Cyclosporine Geksal of the capsule

General characteristics. Structure:

 Active agents:
1 capsule contains 25 mg of cyclosporine
1 capsule contains 50 mg of cyclosporine
1 capsule contains 100 mg of cyclosporine.

Excipients:
Capsule contents: alpha tocopherol, polyethyleneglycol 1000 succinate (TRYS vitamin E), polyethyleneglycol 400, absolute ethanol, макроголя глицерол hydroxystearate (RH 40 cremophore), the water purified.
Cover: gelatin, sorbitol of 70% (uncrystallized), глицерол, a red oxide of iron (Е 172), the water purified.

Pharmacological properties:

The cyclic polypeptide consisting of 11 amino acids. Has selective effect on T lymphocytes. Suppresses development of the reactions of cellular and humoral immunity depending on T lymphocytes including immunity concerning allotransplant. Prevents activation of lymphocytes, inhibiting release of lymphokines. Does not suppress a hemogenesis and does not influence functioning of phagocytal cells.

Pharmacokinetics. At reception Geksal's Cyclosporine is noted stable absorption and almost total absence of influence of meal that provides low variability of pharmacokinetics and the expressed interrelation between effect of drug and the accepted dose.
Absorption: After intake the maximum concentration of cyclosporine in a blood plasma is reached in the range of time 95,0 ± 42,1 minutes.
Distribution: Cyclosporine is distributed generally out of a circulatory bed with the size of the seeming volume of distribution of 3 - 5 l/kg. In plasma from 33 to 47%, in granulocytes – from 5 to 12%, in lymphocytes – from 4 to 9% and in erythrocytes – from 41 to 58% of the administered drug are defined. Linkng with proteins of plasma makes about 90%.
Metabolism: In the course of biotransformation about 15 metabolites are formed. In the main ways of metabolism are mono - and dihydroxylation in various parts of a molecule. Activity of any of metabolites does not surpass more, than for 10% activity of "maternal" substance.
Removal: Elimination from an organism happens generally to bile, only about 6% of the entered dose are allocated with urine in the form of metabolites and about 0,1% - in the form of not changed substance. Sizes of an elimination half-life have considerable fluctuations and make about 6,3 hours at healthy volunteers, about 20,4 hours at patients with a serious illness of a liver and on average 11 hours (from 2 to 25 hours) at transplantation of kidneys. The size of clearance of cyclosporine at children is approximately twice higher, than at adults.
Capsules and solution for internal use of a bioekvivalentna.

Indications to use:

Transplantology:

- Suppression of immunity and prevention of rejection after transplantation of kidneys, a liver, heart, the combined cardiopulmonary transplant, lungs or a pancreas.
- Prevention of graft rejection after bone marrow transplantation.
- Prevention and treatment of reactions a transplant – against - the owner.

Route of administration and doses:

Dosage at organ transplantation:
Adults:
In this case, as a rule, cyclosporine is appointed together with other immunodepressive means. The initial dose makes 10 – 14 mg/kg a day, divided into 2 separate receptions with an interval of 12 hours. This dose is applied within 1 – 2 weeks after operation. After that, carrying out control of level of cyclosporine to blood, gradually reduce the dose to 2 – 6 mg/kg a day which is also divided into 2 receptions. Therapeutic range of drug in blood at the subsequent use makes from 100 to 400 ng/ml.
At transplantation of kidneys it is shown that of a dose on the lower recommended limit, i.e. it is lower than 3 - 4 mg/kg and concentration in blood about 100 ng/ml result in risk of development of reactions of rejection.
At a concomitant use of glucocorticosteroids the dose lower than 5 mg/kg is recommended to some patients in a month after transplantation.

Transplantation of marrow:
The short-term combination of cyclosporine and methotrexate is usually recommended. The dose of drug is selected individually. Generally for 1 – 2 day before operation intravenous administration of cyclosporine in a dose of 2,5 - 5 mg/kg a day is recommended. As soon as oral administration of drug becomes possible, pass to reception of capsules in a dose 12,5 mg/kg a day (divided into 2 receptions) for 3 – 6 months. Further the dose is gradually reduced to the full expiration of a course of treatment.

Therapy of acute reaction a transplant – against - the owner.
The initial dose makes 12,5 – 15 mg/kg of cyclosporine a day divided into 2 receptions. In 50 days begin to lower a dose, every week for 5% before full cancellation of administration of drug in 20 weeks.
If after cyclosporine reception cancellation the acute reaction repeatedly develops, it is necessary to carry out therapy by drug again.
If at reception Geksal's Cyclosporine at organ transplantation, marrow and at acute reaction a transplant – against – the owner passing complaints from outside zheludochno – an intestinal path are observed, it is possible 1/3 recommended to enter a day dose of drug once intravenously with use of infusion solution.

