SANDIMMUN NEORAL
Active material: Cyclosporine
When ATH: L04AD01
CCF: Immunosuppressive drugs
ICD-10 codes (testimony): H30, L20.8, L40, M05, M 21.9, N04, Z94
When CSF: 14.02
Manufacturer: NOVARTIS PHARMA AG (Switzerland)
PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING
Soft Capsules gelatin, Oval, yellowish-white, marked with red color “NVR 10”.
| 1 caps. | |
| cyclosporine | 10 mg |
Excipients: D,L-a-токоферол, ethanol, propylene glycol, Mono-, di- and triglycerides of corn oil, polioksil 40 and hydrogenated castor oil.
The composition of the shell: Titanium dioxide, glycerol 85%, propylene glycol, gelatin.
10 PC. – blisters (6) – packs cardboard.
Soft Capsules gelatin, Oval, grey-blue, marked with red color “NVR 25 mg”.
| 1 caps. | |
| cyclosporine | 25 mg |
Excipients: D,L-a-токоферол, ethanol, propylene glycol, Mono-, di- and triglycerides of corn oil, polioksil 40 and hydrogenated castor oil.
The composition of the shell: iron oxide black, Titanium dioxide, glycerol 85%, propylene glycol, gelatin.
5 PC. – blisters (10) – packs cardboard.
Soft Capsules gelatin, oblong, yellowish-white, marked with red color “NVR 50 mg”.
| 1 caps. | |
| cyclosporine | 50 mg |
Excipients: D,L-a-токоферол, ethanol, propylene glycol, Mono-, di- and triglycerides of corn oil, polioksil 40 and hydrogenated castor oil.
The composition of the shell: Titanium dioxide, glycerol 85%, propylene glycol, gelatin.
5 PC. – blisters (10) – packs cardboard.
Soft Capsules gelatin, oblong, grey-blue, marked with red color “NVR 100 mg”.
| 1 caps. | |
| cyclosporine | 100 mg |
Excipients: D,L-a-токоферол, ethanol, propylene glycol, Mono-, di- and triglycerides of corn oil, polioksil 40 and hydrogenated castor oil.
The composition of the shell: iron oxide black, Titanium dioxide, glycerol 85%, propylene glycol, gelatin.
5 PC. – blisters (10) – packs cardboard.
Oral solution clear, from yellow to light yellow or respectively from brownish-yellow to pale brownish-yellow color, with specific aroma oils and ethanol.
| 1 ml | |
| cyclosporine | 100 mg |
Excipients: D,L-a-токоферол, ethanol, propylene glycol, Mono-, di- and triglycerides of corn oil, polioksil 40 and hydrogenated castor oil.
50 ml – vials of dark glass (1) complete with dosing Kit (syringe thick and pipe for fence solution from the vial) – packs cardboard.
Pharmacological action
Immunosuppressive drugs, is a cyclic polipeptidom, consisting of 11 amino acids. Ciclosporin is a selective immunosuppressant, inhibits the activation of lymphocytes in the kal′cijnevrina phase (G)0 or (G)1 the cell cycle. Thus, prevents the activation of t-lymphocytes and, at the cellular level, Antigen-dependent release of lymphokines, including interleykin-2 (t-cell growth factor). Cyclosporine acts on lymphocytes specific and reversible. Unlike drugs, it does not suppress haematopoiesis and does not affect the function of phagocytes.
Cyclosporine increases the life time of Allogenic skin grafts, hearts, kidney, pancreas, bone marrow, small intestine, light. Cyclosporine suppresses the development of cellular responses against Allograft, delayed-type hypersensitivity skin reactions, experimental allergic encephalomyelitis, Arthritis, caused by Freund adjuvant, disease to the transplant master (BTPH) dependent t-lymphocytes formation of antibodies. Was shown the effectiveness of Sandimmuna® Neorala® bone marrow transplant and solid organs in humans for the prevention and treatment of rejection and BTPH, as well as in the treatment of various conditions, that are autoimmune in nature or can be treated as such.
Dosage forms of the drug is Sandimmune® Neoral® (solution reception inside and soft capsules, which also enclosed solution) have the following feature. The solution is a mikroèmul′sionnyj prekoncentrat, which forms a mikroèmul′siû in the presence of liquid (liquids, which mix solution for the reception inside before taking or in the presence of liquids in the stomach when taking medication in capsule form). This reduces variability and farmakokineticeskih parameters is ensured by a linear relationship between dose and effect of Cyclosporine with more uniform absorption profile and less dependent on the simultaneous intake of food. When examining the mikroèmul′sionnogo prekoncentrata has been shown to, that the correlation between basal concentration of Cyclosporine and its effect more pronounced when applying Sandimmuna® Neorala®, than Sandimmuna®.
Pharmacokinetics
Absorption
When taking Sandimmuna® Neorala® ensures a clear linear relationship between dose and effect of Cyclosporine (AUCB), more permanent absorption profile and less dependence on simultaneous mealtimes and circadian rhythm, that is typical for Sandimmuna®. These properties collectively are due to low variability in pharmacokinetics of Cyclosporine in the same patient and the more pronounced the correlation between basal concentration and biodostupnostthew (AUCB). Due to these additional benefits in dosing mode Sandimmuna® Neorala® It is no longer necessary to consider mealtimes. Besides, When applying Sandimmuna® Neorala® a more uniform effect of Cyclosporine as within 24 hours, and during the course of maintenance therapy.
