Альгерон®

General characteristics. Structure:

Active ingredient: 200 mkg of pegylated interferon alpha 2Ь (tsepeginterferona alpha 2Ь).

Excipients: acetate sodium trihydrate, acetic acid ice - to рН 5,0, sodium chloride, polysorbate-80, dinatrium of an edetat a dihydrate, water for injections.

Pharmacological properties:

Pharmacodynamics. Tsepeginterferon alpha 2Ь is formed by accession to a molecule of interferon alpha 2Ь polymeric structure - polyethyleneglycol (PEG) with a molecular weight of 20 kd (килоДальтон). Biological effects of the drug Algeron® are caused by interferon alpha 2Ь. Interferon alpha 2Ь is produced by a biosynthetic method on technology of recombinant DNA (deoxyribonucleic acid) and produced by a strain of a bacterium of Escherichia coli into which methods of genetic engineering entered a gene of human interferon alpha 2Ь. Interferona have antiviral, immunomodulatory and anti-proliferative effect. The antiviral effect of interferon alpha 2Ь is caused by its linkng with specific cellular receptors that in turn starts the difficult mechanism of the consecutive intracellular reactions including induction of certain enzymes (R protein kinase, 2-5-oligoadenilatsintetaza and proteins of Mkh).

Suppression of a transcription of a virus genome and inhibition of synthesis of virus proteins results. Immunomodulatory action is shown, first of all, by strengthening of cell-mediated reactions of immune system. Interferon increases cytotoxicity of T lymphocytes and natural killers, phagocytal activity of macrophages, promotes differentiation T-helperov, protects T-cells from apoptosis. Immunomodulatory effect of interferon is caused also by influence on products of a number of cytokines (interleykin, interferon scale). All these effects of interferon can mediate its therapeutic activity.

Drugs of pegylated interferon an alpha cause increase of concentration of effector proteins, such as serumal neopterine and 2-5-oligoadenilatsintetaza. When studying a pharmacodynamics of the drug Algeron® at single introduction to volunteers dozozavisimy increase in serumal concentration of neopterine which maximum gain was reached in 48 hours was noted. At administration of the drug Algeron® once a week in a dose of 1,5 mkg/kg serumal concentration of neopterine at patients with chronic hepatitis C was maintained at constantly high level.

Just as unmodified interferon alpha 2Ь, Algeron® had antiviral activity in in vitro experiments.

Pharmacokinetics. In preclinical experiments it was shown what alpha 2Ь leads pegilirovany molecules of interferon to considerable delay of absorption from an injection site, to increase in volume of distribution, reduction of clearance. Reduction of clearance leads more than to 10-fold increase in duration of a terminal elimination half-life (T1/2) in comparison with unmodified interferon alpha 2Ь (32 h against 2,2 h). Removal of the drug Algeron® happened during> 153 h (6,5 days).
 
When studying pharmacokinetics of the drug Algeron® at single introduction to volunteers in a therapeutic dose of 1,5 mkg/kg together with ribaviriny the maximum serumal concentration (Cmax) was reached on average in 31 (18-48) h after introduction and made 1 401 ± 233 (1250 - 1803) »¬ú/ml. "Concentration time" from 0 to 168 h (AUQ(0-168)) averaged the area under a curve 144 212 ± 49 839 (106 845 - 226 062) пкг/мл/ч. The clearance of drug (C1) averaged 9,9 ± 3,2 (5,2 - 13) ml / (час*кг), an elimination half-life (T1/2) - 57,8 ± 8,4 (48-66,5) h. Value of a constant of elimination (Kel) averaged 0.0124±0,002 p-1.
 
At administration of the drug Algeron® subcutaneously once a week within a combination therapy of chronic hepatitis C dozozavisimy gradual increase in concentration of drug up to the 8th week then further cumulation up to 12 weeks of therapy was not observed by the drug Algeron® was observed.
 
Pharmakoknnetika at patients with the broken function of nights. In researches of peginterferon alpha 2а communication between pharmacokinetic parameters and the clearance of creatinine (CC) at patients with a renal failure (KK from 20 to 100 ml/min.) was not revealed. When studying peginterferon alpha 2Ь increase in Cmax was revealed, AUC and T1/2 is proportional to degree of a renal failure.
 
Patients with a renal failure of average and heavy degree need to make careful observation and at emergence of side reactions to reduce a drug Algeron® dose.
 
Pharmacokinetics at patients with an abnormal liver function. Pharmakokinstichesky parameters of drugs of peginterferon an alpha at healthy faces and patients with hepatitis C are identical. Patients with the compensated cirrhosis have same pharmacokinetic characteristics, as at patients without cirrhosis. At patients with the expressed abnormal liver function pharmacokinetics of drugs of peginterferon the alpha was not studied therefore at this group of patients use of the drug Algeron® is not recommended.
 
Pharmacokinetics at elderly people. Parameters of pharmacokinetics of drugs of a peginterferop an alpha do not depend on age therefore change of a dose is not required from elderly people. Pharmakokinstika at patients is more senior than 70 years was not studied.

Indications to use:

Treatment of primary chronic active hepatitis C as a part of a combination therapy with ribaviriny at adult patients from positive HCV RNA (hepatitis virus RNA C), including with clinically stable coinfection of the human immunodeficiency virus (HIV) / chronic hepatitis C, in the absence of liver disease decompensation signs.

Route of administration and doses:

The drug Algeron® is administered subcutaneously, to the area of a front abdominal wall or a hip. It is recommended to alternate places for an injection.

Therapy has to be begun by the doctor having experience of treatment of patients with hepatitis C and further to be carried out under its control.

At a combination therapy with ribaviriny Algeron® it is applied at patients with chronic hepatitis C, including with clinically stable coinfection of HIV, in the form of a subcutaneous injection in a dose of 1,5 mkg on body weight kg once a week. The mode of a drug dosing Algeron® is specified in table 1.

Table 1. The mode of a drug dosing Algeron® at patients with chronic hepatitis C, including with clinically stable coinfection of HIV.

