Интрон® And

General characteristics. Structure:

Active ingredient: 18 million. Piece, 25 million. Piece, 30 million. Piece or 60 million. Piece of recombinant interferon alpha 2b.

Excipients: sodium hydrophosphate anhydrous, dihydrophosphate sodium monohydrate, dinatrium эдетат, sodium chloride, metacresol (preservative), polysorbate 80, water for an injection.

Pharmacological properties:

Pharmacodynamics. Interferon. Antineoplastic, antiviral and immunomodulatory drug. Interferona have effect on cells due to linkng with specific receptors on their surface.

Results of several researches demonstrate that after linkng with a cellular membrane, interferon causes the difficult sequence of intracellular reactions, including induction of certain enzymes. Believe that at least partially these processes and define cellular effects of interferon, including suppression of replication of viruses in the infected cells, oppression of proliferation of cells, and also immunomodulatory properties of interferon, such as strengthening of phagocytal activity of macrophages and increase of specific cytotoxicity of lymphocytes in relation to target cells. This activity can define therapeutic effect of interferon.

Recombinant interferon alpha 2b has anti-proliferative effect as concerning culture of cells of the person and animals, and concerning heterografts of tumors of the person and animals. Considerable immunomodulatory activity of recombinant interferon alpha 2b is shown to in vitro. Recombinant interferon alpha 2b also suppresses replication of in the vitro and in vivo viruses.

Though the exact mechanism of antiviral effect of recombinant interferon alpha 2b is unknown, is established that it breaks metabolism of a cell into which the virus got. It leads to suppression of replication of a virus, and in cases when replication nevertheless happens, virions with the damaged genome are not capable to leave a cell.

Chronic hepatitis B. Clinical trials of use of interferon alpha 2b within 4-6 months show that therapy can lead to elimination of DNA of a virus of hepatitis B (HBV) and improvement of a histologic picture of a liver.

Chronic hepatitis C. Use of the Intron And in the form of monotherapy or in a combination with ribaviriny was studied in 4 randomized clinical trials of the III phase at 2552 patients with chronic hepatitis C who were not receiving earlier therapy by interferon. During the researches efficiency of monotherapy or a combination therapy with ribaviriny was compared. Efficiency of therapy was defined on the basis of lack of replication of a virus in 6 months after the end of treatment.

All patients had the chronic hepatitis C confirmed with positive PTsR-reaction to RNA of a virus of hepatitis C (HCV) (> 100 copies/ml), data of a biopsy of a liver with histologic confirmation of chronic hepatitis and lack of any other reason for its emergence, and increase in activity of ALT.

Интрон® And appointed in a dose 3 million ME 3 times a week as monotherapy or in a combination with ribaviriny. The most part of patients received treatment within a year. All patients were observed within 6 months after the end of therapy for determination of duration of preservation of results. Data of these two researches are provided in table 1.

The combination therapy ribaviriny and the Intron And considerably increased efficiency of therapy at all subgroups of patients. The genotype of HCV and amount of RNA of a virus before therapy are predictive factors. Improvement of results at use of a combination therapy is observed especially at the patients who are difficult giving in to treatment (with a genotype of 1 virus and high content of HCV RNA in blood serum).

Table 1. Number of patients with the resistant virologic answer (%) after a year course of treatment.

* Интрон® And (3 million ME 3 times a week)

** Интрон® And (3 million ME 3 times a week) and рибавирин (1/1.2 g/days)

Strict observance of the scheme of the carried-out therapy considerably improves results of treatment. Irrespective of a virus genotype, the patients who received 80% and more course therapy (рибавирин + Intron® And) had the best long-term results, than patients who received less than 80% of course therapy (the resistant virologic answer in 56% of cases in comparison with 36% - according to the research CI98/580).

Treatment of a recurrence: 345 patients received during the researches Intron® A in the form of monotherapy or in a combination with ribaviriny concerning a recurrence. This group of patients has an addition of a ribavirin to the Intron And caused 10-fold increase in efficiency of treatment in comparison with monotherapy by the Intron And (48.6% and 4.7%) that was shown by elimination of HCV RNA from blood serum (less than 100 copies/ml when carrying out PTsR-reaction), reduction of an inflammation of a liver and normalization of ALT. And these results remained in 6 months after the end of therapy (the resistant virologic answer).

At the patients receiving Intron® And during performing controlled clinical trials defined interferon - neutralized antibodies. Frequency of identification of these antibodies made 2.9% at the patients receiving therapy by the Intron And concerning an oncological disease, and patients have 6.2% with chronic hepatitis. Antiserum capacities were low practically in all cases, and their identification did not contact decrease in efficiency of therapy or other autoimmune disorders.

Preclinical data on safety of drug. In spite of the fact that interferon is considered species-specific substance, researches of its toxicity at animals were conducted.

Administration of human recombinant interferon alpha 2b within 3 months was not followed by toxicity signs at mice, rats, rabbits. Administration of drug to monkeys of a type of Cynomolgus within 3 months daily in a dose 20×106 МЕ/кг/сут also did not lead to emergence of noticeable signs of toxicity. Increase in a dose at monkeys to 100×106 МЕ/кг/сут within 3 months resulted in toxic effect.

