therefore, in this category of patients, renal function should be monitored. In case of development of severe renal dysfunction, joint application of the above medicines should be discontinued. Drugs that reduce or increase the bioavailability of cyclosporine: in patients who undergone transplantation, frequent determination of the concentration of cyclosporin and, if necessary, a change in the dose of cyclosporine, especially at the initial stage of concomitant treatment or during its cancellation. In patients without a transplant, monitoring the concentration of cyclosporine is not so important; For these patients, the relationship between blood concentrations and clinical effects has not been proven with complete certainty. When combined administration of cyclosporine and drugs that increase its concentration, frequent monitoring of kidney function and monitoring of side effects of cyclosporine are more important than determining the concentration of cyclosporine in the plasma.

In patients with gingival hyperplasia on the background of cyclosporine therapy, combined use of nifedipine should be avoided.

NSAID with a marked effect of first passage through the liver (eg diclofenac) should be given in smaller doses than in patients not receiving cyclosporine. When cyclosporine is used simultaneously with digoxin, colchicine, or inhibitors of HMG-CoA reductase (statins), careful clinical observation is needed to timely detect the toxic effects of these drugs and to address the issue of dose reduction or treatment withdrawal.

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

Dosing and Administration

Inside, regardless of food intake. The daily dose of the drug Sandimmun® Neoral® should always be divided into 2 divided doses.

Transition from the drug Sandimmun® to the drug Sandimmun® Neoral®

The available data show that when switching from taking Sandimmun® to taking the drug Sandimmun® Neoral®, while keeping the ratio of doses 1: 1, the values of basal concentrations of cyclosporin determined in whole blood are comparable. In many patients, however, higher Cmax values and longer drug exposure (AUC) may be observed. In a small percentage of patients, these changes are more visible and can be clinically significant. Their value depends, to a large extent, on the individual differences in the absorption of cyclosporin from the originally used drug Sandimmun®, whose bioavailability is characterized by high variability. In patients with variable basal concentrations, or who receive the drug Sandimmun® at very high doses (including those with cystic fibrosis, patients with transplanted liver with concomitant cholestasis or poor bile secretion, in children or some patients with kidney transplantation) , The absorption of cyclosporine may be low or unstable, however, in the transition to the preparation of Sandimmun® Neoral®, an improvement in absorption is possible. Consequently, in this population of patients after the transition from taking the drug Sandimmun® to taking the drug Sandimmun® Neoral®, while maintaining the ratio of doses of 1: 1, an increase in the bioavailability of cyclosporine may be more pronounced than is usually observed. Given this, the dose of the drug Sandimmun® Neoral® should be reduced by individual selection, depending on the range of basal concentrations and the corresponding indications. The absorption of cyclosporine from the drug Sandimmun® Neoral® is less variable and the correlation between basal and bioavailability (AUC values) is much more pronounced than with the use of the drug Sandimmun®. This makes the basal level of cyclosporine concentration in the blood a clearer and more reliable parameter for the therapeutic control of the drug.

Because The transition from the preparation Sandimmun® to the drug Sandimmun® Neoral® can lead to an increase in the exposure of the drug, the following rules should be observed.

In patients after transplantation, treatment with Sandimmun® Neoral® should be started at the same daily dose as was used with the previous use of the drug Sandimmun®. The basal concentration of cyclosporine in whole blood should be monitored within 4-7 days after the transition to the preparation of Sandimmun® Neoral®. In addition, clinical safety parameters such as serum creatinine and blood pressure should be monitored within the first 2 months after the transition. If the basal concentration of cyclosporine in the blood is outside the therapeutic range and / or the clinical safety parameters worsen, the dose should be adjusted accordingly.

In patients treated for indications other than transplantation, treatment with Sandimmun® Neoral® should be started at the same dose as was used with the Sandimmun® drug. After 2, 4 and 8 weeks after the transition should monitor the concentration of creatinine in serum and blood pressure. If serum creatinine concentrations or blood levels are markedly increased compared to those before the transition, or if creatinine concentrations have increased by more than 30% compared to pre-treatment with Sandimmun® in more than one measurement, the dose should be reduced (see (See also "Additional instructions") by 25-50%. If the serum concentration increases by more than 50%, then it is necessary to reduce the dose by 50%. In case of development of toxic effects or in case of ineffective drug should also monitor basal concentrations of cyclosporine in the blood.

