HEBERON ALFA R

Heberon Alfa R immunomodulator

Human recombinant interferon alfa – 2b

– Solution for injection (3, 5, 6 OR 10 M)

Human recombinant interferon-alpha – 2b

The solution contains 3, 5, 6, or 10 x 106 IU human recombinant IFN alfa-2b, which is contained in hermetically sealed vials.

Method of application:

Intramuscular, subcutaneous, intravenous, intraperitoneal, intrathecal, and intralesional

Composition:

Active ingredient: Human recombinant IFN alpha 2-b produced in/from Escherichia coli, at the Center for Genetic Engineering and Biotechnology, Havana (CIGB): 3, 5, 6, or 10 x 106

Other ingredients:

Benzyl alcohol, polysorbate 80, sodium chloride, sodium phosphate, and buffer? (buffer system)

Fact:

Antiviral, antiproliferative, immunomodulator, antisungiogenic, antifibrotic

Indications:

The use of HEBERON ALFA R is useful for patients under the following pathological circumstances:

VIRAL DISEASES

Infections caused by human papillomavirus

In recurrent respiratory papillomatosis (RRP), the use of recombinant IFN alfa-2b (CIGB) as an adjuvant to surgery has shown satisfactory results. Treatment with IFN alpha may cause partial or complete remission of the papilloma. However, in Cuba, it is intended for use to prevent the recurrence of the disease after surgical removal of the tumor. Since 1983, a program for laryngeal papilloma cases has been implemented for this purpose. Since 1994, these programs have been continued, including papillomatous lesions throughout the respiratory tract. The efficacy of recombinant IFN alpha 2-b (CIGB) was demonstrated in Condylomata acuminate in a controlled, double-blind study, combining systemic treatment with topical application of 20,000 IU / g IFN alpha 2-bu hydrophilic cream.

Viral hepatitis

The use of IFN alpha 2-b (CIGB) in subacute necrosis of the liver by the intraperitoneal and intramuscular routes increases the probability of patient survival and promotes histological healing. In chronic hepatitis B with a positive “e” antigen, 50% seroconversion can be obtained after a 4-month regimen with recombinant IFN alpha 2-b (CIGB). The treatment is extremely useful in immunosuppressive patients.

HEBERON ALFA R is also useful for children. 6 months after the six-month regimen, 40% “e” seroconversion of antigen can be achieved. This reaction can be 50% after 3 years of follow-up. Histological progression reaches 69%. HEBERON ALPHA R is also useful in chronic hepatitis C, where its effectiveness has been shown in several clinical studies. Overall, 80% of the enzymatic reaction (ALAT normalization) was achieved versus 22% among the control groups. 41% of the reactions were maintained after a 9-month follow-up. In patients with thalassemia, who frequently receive blood transfusions and are therefore a risk group for this disease, HEBERON ALFA R is effective in 63% by neutralizing viral RNA in serum (55% with concomitant normalization of ALT) after 12 months of treatment with 3 × 106 IU every other day. . Also in patients with chronic renal failure under periodic hemodialysis and with chronic hepatitis C, HEBERON ALFA R produced 75% viral reaction and 87% enzymatic reaction. In combination with ribavirin, the efficacy of treatment with HEBERON ALFA R is increased in chronic hepatitis C virus.

HEBERON ALPHA R has also been useful in children, where chronic hepatitis C is less common and rare reports in the literature. In acute hepatitis C, the use of HEBERON ALPHA R is recommended to prevent chronic disease development.

Patients infected with human immunodeficiency virus

IFN has an anti-retroviral effect and is considered a limiting factor for human immunodeficiency virus infection. Randomized tests have been performed to prevent or delay Acquired Immune Loss Syndrome (AIDS) progression in individuals in the early stages of HIV infection. Long-term treatment with HEBERON ALFA R significantly reduces the proportion of individuals who have had some symptoms or developed AIDS. Further monitoring of these patients allowed analysis of survival rates and other long-term complications. It was concluded that the use of HEBERON ALPHA Ra during the early stage of HIV infection, although no other symptoms of AIDS appeared, is useful and prolongs life.

Dengue (Tropical Fever)

Early application of IFN alpha, during the first 72 hours of infection, can prevent the occurrence of serious hemorrhagic complications and shock.

