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BIOSIDUS S.A- Argentina

BIOFERON
HEMAX
NEUTROMAX

Forms and presentation

Bioferon 3 M IU: Vial of freeze dried powder + 1 solvent ampoule + 2 disposable needles + 1 disposable sterile 2-ml syringe + 1 swab embedded with isopropyl alcohol.

Bioferon 5 M IU: Vial of freeze dried powder + 1 solvent ampoule + 2 disposable needles + 1 disposable sterile 2-ml syringe + 1 swab embedded with isopropyl alcohol.

Composition

Bioferon 3 M IU:

Each vial contains: recombinant human Interferon α 2b (r-Hu-IFNα 2b): 3 MIU.

Each solvent ampoule contains: Water for injection: 1 ml.

Bioferon 5 M IU:

Each vial contains: recombinant human Interferon α 2b (r-Hu-IFNα 2b): 5 MIU.

Each solvent ampoule contains: Water for injection: 1 ml.

Properties

Bioferon has antiviral, antiproliferative and immunomodulating properties.

Indications

Bioferon is specifically indicated for the treatment of: Hairy cell leukaemia, Condylloma acuminatum, Kaposi’s sarcoma associated to AIDS, chronic hepatitis C, chronic hepatitis B, chronic myeloid leukaemia, malignant melanoma, follicular lymphoma.

It is also recommended in other diseases: non-Hodgkin’s lymphoma, multiple myeloma, T cell non-Hodgkin’s lymphoma, renal cell carcinoma, carcinoid syndrome, laryngeal papilloma, polycythemia vera, autoimmune thrombocytopenic purpura, essential thrombocytosis, angiodysplasia and hepatitis D.

Contraindications

Known hypersensitivity to interferon or any component of the formula. Patients with unstable heart failure or arrythmia. Decompensated cirrhosis: ascites, encephalopathy, severe liver failure (bilirubin > 4 mg/dl, albumin < 3 g/dl or prothrombin time prolonged > 3 seconds), history of bleeding by esophageal varices. Severe depression.

Precautions

Bioferon should be administered under the supervision of a physician skilled in the therapeutical management of the respective indications. Correct management of treatment and control of its possible complications require adequate diagnostic and therapeutical facilities. The patients should be informed not only of the benefits of the therapy, but also of the adverse reactions. In case of liver failure, renal failure or mild or moderate myeloid dysfunctions, a strict supervision of these functions is necessary. A periodic and exhaustive neuropsychiatric examination should be carried out in all patients. Special caution should be observed when administering Bioferon in patients with severe myelosuppression, since this drug inhibits the bone marrow activity, causing a decrease in leukocytes (specially granulocytes) and platelet count and, less frequently, in hemoglobin concentration, which increases the risk of bleeding and infection. It is convenient to monitor these effects and perform periodic complete hematimetric controls before and after treatment with Bioferon. In transplanted patients (for example, renal or bone marrow transplantation), the immunostimulating action of interferon can reduce the efficacy of therapeutical immunosuppression. In few occasions, the use of interferon α 2 has been associated with exacerbation or occurrence of psoriasis. Rarely, liver dysfunction or severe liver failure after administration of interferon α 2 have been described. The appearance of several autoantibodies during the treatment with interferon α, specially antibodies to thyroid (associated or not with gland dysfunction), antinuclear antibodies and antibodies to smooth muscle has been reported. Clinical evidences of autoimmune disease during interferon treatment are more frequent in patients prone to autoimmune disorders.

Bioferon can affect reflexes and hinder performance of certain tasks, such as driving motor vehicles and operating machinery. This effect depends on the dose, the dosage schedule and patient’s sensitivity to the drug.

Children: Bioferon should be used cautiously in children, with the exception of chronic hepatitis B, C and chronic myeloid leukaemia, although therapeutical safety and efficacy has not been established in pediatric population yet.

Laboratory tests: Before initiating Bioferon treatment, and during its administration, clinical examinations and laboratory tests should be carried out. Since the responses in hairy cell leukaemia and Kaposi’s sarcoma associated to AIDS are generally observed 1-3 months after starting the treatment, a very careful monitoring of severe blood cell depression during the initial phase should be warranted. In those patients who have preexisting heart abnormalities, electrocardiograms should be performed before and during treatment.