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, for which a radioimmunoassay method based on the use of monoclonal antibodies can be used. Based on the results obtained, determine the dose necessary to achieve the desired concentration of cyclosporine in different patients.

Transplantation

Transplantation of solid organs

Treatment with the drug Sandimmun® Neoral® should be started 12 hours before the operation in a dose of 10 to 15 mg / kg, divided into 2 divided doses. For 1-2 weeks after the operation, 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 divided into 2 divided doses is achieved.

The drug Sandimmun® Neoral® is prescribed in combination with other immunosuppressants (including those with SCS, as well as in a combination of three-component (Sandimmun® Neoral® + GCS + azathioprine) or a four-component (Sandimmun® Neoral® + GCS + azathioprine + Preparations of mono- or polyclonal antibodies) therapy.The four-component regimen is used in patients with a high risk of developing rejection.In the case of using the drug Sandimun® Neoral® as part of the combination therapy schemes, 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 parameters (urea concentration, serum creatinine, blood pressure).

Bone marrow transplantation

The initial dose should be given on the day preceding the transplant. In most cases, I / O is preferred; The recommended dose is 3-5 mg / kg / day. Infusion at the same dose is continued for 2 weeks immediately after the transplant, then go on oral maintenance therapy with the drug Sandimmun® Neoral® at a daily dose of about 12.5 mg / kg divided into 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. If the drug Sandimmun® Neoral® is prescribed for the initial phase of therapy, 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 diseases of the gastrointestinal tract leading to a reduction in absorption, higher doses of the drug Sandimmun® Neoral® or the use of intravenous infusions of the drug Sandimmun® may be required.

After the discontinuation of the administration of the drug Sandimmun®, some patients may develop a "graft-versus-host disease" (TPH), which usually regresses after the resumption of therapy. 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

Endogenous uveitis

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

If one cannot control the situation with a single drug Sandimmun® Neoral®, then to achieve initial remission or to stop the attack of inflammation, you can attach systemic GCS (prednisolone in a daily dose of 0.2-0.6 mg / kg or another GCS in an equivalent dose) .

During maintenance therapy, the dose should be slowly reduced to the lowest effective dose, which should not exceed 5 mg / kg / day during the remission period.

Nephrotic syndrome

To induce remission, the recommended daily dose is 5 mg / kg - for adults and 6 mg / kg - for children in 2 divided doses, provided normal kidney function, not counting proteinuria. In patients with impaired renal function, the initial dose should not exceed 2.5 mg / kg / day. If one cannot achieve a satisfactory effect with the use of one preparation of Sandimmun® Neoral®, especially in steroid-resistant patients, it is recommended that it be combined with low doses of oral GCS. If after 3 months of treatment failed to achieve improvement, the drug Sandimmun® Neoral® should be discarded.

Doses should be selected individually, taking into account the efficacy (proteinuria) and safety (serum creatinine concentration), but do not exceed the 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 a minimum effective dose.

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 may be gradually increased, if tolerability permits, but it should not exceed 5 mg / kg. To achieve full efficacy, up to 12 weeks of therapy with the Sandimmun® Neoral® preparation may be required.

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

The drug Sandimmun® Neoral® can be administered in combination with low doses of GCS and / or NSAIDs. 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 monotherapy. The initial dose of the drug Sandimmun® Neoral® is 2.5 mg / kg / day in 2 divided doses, and the dose can be raised to a level limited by tolerability.

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 may be gradually increased, but should not exceed 5 mg / kg. Treatment should be discontinued if a satisfactory response from psoriasis is not observed 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 an early improvement. If a satisfactory answer is reached, then the drug Sandimmun® Neoral® can be canceled and the subsequent relapse treated with the repeated appointment of the drug Sandimmun® Neoral® in the previous effective dose. Some patients may require prolonged maintenance therapy.