Heavy endogenous uveites:
The initial dose of cyclosporine makes 5 - 10 mg/kg a day, divided into 2 receptions to a zatikhaniye of an inflammation and improvement of visual acuity.
In acute cases it is possible to appoint in addition 0,2 – 0,6 mg/kg of Prednisolonum a day, or other similar glucocorticosteroid.
During a maintenance therapy the dose should be reduced slowly to achievement of a minimal effective dose which during remission of a disease should not exceed 5 mg/kg/days.
Therapeutic level of concentration of cyclosporine in blood makes from 100 to 150 ng/ml.
Children have single data on use of cyclosporine aged 5 years are more senior, experience of use of drug according to these indications at children is younger than 5 years is absent.

Severe forms of psoriasis:
For removal of regressive symptoms the dose of cyclosporine of 2,5 mg/kg divided into 2 receptions is recommended. If in a month improvement of a condition of skin is not observed, it is possible to raise gradually a dose on 1 mg/kg, as much as possible to 5 mg/kg, divided into 2 separate receptions. The dose at repeated treatment has to be minimum effective.
If when using a dose of 5 mg/kg in 6 weeks there does not come significant improvement, it is necessary to cancel administration of drug.

Nephrotic syndrome:
For removal of regressive symptoms of a nephrotic syndrome not higher than 5 mg/kg at adults are recommended to use doses and at children 1 years divided into 2 separate receptions on condition of normal function of kidneys are aged more senior than not higher than 6 mg/kg. For patients with an impaired renal function (creatinine level in blood serum is higher than 200 µmol/l at adults and 140 µmol/l at children are contraindications) the initial dose of cyclosporine should not exceed 2,5 mg/kg.
Level therapeutic of effective concentration of cyclosporine in blood makes from 60 to 160 ng/ml. It is necessary to check the level of concentration at first, whenever possible, daily, and then – each 2 weeks.
In the first 3 months of treatment it is regularly necessary to control creatinine level in serum (at normal function of kidneys - each 2 weeks, at broken – weekly). At the stable level of creatinine it is possible to control this size with an interval of 2 months.
In the presence at the patient of heavy abnormal liver functions it is necessary to reduce an initial dose of cyclosporine by 25 – 50%.
For patients with a nephrotic syndrome, resistant to glucocorticosteroids, if efficiency of one cyclosporine is insufficient, the cyclosporine combination with low doses of glucocorticosteroids is recommended.
If in 3 months of treatment the symptomatology of a nephrotic syndrome remains cyclosporine, it is necessary to stop therapy by drug.

Heavy pseudorheumatism:
The first 6 weeks of therapy the dose of cyclosporine of 2,5 mg/kg divided into 2 receptions is recommended. If drug is badly transferred, it is possible to lower a dose. Further the dose is established individually depending on clinic of a course of a disease and portability and has to be minimum effective. It is not necessary to exceed a day dose of 4 mg/kg. Increase in a dose of cyclosporine up to 5 mg/kg is in case of emergency possible.
It is possible to appoint cyclosporine in a combination with low doses of glucocorticosteroids and/or with non-steroidal anti-inflammatory drugs.
The course of treatment makes up to 12 weeks.

Severe forms of atopic dermatitis:
For removal of an acute picture of a disease use the dose of cyclosporine of 2,5 mg/kg divided into 2 separate receptions. If in 2 weeks significant improvement is not observed, it is necessary to raise a cyclosporine dose as much as possible to 5 mg/kg.
In isolated most hard cases use of an initial dose of cyclosporine of 5 mg/kg is required. At approach of improvement the gradual dose decline of drug is necessary.
The course of treatment lasting 8 weeks can be sufficient for clarification of integuments, however was shown that therapy by duration till 1 year is effective and is well transferred on condition of obligatory monitoring of all necessary indicators.

Route of administration:
The Geksal's Cyclosporine capsules should be accepted always at the same time day during food.
The day dose of drug always should be divided into 2 separate receptions.
Capsules should be accepted without chewing, washing down with water.
It is impossible to accept capsules with grapefruit juice.

