Intron And

General characteristics. Structure:

Active agent:
Drug in bottles
10 million ME (1 dose of 10 million ME) of recombinant interferon alpha 2b in 1 ml of solution for injections
18 million ME (6 doses on 3 million ME) recombinant interferon alpha 2b in 3 ml of solution for injections
25 million ME (5 doses on 5 million ME) recombinant interferon alpha 2b in 2,5 ml of solution for injections.
Drug in the syringe handles
18 million ME (6 doses on 3 million ME) recombinant interferon alpha 2b in the syringe handle
30 million ME (6 doses on 5 million ME) recombinant interferon alpha 2b in the syringe handle
60 million ME (6 doses on 10 million ME) recombinant interferon alpha 2b in the syringe handle.
Net volume of solution in the syringe handle makes 1,2 ml (for all dosages).

Excipients:
Drug in bottles and the syringe handles
Sodium hydrophosphate anhydrous, dihydrophosphate sodium monohydrate, dinatrium эдетат, sodium chloride, metacresol (preservative), polysorbate-80, water for injections.

Pharmacological properties:

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. These effects 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.

Pharmacodynamics. Though the exact mechanism of antiviral effect of recombinant interferon alpha 2Ь is not known, 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 Introna® 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) (more than 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.
Интрона® 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 Introna® 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 noted 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).
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 + Introna® And) had the best long-term results, than patients who received less than 80% of course therapy (the steady 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 Introna® 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 Intronu® And caused 10-fold increase in efficiency of treatment in comparison with monotherapy of Intronom® 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 steady virologic answer).

Pharmacokinetics. Pharmacokinetics of Introna® And studied at healthy volunteers at single introduction in a dose 5 million ME/sq.m intramusculary, subcutaneously and by means of intravenous infusion within 30 min. Average concentration of interferon in blood serum were comparable after hypodermic and intramuscular introduction. At the same time the maximum serumal concentration was reached in 3-12 h; the elimination half-life both after intramuscular, and after hypodermic introduction made about 2-3 h; content of interferon in blood serum was not defined by 16-24 h. Bioavailability of drug at hypodermic introduction made 100%.
After intravenous administration concentration of interferon in plasma reached the maximum sizes (135-273 ME/ml) at the end of infusion, then decreased slightly quicker, than after subcutaneous or intramuscular injections, and was not defined by 4 h after the end of infusion; the elimination half-life made about 2 h.
Concentration of interferon in urine was below the determined size irrespective of a way of introduction.
At the patients receiving Intron® And during performing controlled clinical trials defined interferon - neutralized antibodies. Frequency of their identification made 2,9% at the patients receiving therapy of Intronom® 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 cynomolgus within 3 months daily in a dose 20х106 МЕ/кг/сутки also did not lead to emergence of noticeable signs of toxicity. Increase in a dose at monkeys to 100x106 МЕ/кг/сутки 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 does not influence the course of pregnancy, fetation and reproductive function at posterity of treated rats.
In the researches conducted on macaques Rhesus factors it is shown that use of the high doses (exceeding recommended in 90 and 180 times) of interferon alpha 2b causes abortions. When carrying out the corresponding researches it is not established mutagen effect of interferon alpha 2b.

Indications to use:

- Chronic hepatitis B
Treatment of adults and children (of 1 year) with chronic hepatitis B 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 adult patients with chronic hepatitis C 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 chronic hepatitis C at the children (of 3 years) with the compensated disease of a liver who were earlier not receiving treatment by interferon alpha 2b and at adult patients with a recurrence after therapy with interferon alpha 2b it is more preferable 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 with a throat papillomatosis.
- Hairy cell leukosis
Treatment of a hairy cell leukosis at adults in the form of monotherapy or in a combination with ribaviriny.
- Myelosis
Monotherapy: treatment of adult patients with a myelosis in the presence of the Philadelphian chromosome (Ph+) or a translocation of bcr/abl.
Clinical data show that hematologic remission and the cytogenetic answer (big/small) is 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 Introna® 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 with interferon alpha 2b after 3 years of treatment.
- A thrombocytosis at patients with a myelosis (HML)
The thrombocytosis often arises at a myelosis. Интрон® And applied with some effect at adult patients with the thrombocytosis connected with HML.
- Multiple myeloma
As 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 adult patients. 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 of Intronom® And patients with follicular nekhodzhkinsky lymphoma of low degree have zlokachestvennost and was not established by low tumoral loading.
- Kaposha's sarcoma connected with acquired immunodeficiency syndrome (AIDS)
Treatment of patients with Kaposha's sarcoma against the background of AIDS in the absence of opportunistic infections if the number of cells of CD4 exceeds 250/mm3.
- Kidney cancer
Treatment of adult patients with the progressing kidney cancer.
- Carcinoid tumors
Treatment of carcinoid tumors at adult patients when involving lymph nodes or with metastasises in a liver and with "a carcinoid syndrome".
- Malignant melanoma
Adjuvant therapy of the adult patients operated concerning primary tumor with high risk of a system recurrence.