For maintenance therapy, doses should be individually selected at the lowest effective level, they should not exceed 5 mg / kg / day.

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 allow a satisfactory response within two weeks, the daily dose can be rapidly increased to a maximum of 5 mg / kg. In very severe cases, rapid and adequate control of the disease can be achieved by initially applying a dose of 5 mg / kg / day. When a satisfactory response is achieved, the dose should be gradually reduced and, if possible, the drug Sandimmun® Neoral® should be discontinued. In the event of relapse, a second course of the drug, Sandimmun® Neoral®, may be performed.

Although a course of treatment lasting 8 weeks may be sufficient to purify the skin, it has been shown that therapy of up to 1 year is effective and well tolerated, provided that all necessary indications are mandatory.

Use in elderly patients

The experience of using the drug Sandimmun® Neoral® in elderly patients is limited.

In clinical studies on the use of cyclosporine for the treatment of rheumatoid arthritis, the proportion of patients aged 65 years and older was 17.5%. It has been shown that these patients are more likely to develop systolic hypertension, and more likely to increase serum creatinine concentrations by more than 50% above baseline after 3-4 months of cyclosporine therapy.

The number of patients aged 65 years and older included in the clinical trials of the drug Sandimmun® Neoral® in patients with grafts, as well as 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 younger patients. Based on other available information on the use of cyclosporine in clinical practice, it can be concluded that the response to treatment in older and younger patients is not different. Dosage should be carefully selected for elderly patients; Usually treatment starts with the lowest dose, taking into account the greater frequency of violations of the liver, kidney or heart, as well as taking into account co-morbidities or other concomitant therapy.

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

Since the drug Sandimmun® Neoral® can disrupt the function of the kidneys, a reliable baseline serum creatinine concentration must be established in at least two measurements prior to treatment. The concentration of creatinine should be monitored at 2-week intervals during the first 3 months of therapy. In the future, if the creatinine concentration remains stable, measurements should be made monthly. If the serum creatinine concentration rises and remains elevated by more than 30% of the baseline values in more than one dimension, then a dose reduction of 25-50% is necessary. These recommendations should be followed even if the values of creatinine concentration continue to remain within the laboratory standard. If dose reduction does not lead to a decrease in creatinine concentration within one month, treatment with the drug Sandimmun® Neoral® should be discontinued.

The termination of treatment is also necessary when an uncontrolled increase in blood pressure occurs during treatment with the drug Sandimmun® Neoral®.

Additional information on the dosage regimen for nephrotic syndrome

Since the drug Sandimmun® Neoral® can cause renal dysfunction, it is often necessary to control it. If the serum creatinine concentration remains elevated by more than 30% of the baseline values and more than one dimension, a reduction in the dose of the drug Sandimmun® 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 instructions on the dosage regimen for rheumatoid arthritis

Since the preparation of Sandimmun® Neoral® can disrupt kidney function, a significant initial serum creatinine concentration must be established in at least two measurements prior to treatment. The concentration of creatinine should be monitored at 2-week intervals during the first 3 months of therapy and in the future - monthly. After 6 months of therapy, the serum creatinine concentration should be determined every 4 to 8 weeks, depending on the stability of the underlying disease, concomitant therapy and concomitant diseases. More frequent monitoring is necessary with an increase in the dose of the drug Sandimmun® Neoral®, with the addition of concomitant therapy with NSAIDs or an increase in their dose.

If the serum creatinine concentration remains elevated by more than 30% of the baseline values and more than one dimension, then a dose reduction is necessary. If the serum creatinine concentration increases by more than 50%, then it is necessary to reduce the dose by 50%. These recommendations should be followed even if the values of creatinine concentration continue to remain within the laboratory standard. If dose reduction does not lead to a decrease in creatinine concentration within one month, treatment with the drug Sandimmun® Neoral® should be discontinued.

The termination of treatment is also necessary when an uncontrolled increase in blood pressure occurs during treatment with the drug Sandimmun® Neoral®.