In researches using interferon at not humanoid primacies disturbances of a menstrual cycle were observed.

Results of researches of influence of interferon alpha 2b on reproductibility at animals indicate lack of teratogenic effect at rats and rabbits. Drug, also, did not exert impact on the course of pregnancy, fetation and on reproductive function at posterity of treated rats.

In the researches conducted on macaques a Rhesus factor it is shown that use of high doses of interferon alpha 2b in the high doses (exceeding recommended in 90 and 180 times) causes abortions.

When carrying out the corresponding researches it is not established mutagen effect of interferon alpha 2b.

Pharmacokinetics. Pharmacokinetics of the Intron And studied at healthy volunteers at single introduction in doses 5 million ME/sq.m and 10 million ME/sq.m п / to, 5 million ME/sq.m in oil and 5 million ME/sq.m in/in in the form of infusion.

Average concentration of interferon in plasma were comparable after п / to and introductions in oil. At this Cmax in a blood plasma it was reached in 3-12 h and in 6-8 h respectively. Both after in oil, and after п / to introduction of T1/2 made about 2-3 h. Concentration of interferon in plasma was not defined by 16-24 h.

Bioavailability of drug at п / to introduction made 100%.

Later in/in introductions concentration of interferon in plasma reached the maximum sizes (135-273 ME/ml) at the end of infusion, then decreased slightly quicker, than after п / to or injections in oil, and was not defined by 4 h after the end of infusion; T1/2 made about 2 h.

Concentration of interferon in urine was below the determined size irrespective of a way of introduction.

Indications to use:

Chronic hepatitis B:

— treatment of adults and children (of 1 year) with the confirmed replication of a virus of hepatitis B (availability of HBV or HBeAg DNA in blood serum) in combination with increase in activity of ALT in a blood plasma and histologically the confirmed active inflammatory process and/or fibrosis of a liver.

Chronic hepatitis C:

— monotherapy or in a combination with ribaviriny adults who have a hyperactivity of transaminases have no signs of a decompensation of function of a liver and HCV RNA or antibodies to a hepatitis virus decides On (anti-HCV) in blood serum;

— at children at the age of 3 years is also more senior with the compensated disease of a liver, earlier not receiving treatment iterferony alpha 2b, and at adults with a recurrence is after therapy iterferony alpha 2b preferably to appoint Intron® And in a combination with ribaviriny.

Before a combination therapy it is necessary to study the application instruction of a ribavirin.

Throat papillomatosis:

— treatment of adults and children for 1 year.

Hairy cell leukosis:

— treatment of adults in the form of monotherapy or in a combination with ribaviriny.

Myelosis:

— monotherapy: treatment of adults in the presence of the Philadelphian chromosome (Ph+) or a translocation of bcr/abl (clinical data show that hematologic remission and the big/small cytogenetic answer are reached at most of patients, at the same time the big cytogenetic answer is defined as quantity Rh+-leykoznykh of cells in marrow <34%, and small - from 34% to 90%;

— combination therapy: purpose of the Intron And in combination with Cytarabinum during the first 12 months of treatment allows to increase significantly number of big cytogenetic answers and to considerably increase the general survival of patients in comparison with monotherapy by interferon alpha 2b after 3 years of treatment).

Thrombocytosis at patients with a myelosis (HML):

— the thrombocytosis often arises at a myelosis (Intron® And applied with some effect at adult patients with the thrombocytosis connected with HML).

Multiple myeloma:

— quality of a maintenance therapy at the adult patients who reached the partial answer (reduction of level of a paraprotein in blood serum for 50%) after initial induction therapy (the maintenance therapy extends a plateau phase, however influence of drug on the general survival is not finalized).

Follicular lymphoma (nekhodzhkinsky lymphoma):

— treatment of a follicular lymphoma with a high tumoral weight - in combination with adequate induction chemotherapy (for example, the SNOR-mode) at adults. Follicular lymphoma in the presence of at least one of the listed signs concern to this group: the big size of a tumor (> 7 cm), involvement of 3 or more lymph nodes (everyone> 3 cm), the general symptoms (decrease in body weight more than for 10%, fervescence more than 38 °C during more than 8 days, the increased sweating at night), a splenomegaly (the border of a spleen goes beyond area of a navel), a prelum of important bodies or emergence of a compression syndrome, involvement of an epidural space or orbital area, leukemia, a considerable exudate.

Efficiency of therapy was not established by the drug Intron® A at patients with follicular nekhodzhkinsky lymphoma of low degree of a zlokachestvennost and low tumoral loading.

Kaposha's sarcoma against the background of AIDS:

— treatment of patients in the absence of opportunistic infections if the number of cells of CD4 exceeds 250/mm3.

Kidney cancer:

— the progressing kidney cancer at adults.

Carcinoid tumors:

— carcinoid tumors at adults when involving lymph nodes or with metastasises in a liver and with a carcinoid syndrome.

