Roferon^®-A (Solution) Instructions for Use

ATC Code

L03AB04 (Interferon alfa-2a)

Active Substance

Interferon alfa-2a

Interferon alfa-2a (USAN)

Clinical-Pharmacological Group

Interferon. Antitumor, antiviral, and immunomodulatory drug

Pharmacotherapeutic Group

MIBP-cytokine

Pharmacological Action

Interferon alfa-2a is a highly purified protein containing 165 amino acids, with a molecular weight of about 19,000 daltons. It is produced using recombinant DNA technology with a genetically engineered strain of E.coli, the DNA of which encodes the synthesis of this human protein.

Roferon^®-A exerts an antiviral effect by inducing a state of resistance to viral infections in cells and modulating the immune system’s response aimed at neutralizing viruses or destroying infected cells. Roferon^®-A has an antiproliferative effect on a number of human tumors in vitro and inhibits the growth of some human tumor xenografts in athymic nude mice.

Clinical Efficacy

In human tumor cells treated with Roferon^®-A (in HT29 cells), the synthesis of DNA, RNA, and protein is significantly reduced. A limited number of human tumor cell lines grown in vivo in immunodeficient athymic mice were tested for sensitivity to the effects of Roferon^®-A. The in vivo antiproliferative activity of Roferon^®-A was studied in tumors such as mucoid breast carcinoma and adenocarcinoma of the cecum and transverse colon, as well as the prostate. The degree of antiproliferative activity varies.

Roferon^®-A leads to clinically significant tumor regression or disease stabilization in patients with hairy cell leukemia and in AIDS patients with Kaposi’s sarcoma. Roferon^®-A is also effective for treating patients with multiple myeloma. Roferon^®-A is active in patients with progressive cutaneous T-cell lymphoma who are insensitive or unsuitable for conventional therapy.

Roferon^®-A is effective for treating patients with Ph-positive chronic myeloid leukemia (CML). Roferon^®-A leads to hematological remission in 60% of patients in the chronic phase of CML, regardless of prior therapy. Complete hematological remission is still maintained 18 months after the start of treatment in two-thirds of the studied patients. Unlike cytotoxic chemotherapy, interferon alfa-2a can lead to stable cytogenetic remission lasting more than 40 months. Roferon^®-A in combination with intermittent courses of chemotherapy increases overall survival and inhibits disease progression compared to chemotherapy alone.

Roferon^®-A is effective for treating thrombocytosis in CML and other myeloproliferative diseases. Roferon^®-A reduces the platelet count within a few days, reduces the frequency of associated thrombohemorrhagic complications, and does not have leukemogenic potential.

In patients with low-grade non-Hodgkin’s lymphoma, when added to chemotherapy (with or without radiotherapy), Roferon^®-A prolongs relapse-free survival and progression-free survival.

In patients with advanced renal cell carcinoma, the best therapeutic effect was observed with the administration of high doses of Roferon^®-A (36 million IU daily) as monotherapy or moderate doses of Roferon^®-A (18 million IU 3 times a week) in combination with vinblastine, compared with monotherapy with moderate doses of Roferon^®-A 3 times a week. In patients receiving Roferon^®-A monotherapy in low doses (2 million IU/m² daily), there was no treatment effect. The combination of Roferon^®-A with vinblastine leads only to a slight increase in the frequency of mild and moderate leukopenia and granulocytopenia compared with monotherapy. The duration of response and survival with Roferon^®-A monotherapy and combined Roferon^®-A + vinblastine therapy are similar. Roferon^®-A in combination with vinblastine is more effective in terms of survival compared to chemotherapy alone.

In patients with advanced malignant melanoma, treatment with Roferon^®-A led to objective regression of tumors of cutaneous and visceral localization. Also, Roferon^®-A increases the duration of disease-free time in patients without lymph node involvement and distant metastases after melanoma resection (tumor thickness >1.5 mm).

Roferon^®-A in combination with Avastin as first-line therapy in patients with advanced and/or metastatic renal cell carcinoma compared with the combination of Roferon^®-A and placebo significantly increases progression-free survival (PFS) and the objective response rate.