Features of application and storage of the drug Sandimmun® Neoral®

Capsules of the drug Sandimmun® Neoral® should be left in a blister pack until they are needed. After the opening of the blister pack, a characteristic smell is felt. This is normal. Capsules should be swallowed whole.

Instructions for use of the drug Sandimmun® Neoral® in the form of a solution for oral administration

I. At initial use

1. Remove the plastic cover.

2. Completely tear off the sealing ring.

3. Remove the black plug and discard it.

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

5. Insert the measuring syringe into the white stopper.

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

7. Remove all large bubbles by moving the piston several times back and forth before disconnecting the syringe containing the volume of the solution in accordance with the prescribed dose and the vial. The presence of several very small vesicles does not matter and does not affect the dose in any way.

8. After use, wipe the measuring syringe from the outside with a dry cloth only and place it in a protective case. The white plug and tube must remain in the vial. Close the vial with a lid.

II. For subsequent use, begin with step 5.

Immediately before use, the solution of the drug Sandimmun® Neoral® should be taken from the vial using a measuring syringe (as indicated above), transferred to a glass or a cup and mixed with orange or apple juice. You can also use other soft drinks (according to individual taste). The added beverage and solution should be well mixed. Do not use grapefruit juice, given the possibility of its interaction with the enzyme system of cytochrome P450. Do not allow the measuring syringe to come into contact with the mixing beverage. Do not wash the syringe with water or any other liquid.

The drug Sandimmun® Neoral® in the form of a solution should be used within 2 months from the moment the vial is opened and stored at a temperature of 15 to 30 ° C, preferably at a temperature not lower than 20 ° C for long periods of storage, since the preparation contains oil components of natural origin, Which tend to solidify at low temperature. At temperatures below 20 ° C, the preparation may take a gelatinous consistency, which disappears when the temperature rises to 30 ° C. However, there may be a small amount of flakes or light sedimentation. These phenomena do not affect the efficacy and safety of the drug, and dosage with a measuring syringe remains accurate.

Overdose

Symptoms: The experience with acute overdoses with the drug Sandimmun® Neoral® is limited. When ingested cyclosporine in a dose of up to 10 g (about 150 mg / kg) in most cases, marked clinical manifestations, such as vomiting, dizziness, headache, tachycardia. In some cases reversible renal dysfunction of moderate degree was observed. However, in case of accidental parenteral overdose of 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 washing the stomach.

Cyclosporine is practically not excreted in hemodialysis and hemoperfusion using activated charcoal.

Special instructions

The drug Sandimmun® should be used only by physicians with experience of immunosuppressive therapy and have the ability to provide adequate monitoring of the patient, including regular complete physical examination, measurement of blood pressure and monitoring serum creatinine concentration. Monitoring of patients who have undergone transplantation and receiving the drug should be performed only in those facilities that are provided with trained medical personnel and adequate laboratory resources.

It should be borne in mind that when using cyclosporine, as well as other immunosuppressants, the risk of developing lymphomas and other malignant neoplasms, more often of the skin, is increased. The increased risk of developing this complication is associated mostly with the degree and duration of immunosuppression than with the use of a particular drug.

Therefore, care should be taken when using combined regimens of immunosuppressive therapy, remembering the likelihood of developing lymphoproliferative diseases and solid organ tumors, sometimes leading to fatal outcomes.

Given the potential risk of malignant skin tumors, patients receiving cyclosporine should avoid excessive exposure to direct sunlight, exposure to UV (B) radiation, PUVA therapy (photochemotherapy). The use of cyclosporine, like other immunosuppressants, predisposes to the development of various bacterial, fungal, parasitic and viral infections, often with the involvement of opportunistic pathogens.

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

During the first few weeks of therapy with the drug Sandimmun® Neoral®, a frequent and potentially dangerous complication can occur-an increase in serum creatinine and urea levels. These functional changes are reversible and dose-dependent, normalized with a decrease in the dose of the drug. With prolonged treatment in some patients, it is possible to develop structural changes in the kidneys (for example, interstitial fibrosis), which in patients with renal transplants should be differentiated with changes in chronic rejection.