Drug interactions

Since interferons α alter cell metabolism, there is a possibility that Bioferon modifies the activity of other drugs. A trial recruiting a small number of patients has demonstrated that interferon α 2 affects specific microsomic enzymatic systems, but the clinical importance of this finding is not already known. Interferons α can exert an influence upon the oxidative metabolic process. This fact should be taken into account before prescribing a concomitant treatment with drugs that are metabolised by this route. However, there is no specific information regarding this subject. Bioferon can affect the CNS and therefore, an interaction is possible when drugs that effect CNS are used. Interferons can enhance neurotoxic, hematotoxic or cardiotoxic effects of other medications previously or concomitantly administered.

Pregnancy and lactation

Pregnancy: An effective contraceptive method should be used by women and men when receiving Bioferon. During pregnancy, Bioferon should be administrated only if the benefit to the mother justifies the potential risk to the foetus. Although animal trials have not revealed evidences that Bioferon is teratogenic, the risk of foetus damage when used during pregnancy should not be excluded. An abortive effect statistically significant in Rhesus monkeys that had received the drug during the first half of pregnancy period has been observed with doses exceeding those clinically recommended for humans (20-500 times). In a study with pregnant Rhesus monkeys treated with recombinant human interferon α 2 in doses of 1; 5; or 25 MIU/kg/day during their early to mid-fœtal period (days 22-70 of gestation) teratogenic activity could not be shown. Studies with pregnant women have not been carried out yet.

Lactation: It is not known whether the drug is excreted in mother’s milk. Therefore, when a decision should be made whether to discontinue nursing or medication, therapeutical importance of the drug to the mother should be taken into account.

Side effects

General symptoms: Most patients suffer from flu-like symptoms, such as asthenia, fever, chills, anorexia, myalgia, headache, arthralgia and sweat. These side effects tend to decrease as time progresses. Simultaneous administration of acetaminophen allows the normal relief or elimination of most of them, either by reducing the dose or maintaining the same treatment. Compliance with schedule can cause lethargy, weakness and asthenia.

Digestive tract: Around 2 thirds of the patients suffer from anorexia and approximately a half, nausea. Less frequently, vomiting, disorders of taste, mouth dryness, weight loss, diarrhoea or mild to moderate abdominal pain were observed. Rarely, constipation, flatulence, hypermotility and epigastric pain were reported. Exceptionally, cases of reactivation of peptic ulcer and mild gastrointestinal bleeding have been reported.

Liver function disorders: Mainly, ALT increase but also alkaline phosphatase, LDH and bilirubin increases have been described, though in general a dose adjustment was not required. In patients with hepatitis B, increase in transaminase values can be interpreted as HBeAg seroconversion marker.

CNS: Dizziness, vertigo, visual disorders, decrease of mental status, memory loss, depression, somnolence, confusion, nervousness, and sleep disturbances are not frequent. In rare occasions, intense somnolence, coma, cerebral ictus and transient impotence have occurred.

Peripheral Nervous system: Occasionally paresthesia, numbness, neuropathy and tremor have been described.

Respiratory and cardiovascular systems: Secondary effects in approximately 1 fifth of patients with cancer were observed, generally transient episodes of hypotension or hypertension, oedema, cyanosis, arrythmias, palpitations and chest pain. Rarely, patients have reported cough or mild dyspnea. Isolated cases of pulmonar oedema, congestive heart failure, cardiorespiratory arrest, myocardial infarction have been observed. Cardiovascular adverse reactions were infrequent in patients with hepatitis.

Skin, mucous membrane and appendages: Rarely, exanthema, labial herpes exacerbation, pruritus, dry skin and mucoses, rhinorrhea and epistaxis have been described. Up to 1 fifth of patients developed mild to moderate alopecia, but it was reversible once treatment was discontinued.

Urinary tract: Rarely, renal function is affected. Electrolytic alterations (generally related to anorexia or dehydration), proteinuria and sediment cell count increase have been observed. Exceptionally, urea, creatinine and uric acid increases have been noted.

Hematopoietic system: One third to more than a half of patients have experienced transient leukopenia, but in few occasions the dose had to be reduced. In non-myelosuppressive patients, thrombocytopénie was less frequent and rarely, hemoglobin and hematocrit decrease occurred. In patients without myelosuppression, thrombocytopénie and hemoglobin decrease were more frequent. Generally, severe hematologic alterations were normalized to pre-treatment levels, within 7-10 days after discontinuing interferon α 2 treatment.