Reducing the dose of interferon alfa-2a from 9 million IU to 6 or 3 million IU 3 times a week when used in combination with Avastin did not lead to a decrease in the efficacy of the combination therapy according to event-free survival indicators (see also the instructions for use of Avastin).

Roferon^®-A is effective for treating patients with confirmed compensated (without signs of hepatic decompensation) hepatitis B and C.

Roferon^®-A is effective for treating patients with condylomata acuminata.

Pharmacokinetics

Absorption

After SC or IM administration, bioavailability exceeds 80%. After subcutaneous administration of a 36 million IU dose, C_max in serum (from 1250 to 2320 pg/ml (average, 1730 pg/ml)) was reached, on average, after 7.3 h. After IM administration of a 36 million IU dose, C_max in serum (from 1500-2580 pg/ml (average, 2020 pg/ml)) was reached, on average, after 3.8 h.

Distribution

In humans, the pharmacokinetics of Roferon^®-A in doses from 3 million to 198 million IU is linear. After IV infusion of 36 million IU to healthy volunteers, V_d at steady state ranged from 0.22 to 0.75 l/kg (average, 0.40 l/kg). Both in healthy volunteers and in patients with disseminated cancer, large individual variations in the concentration of interferon alfa-2a in serum are observed.

Metabolism and Excretion

The main route of elimination of interferon alfa is renal catabolism.

Hepatic metabolism and biliary excretion are less significant elimination pathways. In healthy individuals, the T_1/2 of interferon alfa-2a after intravenous infusion of 36 million IU is 3.7-8.5 h (average, 5.1 h), and the total clearance is 2.14-3.62 ml/min/kg (average, 2.79 ml/min/kg).

Pharmacokinetics in Special Patient Groups

After a single IM administration of interferon alfa-2a to patients with disseminated cancer and chronic hepatitis B, the pharmacokinetic parameters are similar to those in healthy volunteers. After a single administration of doses up to 198 million IU, a dose-dependent increase in serum concentrations of interferon alfa-2a is observed. The distribution or elimination of interferon alfa-2a when administered 2 times/day (0.5-36 million IU), 1 time/day (1-54 million IU), or 3 times a week (1-136 million IU) for up to 28 days does not change.

In some patients with disseminated cancer, IM administration of interferon alfa-2a once or several times a day for up to 28 days led to an increase in C_max in serum by 2-4 times compared to that after a single administration. However, repeated administration, according to any of the dosing regimens studied to date, did not change the distribution or elimination parameters of the drug.

Indications

• Neoplasms of the lymphatic system and hematopoietic system: hairy cell leukemia; multiple myeloma, cutaneous T-cell lymphoma, Ph-positive chronic myeloid leukemia, thrombocytosis in myeloproliferative diseases, low-grade non-Hodgkin’s lymphoma (as adjuvant therapy to chemotherapy (with/without radiotherapy));
• Solid tumors: Kaposi’s sarcoma in AIDS patients without a history of opportunistic infections, advanced renal cell carcinoma, metastatic malignant melanoma, melanoma after surgical resection in the absence of lymph node involvement and distant metastases;
• Viral diseases: chronic active hepatitis B in patients with markers of viral replication, i.e., positive for HBV-DNA, DNA polymerase, or HBeAg and elevated ALT (ALT) activity without signs of hepatic decompensation (Child-Pugh class A);
• Chronic active hepatitis C in adults with antibodies to the hepatitis C virus or HCV RNA in serum and elevated ALT (ALT) activity without signs of hepatic decompensation (Child-Pugh class A); for the treatment of chronic hepatitis C, the combination of Roferon^®-A and ribavirin is optimal; Roferon^®-A in combination with ribavirin is indicated both for previously untreated patients and for those who previously responded to interferon alfa therapy and then had a relapse of the disease after discontinuation of therapy;
• Condylomata acuminata.

ICD codes

Dosage Regimen

Solution

Roferon^®-A is administered SC.