Body weight	Dose for introduction once a week	Amount of solution of the drug Algeron®	Minimum volume of the syringe
40 kg	60 mkg	0,3 ml	The syringe on 0,4 ml
41-46 kg	70 mkg	0,35 ml
47-53 kg	80 mkg	0,4 ml
54-60 kg	90 mkg	0,45 ml	The syringe on 0,5 ml
61-66 kg	100 mkg	0,5 ml
67-73 kg	110 mkg	0,55 ml	The syringe on 0,6 ml
74-80 kg	120 mkg	0,6 ml
81-86 kg	130 mkg	0,65 ml	The syringe on 0,8 ml
87-93 kg	140 mkg	0,7 ml
94-100 kg	150 mkg	0,75 ml
101-106 kg	160 mkg	0,8 ml
107-113 kg	170 mkg	0,85 ml	The syringe on 1 ml
114-120 kg	180 mkg	0,9 ml
121-126 kg	190 mkg	0,95 ml
127-133 kg	200 mkg	1 ml

Each syringe / bottle with the drug Algeron® is intended only for single use. It is not necessary to mix the solution which is contained in a syringe/bottle or to enter it in parallel with any other drug. The drug Algeron® cannot be administered intravenously.

Recommendations about use for patients:

1.   Choose time of carrying out an injection, convenient for you. It is desirable for injection to do in the evening before going to bed.

2.   Before administration of drug carefully wash up hands water with soap.

3.   Take one blister strip packaging with the filled syringe /
bottle from a cardboard pack which has to be stored in the refrigerator and sustain it at the room temperature within several minutes in order that temperature of drug was made even to air temperature. In case of condensate on a surface of a syringe/bottle wait some more minutes until condensate does not evaporate.

4.   Before use it is necessary to examine solution in a syringe/bottle. In the presence of suspended particles or discoloration of solution or damage of a syringe/bottle the drug Algeron® should not be used. If there was a foam that happens when the syringe/bottle is shaken or strongly shake, wait until foam accumulates.

5.   Choose area of a body for an injection. Альгерон® it is entered into a hypodermic fatty tissue (a fatty layer between skin and muscular tissue) therefore use places with friable cellulose far from places of stretching of skin, nerves, joints and vessels (see fig. 1 – one of four possible areas for an injection):

·     A hip (the front surface of hips except a groin and a knee);

·     A stomach (except a midline and umbilical area).

Fig. 1 Scheme of an arrangement of places of injections.

It is not necessary to use for an injection the painful points decoloured, the reddened sites of skin or area with consolidations and small knots.

Every time choose the new place for a prick, so you will be able to reduce unpleasant feelings and pain on the site of skin in the place of an injection. In each injection area there are many points for a prick. Constantly change points of injections in specific area.

6. Preparation for an injection. If the patient uses the drug Algeron® in syringes. Take the prepared syringe in a hand to which you write. Remove a protective cap from a needle.

If the patient uses the drug Algeron® in bottles. Take a bottle with the drug Algeron® and carefully put a bottle on a plain surface (table). Tweezers (or other convenient adaptation) uncover a bottle. Disinfect an upper part of a bottle. Take the sterile syringe in a hand to which you write, remove a protective cap from a needle and, without breaking sterility, carefully enter a needle through a rubber cap of a bottle so that the end of a needle (3-4 mm) was visible through bottle glass. Turn a bottle that its neck was directed down.

7. The amount of solution of the drug Algeron® which needs to be entered when carrying out an injection depends on the dose calculated by your doctor. The dose of the drug Algeron® is expressed in micrograms (mkg) and is calculated taking into account body weight. Do not change independently a drug Algeron® dosage if did not tell you it to do your doctor. You do not store the drug remains which remained in a syringe/bottle for reuse.

If the patient uses the drug Algeron® in syringes. Depending on a dose which to you was prescribed by the doctor to you can be required to remove the excess volume of solution of drug from the syringe. In case of such need slowly and accurately press the syringe piston for removal of excess amount of solution. You press on the piston until the piston does not reach a necessary mark in the surface of the syringe.

If the patient uses the drug Algeron® in bottles. Slowly delay the piston back and gain in the syringe from a bottle the necessary volume of solution corresponding to a drug Algeron® dose which to you was prescribed by the doctor. Then, without breaking sterility, remove a bottle from a needle, holding a needle at the basis (you watch that the needle did not come off the syringe). Having turned the syringe a needle up, and, moving the piston, remove vials of air with careful percussion on the syringe and pressing on the piston.

8. Previously having disinfected the site of skin where the drug Algeron® will be administered, slightly collect skin pleated big and index by fingers (fig. 2).

9. Having the syringe perpendicular to the place of an injection, enter a needle into skin at an angle 90º (fig. 3). You administer the drug, evenly pressing the syringe piston down to the end (before its full emptying).

Fig. 2 and Fig. 3

10. Remove the syringe with a needle the movement vertically up.

11. Throw out the used syringes/bottles only to the specially allotted place unavailable to children.

12. If you forgot to administer the drug Algeron®, make an injection immediately as soon as remembered it.

It is not allowed to enter a double dose of drug.

Do not stop use of the drug Algeron® without consultation with the doctor.

Ribavirin it is necessary to accept inside, during food, daily. The daily dose of a ribavirin is calculated depending on body weight
(see table 2).

Table 2. The mode of dosing of a ribavirin at a combination therapy with the drug Algeron® at patients with chronic hepatitis C, including with clinically stable coinfection of HIV.

Body weight, kg	Daily dose of a ribavirin, mg	Dosing mode (in capsules or tablets on 200 mg)
≤ 65	800	400 mg in the morning, 400 mg in the evening
65-85	1000	400 mg in the morning, 600 mg in the evening
86-105	1200	600 mg in the morning, 600 mg in the evening
> 105	1400	600 mg in the morning, 800 mg in the evening

Treatment duration at patients with chronic hepatitis C. Duration of treatment depends on a virus genotype. HCV 1 genotype. Existence of the early virologic answer (disappearance of HCV RNA or decrease in virus load of 2 log10 (by 100 times) and more by 12th week of treatment) can predict achievement of the steady answer. In the absence of the early virologic answer achievement of remission is improbable. In clinical trials of use of peginterferon an alpha at chronic hepatitis About the steady answer it was reached only at 2% of patients with the negative early answer. At achievement of the early virologic answer therapy is recommended to be continued within 9 months (the general duration of treatment of 48 weeks). It is necessary to consider a question of the therapy termination if in 12 weeks of treatment the early virologic answer is not reached or in 24 weeks of therapy of HCV RNA gives in to detection.

Genotype of HCV 2 and 3. If by 12th week of treatment the early virologic answer (disappearance of HCV RNA or decrease in virus load of 2 log10 is reached (by 100 times) and more), it is recommended to carry out treatment for 12 more weeks (the general duration of treatment 24 weeks). More long therapy has no advantages.

