Роферон®-А

General characteristics. Structure:

Active ingredient: 3 million ME, 4.5 million ME, 6 million ME, 9 million ME interferon alpha 2а (11.1 mkg, 16.7 mkg, 22.2 mkg, 33.3 mkg are equivalent).

Excipients: sodium chloride, ammonium acetate, benzyl alcohol, polysorbate 80, acetic acid ice or sodium hydroxide, water for injections.

The medicine which is applied to treatment of viral and tumoral diseases, and also immunodeficiency.

Pharmacological properties:

Pharmacodynamics. Interferon alpha 2а - the high cleaning protein containing 165 amino acids with a molecular weight about 19000 дальтон. It is received on technology from recombinant DNA with use of a genetically engineered strain of E.coli which DNA codes synthesis of this protein of the person.
Роферон®-А has antiviral effect, inducing in cells a condition of resistance to viral infections and modulating the response of immune system directed to neutralization of viruses or destruction of the cells infected with them. Роферон®-А possesses anti-proliferative action on a number of tumors of the person of in vitro and suppresses growth of some heterografts of tumors of the person at bestimusny mice with nude mutation.

Clinical performance. In the tumor cells of the person processed by the drug Roferon®-A (in HT29 cells), synthesis of DNA, RNA and protein authentically decreases. The limited number of cellular lines of the tumors of the person which are grown up by in vivo at bestimusny mice with immune insufficiency were tested on sensitivity to drug Roferon®-A influence. In vivo anti-proliferative activity of the drug Roferon®-A was studied on such tumors as a mucoid carcinoma of a mammary gland and an adenocarcinoma of a blind and poperechnoobodochny gut, and also a prostate. Degree of anti-proliferative activity varies.

Роферон®-А leads to clinically significant regression of a tumor or stabilization of a disease at patients with a hairy cell leukosis and patients have AIDS with Kaposha's sarcoma. Роферон®-А it is also effective for treatment of patients with a multiple myeloma. Роферон®-А has activity at patients with the progressing skin T-cellular lymphoma who are insensitive or are not suitable for traditional therapy.

Роферон®-А it is effective for treatment of patients with a Ph-positive myelosis (HML). Роферон®-А leads to hematologic remission at 60% of patients in a chronic stage of HML, irrespective of the previous therapy. Full hematologic remission still remains in 18 months after an initiation of treatment at two thirds of the studied patients. Unlike cytotoxic chemotherapy, interferon alpha 2а can lead to the stable cytogenetic remission continuing more than 40 months. Роферон®-А in a combination with discontinuous courses of chemotherapy increases the general survival and slows down progressing of a disease in comparison with one chemotherapy.

Роферон®-А it is effective for treatment of a thrombocytosis at HML and other myeloproliferative diseases. Роферон®-А for several days reduces number of thrombocytes, reduces the frequency of the accompanying trombogemorragichesky complications and has no leykozogenny potential.

At patients with a nekhodzhkinsky lymphoma of low degree of a zlokachestvennost at appointment in addition to chemotherapy (with radiation therapy or without it) Roferon®-A extends bezretsidivny survival and survival without progressing.

At patients with a widespread pochechnokletochny carcinoma the best therapeutic effect was observed at purpose of high doses of the drug Roferon®-A (36 million ME a day) as monotherapy or moderate doses of the drug Roferon®-A (18 million ME 3 times a week) in a combination with vinblastine, in comparison with monotherapy by moderate doses of the drug Роферон®-Ç 3 of time a week. At the patients receiving monotherapy of the drug Roferon®-A in small doses (2 million ME/sq.m a day), the effect of treatment was absent. The drug Roferon®-A combination to vinblastine leads only to small increase in frequency of an easy and moderate leukopenia and granulocytopenia in comparison with monotherapy. Duration of the answer and survival at monotherapy by the drug Roferon®-A and a combination therapy of Roferon®-A + vinblastine are similar. Роферон®-А in a combination with vinblastine is more effective concerning survival in comparison with one chemotherapy. At patients with a widespread malignant melanoma treatment with the drug Roferon®-A led to objective regression of tumors of skin and visceral localization. Also Roferon®-A increases time duration without disease recurrence at patients without damage of lymph nodes and the remote metastasises after a melanoma resection (tumor thickness> of 1.5 mm).

Роферон®-А in a combination with drug Avastin as the first line of therapy at patients with a widespread and/or metastatic pochechnokletochny carcinoma in comparison with a combination of the drug Roferon®-A and placebo significantly increases the survival without progressing (SWP) of a disease and frequency of the objective answer.

The dose decline of interferon alpha 2а from 9 million ME to 6 or 3 million ME 3 times a week at use in a combination with drug Avastin did not lead to decrease in efficiency of a combination therapy according to indicators bessobytiynoy survival (see also application instruction of drug Avastin).