For hairy cell leukemia, Roferon^®-A is prescribed at an initial dose of 3 million IU/day SC, daily, for 16-24 weeks. In case of intolerance, the daily dose is reduced to 1.5 million IU and/or the frequency of administration is reduced to 3 times a week.

The maintenance dose is 3 million IU 3 times a week SC. In case of intolerance, the dose is reduced to 1.5 million IU 3 times a week.

The use of Roferon^®-A is continued for 6 months, after which the doctor must decide whether to continue therapy (if there is a positive effect) or stop it (if there is no effect). The maximum duration of treatment is 20 months.

For multiple myeloma, the drug is prescribed at 3 million IU 3 times a week SC. Depending on individual tolerance, the dose can be increased weekly to the maximum tolerated dose (9-18 million IU) 3 times a week.

Treatment according to this scheme is continued for a long time in the absence of disease progression and severe drug intolerance.

For cutaneous T-cell lymphoma, Roferon^®-A may be effective in patients with progressive disease, including those refractory to conventional therapy or unsuitable for its administration.

For patients aged 18 years and older, the drug is administered for 12 weeks, gradually increasing the daily dose from 3 million IU to 18 million IU according to the following scheme: days 1-3 – 3 million IU/day, days 4-6 – 9 million IU/day, days 7-84 – 18 million IU/day.

Maintenance therapy is carried out with the maximum dose tolerated by the patient, but not exceeding 18 million IU, as SC injections 3 times a week.

The duration of treatment before efficacy evaluation should be at least 8 weeks, preferably 12 weeks; if there is a positive effect, treatment is continued, if there is no effect, it is stopped. The maximum duration of treatment is 40 months. In patients responding positively to treatment, it should be continued for at least 12 months to maximize the likelihood of achieving complete remission and increase the likelihood of long-term remission.

Partial remission is usually observed within 3 months of treatment, complete remission within 6 months, although sometimes 12 months of therapy are required to achieve the best effect.

For chronic myeloid leukemia, patients aged 18 years and older are administered the drug for 8-12 weeks, gradually increasing the dose according to the following scheme: days 1-3 – 3 million IU/day, days 4-6 – 6 million IU/day, days 7-84 – 9 million IU/day.

Treatment should be continued for at least 8 weeks, preferably 12 weeks; if there is a positive effect, treatment is continued until complete hematological remission is achieved, but not more than 18 months. If there is no change in hematological parameters, therapy is discontinued. All patients with complete hematological remission should continue treatment with the drug at a dose of 9 million IU/day (optimal dose) daily, or 9 million IU 3 times a week (minimum dose), to achieve cytogenetic remission as soon as possible. Observations of cytogenetic remissions lasting 2 years after the start of treatment have been reported.

The efficacy, safety, and optimal doses of Roferon-A for children with chronic myeloid leukemia have not been established.

Unlike cytotoxic chemotherapy, interferon alfa-2a can lead to stable cytogenetic remission lasting more than 40 months.

Roferon^®-A reduces the platelet count within a few days, reduces the frequency of associated thrombohemorrhagic complications, and does not have leukemogenic potential.

For thrombocytosis in myeloproliferative diseases (except chronic myeloid leukemia), the drug is prescribed on days 1-3 – 3 million IU/day daily; days 4-30 – 6 million IU/day daily. The maintenance dose is 1-3 million IU 2-3 times a week. The maximum tolerated dose should be individually selected for each patient.

For low-grade non-Hodgkin’s lymphoma, the drug is prescribed as maintenance therapy after standard chemotherapy (with or without radiotherapy) at a dose of 3 million IU SC 3 times/week for at least 12 months. Roferon-A treatment should be started as early as possible when the patient’s condition improves, usually 4-6 weeks after chemo- and radiotherapy.

Roferon^®-A can also be prescribed simultaneously with traditional chemotherapy regimens (for example, with a combination of cyclophosphamide, prednisone, vincristine, and doxorubicin) at 6 million IU/m² body surface area SC from day 22 to day 26 of each 28-day cycle. In this case, Roferon-A treatment can be started simultaneously with chemotherapy.