Soft gelatin capsules and solution for the reception inside bioèkvivalentny.
Absolute bioavailability of Cyclosporine varies among different populations of patients.
Tmax is 1.5-2 no, removals Sandimmuna® Neorala® going fast, the average value of Cmax more on plasma 59% and bioavailability above on 29% in comparison with Sandimmunom®.
Distribution
Ciclosporin is distributed mostly outside the bloodstream. In blood 33-47% Cyclosporine is plasma, 4-9% – in lymphocytes, 5-12% – in granoulozitah and 41-58% – in erythrocytes. Plasma protein binding (primarily lipoproteins) is approximately 90%.
Metabolism
Ciclosporin is largely treated biotransformation izofermentom CYP3A4, and, less, in the digestive tract and the kidneys, with the formation of approximately 15 metabolites. There is no one main way metabolism.
Deduction
Ciclosporin write mainly jelchew and only 6% of an oral dose is excreted in the urine (in unaltered form only 0.1%).
The magnitude of the final T1/2 Cyclosporine is extremely variable, that depends on the method of determining the subject and patient population. The final T1/2 When unmodified liver is approximately 6.3 no; in patients with severe liver diseases – about 20.4 no.
Testimony
Transplant
is transplantation of solid organs: Prevention of rejection of kidney-bearing cells and Allografts, liver, hearts, light, pancreas, as well as combined heart-lung transplant; treatment of graft rejection in patients, had been receiving other immunosuppressants;
- Bone marrow transplantation: Prevention of graft rejection after transplantation of bone marrow; Prevention and treatment of disease “graft-versus-host disease”.
Testimony, not related to transplantation
-endogenous uveitis: Active threatening impaired middle or posterior Uveitis noninfectious etiology in cases, When traditional treatment had no effect or the development of severe side effects; uveit Behceta with repeated bouts of inflammation involving the retina;
- Nephrotic syndrome: steroidozavisimyj and steroidorezistentnyj nephrotic syndrome in adults and children, due to pathology clubockov, such as nephropathy minimal changes, focal and segmental glomeruloskleroz, membranoznyj Glomerulonephritis. Sandimmune® Neoral® can be used for induction and maintenance of remission and maintenance of remission, glucocorticosteroids it called, that allows them to cancel;
-treatment of severe forms of active rheumatoid arthritis;
-treatment of severe forms of psoriasis, When traditional therapy is ineffective or impossible;
-severe atopic dermatitis, When you need systemic therapy.
Dosage regimen
The drug is prescribed inside, regardless of the meal.
Daily dose of Sandimmuna® Neorala® always should be divided into 2 admission.
Migrating from Sandimmuna® the Sandimmune® Neoral®
The available data show, that you move with the admission Sandimmuna® at the reception Sandimmuna® Neorala® while maintaining the ratio of doses 1:1 the value of basal concentrations of Cyclosporine, defined in whole blood, are comparable. Many patients, However, You may experience a higher maximum concentration and duration of exposure increase drug (AUC). A small percentage of patients, these changes are more noticeable and can be clinically significant. Their value depends largely on the individual differences of absorption of Cyclosporine from originally used Sandimmuna®, material which is characterized by high variability. In patients with variable values of basal concentrations or receiving Sandimmune® in very high doses (incl. patients cističeskim fibrosis, transplanation patients with associated cholestasis or bad secretion of bile, in children or some patients with a transplanted kidney) absorption of Cyclosporine may be poor or inconsistent, However, when switching to Sandimmune® Neoral® may improve the absorption. Consequently, in this patient population after the jump with the admission Sandimmuna® at the reception Sandimmuna® Neorala® while maintaining the ratio of doses 1:1 the increase in the bioavailability of Cyclosporine may be more pronounced, than there is usually. Considering this, dose Sandimmuna® Neorala® should be reduced by individual selection depending on the range of the basal concentrations and related testimony.
Absorption of Cyclosporine from Sandimmuna® Neorala® less varied and the correlation between basal concentration and biodostupnostthew (by the values of AUC) is much more pronounced, than when applying Sandimmuna®. This makes the basal concentration of Cyclosporine in the blood in a clearer and more reliable option for therapeutic drug monitoring.
Unnecessarily. Migrating from Sandimmuna® the Sandimmune® Neoral® can lead to an increase in drug exposure, You should observe the following rules.
In patients after transplantation treatment Sandimmunom® Neoralom® You should start with the same daily dose, that was when the previous application Sandimmuna®. Basal concentration of Cyclosporine in whole blood should be monitored during 4-7 days after moving to the Sandimmune® Neoral®. Besides, clinical safety settings, such as serum creatinine and hell be monitored during the first 2 months after the jump. If basal concentration of Cyclosporine in the blood is outside the therapeutic range, and/or clinical settings, security has deteriorated, dose should be adjusted accordingly.