Other side effects: In almost half of patients, hypocalcemia has been detected without consequences. Around 1 third of cancer patients has shown a rise in glycemia values. In some isolated cases neutralizing antibodies of interferon α 2 have been detected. No clinical consequences derived from their presence have been reported up to date. In some diseases (cancer, systemic lupus erythematosus, herpes zoster) spontaneous antibodies against human leukocyte interferon in patients that never received exogenous interferon have been detected. Local reactions in the site of injection have been described.

Dosage and administration

Hairy cell leukaemia: Bioferon is indicated in patients who suffer from hairy cell leukemia associated to severe cytopenias (neutrophil count < 1000/mm3, platelet count < 50,000 mm3 and/or hematocrit < 30%), with or without previous splenectomy. In clinical trials, a decrease of the red cell, leukocyte and platelet counts was observed during the first 2 months of treatment. Later, a normalization of the hematimetric parameters was shown in 75% of treated patients and some kind of improvement in 90% of them was reported. The response is similar both in splenectomized or non-splenectomized patients. Patients with hairy cell leukaemia require red cell and platelet transfusions. Neutrophil counts < 500/mm3 also make patients prone to severe infections. Treatment with Bioferon reverts this situation. In relapsed patients, a second course of treatment with Bioferon has shown similar results to those observed in patients without previous treatment. The dose of Bioferon is 3 MIU, 3 times a week, by SC or IM route, during at least 6 months. In those patients with haematological remission, treatment should be extended until completing 12 months. In patients with less than 50,000 platelets/mm3 SC route is recommended. In the event cytopenia worsened during the first months of treatment, the dose of Bioferon should be reduced to 1.5 MIU 3 times a week, until red cell, leukocyte and platelet counts are over the critical levels.

Condilloma acuminatum: Condilloma acuminatum (genital warts) is associated with papillomavirus infection. Bioferon therapy has demonstrated its efficiency and safety in reducing genital lesions, when administered in doses of 1 MIU 3 times a week, intralesionally. Treatment duration ranges from 3-16 weeks. Response was observed between the 2nd and 4th week. The maximum response occurs between the 4th and 8th week. when lesions persist, a second course of treatment is recommended; response increases from 57-85% have been reported.

Kaposi’s sarcoma associated to AIDS: Response to Bioferon therapy in these patients varies according to basal CD4 levels. A 30 MIU dose 3 times a week, subcutaneously has shown a response that ranges between 30% and 70%, being higher in patients with CD4 count over 400/mm3. Clinical status of the patients should be taken into account; those with history of opportunistic diseases or hepatitis B symptoms (weight loss over 10%, fever of unknown origin over 38°C, night sweat) have less chance of responding. Although the dose of Bioferon has not been established, for patients over 18 years old it is recommended to initiate with 30 MIU/m2 of body surface, subcutaneously or intramuscularly, 3 times a week. The dose should be modified according to the patient’s tolerance. Treatment duration has not been established. It is required at least 12 weeks to assess the response. If a decrease of lesions is observed, treatment should be followed until their disappearance.

Concomitant administration of Bioferon with Zidovudine (AZT): It is advisable to use a lower dose of Bioferon in patients receiving AZT since this association increases myelotoxicity. In these cases, it is recommended to start with a 3-5 MIU/day/m2 of body surface. This dose may be increased by 5 MIU at a time, assessing the tolerance until reaching a dose of 15 MIU/m2 of body surface. The dose should be indicated according to the individual patient’s response and tolerance.

Chronic hepatitis C: Bioferon associated with ribavirin is indicated for the treatment of chronic hepatitis C in adults with compensated liver disease. It has been used in children, hemodialysis patients and HIV-infected patients, without being conclusively demonstrated its efficacy in these groups. In 1986, a pilot study showed that interferon α was effective in the treatment of chronic hepatitis non-A, non-B, identified later as hepatitis C. 2 subsequent controlled studies showed that aminotransferases were normalized in approximately 50% of the treated patients with an improvement in their liver histology. However, relapse was a frequent event. 10-25% of the cases maintained normal aminotransferase levels in a long-term follow-up. With the administration of Bioferon, in 48% of the patients aminotransferases reached normal values during a 6-month-treatment and they had a sustained normalization after the end of therapy in 22%. The aminotransferase normalization is not always correlated to the eradication of HCV RNA in serum. A second course of treatment can be effective in some patients with initial response and later relapse but it is not indicated in those who have never responsed. New therapeutical schedules to attain a better response, including higher doses, longer treatments and combinations with other antiviral agents, are being assessed. In patients who have never been treated or in patients that have relapsed after responding to a Bioferon treatment, a sustained response can be obtained by combination of Bioferon with ribavirin, with normalization of aminotransferases and eradication of HCV RNA, in 30-50% of the cases. Currently, for the treatment of these patients, the recommended dose is 3 MIU of Bioferon 3 times a week, subcutaneously, and 1000-1200 mg of ribavirin a day by oral route, during 6 months. Treatment can be extended for an additional 6-month period in responders.