The drug Sandimmun® Neoral® can also cause a dose-dependent reversible increase in serum bilirubin and, rarely, liver enzymes. In these cases, careful monitoring of the indicators of kidney and liver function is required. In case of deviations of these parameters from the norm, a dose reduction may be required.

In elderly patients, renal function should be carefully monitored. To control the concentration of cyclosporine in the blood, it is preferable to use specific monoclonal antibodies (measurement of the amount of unchanged drug). You can use the HPLC method, which also measures the concentration of unchanged substance. If plasma or serum is used, the standard separation procedure (time and temperature) should be followed. To determine the initial concentration of cyclosporin in patients with liver transplants, specific monoclonal antibodies should be used. Parallel determinations using specific and non-specific monoclonal antibodies are also possible to achieve a dose that provides adequate immunosuppression.

It should be remembered that the concentration of cyclosporine in blood, plasma or serum is only one of many factors characterizing the clinical condition of the patient. The results of the determination of the concentration of cyclosporin are only one of the factors determining the dosage regimen and are considered in conjunction with various clinical and laboratory indicators. When treated with the drug Sandimmun® Neoral®, regular monitoring of blood pressure is required. With an increase in blood pressure, appropriate antihypertensive therapy should be prescribed.

Since there are rare reports of minor reversible hyperlipidemia in the treatment with the drug Sandimmun®, it is recommended to begin the treatment and after 1 month after the beginning of the treatment to determine the concentration of lipids in the blood. In case of an increased concentration of lipids, a diet with a 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 also be exercised while using cyclosporine with potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists and potassium-containing drugs, and in cases of a diet enriched with potassium. In these cases it is recommended to control the concentration of potassium in the blood.

Cyclosporine increases the excretion of magnesium from the body, which can lead to symptomatic hypomagnesemia, especially in the peri-transplant period. In this regard, in the peri-transplant period it is recommended to monitor the concentration of magnesium in the blood, especially when neurologic symptoms appear. If necessary, prescribe magnesium preparations. It is recommended to monitor the concentration of uric acid in the serum, especially in patients with previous hyperuricemia. During treatment with cyclosporine, vaccination may be less effective; The use of live attenuated vaccines should be avoided. Additional indications for indications not related to transplantation.

Additional information for use in nephritic syndrome

Due to changes in renal function due to the nephrotic syndrome, it may be difficult for some patients to detect renal dysfunction caused by the drug Sandimmun® Neoral®. This explains the fact that in a number of cases associated with the preparation of Sandimmun® Neoral®, structural changes in the kidneys were observed without an increase in serum creatinine concentration. A kidney biopsy was shown in patients with a steroid-dependent nephropathy of minimal changes who received maintenance therapy with the drug Sandimmun® Neoral® for more than 1 year.

In rare cases, patients with nephrotic syndrome treated with immunosuppressants (including Sandimmun®), noted the appearance of malignant neoplasms (including Hodgkin's lymphoma).

Additional indications for use in rheumatoid arthritis

With prolonged immunosuppressive treatment (including cyclosporine therapy), one should remember about the increased risk of lymphoproliferative disorders. Particular care should be taken when using the drug Sandimmun® Neoral® in combination with methotrexate.

Additional indications for use in psoriasis

The appointment of elderly patients is possible only in cases of disabling psoriasis, with careful monitoring of kidney function. In patients with psoriasis, treated with cyclosporine, as with other conventional immunosuppressive treatment, the occurrence of malignant tumors, especially the skin, has been reported. In the presence of skin lesions that are not typical for psoriasis, and if there is a suspected malignancy or precancerous condition, a biopsy should be performed before starting treatment with the drug Sandimmun® Neoral®. Treatment with the drug Sandimmun® Neoral® patients with malignant or precancerous skin lesions is possible only after appropriate treatment of these lesions and in the absence of alternative effective therapy. The experience of using the drug Sandimmun® Neoral® in children with psoriasis is limited.