Features of use:

Cyclosporine Geksal can be applied by the doctors having experience of performing immunodepressive therapy and treatment of patients after organ transplantation. Use of drug is possible only in specialized medical institutions.
During treatment sizes of arterial pressure, a condition of a liver and kidneys, and also definition of concentration of lipids in blood serum are necessary constant control of laboratory parameters (prior to treatment and after the first month of treatment). At increase in arterial pressure strengthening of hypotensive therapy is recommended.
Cyclosporine can cause a hyperpotassemia or deficit of magnesium therefore, first of all, at the expressed renal failures, it is necessary to control the level of potassium and magnesium in a blood plasma, to avoid excess intake of potassium in an organism (with food, kaliysoderzhashchy drugs).
At use of cyclosporine along with other immunodepressive drugs there is a risk of an excess immunosuppression that can lead to development of infections and formation of lymphoma (preferential Hodzhkin's lymphoma and reticular sarcoma).
At administration of drug regular inspection of skin and histologic control of suspicious sites is necessary.
As cyclosporine can influence function of kidneys, against the background of treatment it is necessary to take, at least, two measurements of initial size of level of creatinine in blood serum. Measurements are repeated weekly within a month, and further within 3 months – with a two-week interval. Then at the stable level of creatinine measurements are taken monthly. More frequent control of level of creatinine is necessary in need of increase in a dose of cyclosporine, or at simultaneous use of non-steroidal anti-inflammatory drugs. If the level of creatinine increased more than by 30% of initial size (in normal limits), it is necessary to reduce a cyclosporine dose by 25 – 50%. If creatinine level in blood serum increased more, than by 50%, it is necessary to lower a cyclosporine dose, at least, for 50%.

At endogenous uveites therapy should be carried out at constant ophthalmologic control, and also when determining level of concentration of cyclosporine to blood.

At a nephrotic syndrome:
It is necessary to define reference values and to carry out regular control of level of serumal creatinine. The dose of drug is korrigirut in this case taking into account dynamics of values of concentration of creatinine in a blood plasma. In the course of treatment systematic control of level of creatinine is carried out by bucketed 2 weeks in the first 3 months of therapy, and further – 1 time in 1 – 2 month. In case of long (more than 1 year) reception of cyclosporine it is recommended to carry out a biopsy of kidneys. Patients should not receive cyclosporine at uncontrollable increase in arterial pressure.
Deterioration in renal function at elderly patients is possible.

At patients with psoriasis the skin damages not typical for psoriasis, it is necessary to subject biopsies prior to treatment. Patients with cancer or precancerous changes of skin have to receive treatment by drug only after performing the corresponding treatment of such changes in a case of lack of alternative forms of effective therapy. It is necessary to avoid long stay in the sun.
The patients who are on therapy Cyclosporine by Geksal have to avoid direct exposure to sunlight and the ultraviolet radiation or PUVA-therapy.
Prior to treatment, and also in the first 3 months of therapy it is necessary to control the level of uric acid in blood and urine.
Increase in sizes of "hepatic" enzymes and bilirubin in blood is allowed most twice.

At treatment of a pseudorheumatism for safety and efficiency of therapy it is necessary to take control measurements of the following indicators:

- regular control of level of creatinine in blood;
- hematologic profile (number of erythrocytes, leukocytes, thrombocytes): prior to treatment and each 4 weeks;
- hepatic indicators: prior to treatment and each 4 weeks;
- analysis of urine: prior to treatment and each 4 weeks;
- measurement of size of arterial pressure: prior to treatment and each 2 weeks within 3 months, further – each 4 weeks;
- level of potassium, lipids in blood: prior to treatment and each 4 weeks.

Medicine contains 25,5 about. alcohol %. At observance of the recommended dosage at each reception of cyclosporine (24 capsules on 25 mg; 12 capsules on 50 mg and 6 capsules on 100 mg) come to an organism to 1,2 g of alcohol. At the same time there is a risk for the state of health at liver diseases, alcoholism, epilepsy, damages of a brain, pregnancy and for small children. The effect of other medicines can weaken at the same time, or amplify.

Side effects:

Side effects of cyclosporine are dependent on a dose and are reduced with reduction of a dose of drug.
Kidneys:
Most often, especially in the first weeks of therapy – the complications connected with increase in level of creatinine and urea in blood serum. These phenomena are connected with functional change of kidneys, they depend on a dose and decrease at a dose decline.

Hemopoietic system:
Development of anemia is possible, it is rare – leukopenias. In isolated cases – thrombocytopenia and mikroangiopatichesky hemolitic anemia.

Skin:
Often – excess pilosis of skin, is rare – rash, a hair loss, allergic skin reactions, erubescence, an itch.

Warmly – vascular system:
Often: arterial hypertension, is more rare – coronary heart disease.