Роферон®-А it is effective for treatment of patients with the hepatitis B and C confirmed compensated (without signs of a hepatic decompensation).
Роферон®-А it is effective for treatment of patients with sharp-pointed condylomas.

Pharmacokinetics. Absorption. After hypodermic or intramuscular introduction bioavailability exceeds 80%. After hypodermic introduction of a dose of 36 million ME the maximum concentration in serum (from 1250 to 2320 pg/ml (on average, 1730 pg/ml)) were reached, on average, in 7.3 hours. After intramuscular introduction of a dose of 36 million ME the maximum concentration in serum (from 1500-2580 pg/ml (on average, 2020 pg/ml)) were reached, on average, in 3.8 hours.

Distribution. At the person the drug Roferon®-A pharmacokinetics in doses from 3 million to 198 million ME has linear character. After intravenous infusion of 36 million ME to healthy volunteers distribution volume in an equilibrium state fluctuated from 0.22 to 0.75 l/kg (on average, 0.40 l/kg). Both at healthy volunteers, and at patients with the disseminated cancer big individual fluctuations of concentration of interferon alpha 2а in serum are observed.

Metabolism and removal. The alpha is the main way of removal of interferon a renal catabolism.

Hepatic metabolism and removal with bile represent less significant ways of elimination. At healthy faces the elimination half-life of interferon alpha 2а after intravenous infusion of 36 million ME makes 3.7-8.5 hours (on average, 5.1 hours), and the general clearance - 2.14-3.62 ml/min. (on average, 2.79 ml/min.).

Pharmacokinetics at special groups of patients. After single intramuscular administration of interferon alpha 2а the patient with the disseminated cancer and chronic hepatitis In pharmacokinetic indicators are similar to that at healthy volunteers. After single introduction of doses to 198 million ME dozozavisimy increase in concentration of interferon alpha 2а in serum is observed. Distribution or removal of interferon alpha 2а at its introduction two times a day (0.5-36 million ME), once a day (1-54 million ME) or 3 times a week (1-136 million ME) on an extent up to 28 days do not change.

Some patients with the disseminated cancer have an intramuscular administration of interferon alpha 2а one or several times in days lasting up to 28 days led to increase of the maximum concentration in serum by 2-4 times in comparison with those after single introduction. However repeated introduction, agrees to any of the dosing modes studied so far, did not change parameters of distribution or removal of drug.

Indications to use:

New growths of lymphatic system and system of a hemopoiesis:
hairy cell leukosis, multiple myeloma, skin T-cellular lymphoma, Ph-positive myelosis, thrombocytosis at myeloproliferative diseases, a nekhodzhkinsky lymphoma of low degree of a zlokachestvennost (in the form of adjuvant therapy to chemotherapy (with/without radiation therapy)).

Solid tumors: Kaposha's sarcoma at patients AIDS without anamnestic instructions on opportunistic infections, a widespread pochechnokletochny carcinoma, a metastatic malignant melanoma, a melanoma after a surgical resection in the absence of damage of lymph nodes and the remote metastasises.

Viral diseases:
- chronic active hepatitis B at the patients having markers of virus replication that is positive on HBV-DNK, a DNA polymerase or HBeAg and increase in activity of alaninaminotranspherase (ALAT) without signs of a hepatic decompensation (a class A on Chayld-Pyyu);
- chronic active hepatitis C at the adults having antibodies to a virus of hepatitis of C or HCV of RNA in serum and increase in activity of alaninaminotranspherase (ALAT) without signs of a hepatic decompensation (a class A on Chayld-Pyyu); at treatment of chronic hepatitis C the combination of the drug Roferon®-A and a ribavirin is optimum; Роферон®-А in a combination with ribaviriny it is shown as the patients who were earlier not receiving therapy, and those who answered therapy with interferon an alpha and then having a disease recurrence after therapy cancellation earlier;
 - sharp-pointed condylomas.

Route of administration and doses:

Роферон®-А enter subcutaneously (п / to).

Hairy cell leukosis. Initial dose: 3 million ME daily within 16-24 weeks. At intolerance the daily dose is reduced to 1.5 million ME and/or reduce frequency rate of introduction to three weekly.

Maintenance dose: 3 million ME 3 times a week. At intolerance the dose is reduced to 1.5 million ME by 3 times a week.         

Treatment duration: in the absence of positive effect in 6 months therapy is stopped, and with effect - therapy is continued. The maximum duration of treatment made 20 months.

Multiple myeloma. Initial dose: 3 million ME 3 times a week. Maintenance dose: depending on individual portability, the dose can be increased weekly before achievement of the maximum tolerable dose (9-18 million ME) 3 times a week.

Treatment duration: treatment according to this scheme is continued in the absence of progressing of a disease and the expressed intolerance of drug for a long time.