Route of administration and doses:

Treatment is appointed by the doctor having experience of treatment of the corresponding disease. According to the decision of the doctor the patient can administer independently to himself the drug subcutaneously 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 subcutaneously, or in a dose of 5 million ME daily, or 10 million ME three times a week within 4 months (16 weeks).
To children from 1 year to 17 years inclusive Intron® And enters subcutaneously in an initial dose of 3 million ME/sq.m three 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 to 10 million ME/sq.m) three 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 less than 1500/mm3, granulocytes less than 1000/mm3 at children and less than 750/mm3 at adults, thrombocytes less than 100000/mm3 at children and less than 50000/mm3 at adults). Therapy should be stopped in case of the expressed leukopenia (leukocytes less than 1200/mm3), neutropenias (granulocytes less than 750/mm3 at children and less than 500/mm3 at adults) or thrombocytopenia (thrombocytes less than 70000/mm3 at children and less than 30000/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.

Chronic hepatitis C.
Интрон® And appoint subcutaneously in a dose 3 million ME 3 times a week (every other day) as monotherapy or in a combination with ribaviriny (doses and recommendations about their selection - see the application instruction of a ribavirin in capsules as a part of a combination therapy).
Treatment of patients with a recurrence after a monotherapy course alpha interferon. Интрон® 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.
Treatment of the patients who were earlier not receiving therapies. Efficiency of Introna® And increases 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 Introna® 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 RNA) 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.
When using Nitrona® 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 subcutaneously on 3 million ME/sq.m two times a week in a combination with oral administration of a ribavirin in a dose 15 mg/kg daily, dividing this dose on morning and evening.
Monotherapy of Nitronom® 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 Nitrona® And makes 3 million ME/sq.m subcutaneously three 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 Introna® And for hypodermic 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 of Intronom® 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 Introna® And makes from 4 to 5 million ME/sq.m daily, subcutaneously.
In certain cases the combination of Introna® And in a dose of 5 million ME/sq.m, appointed daily subcutaneously, with Cytarabinum is effective (Ara-c) in a dose of 20 mg/sq.m subcutaneously within 10 days a month (the maximum daily dose of 40 mg). After normalization of number of leukocytes of Intron® And enter in the maximum tolerable dose (from 4 to 5 million ME/sq.m a day) 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 is noted (number of thrombocytes more than 500x109/l). Decrease in number of thrombocytes managed to achieve from all patients after 2 months of treatment. The number of thrombocytes never was less than 80x109/l, at monthly control.

Multiple misloma.
Maintenance therapy: 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 monotherapy - subcutaneously in a dose of 3-5 million ME/sq.m 3 times a week.

Follicular lymphoma.
Интрон® And appoint in combination with chemotherapy subcutaneously in a dose 5 million ME 3 times a week (every other day) within 18 months. Clinical data are available only on use of the scheme CHVP (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 Introna® And in a dose of 30 million ME/sq.m is shown, at introduction 3-5 weekly subcutaneously. Drug was also used in smaller doses (10-12 million МЕ/м2/сутки) without noticeable decrease in efficiency. If the disease is stabilized or the clinical effect is noted, therapy is continued 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. Therapy of Intronom® And these patients can be carried out in out-patient conditions.
Simultaneous use with a zidovudine. In clinical trials patients with 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 daily; zidovudine of 100 mg each 4 h. The neutropenia was the main toxic effect limiting a dose.
Treatment of Intronom® And it is possible to begin 3-5 million МЕ/м2/сутки with a dose. In 2-4 weeks the dose of Introna® And can be increased by 5 million МЕ/м2/сутки - to 10 million МЕ/м2/сутки, 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 are not established. Интрон® And applied subcutaneously in doses from 3 to 30 million ME/sq.m three or five weekly or daily. The maximum effect was observed at hypodermic use of Introna® And in doses from 3 to 10 million ME/sq.m three times a week.
In a combination with other medicines - such, as interleykin-2. The optimum dose is not established. In a combination with interleykinom-2 Intron® And applied subcutaneously in doses from 3 to 20 million ME/sq.m. In clinical trials the frequency of the response to treatment was maximum at hypodermic introduction of Introna® And in a dose of 6 million ME/sq.m three times a week; the dose was selected individually during treatment.