Chronic hepatitis B: Bioferon is indicated in adults with compensated liver disease and HBV replication marked by HBsAg and/or HBV DNA positivity. Several controlled studies demonstrated that 32-44% of the patients with those characteristics responded to interferon α assessed by serum HBsAg and HBV DNA negativization. Clearance of viremia is associated with serum aminotransferase normalization and improvement of liver histology. Only 7-16% of treated patients eliminated B virus with HBsAg negativization. Contrarily to what has been reported in chronic hepatitis C, relapse was an unusual event in patients with chronic hepatitis B who responded to treatment and it was observed that many patients eliminated the HBsAg several years after treatment. The recommended doses of Bioferon for chronic hepatitis B are 5 MIU a day or 10 MIU 3 times a week, subcutaneously, during 16 weeks. There is no apparent benefit in extending treatment beyond this period.

Chronic myeloid leukaemia: This disease is characterized by leukocytosis, anemia, splenomegaly and bone marrow hypercellularity. Its evolution undergoes 3 phases (chronic, accelerated and blastic crisis) and it is generally associated with the presence of the Philadelphia chromosome. Treatment of chronic myeloid leukaemia with interferon α, specially during the chronic phase, has achieved haematological remission in around 60% of the cases and cytogenetic remission with disappearance of Philadelphia chromosome in approximately 15%. The recommended initial dose of Bioferon is 5 MIU/m2 a day, subcutaneously or intramuscularly. This schedule can be reduced to 3 times a week when stabilization of haematological parameters is obtained. Generally, haematological response is attained between the second and third month but cytogenetic response appears later, requiring up to 18 months of treatment. Initially, hydroxyurea can be associated with Bioferon, especially in those patients with leukocyte counts over 50,000/mm3. In these cases it is convenient to start with a lower dose of Bioferon, which may be 4.5 MIU a day, subcutaneously or intramuscularly. Hydroxyurea and Bioferon doses should be adjusted to maintain neutrophil levels between 1,500 and 4,000/mm3 and platelet level over 75,000/mm3.

Malignant melanoma: Bioferon is used during the treatment of malignant melanoma, associated with surgery in the early stage of the disease or chemotherapy in the advanced phases. Recently, it has been demonstrated that patients with an early stage disease treated with interferon α after surgery had a longer survival and a free disease period as compared to those without further treatment. The used doses ranged from 10-30 MIU, 3 times a week, IV or subcutaneously, during 12 weeks. In post-surgical treatment the duration is variable and depends on the therapeutical response.

Follicular lymphoma: In patients with indolent subtype lymphoma, the use of Interferon α 2b together with chemotherapy schedules containing antracyclines has demonstrated to prolong the life span free from disease. The therapeutic schedule is 5 MIU 3 times a week, subcutaneously, associated with chemotherapy during 18 months. The initial dose should be adjusted according to haematological toxicity that may be aggravated by the combination with chemotherapy agents.

Storage conditions

Bioferon should be kept refrigerated (2-8° C). Do not freeze. Do not freeze the ampoule containing water for injection since it can be leaked. Once Bioferon is reconstituted, it should be used within the following 24 hrs, storing the solution refrigerated (2-8° C) and following strict aseptic conditions during powder reconstitution. Vials containing reconstituted solution should be used within 2 hrs if they are kept at room temperature, or within 24 hrs if they are stored at 2-8° C. This preparation does not contain preservative agents. Therefore, it is advisable not to extract more than 1 dose from the vial to prevent contamination.

Important: Once reconstituted, mix the suspension with gentle rotation movements, do not shake vigorously.

 

Origin: Argentina

Laboratories: Bio Sidus

Distributor: Droguerie Phenicia

Number & Year of Registration

3 M: 973352/2001

5 M: 973353/2001