NEOPLASIA

Hematopoietic tissue

Hairy cell leukemia: As for other interferon-alpha preparations, HEBERON ALFA R causes disease regression or significant clinical stabilization even if the patient has previously had a splenectomy. Chronic myeloid leukemia: It is possible to achieve remission using IFN alpha, but HEBERON ALFA is recommended to maintain remission previously achieved with chemotherapy. Return is prevented for a year, life is prolonged, and there is a significant reduction in the proportion of Philadelphia chromosome + cells. In multiple myeloma, HEBERON ALFA R is used as maintenance therapy after complete or partial remission with melphalan-prednisone. Non-Hodgkin’s lymphoma of low and medium degree of malignancy: The use of IFN alpha 2-b (CIGB) is recommended when remission is achieved by chemotherapy or radiotherapy. The frequency of relapse is significantly reduced, and life prolongation is achieved. In cutaneous T-cell lymphoma (Mycosis Fungoide, Sezary’s syndrome, and others), the effectiveness of treatment with IFN alpha has been proven. A high response rate (more than 50%) was achieved even after 3 years of follow-up. Also, most non-responders had stable disease, so the disease’s control rate (no progression) was 95, 91, 90, 82, and 76% through 6, 12, 18, 24, 36 months of follow-up.

Solid tumors

HEBERON ALFA R is used to treat solid tumors known as indications for this type of product, such as kidney cancer, Kaposi’s sarcoma (in conjunction with AIDS), basal cell carcinoma, and superficial bladder cancer. Also, some tumors are recognized as indications for IFN alpha, such as malignant melanoma and a carcinoid tumor, where HEBARON ALFA R is equally effective. On the other hand, some results show the effectiveness of HEBARON ALPHA Ra in fibroids and hemangiomas in babies, which can have serious consequences for the patient even though they are benign.

Basal cell skin cancer:

HEBERON ALFA R is an alternative treatment in cases where surgical removal is not possible or desirable. 90% objective response was obtained by intralesional application of 1.5 x 106 IU, 3 times a week for 3 weeks. Patients who responded remained relapsed after one year of follow-up.

Superficial bladder cancer:

HEBARON ALPHA R can be used by intravesical implantation as an adjuvant to prevent encapsulation after surgical removal of lesions by partial cystectomy or endoscopy. The two-year relapse rate was similar to that obtained with BGG, with fewer adverse reactions.

Hemangiomas in infants:

In a study using HEBARON ALFA R subcutaneously, the overall response rate was 66%. In children younger than one year, 65% had a regression, and none had progression. During the first months of life, tumors are still in the proliferative phase. Therefore, spontaneous regression is rare, and therefore even stabilization can be considered a satisfactory result in patients between 1. and 5. Goodine’s age, the regression rate is 83%. Even in patients older than 5 years, there was a 44% response to treatment. They did not affect physical and psychomotor development. The second study was conducted using HEBARON ALFA R intralesionally, 3 x 106 IU, twice a week for 8 months. Tumor regression was achieved in 81% of patients and 19% of stable disease. There was no progression. Regression was more common (85%) in patients aged between 1. And 5 years in children without a known family history of hemangiomas and tumors at birth.

Kaposi’s sarcoma (associated with AIDS):

HEBARON ALFA R is used as a treatment for this tumor. Complete remission can be achieved after 12-24 months of treatment. The intralesional application can be used.

Kidney cancer:

Metastatic renal cell carcinoma is one of the known indications of IFN alpha 2-b. Two reports of patients treated with recombinant HEBERON ALFA R were conducted. These include metastatic disease cases or those that have been operated on, and IFN has been used as an adjuvant to surgery as maintenance therapy. During the first Wednesday, 55% objective response and 33% disease stabilization were obtained. Response to therapy or stabilization lasted more than 18 months in 50% of them. In another study, recombinant IFN alpha 2-b (CIGB) was used in combination with chemotherapy in cases of metastasis or advanced inoperable tumor. Extended life (42 months) was achieved in one case. On the other hand, in cases where HEBERON ALFA R was used by post-nephrectomy or after conservative tumor surgery, the average survival was more than 40 months, and more than 50% of patients lived longer than 5 years.

Peyronie’s disease:

In a study where HEBERON ALFA R was performed intralesionally, 1 ml with 10 x 106 IU, twice a week until total lesion regression or up to 14 weeks, a complete clinical response was obtained in 47% of patients. Sexual dysfunction disappeared in 79% of patients who suffered from it, palpable lesions disappeared in 62% of them, angle in erection in 47%, and pain in 94%. The immunological response rate was 88%, 53% is a complete response. The main systemic adverse reaction observed was the expected pseudo-influenza syndrome (mild or moderate). The main locally harmful reaction was developing a small hematoma, edema, cysts in two patients and venous fungi in one case.

CONTRAINDICATIONS:

Hu-r aplfa-2b IFN is contraindicated in patients with hypersensitivity to alpha interferon, benzyl alcohol, polysorbate 80, or to any salts present in the preparation.