Carcinoid tumors.
The standard dose of Introna® And makes 5 million ME (3-9 million ME) subcutaneously 3 times a week (every other day). At patients with widespread process use of a dose to 5 million ME daily can be required.
At surgical treatment therapy of Intronom® And is temporarily 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 post-operational remission of Intron® And appoint intravenously in a single dose 20 million ME/sq.m a day 5 days a week for 4 weeks. The dose calculated thus add 0,9% of solution of sodium of chloride to 100 ml and enter in the form of infusion within 20 min. Treatment should be begun within 56 days after surgical intervention. For a maintenance therapy the recommended single dose makes 10 million ME/sq.m, it is entered subcutaneously by 3 times a week (every other day) within 48 weeks. At development of heavy side effects during therapy of Intronom® And (in particular at decrease in number of granulocytes less than 500/mm3 or increase in ALT/AST to the values exceeding the upper bound of norm by 5 times) drug use is temporarily 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 the upper bound of norm 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.
Contents of a bottle or the syringe handle use for treatment only of one patient. Интрон® And solution for injections in bottles it is possible to use for intravenous or hypodermic administration 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 intravenous administration. 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 100 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 Intronom® And.
Use of other other solvents is inadmissible.
Интрон® And solution for injections enter into the syringe handles subcutaneously 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 heated up to room temperature (to 25 °C).
After packaging opening drug is recommended to be used within 4 weeks on condition of storage at a temperature from 2 to 8 °C. For introduction of each dose it is necessary to use a new needle. After an injection the needle should be thrown out, and immediately to place the handle in the refrigerator.
Utilization of the used bottles and the syringe handles are carried out according to the operating order.

Features of use:

For all patients.
In case of development of reactions of immediate hypersensitivity (a small tortoiseshell, a Quincke's disease, a bronchospasm, an anaphylaxis) at use of Introna® And, drug it is necessary to cancel and appoint the corresponding treatment immediately. 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 Introna® 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 Introna® And or within 2 days after cancellation of treatment development of the arterial hypotension demanding purpose of the corresponding therapy is possible.
At treatment of Intronom® And it is necessary to provide adequate hydration of an organism by additional administration of liquid since 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 2Ь, 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 chronic obstructive pulmonary diseases, 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 Intronom® 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 needs to conduct X-ray inspection of a thorax. At identification of infiltrate or other dysfunctions of lungs it is necessary to watch the patient carefully, and if necessary, to cancel therapy of Intronom® And. Timely cancellation of interferon an alpha and purpose of GKS promotes stopping of pulmonary syndromes.
Disturbances from an organ of sight appear usually after several months of treatment, but their emergence is described also after less long therapy. All patients need to conduct ophthalmologic examination prior to therapy. At complaints to a vision disorder, change of fields of vision or any other ophthalmologic disturbances, immediate consultation of the oculist is necessary. 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 of Intronom® And to regularly have ophthalmologic examination. At emergence or aggravation of visual disturbances it is necessary to consider a question of the termination of therapy of Intronom® And
Serious mental violations, in particular depression, suicide thoughts and attempts, psychosis, including hallucinations, an agressive behavior, т.ч. directed to other people, are the known side effects alpha интерферонов. 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 anamnestic instructions 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 of Intronom® And yes to provide consultation of the psychiatrist.
At some patients, especially elderly, receiving drug in high doses, disturbance of consciousness, a lump and a spasm, including cases of development of encephalopathy were observed. In case of inefficiency of a dose decline and/or medicamentous correction of these disturbances, it is necessary to resolve an issue of the termination of therapy of Intronom® And.
Patients with diseases of cardiovascular system (for example, a myocardial infarction, chronic heart failure, arrhythmias) need careful medical observation at purpose of Introna® A. Patsiyentam with heart diseases and/or the progressing oncological disease recommends carrying out an ECG to and during therapy of Intronom® And. The arising arrhythmias (generally supraventricular), as a rule, give in to standard therapy, but can demand also cancellation of Introna® And.
Интрон® But do not appoint 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 .interferony 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 alpha interferon is not established with therapy.
At treatment alpha интерферонами emergence of autoantibodies and developing of autoimmune diseases were 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 of Nitronom® And were seldom observed 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 of Intronom® And it is necessary to define 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 Introna® 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 of Intronom® And can be continued if the TTG level manages to be supported within norm by means of medicamentous means. Cancellation of Introna® But did not lead to recovery of function of a thyroid gland.
It is necessary to stop therapy of Intronom® And patients with chronic hepatitis when lengthening a blood clotting time since it can be a sign of a decompensation of function of a liver.