HCV 4 genotype. In general, patients with a genotype 4 will difficult respond to treatment. Lack of special researches causes a possibility of use of the same tactics of treatment, as at a genotype 1.

Treatment duration at patients with HIV coinfection / chronic hepatitis C. The recommended duration of treatment makes 48 weeks, irrespective of a hepatitis C virus genotype.

Correction of the mode of dosing. At emergence of the undesirable phenomena or deviations of laboratory indicators of moderate severity it is necessary to lower doses of the drug Algeron® or a ribavirin, or to suspend treatment. At normalization of a state or laboratory indicators it is possible to consider a question of increase in a dose, up to initial. If after dose adjustment portability of therapy does not improve, treatment is recommended to be stopped.

Hematologic disturbances. At decrease in peripheral blood of number of leukocytes less than 1,5Õ109/l, neutrophils less than 0,75Õ109/l, numbers of thrombocytes less than 50Õ109/l it is recommended to lower a drug Algeron® dose at a size equal 1/3 from a therapeutic dose (1/3 TD). If the number of neutrophils and thrombocytes does not raise, the dose of the drug Algeron® is recommended to be lowered for 1/3 TD. It is recommended to raise a dose if the number of leukocytes exceeds 2,0Õ109/l, neutrophils – 1Õ109/l, and thrombocytes – 90Õ109/l for not less than 4 weeks.

Dose adjustment of a ribavirin. At decrease in hemoglobin to level less than 100 g/l about 600 mg/days are recommended to lower a dose of a ribavirin. Treatment in a former dose can be resumed after the level of hemoglobin exceeds 100 g/l for not less than 4 weeks. At decrease in level of hemoglobin less than 85 g/l of Algeron® and рибавирин need to be cancelled. At patients with diseases of cardiovascular system (in compensation phase) at decrease in hemoglobin by ≥20 g/l within any 4 weeks of treatment it is recommended to lower a drug Algeron® dose to a half therapeutic and a ribavirina to 600 mg a day and to constantly use a reduced dose. If hemoglobin level at patients with diseases of cardiovascular system (in compensation phase) less than 120 g/l in 4 weeks after a dose decline – administration of the drug Algeron® and reception of a ribavirin cancel.

After the termination of reception of a ribavirin at normalization of level of hemoglobin resuming of treatment in a reduced dosage – 600 mg a day, without further increase in a dose is possible.

Disturbances from a liver. At the compensated cirrhosis of dose adjustment of the drug Algeron® it is not required. At a decompensation of hepatic function use of drug is not recommended.

If concentration of free bilirubin increases to 85,5 µmol/l, the dose of a ribavirin is recommended to be lowered to 600 mg/days.

At the progressing increase in activity of alaninaminotranspherase (ALT) or aspartate aminotransferase (nuclear heating plant) more than twice from a reference value or more than by 10 times from the upper bound of norm (UBN), administration of the drug Algeron® and reception of a ribavirin cancel. If concentration of the connected bilirubin more than by 2,5 times from VGN or free bilirubin> 68,4 µmol/l within not less than 4 weeks with signs of a decompensation of function of a liver, Algeron® increases and рибавирин it is necessary to cancel.

Patients with a depression. At a depression of easy extent of dose adjustment it is not required. At development of a moderately severe depression the dose of the drug Algeron® is recommended to be lowered on 1/3 TD if it is required – for 1/3 TD. If the state does not change, treatment is recommended to be continued in a reduced dosage. If there occurs improvement which is noted for not less than 4 weeks, it is possible to raise a drug Algeron® dose. At development of a depression of heavy degree, and also suicide thoughts it is necessary to cancel Algeron® and рибавирин and to carry out specific treatment under observation of the psychiatrist.

Renal failure. At purpose of a combination therapy at a slight renal failure (KK> of 50 ml/min.) it is necessary to be careful concerning development of anemia. At KK less than 50 ml/min. the combination therapy the drug Algeron® and ribaviriny should not be appointed. If during therapy concentration of creatinine increases> 0,177 mmol/l, Algeron® and рибавирин needs to cancel.

Table 3. An algorithm of correction of doses of the drug Algeron® and a ribavirin at emergence of side reactions.

Laboratory indicators	Dose decline of a ribavirin to 600 mg a day **	Drug Algeron® dose decline	Termination of administration of the drug Algeron® and reception of a ribavirin
Hemoglobin content *	<100 g/l	–	<85 g/l
Number of leukocytes	–	<1,5Õ109/l ***	<1,0Õ109/l
Number of neutrophils	–	<0,75Õ109/l ***	<0,5Õ109/l
Number of thrombocytes	–	<50Õ109/l ***	<25Õ109/l
Content of the connected bilirubin	–	–	> 2,5 VGN
Content of free bilirubin	> 85,5 µmol/l	–	> 68,4 µmol/l (> 4 weeks)
Content of creatinine	–	–	> 0,177 mmol/l
Activity of ALT, nuclear heating plant	–	–	2kh (from a reference value) or> 10 VGN

* At patients with diseases of cardiovascular system (in compensation phase) at decrease in hemoglobin by ≥20 g/l within any 4 weeks of treatment it is recommended to lower a drug Algeron® dose to a half therapeutic and a ribavirina to 600 mg a day and to constantly use a reduced dose.

If hemoglobin level at patients with diseases of cardiovascular system (in compensation phase) less than 120 g/l in 4 weeks after a dose decline – administration of the drug Algeron® and reception of a ribavirin cancel.

** Ribavirin in a dose of 600 mg a day accept on 1 capsule 200 mg in the morning and 2 capsules on 200 mg in the evening, during food.

*** The first dose decline of the drug Algeron® on 1/3 TD (to 1,0 mkg/kg/week), the second decrease (if necessary) the drug Algeron® - reduction for 1/3 TD (to 0,5 mkg/kg/week).

Use for special groups of patients. Elderly patients. Dose adjustment is not required from elderly people.

Children. Children and teenagers aged up to 18 years have an efficiency and safety of the drug Algeron® in a combination with ribaviriny was not studied.

Patients after transplantation of a liver and other bodies. Efficiency and a drug safety of peginterferon an alpha is not established.