Roferon^®-A, prescribed in addition to chemotherapy (with or without radiotherapy), prolongs relapse-free survival and progression-free survival.

For Kaposi’s sarcoma in AIDS patients, the likelihood that patients with Kaposi’s sarcoma and AIDS will respond positively to therapy is higher if they have no history of opportunistic infections, symptoms of group B (weight loss of more than 10%, temperature above 38°C (100.4°F) in the absence of a known source of infection, night sweats), and the initial number of T4-lymphocytes exceeds 200/µl.

For patients aged 18 years and older, the drug is prescribed at an initial dose of 3 million IU/day daily for 10-12 weeks, gradually increasing the daily dose to 18 million IU/day daily, and if possible, to 36 million IU/day daily according to the following scheme: days 1-3 – 3 million IU/day daily, days 4-6 – 9 million IU/day daily, days 7-9 – 18 million IU/day daily, if tolerated, increasing the dose on days 10-84 to 36 million IU/day daily.

The maintenance dose is the maximum tolerated dose, but not more than 36 million IU/day, 3 times/week.

The duration of treatment before evaluating the response to therapy should be at least 10 weeks, preferably 12 weeks. If there is a positive effect, therapy is continued; if there is no effect, it is stopped. To determine the response to treatment, tumor dynamics should be documented. The effect usually appears after 3 months of treatment. The maximum duration of treatment was 20 months. If there is an effect, treatment should be continued at least until the tumor disappears. After discontinuation of Roferon-A therapy, Kaposi’s sarcoma often recurs.

For advanced renal cell carcinoma in patients with tumor recurrence or metastases, the best therapeutic effect is observed with the administration of Roferon-A in high doses (36 million IU/day) as monotherapy or in moderate doses (18 million IU 3 times a week) in combination with vinblastine, compared with monotherapy with moderate doses 3 times a week. The duration of response and survival with Roferon-A monotherapy or combined Roferon-A with vinblastine therapy are similar. In patients receiving Roferon^®-A (2 million IU/m²/day) in low doses, the treatment was ineffective. The combination of Roferon-A with vinblastine leads only to a slight increase in the frequency of mild and moderate leukopenia and granulocytopenia compared with monotherapy.

For monotherapy, Roferon^®-A is prescribed at an initial dose of 3 million IU/day with a gradual dose increase over 8-12 weeks to 18 million IU/day, and if possible, to 36 million IU/day, according to the following scheme: days 1-3 – 3 million IU/day, days 4-6 – 9 million IU/day, days 7-9 – 18 million IU/day, if tolerated, increasing the dose on days 10-84 to 36 million IU/day.

For maintenance therapy, Roferon^®-A is administered at the maximum dose tolerated by the patient, but not more than 36 million IU/day 3 times/week.

The duration of treatment is at least 8 weeks, preferably 12 weeks. If there is a positive effect, therapy is continued; if there is no effect, it is stopped. The maximum duration of treatment is 16 months.

For combination therapy with vinblastine, Roferon^®-A is prescribed in the first week at a dose of 3 million IU 3 times a week, in the second week – 9 million IU 3 times a week, then – 18 million IU 3 times a week (in case of intolerance, the dose can be reduced to 9 million IU 3 times a week). During this period, vinblastine should be administered IV according to the instructions for use of the drug at a dose of 100 µg/kg body weight once every 3 weeks. The duration of treatment is at least 3 months, up to a maximum of 12 months or until disease progression begins. In case of complete remission, treatment can be discontinued 3 months after its onset.

For metastatic melanoma, Roferon^®-A is prescribed at a dose of 18 million IU subcutaneously three times a week or at the maximum tolerated dose for 12 weeks. The duration of treatment until therapy efficacy assessment is preferably at least 12 weeks. If there is a positive effect, therapy is continued; in its absence, it is discontinued. The maximum duration of treatment is 24 months. In patients with advanced malignant melanoma, treatment with Roferon-A led to objective regression of tumors of cutaneous and visceral localization.