Malignant melanoma:

— adjuvant therapy at adult patients, later surgical treatment concerning primary tumor, with high risk of a system recurrence.

Route of administration and doses:

By Intron And the doctor having experience of treatment of the corresponding disease has to carry out treatment. According to the decision of the doctor the patient can independently administer to himself the drug п / to for continuation of the picked-up therapy mode.

Chronic hepatitis B. The recommended dose for adults makes from 30 to 35 million ME a week п / to, or in a dose of 5 million ME daily, or 10 млн.ME 3 times a week within 4 months (16 weeks).

To children from 1 year to 17 years inclusive Intron® And enter п / to in an initial dose of 3 million ME/sq.m 3 times a week (every other day) within the first week of treatment with the subsequent increase in a dose up to 6 million ME/sq.m (at most up to 10 million ME/sq.m) 3 times a week (every other day). Duration of a course of treatment is 4-6 months (16-24 weeks).

Treatment is stopped in the absence of positive dynamics (according to research DNA of a virus of hepatitis B / HBV/) after 3-4 months of treatment by drug in the maximum tolerable dose.

Recommendations about dose adjustment. The dose of drug should be reduced by 50% at development of disturbances from system of a hemopoiesis (leukocytes <1500/mm3, granulocytes <1000/mm3 at children and <750/mm3 at adults, thrombocytes <100 000/mm3 at children and <50 000/mm3 at adults).

Therapy should be stopped in case of the expressed leukopenia (leukocytes <1200/mm3), neutropenias (granulocytes <750/mm3 at children and <500/mm3 at adults) or thrombocytopenia (thrombocytes <70 000/mm3 at children and <30 000/mm3 at adults).

Treatment can be resumed in a former dose after normalization or return to the initial level of number of leukocytes, granulocytes and thrombocytes.

The chronic hepatitis C. Intron® A is appointed п / to in a dose 3 млн.ME by 3 times a week (every other day) as monotherapy or in a combination with ribaviriny (doses and recommendations about their selection in the application instruction of a ribavirin in capsules as a part of a combination therapy).

At treatment of patients with a recurrence after a monotherapy course interferon an alpha of Intron® And appoint only in a combination with ribaviriny. On the basis of results of the clinical trials conducted within 6 months, the recommended duration of the combined treatment with ribaviriny makes 6 months.

At treatment of the patients who were earlier not receiving therapy, efficiency of the Intron And raises at simultaneous use with ribaviriny. Monotherapy by drug is carried out only in the presence of contraindications to use or intolerance of a ribavirin.

Use of the Intron And in a combination with ribaviriny. On the basis of results of the clinical trials conducted within 12 months, the recommended duration of a combination therapy with ribaviriny makes, at least, 6 months.

At patients with a genotype of 1 virus and high content of RNA of a virus (by results of the research conducted prior to therapy) at which by the end of the first 6 months of therapy in blood serum RNA of a virus of hepatitis C (HCV) is not defined, treatment is continued by 6 more months (i.e. in total 12 months). At making decision on carrying out a combination therapy within 12 months it is also necessary to take into account other negative predictive factors: the age is more senior than 40 years, a male, the progressing fibrosis.

At conduct of clinical trials it is established that at patients at whom after 6 months of therapy HCV RNA is still defined continuation of treatment does not lead to HCV RNA elimination.

At use of the Intron And in a combination with ribaviriny it is necessary to make careful observation of patients with abnormal liver functions and patients 50 years in connection with possible development of anemia are more senior.

To children of 3 years Intron® is also more senior And appoint п / to 3 million ME/sq.m 2 times a week in a combination with oral administration of a ribavirin in a dose of 15 mg/kg daily, dividing this dose on morning and evening.

Monotherapy by the Intron And. Интрон® And recommend to apply within, at least, 3-4 months, after that it is necessary to carry out HCV RNA definition. Then treatment is continued only if HCV RNA is not revealed.

For the patients who are well transferring therapy with normalization of ALT on the 16th week of treatment, the recommended course of treatment makes from 18 to 24 months.

Throat papillomatosis. The recommended dose of the Intron And makes 3 million ME/sq.m п / to 3 times a week (every other day). Treatment is begun after surgical (laser) removal of tumoral fabric. The dose is increased taking into account portability of drug. For achievement of affirmative answer performing therapy within more than 6 months can be required.

Hairy cell leukosis. The recommended dose of the Intron And for п / to introduction to patients after a splenectomy and without it makes 2 million ME/sq.m 3 times a week. In most cases normalization of one and more hematologic indicators occurs in 1-2 months of treatment. For normalization of indicators of peripheral blood (number of leukocytes, thrombocytes and level of hemoglobin) can be required up to 6 months of treatment by the Intron And. It is necessary to adhere to this mode of dosing constantly if only at the same time there is no bystry progressing of a disease or emergence of heavy intolerance of drug.

Myelosis. The recommended dose of the Intron And makes 4-5 million ME/sq.m п / to daily. In certain cases the combination of the Intron And in a dose of 5 million ME/sq.m, appointed daily п / to, with Cytarabinum (Ara-c) in a dose of 20 mg/m п / to within 10 days a month is effective (the maximum daily dose - 40 mg).