In patients, treated over testimony, not related to transplantation, treatment Sandimmunom® Neoralom® to start with the same dose, that was when applying Sandimmuna®. Through 2, 4 and 8 weeks after the transition should monitor the concentration of creatinine in the serum and HELL. If the concentration of creatinine in the serum or the ad increased markedly in comparison with those before moving, or if the concentration of creatinine values increased by more than 30% compared with before treatment Sandimmunom® in more than one dimension, the dose should be reduced to 25-50%. If the serum concentration increases more than 50%, It is necessary to reduce the dose to 50%. In the case of toxicity or ineffectiveness of drug should also monitor basal concentration of Cyclosporine in the blood.
The following ranges of doses for the reception inside should be viewed only as recommendations. Should be generally accepted control of the concentration of Cyclosporine in the blood, What can be applied radioimmunologičeskij method, based on the use of monoclonal antibodies. Based on the results, determine the value of dose, necessary to achieve the desired concentration of Cyclosporine in different patients.
Transplant
At transplantation of solid organs treatment Sandimmunom® Neoralom® should be started for 12 hours before the operation in the dose of 10 to 15 mg / kg body weight, razdelennoy of 2 admission. During 1-2 weeks after the surgery, the drug appoint daily in 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 2-6 mg / kg / day (in 2 admission).
Sandimmune® Neoral® administered in combination with other immunodepressantami, incl. with SCS, as well as in a combination triple (Sandimmune® Neoral® + GCS + azathioprine) or rectangular (Sandimmune® Neoral® + GCS + azathioprine + drugs Mono- or Polyclonal Antibodies) therapy. Four-pillar scheme is applied in patients with a high risk of exclusion. In case of use of Sandimmuna® Neorala® combination therapy regimens composed his dose can be reduced at an early stage of therapy (3-6 mg / kg / day 2 admission) or adjusted during the treatment, taking into account the concentration of Cyclosporine in the blood plasma and security performance (the concentration of urea, creatinine in serum, FROM).
At bone marrow transplantation the initial dose should be imposed per day, prior to transplanting. In most cases it is preferable in/with the introduction of; The recommended dose is 3-5 mg / kg / day. Infusion in this same dose continued for 2 weeks after transplantation, then move on to oral supportive care Sandimmunom® Neoralom® a daily dose of about 12.5 mg / kg, razdelennoy of 2 admission. Supportive therapy spend at least 3 Months (preferably 6 Months), after which the dose is gradually reduced to zero during 1 one year after transplantation. If Sandimmune® Neoral® assigned for the initial phase of therapy, the recommended daily dose is 12.5-15 mg / kg (in 2 admission) starting from the date of, previous transplant.
In the presence of gastrointestinal diseases, to reduce suction, may require higher doses of Sandimmuna® Neorala® or, in some cases, the application in/infusions Sandimmuna®.
After cessation of Sandimmuna® some patients may develop a disease BTPH, that usually regresses after resumption of therapy. To treat this condition with his chronic course in a subtle form, you should use the Sandimmune® Neoral® low dose.
Testimony, not related to transplantation
At endogenous uveite to remission induction the drug is administered in an initial daily dose of 5 mg/kg oral 2 admission to the disappearance of signs of active inflammation and improve Visual acuity. In cases, difficult to treat, the dose may be increased to 7 mg/kg/day for a short period.
If you are unable to control the situation by using one of Sandimmuna® Neorala®, in order to achieve initial remission or to attack heavily inflammation you can attach system GCS (a daily dose of prednisone 0.2-0.6 mg/kg or other equivalent dose glukokorticosteroid).
In the course of maintenance therapy dose should be slowly decrease until reaching the smallest effective dose, that in the period of remission of the disease should not exceed 5 mg / kg / day.
At nephrotic syndrome to remission induction The recommended daily dose Adult is 5 mg / kg, to children – 6 mg / kg (in 2 admission) subject to normal kidney function, not counting the proteinuria. In patients with impaired renal function initial dose should not exceed 2.5 mg / kg / day.
If you use one Sandimmuna® Neorala® Unable to reach a satisfactory effect, especially in steroidorezistentnyh patients, It is recommended that you combine it with oral CORTICOSTEROIDS in low doses. If the 3 months of treatment failed to achieve improvement, Sandimmune® Neoral® should be abolished.
The dose should be chosen individually, taking into account the performance indicators (proteinuria) and security (the concentration of creatinine in the serum), but do not exceed the dose 5 mg/kg/day for adults and 6 mg/kg/day for children.
To maintenance therapy the dosage should be gradually reduced to the minimum effective.
At revmatoidnom ARTHRO in During the first 6 weeks of treatment the recommended dose is 3 mg / kg / day 2 admission. In case of insufficient effect dose can be gradually increased, If portability, but it should not exceed 5 mg / kg. To achieve full effectiveness, it may take up to 12 weeks of therapy Sandimmunom® Neoralom®.
To maintenance therapy dose should be adjusted individually depending on the acceptability of the drug.
Sandimmune® Neoral® You can assign in combination with low doses of CORTICOSTEROIDS and/or NSAIDS. Sandimmune® Neoral® You can also combine a weekly course in low doses of methotrexate in patients with poor response to methotrexate aciclovir. Initial dose Sandimmuna® Neorala® is 2.5 mg / kg / day (in 2 admission), When this dose can be increased to a level, limitiruemogo tolerance.