For melanoma after surgical resection, adjuvant therapy with low doses of Roferon-A increases the duration of disease-free time in patients without lymph node involvement and distant metastases after melanoma resection (tumor thickness greater than 1.5 mm). Treatment should be started no later than 6 weeks after surgery. The dose is 3 million IU three times per week. The duration of treatment is 18 months.

For chronic viral hepatitis B, Roferon^®-A is prescribed at 4.5-9 million IU three times a week for 4-6 months. Further dose adjustment is carried out depending on the drug’s tolerability. If there is no improvement after 3-4 months, the issue of discontinuing therapy should be considered.

For chronic viral hepatitis B in children aged 3 years and older, the use of a dose of 7.5 million IU/m² of body surface area is safe and effective.

For chronic hepatitis C, the efficacy of Roferon-A is increased if it is prescribed in combination with ribavirin. When conducting combination therapy in previously untreated patients, Roferon^®-A is prescribed at 3 million IU three times a week for at least 6 months. Ribavirin is prescribed at the dose specified in the ribavirin prescribing information.

When conducting combination therapy for disease relapse in adults whose prior interferon alpha monotherapy provided a temporary effect, Roferon^®-A is prescribed at 4.5 million IU three times a week for 6 months. Ribavirin is prescribed at the dose specified in the ribavirin prescribing information.

The standard duration of therapy for patients with chronic hepatitis C depends on the virus genotype and is 6-12 months.

Monotherapy with Roferon-A is conducted in case of ribavirin intolerance and/or presence of contraindications to its use. The dose of Roferon-A is 3-6 million IU three times a week for 6-12 months. If after 3 months of treatment the serum ALT level does not normalize, therapy should be discontinued. In case of tolerability and a partial or complete response to Roferon-A therapy, but with disease relapse after its discontinuation, an effect from repeated Roferon-A therapy at the same or a higher dose is possible.

For condylomata acuminata, Roferon^®-A is prescribed subcutaneously at 1-3 million IU three times a week for 1-2 months.

Drug Handling Instructions

Multidose cartridges (18 million IU in 0.6 ml) are intended for use by only one patient. They are used only in the Roferon^®-Pen syringe pen. Penfine needles must be used together with the syringe pen and cartridge. A new sterile needle should be used for each injection. Cartridges with Roferon-A should be used within 30 days after the first injection. After each injection, the Roferon^®-Pen syringe pen with the inserted cartridge should be stored in a refrigerator, protected from light; however, if necessary, it can also be stored at room temperature (up to 25°C (77°F)) for up to 28 days.

The date of first use of the cartridge should be marked on the sticker supplied with the cartridge, and the sticker should be placed on the syringe pen box. Detailed instructions for using the Roferon^®-Pen are included in the syringe pen packaging.

Adverse Reactions

The following data on the drug’s adverse effects are based on experience in treating patients with various malignant diseases, often refractory to previous treatment and in advanced stages, as well as patients with chronic hepatitis B and chronic hepatitis C.

Clinical Studies

General symptoms. Common – flu-like syndrome (lethargy, fever, chills, loss of appetite, muscle and headaches, joint pain, and sweating), weight loss. These acute adverse effects usually diminish or are eliminated with concurrent paracetamol administration, and their severity during treatment or upon dose adjustment of Roferon^®-A tends to decrease, although drowsiness, weakness, and lethargy may occur with continued therapy.

Gastrointestinal tract. Common – in approximately two-thirds of cancer patients – anorexia, in half – nausea. Quite common – vomiting, altered taste sensation, dry mouth, diarrhea, as well as mild or moderate abdominal pain. Rare – constipation, flatulence, increased peristalsis, heartburn, exacerbation of peptic ulcer, non-life-threatening gastrointestinal bleeding, pancreatitis.

Changes in liver function. Sometimes – increased levels of ALT, alkaline phosphatase, LDH, and bilirubin, which generally do not require dose adjustment. Rare – changes in transaminase activity in hepatitis B usually indicate an improvement in the patient’s clinical condition.