After normalization of number of leukocytes of Intron® And enter in the maximum tolerable dose (4-5 million МЕ/м2/сут) for maintenance of hematologic remission.

Интрон® And it is necessary to cancel in 8-12 weeks of treatment if by this time, at least, partial hematologic remission or clinically significant decrease in number of leukocytes is not reached.

Thrombocytosis at patients with a myelosis. The same doses are recommended, as at treatment of a myelosis. The dose adjustment used for control of number of leukocytes can be applied to control of number of thrombocytes also.

Clinical data demonstrate that approximately at one quarter (26%) of patients with a myelosis the accompanying thrombocytosis (number of thrombocytes> 500×109/л is noted). Decrease in number of thrombocytes managed to achieve from all patients after 2 months of treatment. The number of thrombocytes never was <80×109/л, at monthly control.

Multiple myeloma. Patients at whom as a result of induction therapy the plateau phase (reduction of a paraprotein more than for 50%), is reached by Intron® And can appoint as the supporting monotherapy in a dose 3-5 million ME/sq.m п / to 3 times a week.

Follicular lymphoma. In combination with chemotherapy of Intron® And appoint п / to in a dose of 5 million ME 3 times a week (every other day) within 18 months. Clinical data are available only on CHVP use (a combination of cyclophosphamide, doxorubicine, a tenipozid and Prednisolonum) in the form of 6-month cycles and the subsequent 6 cycles which are carried out 1 time in 2 months.

Kaposha's sarcoma connected about AIDS. The optimum dose is not established. Efficiency of the Intron And in a dose of 30 million ME/sq.m is shown at п / to introduction 3-5 weekly. Drug was also used in smaller doses (10-12 million МЕ/м2/сут) without noticeable decrease in efficiency.

If the disease is stabilized or there is a clinical response to treatment, therapy continue until growth of a tumor is noted or drug withdrawal because of development of a heavy opportunistic infection or side effect will not be required. At these patients therapy by the Intron And can be carried out in out-patient conditions.

Simultaneous use with a zidovudine. In clinical trials patients about AIDS and Kaposha's sarcoma received Intron® And in combination with a zidovudine. In most cases the following scheme of treatment was well transferred by patients: Интрон® And in a dose of 5-10 million ME/sq.m; zidovudine of 100 mg each 4 h. The neutropenia was the main toxic effect limiting a dose.

Treatment And it is possible to begin with the Intron with a dose 3-5 million МЕ/м2/сут. In 2-4 weeks the dose of the Intron And can be increased by 5 million МЕ/м2/сут - to 10 million МЕ/м2/сут, taking into account portability; the dose of a zidovudine can be raised to 200 mg / 4 h. The dose should be selected individually, taking into account efficiency and portability.

Kidney cancer. Monotherapy. The optimum dose and the scheme of use at monotherapy are not established. Интрон® And applied in doses 3-30 million ME/sq.m п / to 3-5 weekly or daily. The maximum effect was observed at п / to use of the Intron And in doses of 3-10 million ME/sq.m 3 times a week.

In a combination with other medicines (including interleykinom-2) the optimum dose is not established. In a combination with interleykinom-2 the Intron And was applied п / to in doses of 3-20 million ME/sq.m. In clinical trials the frequency of the response to treatment was maximum at п / to introduction of the Intron And in a dose of 6 million ME/sq.m 3 times a week (the dose was selected individually during treatment).

Carcinoid tumors. The standard dose of the Intron And makes 5 million ME/sq.m (3-9 million ME) п / to 3 times a week (every other day). At patients with widespread process use of a dose to 5 million ME/sq.m daily can be required.

At surgical treatment therapy by the Intron And is stopped for the period of operation and the recovery period after it. Therapy by drug is continued until the clinical response to the carried-out treatment is observed.

Malignant melanoma. For induction of remission of Intron® And appoint in/in in a dose of 20 million МЕ/м2/сут 5 days in a week for 4 weeks. The dose calculated thus is added to 0.9% to solution of sodium of chloride and entered in the form of infusion within 20 min. Treatment should be begun within 56 days after surgical intervention. For a maintenance therapy the recommended dose makes 10 million ME/sq.m п / to 3 times a week (every other day) within 48 weeks.

At development of heavy side effects during therapy by the Intron And (in particular at decrease in number of granulocytes <500/mm3 or increase in ALT/nuclear heating plant to the values exceeding VGN by 5 times) use of drug is stopped before normalization of indicators. Then treatment is resumed, using the dose reduced by 50%. If the intolerance remains or if the number of granulocytes decreases to 250/mm3, or activity of ALT and/or ACT increases up to the values exceeding VGN by 10 times, drug is cancelled.

Though the optimum (minimum) dose for achievement of adequate clinical effect is not established, Intron® And should appoint in the recommended doses taking into account their possible correction because of toxic action as it is described above.

Rules of preparation and administration of solutions. Before introduction it is necessary to be convinced visually of lack of visible particles and discolorations of solution.