The appointment of elderly patients is possible only in cases of disabling psoriasis, with careful monitoring of kidney function. In patients with psoriasis, treated with cyclosporine, as with other conventional immunosuppressive treatment, the occurrence of malignant tumors, especially the skin, has been reported. In the presence of skin lesions that are not typical for psoriasis, and if there is a suspected malignancy or precancerous condition, a biopsy should be performed before starting treatment with the drug Sandimmun® Neoral®. Treatment with the drug Sandimmun® Neoral® patients with malignant or precancerous skin lesions is possible only after appropriate treatment of these lesions and in the absence of alternative effective therapy. The experience of using the drug Sandimmun® Neoral® in children with psoriasis is limited.

Additional indications for use in atopic dermatitis

The appointment of the drug Sandimmun® to elderly patients is possible only in cases of a disabling course of the disease, with careful monitoring of kidney function. Benign lymphadenopathy is usually associated with sudden exacerbations of atopic dermatitis. It passes either alone or against a background of general improvement in the course of the disease. Lymphadenopathy, which appeared on the background of treatment with cyclosporine, should be regularly monitored. Lymphadenopathy, which persists despite a decrease in the activity of the disease, should be biopsy to exclude the presence of lymphoma. Cases of simple active herpes simplex should be cured before treatment with the drug Sandimmun® Neoral®, but the appearance of herpes simplex is not a reason to discontinue the drug if the treatment has already begun, except in severe cases. Skin infectious diseases caused by Staphylococcus aureus are not an absolute contraindication for therapy with the drug Sandimmun® Neoral®, but should be controlled by the use of appropriate antibacterial drugs. The experience of using the drug Sandimmun® Neoral® in children with atopic dermatitis is limited.

Additional indications for use in endogenous uveitis

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

Influence on the ability to drive a car and work with machinery. Currently there is no evidence of the effect of the drug Sandimmun® Neoral® on the ability to drive a car and work with mechanisms.

Release form

Capsules soft 10 mg. For 10 pcs. In a blister of a double layer of aluminum foil. 6 blisters are placed in a cardboard box.

Capsules soft 25 mg. For 5 pcs. In a blister of a double layer of aluminum foil. 10 blisters are placed in a cardboard box.

Capsules soft 50 mg. For 5 pcs. In a blister of a double layer of aluminum foil. 10 blisters are put together in a cardboard box.

Capsules soft 100 mg. For 5 pcs. In a blister of a double layer of aluminum foil. 10 blisters are placed in a cardboard box.

Solution for oral administration 100 mg / ml. 50 ml in a vial of dark glass, closed with a rubber stopper and an aluminum lid with a plastic cap, complete with a screw cap and a dosing set (a measuring syringe, a tube for drawing a solution from the vial). The bottle, complete with a lid and a set for dosing, is placed in a cardboard box.

Manufacturer

Capsules

Novartis Pharma AG, Switzerland.

Produced by R.P. Scherer GMBH & CO. KG, Germany.

Novartis Pharma AG, Switzerland.

Manufactured by R.P, Scherer GMBH & Co. KG, Germany.

Solution for oral administration

Novartis Pharma AG, Switzerland.

Produced by Novartis Pharma SA, France.

Novartis Pharma AG, Switzerland.

Manufactured by Novartis Pharma S.A.S., France.

Lichtstrasse, 35, CH-4002, Basel, Switzerland.

Lichtstrasse 35, CH-4002 Basel, Switzerland.

Conditions of supply of pharmacies

On prescription.

Storage conditions of the drug Sandimmun Neoral

At a temperature no higher than 30 ° C.

Keep out of the reach of children.

Shelf life of the drug Sandimmun Neoral

Capsules gelatinous soft 10 mg - 2 years.

Capsules gelatinous soft 25 mg - 2 years.

Capsules gelatinous soft 50 mg - 2 years.

Capsules gelatinous soft 100 mg - 2 years.

Solution for oral administration 100 mg / ml - 3 years.

Do not use after the expiry date printed on the package.

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