At psoriaze the dosage should be selected individually. To remission induction The recommended starting dose is 2.5 mg / kg / day 2 admission. If there is no improvement after 1 months of therapy daily dose can be gradually increased, but should not exceed 5 mg / kg. Treatment should be discontinued, If a satisfactory response was not achieved by the manifestations of psoriasis after 6 weeks of treatment dose 5 mg/kg/day, or if the effective dose not meet security settings.
Application of higher initial dose 5 mg/kg/day may be warranted in patients, which requires speedy improvements. If a satisfactory response is reached, What is Sandimmune® Neoral® You can cancel the, and subsequent relapse treated reappointment Sandimmuna® Neorala® in the previous effective dose. Some patients may require prolonged maintenance therapy.
To maintenance therapy doses should be picked up individually at the minimum effective level and must not exceed 5 mg / kg / day.
At atopic dermatitis the dosage should be selected individually. The recommended starting dose is 2.5-5 mg / kg / day 2 admission. If the initial dose 2.5 mg/kg/day fails to achieve a satisfactory response within 2 weeks, the daily dose can be quickly increased to maximum – 5 mg / kg. In very severe cases, rapid and adequate control of the disease can be achieved, applying initially a dose 5 mg / kg / day. When you reach a satisfactory response dose should be gradually reduced, and if possible, What is Sandimmune® Neoral® should be abolished. In case of relapse can be held again course Sandimmuna® Neorala®.
Despite, the course of treatment for a period of 8 weeks may be enough to cleanse the skin, It was shown, that therapy for up to 1 the year is effective and well tolerated subject to compulsory monitoring of all necessary indicators.
Experience of application of Sandimmuna® Neorala® in elderly patients limited.
Clinical studies on the application of Cyclosporine for the treatment of rheumatoid arthritis, the proportion of patients aged 65 years and over was 17.5%. It has been shown, these patients are more likely to develop the systolic hypertension, as well as more likely to increase in the concentration of creatinine in the serum of more than 50% above source after 3-4 months of therapy ziklosporinom.
The number of patients aged 65 and older, included in the clinical studies of Sandimmuna® Neorala® in patients with transplants, as well as in patients with psoriasis, It was not sufficient to, to determine, does the response to treatment for this category of patients from the response to treatment in younger patients. Based on other available information concerning the application of Cyclosporine in clinical practice, it can be concluded, that the response to treatment in elderly and younger patients did not differ.
Selection of dose older patients should be carefully; Typically, treatment starts with the lowest dose, in view of the greater frequency of the liver, kidney or heart, as well as taking into account the concomitant diseases or other concomitant therapy.
Further guidance on dosing regime when endogenous uveite, psoriasis and Atopic Dermatitis
Because Sandimmune® Neoral® can disrupt kidney function, It must be installed reliable initial serum creatinine concentration in at least two dimensions, previous treatment. The concentration of creatinine should be monitored with 2-week intervals during the first three months of therapy. Further, If the creatinine concentration remains stable, measurement should be monthly. If the concentration of creatinine in the serum increased and remained high for more than 30% from the original values more, than one dimension, It is necessary to reduce the dose to 25-50%. These recommendations should be carried out, even if the concentration of creatinine values remain within the lab rules. If reducing the dose does not result in a decrease in creatinine concentration within one month, the treatment of Sandimmunom® Neoralom® It should be discontinued.
Cessation of treatment, it is necessary and, When during treatment Sandimmunom® Neoralom® raises the uncontrolled increase of HELL.
Further guidance on dosing regime in nefroticescom syndrome
Because Sandimmune® Neoral® may cause violations of the kidney, You must frequently monitor. If the concentration of creatinine in serum remained elevated for more than 30% from the original values and in more than one dimension, It requires lower doses of Sandimmuna® Neorala® on 25-50%. For patients with compromised renal function initial dose should be 2.5 mg / kg / day. There is a need to ensure thorough monitoring of these patients.
Further guidance on dosing regimen in rheumatoid arthritis
Because Sandimmune® Neoral® can disrupt kidney function, the reliable source must be installed on the concentration of creatinine in the serum as a minimum in two dimensions, previous treatment. The concentration of creatinine should be monitored with 2-week intervals during the first three months of therapy and in the future – monthly. After 6 months of therapy the concentration of creatinine in the serum to define every 4-8 weeks depending on the stability of the basic disease, at the same time therapies and related diseases. More frequent monitoring is necessary if the dose of Sandimmuna® Neorala®, When you attach a concomitant therapy nonsteroidal anti-inflammatory drugs or increase their dose.
If the concentration of creatinine in serum remained elevated for more than 30% from the original values and in more than one dimension, It is necessary to reduce the dose. If the concentration of creatinine in the serum increases more than 50%, It is necessary to reduce the dose to 50%. These recommendations should be carried out, even if the concentration of creatinine values remain within the lab rules. If reducing the dose does not result in a decrease in creatinine concentration within one month, the treatment of Sandimmunom® Neoralom® It should be discontinued.