Features of use:

Pregnancy and lactation. an alpha it is not necessary to appoint reparata of a pegiiterferon at pregnancy. Teratogenic effects of drugs of peginterferon an alpha were not studied. Use of interferon alpha 2а in high doses led to reliable increase in number of spontaneous abortions at animals. At the posterity which is given rise in time teratogenic effects were not noted. However at treatment by interferon drugs an alpha women of childbearing age should apply effective methods of contraception. There are no data on peginterferon penetration an alpha in breast milk therefore in order to avoid undesirable impact on the child it is necessary to cancel either breastfeeding, or therapy, taking into account potential advantages to mother. The combination of drugs of peginterferon an alpha with ribaviriny is contraindicated for appointment during pregnancy. In researches рибавирин rendered the expressed teratogenic effects on animals and caused fruit death. Ribavirin is contraindicated to pregnant women and men whose partners are pregnant. Ribaviriny it is not necessary to appoint therapy before obtaining the negative test for pregnancy which is carried out just before the beginning of therapy. The women capable to a child-bearing, or men whose partners are capable to a child-bearing have to be informed on teratogenic effects of a ribavirin and need of carrying out effective contraception (not less than 2 ways) during treatment and within 7 months after the end of therapy. In monotherapy or a combination with ribaviriny persons under 18, and also at patients have an efficiency and safety of the drug Algeron® after transplantation of a liver or other bodies are not established.

Альгерон® it is necessary to apply with care at such diseases as a chronic obstructive disease of lungs or a diabetes mellitus with a tendency to development of ketoacidosis. It is also necessary to be careful at patients with disturbance of coagulability of blood (for example, at thrombophlebitis, a thromboembolism of a pulmonary artery) or the expressed miyelosupressiya.

Mental sphere and central nervous system (CNS). Serious violations from TsNS, especially a depression, suicide thoughts and attempts of a suicide, were observed at some patients against the background of therapy by interferon drugs an alpha, and also after the therapy termination (generally within 6 months). Other disturbances from TsNS, including an agressive behavior (in certain cases directed to other people, for example, to a thought of murder), bipolar disorders, manias, confusion of consciousness and change of the mental status, were observed at the patients receiving therapy by interferon an alpha. It is necessary to watch carefully patients for identification of any signs or symptoms of mental disorders. At emergence of such symptoms it is necessary to estimate potential danger and to consider need of medicinal therapy of these states. At preservation or deterioration in mental disorders or emergence of suicide thoughts it is recommended to stop therapy by the drug Algeron® and to continue observation of the patient, in case of need to provide consultation of the psychiatrist. 

At some patients, usually at elderly, receiving interferon an alpha in high doses for therapy of an oncological disease, disturbance of consciousness, a lump, including cases of development of encephalopathy were observed. Though these disturbances were, as a rule, reversible, for their full involution it was required from some patients up to 3 weeks. Very seldom at interferon use an alpha in high doses at patients epileptic spasms developed.

Patients with heavy mental disorders, including in the anamnesis. In need of purpose of the drug Algeron® to patients with heavy mental disturbances (including to the patients having instructions on such disturbances in the anamnesis) treatment can be begun only after carrying out careful individual inspection and the corresponding therapy of a mental disorder.

The patients using narcotic substances. At the patients infected with a virus of hepatitis C, using narcotic substances (alcohol, marijuana and so forth), the risk of development of frustration of mentality (or deteriorations in flowing) increases at therapy by interferon an alpha. If at such patients therapy using interferon the alpha is necessary, then before therapy it is necessary to estimate carefully existence of the accompanying mental diseases and risk of the use of narcotic substances, to carry out adequate therapy. If necessary observation of the psychiatrist or narcologist for carrying out inspection, therapy and maintaining such patients is shown. Careful observation of such patients in time and after completion of therapy by interferon is necessary. It is recommended to take timely measures for prevention of a recurrence or aggravation of mental disorders, and also resuming of the use of drugs.

Cardiovascular system. Patients with heart failure, a myocardial infarction and/or arrhythmias (including) have to be in the anamnesis under constant observation. At patients with heart diseases before the beginning and during treatment it is recommended to carry out the ECG (electrocardiography). Arrhythmias (generally supraventricular), as a rule, give in to usual therapy, but can demand drug withdrawal of Algeron®. The anemia caused by reception of a ribavirin can aggravate the course of cardiovascular diseases. In case of deterioration in a course of cardiovascular diseases therapy should be interrupted or cancelled.

Hypersensitivity. In rare instances therapy by peginterferon drugs the alpha was complicated by reactions of immediate hypersensitivity. At development of anaphylactic reactions, small tortoiseshells, a Quincke's disease, a bronchospasm cancel drug and immediately appoint the corresponding therapy. Passing rash does not demand therapy cancellation.

Function of kidneys. It is recommended to conduct a research of function of kidneys at all patients prior to therapy by the drug Algeron®. At KK less than 50 ml/min. the combination therapy and ribaviriny should not be applied by the drug Algeron®. In case of increase in concentration of creatinine > 0,177 mmol/l in the course of performing therapy administration of the drug Algeron® and reception of a ribavirin need to be cancelled.

At patients with reduced function of kidneys, and also 50 years at use of the drug Algeron® in a combination with ribaviriny are aged more senior it is necessary to trace carefully their state concerning possible development of anemia.

Function of a liver. At development of a liver failure treatment by the drug Algeron® and ribaviriny is cancelled.

Fever. Fever can be observed within a grippopodobny syndrome which is often registered at treatment of an interferonama, nevertheless, it is necessary to exclude other reasons of persistent fever.

Hydration. It is recommended to provide adequate hydration of patients as at some patients at treatment peginterferon alpha 2b observed the arterial hypotension connected with reduction of volume of liquid in an organism.

Diseases of lungs. In rare instances at the patients receiving interferon an alpha in lungs infiltrates of not clear etiology, pneumonites or pneumonia, including with a lethal outcome developed. At emergence of fever, cough, asthma and other respiratory symptoms by all patient it is necessary to carry out a thorax X-ray analysis. In the presence of infiltrates on the roentgenogram of lungs or signs of dysfunction of lungs it is necessary to establish more careful observation of patients and, if necessary, to cancel Algeron®. Immediate cancellation of interferon and purpose of glucocorticosteroids lead to disappearance of the undesirable phenomena from lungs.

Autoimmune disorders. At treatment by interferon an alpha in some cases noted emergence of autoantibodies. Clinical displays of autoimmune diseases arise at treatment of the patients predisposed to development of autoimmune disorders more often. At emergence of the symptoms similar to displays of autoimmune diseases, it is necessary to conduct careful examination of the patient and to estimate a possibility of continuation of therapy by interferon. At the patients with chronic hepatitis C receiving therapy of an interferonama cases of development of a syndrome of Fogta-Koyanagi-Harady were reported. This syndrome is the granulematozny inflammatory disease influencing an organ of sight, an acoustic organ, a soft meninx and skin. In case of suspicion on a syndrome of Fogta-Koyanagi-Harady it is necessary to stop anti-virus therapy and to consider need of use of glucocorticosteroids.