Immune system:
Malignant and limfoproliferativny disturbances are possible. At therapy of psoriasis high-quality limfoproliferativny disturbances, and also In - and T - cellular lymphoma which can disappear at cancellation of administration of drug are possible.

Alimentary system:
Often: anorexia, nausea, vomiting, abdominal pains, diarrhea, a hyperplasia of gums, an abnormal liver function (is followed by increase in level of bilirubin and "hepatic" enzymes in blood serum); seldom – pancreatitis.

Muscular system:
Seldom: muscular spasms, muscular pains, muscular weakness.

Nervous system and sense bodys:
Often: a tremor, fatigue, paresthesia – generally in the first weeks of therapy.
Seldom: motor polyneuropathy, symptoms of encephalopathy (spasms, block, disorientation, slowness of reactions, psychomotor excitement, sleep disorder, visual frustration, cortical blindness, coma, paresis, cerebellar ataxy).

Laboratory indicators, metabolism:
Often: reversible small increase in maintenance of lipids in blood serum, and also increase in body weight, a hyperglycemia, a hyperuricemia, a hyperpotassemia, a hypomagnesiemia.

Interaction with other medicines:

Cyclosporine in combination with potassium - saving diuretics can cause a hyperpotassemia or deficit of magnesium therefore, it is necessary to control the level of potassium and magnesium and to avoid excess intake of potassium in an organism with food.

At simultaneous use Geksal's Cyclosporine with other immunodepressive drugs raises risk of developing of infections and limfoproliferativny diseases.
The risk of development of nephrotoxicity at co-administration increases Geksal's Cyclosporine and such drugs as aminoglycosides (gentamycin and Tobramycinum), Amphotericinum In, ciprofloxacin, Melphalanum, Trimethoprimum, Vancomycinum, non-steroidal anti-inflammatory drugs (diclofenac, Naproxenum).
At a concomitant use with nifedipine injury of gums can develop (hyperplasia).
At organ transplantation in case of simultaneous use of a fibratama (for example, безафибрат, фенофибрат) more expressed and permanent deterioration in renal function is sometimes observed.
The drugs increasing concentration of cyclosporine in blood: кетоконазол, флуконазол, итраконазол, some makrolidny antibiotics (for example, erythromycin, кларитромицин, джозамицин, позиномицин and пристинамицин), doxycycline, oral contraceptives, пропафенон, Methylprednisolonum (in high doses), метоколопрамид, даназол, Amiodaronum, holiyevy acid and its derivatives, and also antagonists of calcium (for example, diltiazem, никардипин, verapamil, mibefradit).
The drugs lowering concentration of cyclosporine in blood: barbiturates, carbamazepine, Phenytoinum, metamizol, rifampicin, нафциллин, орлистат, октреотид, probucol, троглитазон both Sulfadimidunum and Trimethoprimum at intravenous administration, and also the drugs containing a St. John's Wort grass.

If it is impossible to avoid the combined use, careful individual selection of doses of cyclosporine is necessary.
At simultaneous use of a takrolimus development of nephrotoxic effect of cyclosporine, and also increase in the period of its semi-removal is possible.
Cyclosporine reduces clearance and increases toxicity of digoxin, colchicine, a lovastatin and Prednisolonum.
Due to the immunodepressive effect of cyclosporine it is impossible to exclude development of atypical potentially dangerous reactions at vaccination therefore it is necessary to avoid use of live attenuated vaccines.
The Flavonovy substances which are in grapefruit juice exert impact on P 450 cytochrome in this connection increase in level of cyclosporine in blood is possible. Therefore it is not recommended to drink grapefruit juice in the range of 1 hour before administration of drug.

Contraindications:

- Hypersensitivity to cyclosporine and to other components of drug.
- Pregnancy and period of feeding:
Administration of drug by pregnant women is possible only in that case when the expected advantage justifies potential risk for a fruit.
During feeding by a breast it is necessary to cancel administration of drug as penetration of cyclosporine into maternal milk is possible.

Overdose:

Data on overdose of drug are limited. In the presence of the corresponding indications (consciousness disturbance, a headache, tachycardia and in certain cases – a reversible renal failure) carry out symptomatic therapy. Cyclosporine is not removed from an organism at a hemodialysis and hemoperfusion with use of absorbent carbon. Nonspecific methods of removal, such as gastric lavage are shown.

Storage conditions:

To store at a temperature not above 30 °C
To store medicine in the place, unavailable to children!

Issue conditions:

According to the recipe

Packaging:

Capsules on 25, 50 or 100 mg
On 5 capsules on 25, 50 or 100 mg in blisters from Al/Al.
On 10 or 20 blisters together with the application instruction in a cardboard box.