WARNINGS AND PRECAUTIONS FOR USE

Although no direct cardiotoxic effect has been described for HEBERON ALFA R, some of its side effects (e.g., fever, tremor, malaise) may worsen the previous cardiac change. As one of the toxic effects of HEBERON ALFA R may be leukopenia, care should be taken in patients with myelosuppression. Since the kidney is the site where IFN alpha is eliminated, care should be taken when using HEBARON ALFA R in patients with impaired renal function. Dose reduction should be considered, if necessary. The use of various IFN alpha preparations is associated with an increase in allergic and autoimmune disorders such as bronchoconstriction, lupus erythematosus, psoriasis, atopic dermatitis, myasthenia gravis, or thyroiditis. These changes are rarely reported/reported when using HEBERON ALFA Ra. However, care should be taken when using it in patients with a history of these diseases. Adverse reactions due to HEBERON ALFA Ra are reversible. If severe side effects, the dose should be reduced or discontinued. By the patient’s status, adequate measures should be taken. The general experience is that the intensity of side effects due to HEBERON ALFA Ra tends to decrease as treatment is continued. However, this should be followed carefully.

Carcinogenicity

There is no evidence, experimental or in the literature, to indicate any carcinogenic potential of IFN alpha. In contrast, IFN alpha -2b (CIGB) shows opposite effects, promoting cell differentiation in transformed cell lines and animals’ tumors.

Mutagenicity

None of the tests showed or suggested that IFN alpha -2b (CIGB) could be mutagenic. This includes the Ames test with different strains and the test with human lymphocytes in a culture searching for chromosomal damage.

Teratogenesis or effects on fertility

Tests performed on rats did not show any teratogenetic reaction or effect on fertility, due to IFN alfa-2b (CIGB).

Pregnancy

There are no controlled studies on HEBERON ALFA Ra’s use in pregnant women. Therefore, it has not been determined whether it is safe to use it during pregnancy. If the pregnant woman has indications, the doctor should do a risk and benefit analysis individually.

Use in pediatrics:

HEBERON ALFA R has been used in children with viral hepatitis C and laryngeal papillomatosis and periodic respiratory papillomatosis, benign and malignant neoplasms. The side effects are similar to those in adults, mostly fever and malaise. No changes in growth or psychomotor development were reported, even several months after treatment. This product contains benzyl alcohol and should not be used in newborns.

Adverse reactions

HEBERON ALFA R

The main side effects that occur with the use of HEBERON ALFA R are similar to those reported for other IFN alpha preparations. These side effects are dose-dependent and reversible. Their intensity is generally mild (does not require treatment) or moderate (response to symptomatic treatment). Patients receiving doses ≥6 x 106 IU may have severe reactions requiring additional measures, hospitalization, prolonged hospitalization, or suspension treatment. Adverse reactions reported by 809 patients from different clinical studies are listed below. Isolated cases with mild allergic reactions (rash, itching), hair loss, and cardiovascular toxicity have also been reported.

Frequency of major adverse reactions after use of HEBERON ALPHA Ra

Analysis of 809 patients from various clinical studies.

HEBERON ALFA Ra’s pharmacovigilance in patients with hematological diseases, mainly chronic myeloid leukemia, showed a similar adverse reaction profile. This report includes a case of hemolytic anemia, apparently after the development of anti-erythrocyte autoantibodies.

Immunogenicity HEBERON ALFA R

Recombinant IFN alpha preparations are immunogenic in variable proportions of patients treated with them. Antibodies can neutralize IFN activity and, therefore, can prevent or restore response to treatment. HEBERON ALFA R’s immunogenicity has been observed through various clinical trials conducted with this product. OF the 563 patients treated with HEBERON ALPHA R, whose sera were evaluated, 14 (2.5%) had anti-IFN alpha neutralizing activity. In conclusion, different studies and adverse reactions observed during HEBERON ALPHA R therapy show a similar adverse reaction profile than those reported for other formulations containing IFN alpha 2-b as an active principle.

Interactions with other drugs and other forms of interaction

HEBERON ALFA R has a synergistic effect with some anti-tumor drugs connected with their antiproliferative effect, which must be taken into account in combination therapy since the effects of myelosuppression are also enhanced. It also shows/indicates synergism, both in antiproliferative and anti- (not seen on paper) with interferon-gamma—drug overdose studies. Adverse reactions to HEBERON ALFA R are dose-dependent. At doses greater than 10 x 106 IU / m2 body surface area, the same side effects occur more intensely. intense asthenia and depression have been described at high doses. These actions are reversible.