Psoriasis and sarcoidosis. In connection with the messages on an aggravation of a course of psoriasis or a sarcoidosis at the patients receiving therapy by interferon an alpha, use of the drug Algeron® for patients with these diseases is recommended only in cases when the estimated advantage of treatment justifies potential risk. At an exacerbation of psoriasis or a sarcoidosis at the patients receiving therapy by the drug Algeron® the question of drug withdrawal has to be considered.

Changes from an organ of sight. Disturbances from an organ of sight (including a retinal apoplexy, exudates in a retina, obstruction of veins or arteries of a retina) were reported in rare instances after therapy by interferon an alpha. All patients need to conduct ophthalmologic examination prior to therapy. Each patient receiving therapy by the drug Algeron® should conduct ophthalmologic examination in case of complaints to decrease in visual acuity or restriction of fields of vision. With diseases at which there can be changes of a retina, for example, a diabetes mellitus or arterial hypertension it is recommended to patients during therapy by the drug Algeron® regularly to have ophthalmologic examination. At emergence or aggravation of visual disturbances it is necessary to consider a question of the therapy termination by the drug Algeron®.

Changes from teeth and a periodontium. At the patients receiving a combination therapy peginterferon alpha 2b and ribaviriny pathological changes from teeth were noted and peridental fabrics. Dryness in a mouth at long therapy can promote injury of teeth and a mucous membrane of an oral cavity. Patients are recommended to observe hygiene of an oral cavity and to regularly have examination at the stomatologist.

Condition of a thyroid gland. The interferon influence mechanism an alpha on function of a thyroid gland is unknown. At the patients with chronic hepatitis C receiving interferon alpha 2b the hypothyroidism or a hyperthyroidism developed in 2,8% of cases. These disturbances controlled by means of standard therapy. Prior to treatment it is necessary to determine by the drug Algeron® at patients serumal concentration of TTG and at identification of dysfunctions of a thyroid gland to appoint standard therapy. Concentration of TTG should be determined also at emergence of symptoms of dysfunction of a thyroid gland against the background of treatment by interferon an alpha. Treatment by the drug Algeron® should not be carried out if activity of TTG at the normal level does not manage to be maintained.

Laboratory researches. Prior to treatment it is necessary to carry out by the drug Algeron® standard clinical and biochemical analyses of blood. Also them it is recommended to spend each 2 weeks (clinical blood test) and each 4 weeks (biochemical analysis of blood) to therapy time. Альгерон® it is possible to apply at the following laboratory indicators: hemoglobin of ≥120 g/l (woman) and ≥130 g/l (man), number of thrombocytes> 90Õ109/l, absolute number of neutrophils –> 1,5Õ109/l, concentration of TTG and thyroxine within norm or function of a thyroid gland is medicamentally controlled.

At the expressed gipertriglitseridemiya before adjusting a drug Algeron® dose, it is necessary to appoint a diet or medicamentous therapy taking into account concentration of triglycerides in blood serum on an empty stomach. After drug withdrawal the gipertriglitseridemiya quickly disappears.

Therapy by interferon an alpha can be followed by development of ulcer and hemorrhagic and/or ischemic colitis within 12 weeks from the moment of the beginning of therapy. Abdominal pains, availability of blood in Calais, fever – typical symptoms of manifestation of colitis. At emergence of the corresponding complaints Algeron® it has to be immediately cancelled. Recovery usually occurs in 1-3 weeks after drug withdrawal.

At treatment peginterferon alpha 2а in a combination with ribaviriny noted cases of development of pancreatitis, sometimes fatal. At development of symptoms of pancreatitis therapy by the drug Algeron® and ribaviriny should be cancelled.

At interferon administration of drugs an alpha serious infectious complications (bacterial, virus, fungal), sometimes fatal are described. Some of them were followed by development of a neutropenia. At emergence of heavy infectious complications it is necessary to cancel therapy and to appoint the corresponding treatment.

HIV coinfection / chronic hepatitis C. Before an initiation of treatment it is necessary to get acquainted with possible side effects of anti-retrovirus drugs which the patient will accept together with drugs for therapy of chronic hepatitis C attentively. At the patients who were at the same time receiving ставудин and interferon with or without ribavirin, the frequency of developing of pancreatitis and/or a lactacidemia made 3%.

Patients with HIV coinfection / chronic hepatitis C, VAART, can be in risk group concerning development of a lactacidemia. Therefore it is necessary to be careful at addition of the drug Algeron® and a ribavirin to VAART (see the instruction on a medical use of a ribavirin).

Simultaneous use of a ribavirin and zidovudine is not recommended because of the increased risk of developing of anemia. Careful monitoring regarding identification of signs and symptoms of a hepatic decompensation is necessary (including ascites, encephalopathy, bleeding from varicose expanded veins, disturbance of synthetic function of a liver; an indicator of ≥7 points on a scale of Chayld-Pyyu) at patients with coinfection. The indicator on a scale of Chayld-Pyyu not always authentically reflects existence of a hepatic decompensation and the hypoalbuminemia owing to medicamentous therapy can change under the influence of such factors as the increased concentration of indirect (free) bilirubin in blood. At development of a hepatic decompensation therapy by the drug Algeron® should be cancelled immediately.

It is necessary to show care at purpose of the drug Algeron® to patients with the low CD4+ level of lymphocytes. The alpha at patients with HIV coinfection / chronic hepatitis C with quantity of CD4+ of lymphocytes less than 200 cells / мкл is not enough data on efficiency and safety of use of drugs of pegylated interferon.

Organ transplantation. Efficiency and safety of use of the drug Algeron® (in a combination with ribaviriny or at monotherapy) for therapy of hepatitis C at recipients at organ transplantation were not studied. Preliminary data demonstrate that therapy by interferon the alpha can increase risk of graft rejection of a kidney. It was reported also about liver graft rejection.

Influence on ability to manage vehicles, mechanisms. When performing treatment emergence of weakness, dizziness, drowsiness, confusion of consciousness is possible. At emergence of these phenomena it is necessary to refuse driving of the car or work with cars and mechanisms.

Side effects:

When carrying out a combination therapy the drug Algeron® in a dose of 1,5 mkg/kg/week and ribaviriny side reactions generally were easy or moderately expressed and did not demand the treatment termination.