Cessation of treatment, it is necessary and, When during treatment Sandimmunom® Neoralom® raises the uncontrolled increase of HELL.
Rules for the use and storage of Sandimmuna® Neorala®
Instructions for use of the drug in the form of soft capsules
Soft capsules in blister packs must be left until, until needed. After opening the blister packaging there is a characteristic odor. This is normal.
The capsules should be swallowed whole.
Instructions for use of the drug in the form of solution for the reception inside
When you initially use:
1. Remove the plastic cover.
2. Completely tear zapechatyvajushhee ring.
3. Remove the black cap and throw it away.
4. Push the tube firmly with a white stopper in the neck of the bottle.
5. Enter graduated syringe in the White Cap.
6. Type in measuring syringe volume solution, the appropriate assigned dose.
7. Banish all large bubbles, moving the plunger several times back and forth, before you disconnect the syringe, contains the volume of solution in accordance with the assigned dose, and bottle. The existence of a few very small bubbles is irrelevant and in no way affects the dose.
8. After use clean measuring syringe from the outside only with a dry cloth and place it in the protective case. White tube and the tube should remain in a bottle. Close the bottle lid.
The next time you use the solution should begin with a p. 5.
Before taking the solution Sandimmuna® Neorala® should take from the bottle using dimensional syringe (as stated above), move into a glass or Cup and mix with orange or Apple juice. You can also use other non-alcoholic drinks (According to individual taste). Added the drink and the solution should be mixed well. For dilution should not use grapefruit juice, taking into account the possibility of its interaction with the P450-dependent enzyme system. Avoid contact graduated syringe with a drink for mixing. You should not wash the syringe with water or any other liquid.
Sandimmune® Neoral® solution reception inside should be used within 2 months from the date of opening the bottle and store at a temperature between 15° to 30° c, preferably at a temperature of not less than 20° c during long storage periods, because the drug contains oil components of natural origin, who are prone to otverdeniu at low temperature. At temperatures below 20° c it is possible to switch to the rinse status, which once again gives way to a liquid at higher temperatures up to 30° c. It may remain small residue or flakes. These phenomena do not affect the safety and efficacy of the drug and dosing accuracy using dimensional syringe.
Side effect
Many side effects, associated with the use of Cyclosporine, dozozawisima reversible at the same time reducing the dose. Range of side effects, in General, identical in the various testimonies, Although the frequency and severity of side effects may vary. Patients, transplant, due to the higher doses and longer duration of treatment side effects are common and usually more pronounced, than in patients with other indications.
The on/in the introduction of Cyclosporine incidents of anaphylactoidnykh reactions. Patients, receiving immunosupressivne treatment ziklosporinom or combination therapy, comprising cyclosporin, increases the risk of local or generalized infections (viral, bacterial, fungal etiology) and parasitic infestations. Also may exacerbate previously existing infectious diseases. Cases were reported of the development of infectious fatal lesions.
Patients, receiving immunosupressivne treatment ziklosporinom or combination therapy, comprising cyclosporin, increased risk of lymphomas, Lymphoproliferative Disorders and malignancies, particularly of the skin. The incidence of cancer increases with the intensity and duration of immunosuppressive therapy.
The incidence of adverse events was estimated as follows:: Often (≥1/10), often (≥1/100; <1/10), sometimes (≥1/1000; <1/100), rarely (≥1/10 000; <1/1000), rarely (<1/10 000), including isolated reports.
From the urinary system: Often – impairment of renal function.
Cardio-vascular system: Often – increased blood pressure.
From the central and peripheral nervous system: Often – tremor, headache; often – paresthesia; sometimes – signs of encephalopathy, for example seizures, lethargy, disorientation, delayed reaction, excitation, sleep disturbance, visual disturbances, korkovaya blindness, coma, paresis, Cerebellar ataxia; rarely – motor polyneuropathy; rarely – papilledema (including the nipple of the optic nerve), secondary relative to benign intracranial hypertension.
From the digestive system: often – anorexia, nausea, vomiting, stomach ache, diarrhea, giperplaziya right, abnormal liver function; rarely – pancreatitis.
Metabolism: Often – hyperlipidemia; often – hyperuricemia, hyperkalemia, gipomagniemiya; rarely – giperglikemiâ.
On the part of the musculoskeletal system: often – muscle spasms, mialgii; rarely – muscular weakness, myopathy.
From the hematopoietic system: sometimes – anemia, thrombocytopenia; rarely – mikroangiopaticheskaja hemolytic anemia, hemolytic uremic syndrome.
Dermatological reactions: often – hypertryhoz; sometimes – allergic rash.
From the body as a whole: often – fatiguability; sometimes – swelling, weight gain.
On the part of the endocrine system: rarely – menstrual disorders, gynecomastia.
Contraindications
-hypersensitivity to ciklosporinu and other components of the drug.
For testimony, not related to transplantation
Nor should appoint Cyclosporine patients with the human kidney (with the exception of patients with nephrotic syndrome with a permissible degree of these violations), uncontrolled hypertension, malignant neoplasms, infectious diseases, beyond adequate therapy.