For patients with chronic hepatitis C. At use of Nitrona® 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 tests to all patients before therapy of Intronom® And carried out a liver biopsy. However in certain cases (including at 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. In this regard at purpose of Introna® 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 Introna® 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 Introna® And in a combination with chemotherapeutic drugs (Cytarabinum, cyclophosphamide, doxorubicine, тенипозид) increases risk of development of toxic effects (promotes strengthening of their weight and increase in 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 Introna® And yes chemotherapeutic means.

Data of laboratory researches. Before an initiation of treatment of Intronom® And yes systematically in the course of therapy to all patients carry out the general clinical blood test (with definition of a leukocytic formula and number of thrombocytes), biochemical indicators of blood, including determination of level of electrolytes, liver enzymes, bilirubin, crude protein and creatinine.
During therapy of patients with 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 his need. If ALT raises up to the size, twice or more exceeding a reference value, treatment of Intronom® 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, alkaline phosphatase, 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.
At purpose of Introna® And in a combination with ribaviriny to patients with reduced function of kidneys 50 years are also aged more senior, behind them it is necessary to establish careful observation in connection with possible development of anemia.

Use in pediatrics. Интрон® And it can be applied at children of 1 year at chronic hepatitis B and a papillomatosis of a throat. Clinical data on use of Introna® And at children with other pathology are absent.

Use at pregnancy and during breastfeeding. Clinical data on use of interferon alpha 2b during pregnancy are absent.
In pilot studies on animals toxic action on reproductibility is revealed. Value of these data for the person is not known.
During pregnancy of Intron® And apply only when the expected advantage of therapy for mother exceeds potential risk for a fruit.
It is not known 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.
Female patients and partners of male patients have to apply two ways of contraception during treatment and 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.

INFLUENCE ON ABILITY TO CONTROL OF VEHICLES AND MECHANISMS.
The patient needs to 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 undesirable phenomena. Fever and fatigue passed in the 72nd hour after the termination of administration of drug. Though fever can be one of symptoms of the so-called "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 patients with chronic hepatitis C. of receiving Intron® And in the form of monotherapy or in a combination with ribaviriny during 1 year. All patients received 3 million ME Introna® And 3 times a week. In table 2 the undesirable phenomena noted with a frequency of bigger or equal 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 phenomena were easy or moderately expressed.
             

Local reactions: Inflammatory reactions in an injection site.
General reactions:
- Headache
- Fatigue
- Fever
- Fever
- Grippopodobny syndrome
- Adynamy
- Decrease in body weight.

Reactions from a GIT:
- Nausea
- Anorexia
- Diarrhea
- Abdominal pains
- Vomiting.

Reactions from a musculoskeletal system:
- Mialgiya
- Arthralgia
- Ostealgia and muscles.

Reactions from TsNS:
- Depression
- Irritability
- Sleeplessness
- Concern
- Disturbance of ability to concentration of attention
- Emotional lability.

Reactions from skin:
- Alopecia
- Itch
- Xeroderma
- Rash.

Reactions from respiratory system:
- Pharyngitis
- Cough
- Dispnoye.

Others:
- Dizziness
- Viral infection.