For the description of frequency of side reactions the following categories were used: very often (≥1/10), it is frequent (≥1/100; <1/10), infrequently (≥1/1000; <1/100), it is rare (≥1/10000; <1/1000), it is very rare (<1/10000).

Very frequent side reactions (≥ 1/10) were:

From the central and peripheral nervous system: headache, dizziness.

From mentality: irritability, emotional lability, depression.

From digestive tract: diarrhea, nausea.

From respiratory system, bodies of a thorax and a mediastinum: dry cough.

From skeletal and muscular and connecting fabric: joint pains, muscular pains.

From skin and a hypodermic fatty tissue: alopecia, dryness and peeling of skin, skin itch, rash.

Reactions in an injection site: an inflammation and an itch in an injection site.

General symptoms: fever, grippopodobny syndrome, adynamy, increased fatigue, decrease in body weight.

From system of blood and lymphatic system: leukopenia, anemia, neutropenia, thrombocytopenia, increase in SOE (blood sedimentation rate), lymphocytosis, monocytosis. Decrease in hematologic indicators was, as a rule, noted in the first four weeks of treatment; they improved after dose adjustment within 4–8 weeks. Thrombocytopenia less than 75Õ109/l was observed approximately at 6% of patients. In most cases changes of indicators of blood managed to be eliminated by means of drugs of a colony stimulating granulotsitarny factor or by a dose decline therefore the revealed deviations did not lead to the early termination of treatment. Modification of a dose of a ribavirin concerning anemia was required approximately at 7% of patients.

Laboratory indicators: hyperbilirubinemia, gipertriglitseridemiya, hypercholesterolemia, hypoglycemia, hyperglycemia, increase in concentration of thyritropic hormone (TTG).

Frequent side reactions (≥1/100; <1/10):

From the central and peripheral nervous system: paresthesias.

From mentality: sleep disorders, dysmnesia and attention, uneasiness, concern.

From digestive tract: a loss of appetite, abdominal pains, dryness in a mouth, vomiting, heartburn, taste change.

From respiratory system, bodies of a thorax and a mediastinum: rhinitis, nose congestion, irritation, pharyngalgia, nasal bleeding, asthma, pneumonia.

From an acoustic organ and labyrinth disturbances: sonitus.

From skeletal and muscular and connecting fabric: ossalgiya.

From cardiovascular system: pains in heart, tachycardia, arterial hypotension, arterial hypertension.

From skin and a hypodermic fatty tissue: the increased perspiration, a furunculosis.

From mucous membranes: blepharitis, conjunctivitis, stomatitis, ulitis, angular stomatitis.

Reactions in an injection site: pain, infiltrate.

General symptoms: thirst, syncope.

Infectious and parasitic diseases: acute respiratory viral infections, the infection caused by a herpes simplex virus.

From system of blood and lymphatic system: lymphopenia, lymphadenopathy, эозинофилез, monocytopenia.

From endocrine system: hypothyroidism.

From immune system: pollinosis.

From kidneys and urinary tract: disturbance of indicators of urine.

From generative organs and a mammary gland: dysmenorrhea.

Laboratory indicators: decrease in concentration of TTG, hypochilesterinemia.

When using the drug Algeron® in a dose of 2,0 mkg/kg/week in combination with ribaviriny in addition to the undesirable phenomena which were observed at use of the drug Algeron® in a dose of 1,5 mkg/kg/week, the following side reactions were also noted: a menorrhagia (2%), in injection sites (2%) – cyanosis, dot hemorrhage, a furuncle.

Infrequent side reactions (≥1/1000; <1/100):

From the central and peripheral nervous system: muscular weakness, lack of coordination of movements, confusion of the speech.

From digestive tract: erosive gastritis, cholecystitis, pancreatitis, cheilitis, glossitis.

From respiratory system, bodies of a thorax and a mediastinum: bronkhoobstruktivny syndrome, tonsillitis.

From skeletal and muscular and connecting fabric: periostitis.

From cardiovascular system: arrhythmia.

From skin and a hypodermic fatty tissue: erythema, rozatsea.

From system of blood and lymphatic system: poikilocytosis.

From endocrine system: thyrotoxicosis, thyroiditis.

The side effects observed at use of the drug Algeron® for treatment of chronic hepatitis C at HIV-positive patients:

At patients with coinfection is the HIV / chronic hepatitis C receiving therapy by the drug Algeron® in a combination with ribaviriny the following undesirable phenomena which were absent at patients with monoinfection were observed: dentagra (2,86%), block (1,43%), apathy (1,43%), hallucinations (1,43%), hypomania (1,43%), dorsodynia (5,71%), yellowness of skin (1,43%), ear pain (1,43%); among laboratory deviations – increase in activity of nuclear heating plant (40%), ALT (35,71%), gammaglutamiltranspeptidaza (30%), an alkaline phosphatase (10%); hyper albuminemia (22,86%); increase (15,71%) or decrease (2,86%) in concentration of creatinine; neutrocytosis (2,86%), leukocytosis (1,43%), thrombocytosis (1,43%). At HIV-positive patients decrease in number of CD4+ of lymphocytes (11,43%) was noted and more often than at patients with monoinfection, the lymphopenia (61,43%) was registered.

The side effects observed at use of similar drugs of peginterferon alpha 2b at adult patients in combination with ribaviriny or without it:

Very frequent side reactions (≥1/10):

From the central and peripheral nervous system: headache, dizziness.

From mentality: depression, uneasiness, emotional lability concentration disturbance, sleeplessness.

From digestive tract: vomiting, nausea, an abdominal pain, diarrhea, dryness in a mouth.

From respiratory system, bodies of a thorax and a mediastinum: short wind, cough.

From skeletal and muscular and connecting fabric: mialgiya, arthralgia, musculoskeletal pains.

From skin and a hypodermic fatty tissue: alopecia, itch, xeroderma, rash.

Reactions in an injection site: reaction in an injection site, an inflammation in an injection site.

General symptoms: fatigue, adynamy, sensitivity, fever, fervescence, grippopodobny syndrome, pain.

Infectious and parasitic diseases: viral infections, pharyngitis.

From system of blood and lymphatic system: anemia, neutropenia.

From a metabolism and food: anorexia.

Laboratory and tool data: decrease in body weight.

Frequent side reactions (≥1/100; <1/10):

From the central and peripheral nervous system: amnesia, dysmnesias, syncope, migraine, ataxy, confusion of consciousness, neuralgia, paresthesia, hypesthesia, hyperesthesia, hyper tone of muscles, drowsiness, disturbance of attention, tremor, dysgeusia.