The Skin T-cellular Lymphoma (STCL) (since 18 years). Initial dose: 3 million ME/days, gradually increasing a dose to 18 million ME/days within 12 weeks according to the scheme:
1-3 day - 3 million ME/days daily;
4-6 day - 9 million ME/days daily;
7-84 day - 18 million ME/days daily.

Maintenance dose: the most tolerable dose (but not exceeding 18 million ME), 3 times a week.

Treatment duration: treatment duration to assessment of reaction to therapy has to make not less than 8 weeks, it is more preferable - 12 weeks; with positive effect treatment is continued, at its absence - stopped. The maximum duration of treatment made 40 months. At the patients who are positively reacting to treatment it is necessary to continue it not less than 12 months as much as possible to increase probability of achievement of full remission and to increase probability of long remission.

Partial remission is observed usually within 3 months of treatment, and full - within 6 months though sometimes achievement of the best effect requires 12 months of therapy.

Myelosis. The thrombocytosis connected with a myelosis (from 18 years is also more senior). Initial dose: 3 million ME/days with gradual increase in a dose up to 9 million ME/days for 8-12 weeks according to the scheme:
1-3 day - 3 million ME/days daily;
4-6 day - 6 million ME/days daily;
7-84 day - 9 million ME/days daily.

Treatment duration: not less than 8 weeks, it is preferable - 12 weeks; with effect - therapy is continued before achievement of full hematologic remission, but by no more than 18 months. In the absence of dynamics of hematologic indicators therapy is stopped. At full hematologic remission treatment 3 times a week (the minimum dose), before achievement of cytogenetic remission as soon as possible continue in a dose 9 million ME/days (an optimum dose) daily or 9 million ME. There are observations of cytogenetic remissions lasting 2 years after an initiation of treatment.

Efficiency, safety and optimum doses of the drug Roferon®-A for children with HML are not established.           

The thrombocytosis connected with myeloproliferative diseases (except a myelosis).
1-3 day - 3 million ME/days daily;
4-30 day - 6 million ME/days daily.

For maintenance of number of thrombocytes within norm the dose is usually enough and well transferred to 1-3 million ME/days 2-3 times a week. Each patient should select the most tolerable dose individually.

Nekhodzhkinsky lymphoma of low degree of a zlokachestvennost. As a maintenance therapy after standard chemotherapy (with radiation therapy or without it): 3 million ME 3 times a week within not less than 12 months. Treatment needs to be begun as soon as possible at improvement of a condition of the patient, usually in 4-6 weeks after himio-and radiation therapy. In a combination with traditional schemes of chemotherapy (for example, with a combination of cyclophosphamide, Prednisolonum, Vincristinum and doxorubicine) - 6 million ME/sq.m from 22 to 26 day of each 28-day cycle. In this case treatment by the drug Roferon®-A can be begun along with chemotherapy.

Kaposha's sarcoma at patients AIDS. Роферон®-А AIDS without anamnestic instructions on opportunistic infections is shown for treatment of sarcoma of Kaposha at patients.

Initial dose (from 18 years is also more senior): 3 million ME/days daily, with gradual increase in a dose within 10-12 weeks to 18 million ME/days daily whenever possible - to 36 million ME/days daily according to the scheme:
1-3 day - 3 million ME/days daily,
4-6 day - 9 million ME/days daily,
7-9 day - 18 million ME/days daily,
in case of portability: 10-84 day - to 36 million ME/days daily.

Maintenance dose: the most tolerable dose, but not exceeding 36 million ME, 3 times a week.

Treatment duration: for the purpose of definition of reaction to treatment it is necessary to document and estimate dynamics of change of a tumor. Treatment duration to assessment of reaction to therapy has to make not less than 10 weeks, it is preferable - 12 weeks. With positive effect therapy is continued, at its absence - stopped. Usually the effect begins to be shown in 3 months of treatment. The maximum duration of treatment made 20 months. With effect treatment needs to be continued at least before disappearance of a tumor.

Note: after the therapy termination by the drug Roferon®-A Kaposha's sarcoma often recurs.

Widespread pochechnokletochny carcinoma.
a) Monotherapy by the drug Roferon®-A
Initial dose: 3 million ME/days with gradual increase in a dose within 8-12 weeks to 18 million ME/days, and whenever possible - to 36 million ME/days according to the following scheme:
1-3 day - 3 million ME/days daily;
4-6 day - 9 million ME/days daily;
7-9 day - 18 million ME/days daily;
at portability increasing a dose for 10-84 day to 36 million ME/days daily.

Podderzhivashchy dose: in the most tolerable dose, but without exceeding 36 million ME 3 times a week.

Treatment duration: not less than 8 weeks, it is preferable - not less than 12 weeks. With effect therapy is continued, at its absence - stopped. The maximum duration of treatment made 16 months.

b) Роферон®-А + vinblastine