Pregnancy and lactation
Experience of application of Sandimmuna® Neorala® in pregnant women is limited. Pregnant women, organ transplant patients receiving Cyclosporine treatment immunosupressivne or combination therapy, comprising cyclosporin, There is the risk of preterm birth (occurring before pregnancy 37 weeks). There are a limited number of observations for children (until they reach the age of 7 years), exposed to the effects of Cyclosporine during fetal development. Kidney function and hell these children were normal. But, adequate and well-controlled studies in pregnant women has not been, Therefore, you should not use the drug in pregnancy, except, When the expected benefit to the mother justifies the potential risk to the fetus.
IN experimental studies shows the toxic effect of the drug on the reproductive function.
Ciclosporin enters breast milk. Mothers, receiving Sandimmune® Neoral®, You should stop breast-feeding.
Cautions
Sandimmune® Neoral® should only be used by physicians, with experience immunosupressivna therapy and having the ability to provide adequate monitoring of patients, including regular full physical examination, measurement and control of HELL the concentration of creatinine in the serum. Monitoring of patients, after transplant and receiving medication, should only be carried out in the institutions, which are provided by trained health personnel, adequate laboratory and other resources.
It will be appreciated, that, in the application of Cyclosporine, as well as other immunosuppressants, increased risk of lymphomas and other malignancies, often the skin. Increased risk of this complication is associated more with the degree and duration of immunosuppression, than using a particular drug. Thus, caution must be exercised in applying combined modes of immunosuppressive therapy, Mindful of the likelihood of Lymphoproliferative Disorders and solid organ tumors, sometimes causing fatal.
Given the potential risk of developing malignant neoplasms of skin, patients, receiving therapy ziklosporinom, You should avoid excessive direct sunlight, exposure to ultraviolet UV-B radiation, PUVA therapy (photochemotherapy).
The application of Cyclosporine, as well as other immunosuppressants, predisposes to the development of various bacterial, fungal, parasitic and viral infections, often involving opportunistic pathogens. Given the potential risk of these infections to a patient's life, should apply an effective system of preventive and curative interventions, particularly in cases of prolonged use of combined immune treatment.
During the first few weeks of therapy Sandimmunom® Neoralom® You may receive frequent and potentially dangerous complication – increased creatinine and urea in serum. These functional changes are reversible and dozozawisima, normalized when lower doses. In long-term care, some patients may develop in the kidneys of structural changes (eg, interstitial fibrosis), that in patients with kidney transplants should be differentiated with changes in chronic rejection. Sandimmune® Neoral® can also cause a dose-dependent increase in serum bilirubin and reversible, rarely, liver enzymes. In these cases requires careful monitoring of indicators of kidney and liver. In case of deviations from the norm these indicators may require lower doses.
Older patients should be especially carefully carry out monitoring of the kidneys.
To monitor concentrations of Cyclosporine in the blood, preferably using specific monoclonal antibodies (measurement of amount of unchanged drug). You can use the method of HPLC, which also measured the concentration of unchanged substance. If you are using a plasma or serum, It should follow a standard methodology Division (time and temperature). The initial determination of the concentration of Cyclosporine in patients with liver transplants should use specific monoclonal antibodies. It is also possible to conduct parallel definitions by using specific and non-specific monoclonal antibodies, to achieve a dose, providing adequate immunosuppression.
It should be remembered, that the concentration of Cyclosporine in the blood, plasma or serum – This is only one of many factors, characterizing the clinical condition of the patient. Results for determining the concentration of Cyclosporine are only one factor, determining the dosage, and considered in relation to different clinical and laboratory indicators.
When treating Sandimmunom® Neoralom® requires regular monitoring ad. When you raise HELL must be assigned appropriate antihypertensive therapy.
Because there are rare reports of reversible minor increase in blood lipid therapy Sandimmunom® Neoralom®, It is recommended before treatment and after 1 months after it began to hold the concentrations of lipids in the blood. In case of detection of elevated concentrations of lipids should recommend a diet with restriction of fats and, if necessary, reduce the dose of the drug.
Cyclosporine increases the risk of giperkaliemii, especially in patients with impaired renal function. You should also use caution while applying Cyclosporine with kalisberegatmi dioretikami, ACE inhibitors, Angiotensin II receptor antagonists and kalisoderjasimi drugs, as well as in cases of diet, enriched with potassium. In these cases it is recommended to control the concentration of potassium in the blood.
Cyclosporine increases excretion from the body of magnesium, that can lead to clinically significant gipomagniemii, especially in the peritransplantacionnom period. In this connection, the peritransplantacionnom period is recommended to control the concentration of magnesium in the blood, especially with the appearance of neurological symptoms. If necessary appoint magnesium products.
It is recommended that you monitor the concentration of uric acid in the serum, especially in patients with prior hyperuricemia.
During treatment with ziklosporinom vaccination can be less effective; avoid using live attenuated vaccines.
Additional precautions for testimony, not related to transplantation
Additional guidance for use in nefroticescom syndrome
Due to changes in kidney function, deriving from nefroticski syndrome, some patients can be difficult to identify the violation of kidney function, caused by Sandimmunom® Neoralom®. This explains the fact, that, in some cases associated with Sandimmunom® Neoralom® structural changes in the kidney have been observed without increasing the concentration of creatinine in the serum. Kidney biopsy shows a steroid-dependent nephropathy patients with minimal changes, receiving supportive therapy Sandimmunom® Neoralom® more 1 year.