The bottle or the syringe handle are used for treatment only of one patient. Интрон® And solution for injections in bottles it is possible to enter at once after set of a bottle of a necessary dose by means of the sterile syringe for injections (glass or plastic).

Preparation of solution for in/in introductions. Infusion should be carried out immediately after solution preparation. For measurement of a required dose of drug it is possible to use a bottle of any volume; at the same time final concentration of interferon alpha 2b in solution of sodium of chloride has to be not less than 0.3 million ME/ml. The corresponding dose of drug is gathered from a bottle, add to 50 ml 0.9% of solution of sodium of chloride to a bag from PVC or to a glass bottle for infusions and entered in/in kapelno within 20 min.

Unacceptably simultaneous administration of other drugs together with the Intron And.

Интрон® And solution for injections enter into the syringe handles п / to at once after accession of an injection cannula and a set of a necessary dose. Drug should be got from the refrigerator in 30 min. prior to carrying out an injection that solution got warm to room temperature (to 25 °C).

For introduction of each dose it is necessary to use a new needle. After packaging opening drug is recommended to use within 4 weeks on condition of storage at a temperature from 2 ° to 8 °C. After an injection the needle should be thrown out, and immediately to place the handle in the refrigerator.

The syringe handle Intron® A happen three types, depending on contents in them active agent - recombinant interferon alpha 2b - 18 million ME, 30 million ME or 60 million ME. Everyone the syringe handle is intended for introduction of several therapeutic doses. The doctor has to specify to the patient dose volume for each introduction. Color of the strip located on a case circle the syringe handle and buttons is individual for each look the syringe handle and depends on its dosage - brown for 18 million ME, blue for 30 million ME and pink for 60 million ME.

Before an injection it is necessary to be convinced that the syringe handle corresponds to that dose which was appointed by the doctor. For this purpose it is necessary to check color of a strip and the button and the dosage specified on packaging.

The injection should be carried out with observance of conditions of an asepsis and antiseptics.

Choice of the place of an injection: it is recommended to make an injection under skin of a hip, the outside surface of a shoulder or a stomach (except area of a navel and a waist). If the hypodermic fatty tissue in a stomach is insufficiently developed, it is necessary to carry out injections only to a hip or the outside surface of a shoulder (assistance can be necessary for the patient for an injection to this area). Every time should be chosen the new place for an injection.

After the full number of doses from the syringe handle is entered (usually 6 or so much how many the doctor appointed), in it there will be a small amount of solution. This rest cannot use, considering impossibility of exact dosing. Existence of excess amount of solution is necessary in order that it was possible to remove air from a needle before an injection, having kept at the same time necessary quantity of doses.

Features of use:

Use at pregnancy and feeding by a breast. Clinical data on use of interferon alpha 2b at pregnancy are absent.

Use of drug at pregnancy is possible only in that case when the estimated advantage for mother surpasses potential risk for a fruit.

It is unknown whether components of the drug Intron® A with breast milk are allocated. Because of possible risk of undesirable effects of drug at the babies who are on breastfeeding in need of use of drug for mother it is necessary to stop feeding by a breast.

Women of childbearing age and partners of male patients have to use two methods of contraception during treatment by the Intron And yes within 6 months after its end.

At the women receiving therapy by human leukocytic interferon decrease in level of oestradiol and progesterone was noted.

Drug should be used with care at men of reproductive age.

In pilot studies on animals toxic action on reproductibility is revealed. Value of these data for the person is unknown.

In researches using interferon at not humanoid primacies disturbances of a menstrual cycle were observed.

Results of researches of influence of interferon alpha 2b on reproductibility at animals indicate lack of teratogenic effect at rats and rabbits. Drug, also, did not exert impact on the course of pregnancy, fetation and on reproductive function at posterity of treated rats.

In the researches conducted on macaques a Rhesus factor it is shown that use of high doses of interferon alpha 2b in the high doses (exceeding recommended in 90 and 180 times) causes abortions. It is known, as other interferona the alpha and a beta at use in high doses cause anovulation and abortions in macaques a Rhesus factor (these effects of a dozozavisima).

Use at abnormal liver functions. Use of drug at the expressed abnormal liver functions is contraindicated (including caused by metastasises).

Use at renal failures. Use of drug at the expressed renal failures is contraindicated (including caused by metastasises) at KK <50 ml/min.

Use for children. Интрон® And it is possible to apply at children of 1 year at chronic hepatitis B and a papillomatosis of a throat. Clinical data on use of the Intron And according to other indications are not available for children.

Special instructions for all patients. At use of the Intron And reactions of immediate hypersensitivity (a small tortoiseshell, a Quincke's disease, a bronchospasm, an anaphylaxis) were in rare instances observed. In such cases, it is necessary to cancel immediately drug and to take the appropriate measures. Passing skin rash does not demand the treatment termination.

At development of heavy and medium-weight side effects correction of the mode of dosing or, in certain cases, the therapy termination can be required. In case of emergence against the background of use of the Intron And signs of an abnormal liver function for the patient it is necessary to establish careful observation and when progressing symptoms to cancel drug.