From mentality: aggression, excitement, anger, change of mood, change of behavior, nervousness, sleep disorders, decrease libido, apathy, unusual dreams, tearfulness.

From digestive tract: dyspepsia, a gastroesophageal reflux disease, stomatitis, a stomacace, a glossodynia, bleeding of gums, a lock, a meteorism, hemorrhoids, a cheilitis, abdominal distention, an ulitis, a glossitis, disturbances from teeth.

From a liver and biliary tract: hyperbilirubinemia, hepatomegalia.

From cardiovascular system: heart consciousness, tachycardia, arterial hypertension, arterial hypotension, inflows.

From respiratory system, bodies of a thorax and a mediastinum: a dysphonia, bleeding from a nasal cavity, disturbances from respiratory system (breath), impassability of respiratory tracts, hypostasis of a mucous membrane of adnexal bosoms of a nose, a nose congestion, a rhinorrhea, increase in secretion mucous upper respiratory tracts, throat and throat pain.

From an acoustic organ and labyrinth disturbances: disturbance/hearing loss, sonitus, вертиго.

From skeletal and muscular and connecting fabric: arthritis, dorsodynia, muscular spasms, extremity pain.

From skin and a hypodermic fatty tissue: psoriasis, photosensitivity reactions, makulo-papular rash, dermatitis, erythematic rash, eczema, night perspiration, a hyperhidrosis, an acne, a furuncle, an erythema, a small tortoiseshell, disturbance of structure of hair, disturbances from nails.

Reactions in an injection site: pain in the place of an injection.

General symptoms: a stethalgia, discomfort in breasts, an indisposition, a face edema, peripheral hypostasis, feeling of discomfort, thirst.

Infectious and parasitic diseases: bacterial infections (including sepsis), fungal infections, flu, upper respiratory tract infections, bronchitis, the infection caused by a herpes simplex virus, sinusitis, average otitis, rhinitis.

From system of blood and lymphatic system: hemolitic anemia, leukopenia, thrombocytopenia, lymphadenopathy.

From endocrine system: hypothyroidism, hyperthyroidism.

From an organ of sight: vision disorder, sight illegibility, photophobia, conjunctivitis, irritation of eyes, disturbances of a slezootdeleniye, eye pain, xerophthalmus.

From a metabolism and food: hypocalcemia, hyperuricemia, dehydration, increase in appetite.

From kidneys and urinary system: the speeded-up urination, a polyuria, disturbance of indicators of urine.

From generative organs and a mammary gland: an amenorrhea, a mammary gland pain, a menorrhagia, disturbance of a menstrual cycle, disturbance from ovaries, disturbance from a vagina, sexual dysfunction, prostatitis, erectile dysfunction.

Infrequent side reactions (≥1/1000; <1/100):

From the central and peripheral nervous system: neuropathy, peripheral neuropathy.

From mentality: suicide, attempt of suicide, thought of suicide, psychosis, hallucinations, panic attacks.

From digestive tract: pancreatitis, stomatalgia.

From cardiovascular system: myocardial infarction.

From an acoustic organ and labyrinth disturbances: ear pain.

From skeletal and muscular and connecting fabric: ostealgia, muscular weakness.

Infectious and parasitic diseases: infections in an injection site, a lower respiratory tract infection.

From immune system: reactions of hypersensitivity to medicine.

From a metabolism and food: diabetes mellitus, gipertriglitseridemiya.

From an organ of sight: exudate in a retina.

Rare side reactions (≥1/10000; <1/1000):

From the central and peripheral nervous system: spasms.

From mentality: bipolar disorders.

From digestive tract: ischemic colitis.

From cardiovascular system: congestive heart failure, cardiomyopathy, arrhythmia, pericardis, vasculitis.

From skeletal and muscular and connecting fabric: рабдомиолиз, miositis, pseudorheumatism.

From skin and a hypodermic fatty tissue: skin form of a sarcoidosis (skin sarcoidosis).

Reactions in an injection site: a necrosis in an injection site.

From immune system: sarcoidosis.

From a metabolism and food: diabetic ketoacidosis.

From an organ of sight: loss of visual acuity or restriction of fields of vision, retinal apoplexy, retinopathy, obstruction of arteries of a retina, obstruction of veins of a retina, optic neuritis, papilledema, macula lutea hypostasis.

From kidneys and urinary system: renal failure.

Very rare side reactions (<1/10000):

From the central and peripheral nervous system: cerebrovascular bleeding, cerebrovascular ischemia, encephalopathy.

From digestive tract: ulcer colitis.

From cardiovascular system: heart ischemia.

From respiratory system, bodies of a thorax and a mediastinum: intersticial pulmonary disease.

From skin and a hypodermic fatty tissue: Stephens-Johnson's syndrome, toxic epidermal necrolysis, multiformny exudative erythema.

From system of blood and lymphatic system: aplastic anemia.

From immune system: sarcoidosis (or sarcoidosis aggravation).

Frequency is not established:

From the central and peripheral nervous system: paralysis of a facial nerve, mononeuropathy.

From mentality: thoughts of murder, mania.

From cardiovascular system: pericardiac exudate.

From system of blood and lymphatic system: true erythrocyte aplasia.

From immune system: reactions of immediate hypersensitivity, including a Quincke's disease, an anaphylaxis and anaphylactic reactions, including an acute anaphylaxis, an idiopathic Werlhof's disease, a system lupus erythematosus.

From an organ of sight: serous amotio of a retina.

The side effects observed at use of similar drugs of peginterferon alpha 2b for treatment of chronic hepatitis C at HIV-positive patients

At the HIV-positive patients with chronic hepatitis C receiving similar drug of peginterferon alpha 2b in a combination with ribaviriny in large researches the following side reactions with a frequency over 5% which were absent at patients with monoinfection were observed: oral cavity candidiasis (14%), the acquired lipodystrophy (13%), decrease in number of CD4+ of lymphocytes (8%), a loss of appetite (8%), increase in activity of a gammaglutamiltranspeptidaza (9%), a dorsodynia (5%), increase in activity of amylase in blood (6%), increase in concentration of lactic acid in blood (5%), hepatitis with a cytolysis (6%), increase in activity of a lipase (6%) and extremity pain (6%).

Interaction with other medicines:

Pharmacokinetic interaction between peginterferon drugs an alpha and ribaviriny is not revealed.