On rare occasions in patients with nephrotic syndrome, treated immunodepressantami (in t. no. Sandimmunom®), pointed to the emergence of malignant neoplasms (including Hodgkin's lymphoma).
Additional guidance for use in rheumatoid arthritis
As with other long-term immunosuppressive treatment (including therapy ziklosporinom), You should be aware of the increased risk of lymphoproliferative violations. Special caution should be exercised when using Sandimmuna® Neorala® in combination with methotrexate.
Additional guidance for use in Psoriasis
The appointment of older patients is only possible in cases of psoriasis invalidizirujushhego, If this requires careful monitoring of renal function.
In patients with psoriasis, receiving therapy ziklosporinom, as with other conventional immunosuppressive treatment, It was reported on the occurrence of malignant neoplasms, particularly of the skin. In the presence of skin lesions, not typical for psoriasis, and their suspected malignancy or pre-cancer, should conduct a biopsy before starting treatment Sandimmunom® Neoralom®. Treatment Sandimmunom® Neoralom® patients with malignant or pre-cancerous lesions of the skin is possible only after appropriate treatment for these lesions and in the absence of an alternative effective therapies.
Experience of application of Sandimmuna® Neorala® children with psoriasis is limited.
Additional guidance for use in atopic dermatitis
Appointment Of Sandimmuna® sick elderly is only possible in cases of invalidizirujushhego disease, If this requires careful monitoring of renal function.
Benign Lymphadenopathy usually associated with sudden exacerbation of atopic dermatitis. It runs either independently, or against the backdrop of an overall improvement in the course of the disease. Limfadenopatiju, treatment appears ziklosporinom, should regularly monitor the. Lymphadenopathy, the continuing, Despite the reduction in disease activity, shall be subject to the availability of exceptions biopsy for lymphoma.
Cases of Herpes Simplex active currents should be cured before starting treatment Sandimmunom® Neoralom®, but the appearance of Herpes Simplex, is not the reason for the preparation, If the treatment has already begun, except in severe cases.
Skin infections, caused by Staphylococcus aureus, are not absolute contraindications to therapy Sandimmunom® Neoralom®, but must be controlled by the application of appropriate antimicrobial medications.
Experience of application of Sandimmuna® Neorala® in children with atopic dermatitis is limited.
Additional guidance for use in endogenous uveite
Experience of application of Sandimmuna® Neorala® in children with endogenous Uveitis limited.
Effects on ability to drive vehicles and management mechanisms
There are currently no data on the impact of Sandimmuna® Neorala® on the ability to drive and operate moving mechanisms.
Overdose
Symptoms: experience regarding overdose Sandimmuna® Neorala® limited. Possible development of kidney, that, probably, reversible with withdrawal. The ingestion of Cyclosporine in the dose to 10 g (about 150 mg / kg) in most cases there have been slightly pronounced clinical manifestations, such as vomiting, dizziness, headache, tachycardia. In some cases, experienced reversible kidney moderate degree. However, accidental parenteral overdose of Cyclosporine in preterm infants in the neonatal period on development reported heavy toxic complications.
Treatment: simptomaticheskaya therapy, There is no specific antidote. During the first 2-x h after intake of the drug can be removed from the organism causing vomiting or by gastric lavage. Ciclosporin is practically not displayed by hemodialysis and hemoperfusion with activated carbon.
Drug Interactions
Drugs are listed below:, for which interaction with ziklosporinom is confirmed and clinically significant.
Various medications can increase or decrease the concentration of Cyclosporine in plasma or blood due to suppression or induction of enzymes, participating in the metabolism of Cyclosporine, in particular, izofermentov zitohroma CYP3A4. Since Cyclosporine is an inhibitor of cytochrome CYP3A4 and membrane carrier molecules p-glycoprotein, together with the application Sandimmunom® Neoralom® perhaps increasing the concentration of drugs, are substrates of cytochrome CYP3A4 and/or carrier membrane p-glycoprotein.
Preparations, reducing the concentration of Cyclosporine: barbiturates, Carbamazepine, phenytoin; nafцillin, sulfadimidin when it is on/in the introduction; rifampicin; Octreotide; probukol; Orlistat; preparations, containing St. John's wort (Hypericum perforatum); ticlopidine, sulfinpirazon, terʙinafin, bozentan.
Preparations, increasing the concentration of Cyclosporine: some antibiotics-macrolides (mainly erythromycin and clarithromycin); ketoconazole, fluconazole, itraconazole, voriconazole; diltiazem, nikardipin, verapamil; metoclopramide; oral contraceptives; danazol; methylprednisolone (high dose); allopurinol; Amiodarone; holievaja acid and its derivatives; protease inhibitors, Imatinib, Colchicine; nefazodon.
Caution must be exercised while applying Sandimmuna® Neorala® and preparations, having nefrotoksicheskimi effects, for example, aminoglycosides (incl. gentamicin, tobramycin), Amphotericin B, ciprofloxacin, vancomycin, Trimethoprim (+sulfamethoxazole); NSAIDs (incl. diclofenac, naproxen, sulindac); melphalan, blockers gistaminovykh H2-receptors (incl. cimetidine, ranitidine), methotrexate.