Against the background of use of the Intron And or within 2 days after cancellation of treatment development of the arterial hypotension demanding purpose of the corresponding therapy is possible.

At treatment And it is necessary to provide with the Intron adequate hydration of an organism by additional administration of liquid as in certain cases arterial hypotension can develop as a result of reduction of OTsK.

Fever can be manifestation of the grippopodobny syndrome which is often meeting at use of interferon alpha 2b, however it is necessary to exclude other reasons of its emergence.

Интрон® And with care appoint to patients with a serious chronic illness, such as HOBL, a diabetes mellitus with tendency to ketoacidosis. Extra care is required at use of drug for patients with disturbances of coagulability of blood (including with thrombophlebitises, thromboembolisms of a pulmonary artery), and also at the expressed miyelosupressiya.

At the patients receiving therapy by interferon an alpha (including and the Intron And), pneumonites and pneumonia (in certain cases with a lethal outcome) not clear etiology are in rare instances observed. Similar symptoms met more often against the background of use "шосаикото" - means of the Chinese traditional medicine of a plant origin. Any patient with cough, fever, short wind or other symptoms from respiratory system should conduct X-ray inspection of a thorax. If infiltrate is as a result revealed, or there are dysfunctions of lungs, then it is necessary to watch the patient carefully and if necessary to cancel therapy by the Intron And. Timely cancellation of interferon an alpha and purpose of GKS promotes stopping of pulmonary syndromes.

Disturbances from an organ of sight appear after several months of treatment, but are possible also after less long therapy. All patients should conduct ophthalmologic examination prior to therapy. Immediate consultation of the oculist is necessary for any patient who at treatment by the Intron And has complaints to a vision disorder, change of fields of vision or any other ophthalmologic disturbances. To patients with diseases at which there can be changes of a retina for example of a diabetes mellitus or arterial hypertension, it is recommended during therapy by the Intron And to regularly have ophthalmologic examination. At emergence or aggravation of a visual disturbance it is necessary to consider a question of the therapy termination by the Intron And.

Serious mental violations, in particular depression, suicide thoughts and attempts, psychosis, including hallucinations, an agressive behavior, including directed to other people are the known side effects of interferon alpha. Suicide thoughts and attempts were more often noted at patients children's, first of all teenage age (2.4%), than at adults (1%).

It is necessary to use with care drug at patients with instructions in the anamnesis on existence of mental disorders.

In case of development in the patient of changes from the mental sphere and/or TsNS, including development of a depression, observation of the doctor of such patient during the entire period of treatment, and also within 6 months after its termination is recommended. The specified side effects usually are quickly reversible after the therapy termination, however in certain cases it was required up to 3 weeks for their full involution. If symptoms of frustration of mentality do not regress or there are suicide thoughts or the agressive behavior directed to other people, it is recommended to stop treatment by the Intron And yes to provide consultation of the psychiatrist.

At some patients, especially elderly, receiving drug in high doses, disturbance of consciousness and a lump and a spasm, including cases of development of encephalopathy were observed. At inefficiency of a dose decline and/or medicamentous correction of these disturbances, it is necessary to resolve an issue of the therapy termination by the Intron And.

Patients with diseases of cardiovascular system (including a myocardial infarction, chronic heart failure, arrhythmias) need careful medical observation at purpose of the Intron A. Patsiyentam with heart diseases and/or the progressing oncological disease recommends carrying out an ECG to and during therapy by the Intron And. The arising arrhythmias (generally supraventricular), as a rule, give in to standard therapy, but can demand also cancellation of the Intron And.

The intron But is not appointed to patients with psoriasis and a sarcoidosis because of a possibility of an exacerbation of these diseases, except for cases when the estimated advantage of treatment justifies potential risk.

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, however relationship of cause and effect of this phenomenon interferon an alpha is not established with therapy.

At treatment of an interferonama an alpha emergence of autoantibodies and developing of autoimmune diseases was noted. The risk of these phenomena is higher at patients with the available predisposition to autoimmune diseases. 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 monotherapy And were seldom observed by the Intron hypo - or a hyperthyroidism. In clinical trials at 2.8% of the patients receiving Intron® And, pathology of a thyroid gland which was controlled by the corresponding therapy developed. The mechanism of development of such action is unknown. Before therapy And it is necessary to determine by the Intron concentration of TTG. At detection of any pathology it is necessary to carry out the corresponding treatment. If medicamentous therapy allows to support TTG up to the standard, then purpose of the Intron And is possible. If during treatment there was a suspicion on dysfunction of a thyroid gland, it is necessary to determine the TTG level. At the broken function of a thyroid gland treatment by the Intron And can be continued if the TTG level manages to be supported within norm by means of medicamentous means. Cancellation of the Intron But did not lead to recovery of function of a thyroid gland.

It is necessary to stop therapy by the Intron And at patients with chronic hepatitis when lengthening a blood clotting time as it can be a sign of a decompensation of function of a liver.

For patients with chronic hepatitis C. At use of the Intron And in a combination with ribaviriny it is necessary to be guided also by the Instruction on a medical use of a ribavirin.