Therapy by peginterferon alpha 2а in a dose of 180 mkg a week within 4 weeks did not influence a pharmacokinetic profile of Tolbutamidum (CYP 2C9), Mephenytoinum (CYP 2C19), debrisoquine (CYP 2D6) and dapsone (CYP 3A4) at healthy men of volunteers. Therapy by peginterferon alpha 2b (on 1,5 mg/kg a week within 4 weeks) did not influence activity of isoenzymes of CYP1A2, CYP3A4 or N-acetyltransferase, however increase in activity of isoenzymes of CYP2C8/C9 and CYP2D6 is noted.

Therefore it is necessary to be careful at purpose of the drug Algeron® together with medicines in which metabolism isoenzymes of CYP2C8/C9 or CYP2D6 participate.

Considering property of peginterferon the alpha to inhibit activity of an isoenzyme 1A2 of P450 cytochrome and to increase AUC theophylline (approximately by 25%) at a concomitant use of the drug Algeron® and theophylline, it is necessary to control concentration of theophylline in serum and to carry out the corresponding correction of its dose.

Therapy by peginterferon alpha 2а in a dose of 180 mkg a week was associated with increase in the average levels of metabolites of methadone by 10-15%. Though clinical value of this interaction is not defined, it is recommended to control carefully intoxication symptoms methadone during treatment by the drug Algeron®.

At the sick HIV receiving highly active anti-retrovirus therapy (VAART) the risk of development of a lactacidemia is increased. Therefore at addition of a combination of Algeron® + рибавирин to VAART it is necessary to be careful.

Interaction between ribaviriny and nukleozidny inhibitors of the return transcriptase is not revealed (ламивудин, a zidovudine, ставудин). The deterioration in a course of anemia caused by reception of a ribavirin was observed against the background of therapy of HIV using a zidovudine. Combined use of a ribavirin and zidovudine is not recommended as results in the increased risk of development of anemia. The combination of a didanozin and a ribavirin is not recommended. Ribavirin increases exposure of a didanozin and his active metabolite (дидеоксиаденозин 5 triphosphate) that can lead to development of a fatal liver failure, peripheral neuropathy, pancreatitis, a symptomatic lactacidemia.

Results of clinical trial within which studied use of a telbivudin (600 mg daily) in a combination with peginterferon alpha 2а (180 mkg once a week subcutaneously) showed the increased risk of development of peripheral neuropathy when using this combination. The mechanism of this phenomenon is unknown. Besides, safety and efficiency of a telbivudin in a combination from interferona an alpha for treatment of chronic hepatitis B were not confirmed. Combined use of the drug Algeron® and telbivudin contraindicated.

Contraindications:

- Hypersensitivity to interferon drugs, polyethyleneglycol and any other components of the drug Algeron®.

- Hypersensitivity to a ribavirin or any other component of drug.

- Dekompensirovanny cirrhosis (a class B and C but a scale Chayld-Pyyu or bleeding from varicose expanded veins).

- Cirrhosis with existence of a liver failure at patients with coinfection HIV / chronic hepatitis C (the Chayld-Pyyu index> 6).

- Autoimmune hepatitis or other autoimmune diseases in the anamnesis.

- Dysfunctions of a thyroid gland which do not manage to be supported at the normal level by medicamentous therapy.

- Epilepsy and/or dysfunction of the central nervous system.

- A serious illness of cardiovascular system, unstable or uncontrollable within, at least, 6 months preceding treatment.

- Serious illness (including renal failure, KK <50 ml/min., need of carrying out hemodialysis).

- Malignant new growths.

- Rare hereditary diseases, such as a lactose intolerance, deficit of lactase or glyukozo-galaktozny malabsorption (in the presence as a part of drug of a ribavirin of lactose).

- Hemoglobinopathies (for example, thalassemia, sickemia).

- Pregnancy and period of a lactation.

- Performing therapy at men whose partners are pregnant.

- Children's age up to 18 years.

- The expressed oppression of a marrowy hemopoiesis (neutrophils <^0,5Õ109/l, thrombocytes <^25Õ109/l, hemoglobin <85 g/l).

- The serious exhausting conditions.

- A concomitant use with telbivudiny.

With care:
- Serious illness of lungs (for example, chronic obstructive diseases of lungs).

- A serious mental illness, in particular, depressions, suicide thoughts or attempts (including in the anamnesis).

- A diabetes mellitus with a tendency to development of a ketoatsidotichesky coma.

- The disturbances connected with coagulant system of blood (for example, at thrombophlebitis, the postponed embolism of a pulmonary artery).

- Neutrophils <^1,5Õ109/l, thrombocytes <^90Õ109/l, hemoglobin <100 g/l.

- In a combination with miyelotoksichny drugs.

- Patients with coinfection have a HIV / chronic hepatitis C - number of CD4+ of lymphocytes less than 200 cells / мкл or less than 100 cells / мкл at the HIV RNA level more than 5000 copies/ml.

Overdose:

At overdose of drugs of peginterferon alpha 2b the serious undesirable phenomena were not noted. Strengthening of dozozavisimy side effects is possible. At accidental reception of a dose of peginterferon alpha 2b, exceeding recommended no more than twice, serious symptoms of overdose were not observed. The undesirable phenomena pass independently and do not demand drug withdrawal. Cases of use of peginterferon alpha 2b in the doses surpassing recommended by 10,5 times were reported. The maximum daily dose made 1200 mkg. The undesirable phenomena observed at overdose will be coordinated with the available data on a profile of safety of pegylated interferon an alpha.

Cases of overdose of peginterferon alpha 2а are described at administration of drug within two days in a row (without observance of a week interval) and at daily introduction for one week (a total dose of 1260 mkg a week). Any unusual, serious and influencing treatment undesirable phenomena are noted.

The specific antidote is absent. The hemodialysis and peritoneal dialysis are inefficient. If necessary symptomatic therapy is carried out.

Storage conditions:

Period of validity - 2 years. Not to apply after the period of validity specified on packaging. At a temperature from 2 to 8 ºС in the place protected from light. Not to freeze. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Solution for hypodermic introduction, 200 mkg/ml. On 0,4, 0,5, 0,6, 0,8 or 1,0 ml in ternary sterile syringes from colourless neutral glass. On 1 syringe in a blister strip packaging from a film polymeric. On 1 or 4 blister strip packagings together with the application instruction place in a pack from a cardboard. On 1,0 ml in the bottles from colourless neutral glass corked by traffic jams with a teflon covering, which are pressed out by aluminum caps. On 1 or 4 bottles in a blister strip packaging from a film polymeric together with the application instruction place in a pack from a cardboard.