The undesirable phenomena observed at patients with a viral hepatitis With correspond to those which were noted at use of Introna® And according to other indications with some dozozavisimy increase on development frequency.
At use of Introna® And according to other indications (in clinical trials and out of clinical trials) it is rare (> 1/10000, <1/1000) or very seldom (<1/10000) the following undesirable phenomena 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, psoriasis, a fungal infection and a bacterial infection (including sepsis).
- From immune system: very seldom - a sarcoidosis or an aggravation of a sarcoidosis.
At use alpha интерферонов 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 a syndrome of Fogta-Koyanagi-Harady.
It was reported about cases of acute reactions of hypersensitivity, including a small tortoiseshell, angioneurotic allergic swelled also 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, ischemia of a myocardium and a myocardial infarction.
- Co of the party of TsNS and peripheral nervous system: seldom - suicide bents, it is very rare - an agressive behavior, including directed to other people, suicide attempts, a suicide, psychosis (including hallucinations), disturbances of consciousness, neuropathy, polyneuropathy, encephalopathy, cerebrovascular ischemia, a cerebrovascular hemorrhage, peripheral neuropathies, spasms.
- From an acoustic organ: very seldom - a hearing disorder.
- 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. - from a liver and biliary tract: very seldom - a hepatotoxic (including with a lethal outcome).
- Changes from teeth and a periodontium. At the patients receiving a combination therapy of Intronom® And yes ribaviriny pathological changes from teeth and a periodontium were noted. Dryness in a mouth at a long combination therapy ribaviriny and Intronom® 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 metabolism: seldom - a hyperglycemia, a gipertriglitseridemiya.
- From a musculoskeletal system: seldom - рабдомиолиз (sometimes heavy), spasms in legs, a dorsodynia, a miositis.
- From skin: very seldom - a multiformny erythema, Stephens-Johnson's syndrome, a toxic epidermal necrolysis, a necrosis in the place of an injection.
- From respiratory system: seldom - pneumonia, it is very rare - 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 of Introna® And in the form of monotherapy or in a combination with ribaviriny aplastic anemia and a full aplasia of red marrow were noted.
- Co of the party of 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.
- Clinically significant changes of laboratory indicators: (were more often noted at purpose of drug in doses more than 10 million ME a day) - 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 Introna® And according to any indication the undesirable phenomena develop, it is necessary to reduce 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 of Intronom® 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 such as 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 Introna® 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 Introna® And in a combination with chemotherapeutic drugs (Cytarabinum, cyclophosphamide, doxorubicine, тенипозид) the risk of development of toxic effects (their weight and duration) which can be menacing for life increases or lead to a lethal outcome (owing to hypertoxity at combined use of drugs).
At combined use of Introna® And yes hydroxurea the frequency of development of a skin vasculitis can increase. Pharmaceutical interaction
Интрон® And it is impossible to mix with other medicinal substances except 0,9% of solution of sodium of chloride.

Contraindications:

- hypersensitivity to any component of drug.
- serious illness of cardiovascular system (т.ч. heart failure in decompensation stages, recently postponed myocardial infarction, heavy arrhythmias).
- the expressed abnormal liver functions or kidneys, including caused by metastasises, chronic hepatitis with cirrhosis in decompensation stages, chronic hepatitis in the patients receiving or receiving immunodepressants (except for a short-term course of therapy by glucocorticosteroids), autoimmune hepatitis.
- epilepsy and other dysfunctions of TsNS, mental diseases and frustration at children and teenagers.
- an autoimmune disease in the anamnesis.
- use of immunodepressants after transplantation.
- a disease of a thyroid gland if it is not controlled by the corresponding therapy.
- the clearance of creatinine is lower than 50 ml/min. - at appointment in a combination with ribaviriny.
- pregnancy and lactation.
- appointment to men whose partners are pregnant.
- at purpose of Introna® And in a combination with ribaviriny it is also necessary to consider the contraindications specified in the application instruction of a ribavirin.

With ОСТОРОЖНОСТЬЮ.Психические diseases in the anamnesis.

Overdose:

So far the cases of overdose which are followed by any clinical symptoms are not described. However, as well as at overdose of any medicine, it is necessary to carry out symptomatic therapy with monitoring of functions of vitals and with regular control of a condition of the patient.

Storage conditions:

At a temperature from 2 to 8 °C. Not to freeze.
To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

In bottles:
On 10 million ME/1 of ml (1 dose); 18 million ME/3 of ml (6 doses on 3 million ME); 25 million ME/of 2,5 ml (5 doses on 5 million ME) in bottles of colourless glass.
On 1 bottle together with the application instruction in a cardboard pack.
In the syringe handles:
On 18 million ME/1,2 of ml (6 doses on 3 million ME); 30 million ME/1,2 of ml (6 doses on 5 million ME); 60 million ME/1,2 of ml (6 doses on 10 million ME) in the syringe handles.
On 1 syringe handle complete with 6 needles and 6 napkins (for disinfection of skin in an injection site) in the plastic pallet together with the application instruction and a leaf insert with recommendations for patients about preparation and performance of a subcutaneous injection in a cardboard pack.