In clinical trials to all patients before therapy And carried out by the Intron a liver biopsy. However in certain cases (including to patients with genotypes 2 and 3 viruses) treatment can be begun without histologic confirmation of the diagnosis. At the solution of a question of need of preliminary carrying out a biopsy it is necessary to be guided by the existing recommendations about tactics of maintaining such patients.

Combined infection with a virus of hepatitis C and HIV. At the patients infected at the same time with a virus of hepatitis C and HIV and receiving highly active anti-retrovirus therapy (VAART) lactic acidosis can develop. At purpose of the Intron And yes a ribavirina in addition to VAART it is necessary to show the increased care.

In the presence of the created cirrhosis the risk of a decompensation of function of a liver and death at the patients infected at the same time with a virus of hepatitis C and HIV is increased. Purpose of the Intron And (without ribavirin or in a combination with ribaviriny) in addition to the carried-out therapy at this group of patients can increase this risk even more.

Simultaneous carrying out chemotherapy. Use of the Intron And in a combination with chemotherapeutic drugs (Cytarabinum, cyclophosphamide, doxorubicine, тенипозид) increases risk of development of toxic effects (their weight and duration) which can threaten life or lead to a lethal outcome (owing to hypertoxity at combined use of drugs). The most frequent toxic effects are mukozita, diarrhea, a neutropenia, a renal failure and electrolytic balance. Considering risk and weight of toxic effects, it is necessary to select carefully doses of the Intron And yes chemotherapeutic means.

Control of laboratory indicators. Before an initiation of treatment the Intron And yes systematically in the course of therapy to all patients carry out the general clinical blood test (with definition of a leukocytic formula, number of thrombocytes), biochemical indicators of blood (determination of level of electrolytes, liver enzymes, bilirubin, crude protein and creatinine).

During therapy of chronic hepatitis B or C the following scheme of monitoring procedure of laboratory indicators is recommended: 1, 2, 4, 8, 12, 16 weeks and then monthly, even after the therapy termination, to the decision of the doctor on need of control. If ALT raises up to the size, twice or more exceeding a reference value, treatment by the Intron And it is possible to continue, on condition of lack of symptoms of a liver failure. At the same time definition of ACT, a prothrombin time, ShchF, albumine and bilirubin should be carried out every 2 week.

At patients with a malignant melanoma function of a liver and number of leukocytes should be controlled every week during the first phase of treatment (remission induction) and monthly - when carrying out a maintenance therapy.

Use in pediatrics. Интрон® And it is possible to apply at children of 1 year at chronic hepatitis B and a papillomatosis of a throat. Clinical data on use of the Intron And according to other indications are not available for children.

Influence on ability to driving of motor transport and to control of mechanisms. The patient should be warned in a possibility of development of weakness, drowsiness, disturbances of consciousness against the background of therapy and to recommend to avoid control of vehicles and mechanisms.

Side effects:

In the clinical trials conducted at a wide range of indications and with a big range of doses (from 6 million ME/sq.m a week at a hairy cell leukosis to 100 million ME/sq.m a week at a melanoma), fever, fatigue, a headache, a mialgiya were the most often found side reactions. Fever and fatigue passed through 72 h after the termination of administration of drug. Though fever can be one of symptoms of the "grippopodobny syndrome" which is often found at treatment of an interferonama it is necessary to conduct examination to exclude other possible reasons of persistent fever.

The profile of safety given below was received when performing 4 clinical trials at the patients with chronic hepatitis C receiving Intron® And in the form of monotherapy or in a combination with ribaviriny during 1 year. All patients received 3 million ME of the Intron And 3 times a week.

In table 2 the side reactions noted with a frequency of 10% at patients, earlier not treated and receiving Intron® And (or Intron® And in a combination with ribaviriny) during 1 year are given. Generally noted undesirable reactions were easy or moderately expressed.

Table 2.

Side reactions	Интрон® And (n=806)	Интрон® And + рибавирин (n=1010)
Local reactions
Inflammation in an injection site	9-16%	6-17%
Other reactions in an injection site	5-8%	3-36%
General reactions
Headache	51-64%	48-64%
Fatigue	42-79%	43-68%
Fever	15-39%	19-41%
Fever	29-39%	29-41%
Grippopodobny syndrome	19-37%	18-29%
Adynamy	9-30%	9-30%
Decrease in body weight	6-11%	9-19%
From a GIT
Nausea	18-31%	25-44%
Anorexia	14-19%	19-26%
Diarrhea	12-22%	13-18%
Abdominal pains	9-16-7%	9-14%
Vomiting	3-10%	6-10%
From a musculoskeletal system
Mialgiya	41-61%	30-62%
Arthralgia	25-31%	21-29%
Ostealgia and muscles	15-20%	11-20%
From TsNS
Depression	16-36%	25-34%
Irritability	13-27%	18-34%
Sleeplessness	21-28%	33-41%
Concern	8-12%	8-16%
Disturbance of ability to concentration of attention	8-14%	9-21%
Emotional lability	8-14%	5-11%
Dermatological reactions
Alopecia	22-31%	26-32%
Itch	6-9%	18-37%
Xeroderma	5-8%	10-21%
Rash	5-7%	15-24%
From respiratory system
Pharyngitis	3-7%	7-13%
Cough	3-7%	8-11%
Диспноэ	2-9%	10-22%
Others
Dizziness	8-18%	10-22%
Viral infection	0-7%	3-10%

The undesirable reactions observed at patients with a viral hepatitis With correspond to those which were noted at use of the drug Intron® A according to other indications with some dozozavisimy increase on development frequency.