Posology and forms of administration

The usual dose in adults is 3 to 6 x 106 IU. In some special situations in cancer patients, higher doses can be used, bearing in mind that the side effects will be more intense. The usual dose is 3 to 6 x 106 IU / m2 body surface area in children. The frequency of application varies from once a day to three times, twice or once a week. The last two options are more used in prolonged treatment schedules. The method of administration is intramuscular or subcutaneous. However, intravenous, intratracheal, intralesional, and intraperitoneal routes are also possible.

Use code:

HEBERON ALFA R

Periodic respiratory papillomatosis

After surgical removal of the lesion, the following regimen is recommended:

TPW: times a week

Condyloma acuminata

6 × 106.3 times a week, intramuscularly, for 6 weeks, combined with topical application of a cream containing IFN alpha (20,000 IU / g), three times a day.

Viral hepatitis

Subacute hepatitis: 12 to 15 x 106 IU for 3 to 5 days, intraperitoneally or intramuscularly, followed by 6 x 106 IU intramuscularly every other day. Treatment should be continued until the normalization of viral markers and disease markers.

Acute liver failure in infants: 3 to 6 x 106 IU / m2 daily intraperitoneally for one week. In the second week, the same dose is used intramuscularly. Based on the patient’s evolution, the administration frequency can be reduced to 3 times a week from the third week onwards. Treatment should be continued until the normalization of viral markers and disease markers.

Subacute (subfulminant) viral hepatitis in children older than one year: 3 to 6 x 106 IU for one or two weeks, intraperitoneally during the first week, and then intramuscularly. Treatment can be continued with the same dose 3 times a week, by the viral markers and the patient’s clinical status.

Chronic hepatitis B

In adults 6 x106 IU daily intramuscularly for 2 weeks, then 3 times a week for 4 weeks and twice a week for 16 weeks. In children 3 to 6 x106 IU / m2 intramuscularly, 3 times a week for 16 weeks. If the child is older than 12 years, the dose should be 6 x106 IU.

Chronic hepatitis, non-A, non B, C positive: 3 x 106 IU intramuscularly or subcutaneously., 3 x weekly for 9 months. The effectiveness of treatment increases if combined with ribavirin, 200-400mg, 3 times a day for the same period of time.

Human immunodeficiency virus of infected subjects: 3 x 106 IU, 3 times a week during the asymptomatic period. This treatment should be long-term, with hematological and anti-IFN antibody monitoring. In patients with Kaposi’s sarcoma, a higher dose of up to 30 x 106 IU / m2 per day is recommended, as in other IFN alpha preparations. However, in cases where the diagnosis was made early, IFN alpha 2-b (CIGB) caused total remission at 6 x 106 IU for 6 to 12 weeks.

Dengue (Tropical Fever)

IFN alpha 2-b (CIGB) should be used earlier / before 72 hours after the onset of symptoms. In children, 50 to 100,000 IU / kg body weight, daily for 3 days. In adults, 3 to 6 x 106 IU at the same frequency.

Chronic myeloid leukemia

Once hematological remission is achieved, IFN alfa-2b (CIGB) can be given every other day, at 3 x 106 IU / m2 cytogenetic remission, bone marrow transplantation can be performed. Or disease progression occurs.

Non-Hodgkin’s lymphoma of low and medium grade malignancy

After receiving remission with polychemotherapy, 6 x 105 IU 3 times a week for a year or more, until disease progression.

Basal cell carcinoma of the skin

* In patients where surgical removal of the lesion is neither possible nor desirable, 1.5 x 106 IU, intralesionally, 3 times a week for 3 weeks.

Superficial bladder cancer

Intravesical implantation of 20 x 106 IU recombinant IFN alpha-2b (CIGB) in 50 ml, weekly for 8 weeks and then monthly for 2 years

Hemangiomas in newborns

In tumors larger than 2 cm, 3 x 106 IU / m2, subcutaneously, daily for 6 months and then 3 times a week for approximately 12 months. The same dose can be administered intralesionally, twice a week if the tumor is well demarcated.

Malignant melanoma

After surgery, in patients who do not have lesions (lesion free), but with a risk of relapse, 20 x 106 IU intravenously or intramuscularly, 5 days in a row for a week, for 4 weeks, and then 10 x 106 IU 3 times a week for up to a year.

Peyronie’s disease

I eat ml containing 10 x 10 6 IU, intralesionally, twice a week for 14 weeks or less if there is a complete response to therapy before that.

Storage conditions

Bottles should be stored at a temperature of 2 to 8 ◦C.

Presentation / display

HEBERON ALFA R is a liquid (3M, 5M, 6M, and 10M) presented in one, 10, or 25 bottles and thermal cases with one bottle and a syringe.

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