You should avoid use of Cyclosporine with takrolimusom, tk. This can lead to increased risk of Nephrotoxicity.
Combined application of nifedipine and Cyclosporine can lead to more pronounced Gingival Hyperplasia, than with monotherapy ziklosporinom.
Together with the appointment of Cyclosporine and lerkanidipina increase in AUC of lerkanidipina in 3 times and AUC Cyclosporine 21%. Caution must be exercised when combined with the application of Cyclosporine and lerkanidipina.
Detected, that the combined use of diclofenac and Cyclosporine can significantly increase the bioavailability of diclofenac with possible development of reversible kidney. Increase the bioavailability of diclofenac is likely associated with decreased its metabolism when “first pass” through the liver. When applied in conjunction with ziklosporinom NSAIDS with less pronounced effect “first pass” (eg, acetylsalicylic acid) increasing their bioavailability is not expected.
Cyclosporine can reduce the clearance of Digoxin, colchicine, prednisolone and inhibitors of HMG- CoA-reductase (Statins) and etoposide.
It was reported on several cases of severe Glycoside intoxication within a few days after the start of treatment, cyclosporin in patients, receiving digoxin.
There are also reports that, that Cyclosporine may enhance toxic effects of colchicine, eg, development of myopathy or neuropathy, especially in patients with impaired renal function.
While the application of Cyclosporine with digoxin or colchicine careful clinical monitoring to detect toxic effects of these drugs and to address the issue of reducing the dose or eliminate the treatment.
In the application of Cyclosporine in clinical practice, as well as according to the literature, cases were reported of muscular development toxicity, including muscle pain, weakness, Myositis and rabdomioliz amid the simultaneous application of Cyclosporine with lovastatinom, simvastatin, atorvastatin, pravastatinom and, rarely, with fluvastatinom. If necessary, the application of the above drugs simultaneously with Cyclosporine to reduce their dose. Therapy Statins should temporarily suspend or cancel altogether in patients with symptomatic myopathy, as well as in patients, with factors predisposing to severe violations of the kidneys, including kidney failure, has developed due to rhabdomyolysis.
Increasing the concentration of creatinine were observed in studies, which has been studied using iverolimusa or sirolimusa with high doses of Cyclosporine in the form of micro-emulsion. This effect is often reversible after reducing dose of Cyclosporine. Sirolimus and everolimus had little influence on the pharmacokinetic parameters of Cyclosporine. Joint application of Cyclosporine with jeverolimusom or sirolimusom leads to a substantial increase in the concentration of the latest in plasma.
Caution must be exercised in the appointment of Cyclosporine, together with kalisberegatmi drugs (potassium-sparing diuretics, ACE inhibitors, Angiotensin II antagonists) or drugs potassium, tk. While the application of Cyclosporine with above drugs may develop pronounced giperkaliemii.
While the application of Cyclosporine and repaglinida may increase concentration in the blood plasma and increase the risk of hypoglycemia.
With a combination of Cyclosporine with drugs, having nefrotoksicheskimi effects, careful monitoring of the kidneys (in particular, creatinine concentration in plasma). When identifying expressed violation of the kidney dose of these drugs should be reduced or consider alternative treatment.
There are anecdotal reports of substantial development, but reversible kidney (with a corresponding increase in the concentration of creatinine) patients, transplant, While the application of Cyclosporine derivatives fibroeva acid (eg, bezafibrate, fenofibrate). So this category patients must be monitored kidney function. In the case of expressed kidney joint application of the above medicines should stop.
With a combination of Cyclosporine with drugs, reduce or increase its bioavailability, patients, transplant, need frequent determination of the concentration of Cyclosporine and, if necessary, changing the dose of Cyclosporine, especially in the initial phase of collateral treatment or its cancellation. In patients without graft surveillance of Cyclosporine concentration does not have such a significant, tk. for those patients the relationship concentration in blood and clinical effects not proven with full clear.
When combined Cyclosporine and preparations, increase its concentration, frequent monitoring of renal function and to monitor side effects of Cyclosporine are more important, than the determination of the concentration of Cyclosporine in plasma.
In patients with Gingival Hyperplasia in the face of therapy ziklosporinom should avoid combined use of nifedipine.
NSAIDS with pronounced effect “first pass” through the liver (eg, diclofenac) should be appointed in lower doses, than in patients, not receiving ciclosporin.
While the application of Cyclosporine with digoxin, colchicine or inhibitors of HMG-CoA reductase inhibitors (Statins) careful clinical monitoring to detect toxic effects of these drugs and to address the issue of reducing the dose or eliminate the treatment.
There are reports, that grapefruit juice increases the bioavailability of Cyclosporine.
Conditions of supply of pharmacies
The drug is released under the prescription.
Conditions and terms
List B. Soft capsules should be stored in a place inaccessible to children at a temperature of no higher than 25° c. An accidental raising temperatures up to 30° c, does not affect the quality of the drug in capsules. Solution reception inside should be stored at a temperature of no higher than 30° c. Shelf life – 3 year. The drug should not be used after the expiration date.