At use of the Intron And according to other indications (in clinical trials and out of clinical trials) it is rare (> 1/10 000, <1/1000) or very seldom (<1/10 000) the following undesirable reactions were observed.

From an organism in general: very seldom - a face edema. It was reported about asthenic states (an adynamy, an indisposition and fatigue), dehydration, heartbeat, a fungal infection and a bacterial infection (including sepsis).

From immune system: sarcoidosis or aggravation of a sarcoidosis. At use of interferon an alpha it was reported about development of various autoimmune and mediated by immune system disturbances, including an idiopathic Werlhof's disease, a trombotichesky Werlhof's disease, a pseudorheumatism, a system lupus erythematosus, a vasculitis and Fogta-Koyanagi-Harada's syndrome.

Allergic reactions: it was reported about cases of acute reactions of hypersensitivity, including urticaria, Quincke's allergic disease and an anaphylaxis.

From cardiovascular system: seldom - arrhythmias (usually arose at patients with the previous diseases of cardiovascular system in the anamnesis or with the previous cardiotoxic therapy), a passing reversible cardiomyopathy (it is noted at patients without the burdened anamnesis from cardiovascular system); very seldom - arterial hypotension, myocardium ischemia, a myocardial infarction.

From TsNS and peripheral nervous system: seldom - suicide bents; very seldom - an agressive behavior, suicide attempts, a suicide, psychosis (including hallucinations), disturbance of consciousness, a neuropathy, polyneuropathy, encephalopathy, cerebrovascular ischemia, a cerebrovascular hemorrhage, peripheral neuropathies, spasms.

From endocrine system: very seldom - a diabetes mellitus, deterioration in a current of the available diabetes mellitus.

From a GIT: very seldom - pancreatitis, increase in appetite, bleeding of gums, colitis. At the patients receiving a combination therapy the drug Intron® A and ribaviriny pathological changes from teeth and a periodontium were noted. Dryness in a mouth at a long combination therapy ribaviriny and the Intron And can promote injury of teeth and a mucous membrane of an oral cavity. Patients have to brush teeth a brush 2 times a day and regularly have examination at the stomatologist. Besides, at some patients vomiting can be observed.

From a liver and biliary tract: a hepatotoxic (including with a lethal outcome).

From a musculoskeletal system: seldom - рабдомиолиз (sometimes heavy), spasms in legs, a dorsodynia.

From respiratory system: seldom - pneumonia; very seldom - pulmonary infiltrates, pneumonites.

From an urinary system: very seldom - a nephrotic syndrome, renal failures, a renal failure.

From system of a hemopoiesis: very seldom (at use in the form of monotherapy or in a combination with ribaviriny) - aplastic anemia and a full aplasia of marrow.

From an organ of sight: seldom - retinal apoplexies, focal changes of an eyeground, fibrinferments of arteries and veins of a retina, decrease in visual acuity, reduction of fields of vision, an optic neuritis, a papilledema.

From an acoustic organ: very seldom - a hearing disorder.

From a metabolism: seldom - a hyperglycemia, a gipertriglitseridemiya.

From skin: very seldom - a mnogoformny erythema, Stephens-Johnson's syndrome, a toxic epidermal necrolysis, a necrosis in the place of an injection; in isolated cases - psoriasis.

Clinically significant changes of laboratory indicators: were more often noted at purpose of drug in doses more than 10 million ME/days - decrease in number of granulocytes and leukocytes, decrease in level of hemoglobin and number of thrombocytes, increase in activity of ShchF, LDG, level of creatinine and an urea nitrogen of blood serum. Increase in activity of ALT and ACT in a blood plasma is noted as pathological at use according to all indications, except hepatitises, and also at some patients with chronic hepatitis B in the absence of HBV DNA.

If during use of the drug Intron® A according to any indication undesirable reactions develop, it is necessary to change a dose or to temporarily interrupt treatment until the undesirable phenomena are not liquidated. If the constant or repeated intolerance at use of the adequate mode of dosing develops, or the disease progresses, therapy by the Intron And should be cancelled.

Interaction with other medicines:

With care it is necessary to apply Intron® And along with opioid analgetics, hypnotic drugs and sedatives, with the drugs which are potentially rendering myelosuppressive effect and also with a zidovudine.

Interferona can influence oxidizing metabolic processes. It should be considered at simultaneous use with the drugs which are metabolized by oxidation (including with xanthine derivatives - Aminophyllinum and theophylline). At simultaneous use of the Intron And with theophylline it is necessary to control concentration of the last in blood serum, and if necessary to adjust the dosing mode.

At use of the Intron