Central nervous system. Sometimes – systemic and non-systemic dizziness, impaired mental status, forgetfulness, depression, drowsiness, confusion, behavioral disturbances (anxiety, nervousness), and sleep disorders. Rare – severe drowsiness, seizures, coma, cerebrovascular disorders, temporary impotence, as well as suicidal thoughts, suicide attempts, and suicide (suicidal behavior).

Organ of vision. Sometimes – visual impairment. Rare – ischemic retinopathy. Very rare – retinopathy, including retinal hemorrhages and cotton wool exudates, optic disc edema, thrombosis of the central retinal vein and artery, posterior ischemic neuropathy.

Peripheral nervous system. Sometimes – paresthesia, numbness of extremities, neuropathy, itching, and tremor.

Cardiovascular and respiratory systems. Quite common – in approximately one-fifth of cancer patients – transient arterial hypo- and hypertension, edema, cyanosis, arrhythmias, palpitations, and chest pain. Rare – cough and mild shortness of breath, pulmonary edema, pneumonia, congestive heart failure, cardiac arrest and respiratory arrest, myocardial infarction. In hepatitis B patients, cardiovascular disorders are very rare.

Skin, its appendages, and mucous membranes. Quite common – in one-fifth of patients – mild or moderate hair loss, reversible after treatment cessation. Increased hair loss may continue for several weeks. Rare – exacerbation of herpetic eruptions on the lips, rash, itching, dry skin and mucous membranes, nasal discharge, and nosebleeds.

Kidneys and urinary tract. Rare – impaired renal function, acute renal failure (mainly in cancer patients with risk factors such as kidney disease and/or concurrent treatment with nephrotoxic drugs), electrolyte disturbances, especially with anorexia or dehydration, proteinuria, increased cellular elements in urine sediment, increased levels of urea, as well as serum creatinine and uric acid.

Hematopoietic system. Quite common – transient leukopenia (rarely requiring dose reduction), in patients with myelosuppression – thrombocytopenia, decreased hemoglobin level. Sometimes – thrombocytopenia in patients without myelosuppression. Rare – decreased hemoglobin and hematocrit levels. Return of severe hematological disorders to baseline levels was usually observed 7-10 days after discontinuation of Roferon^®-A treatment. Very rare – idiopathic thrombocytopenic purpura.

Other. Rare – hyperglycemia, diabetes mellitus, injection site reactions, including very rarely – necrosis, autoimmune pathology (vasculitis, arthritis, hemolytic anemia, thyroid dysfunction, lupus-like syndrome). Very rare – asymptomatic hypocalcemia, sarcoidosis, hypertriglyceridemia/hyperlipidemia.

In rare cases, therapy with interferon alpha drugs, including Roferon^®-A, in combination with ribavirin is associated with pancytopenia; very rarely – with aplastic anemia.

Antibodies to interferon. In some patients, after administration of drugs containing a homologous protein, neutralizing antibodies to the active protein may form. Therefore, it is likely that in a certain proportion of patients, antibodies to all interferons, both natural and recombinant, will be detected. In some diseases (cancer, systemic lupus erythematosus, herpes zoster), antibodies to human leukocyte interferon can spontaneously occur in patients who have never previously received interferons. There is no indication that for any of the clinical indications, the presence of such antibodies could negatively affect the patient’s response to Roferon^®-A.

When conducting combination therapy with ribavirin – see also ribavirin adverse reactions.

Preclinical study. In rhesus monkeys administered doses of the drug significantly exceeding those recommended for clinical use, transient menstrual cycle disturbances were observed, including prolonged menstrual periods.

Postmarketing Surveillance

As with the use of other interferon alfas, cases of transplant rejection have been observed in patients receiving Roferon^®-A.

Contraindications

• Hypersensitivity to recombinant interferon alfa-2a or any component of the drug;
• Existing or past severe heart disease (there are no indications of a direct cardiotoxic effect of the drug, but there is a possibility that acute, self-limiting toxic effects (e.g., fever, chills) often accompanying treatment with Roferon^®-A may cause exacerbation of existing heart conditions);
• Severe impairment of renal, hepatic, or myeloid hematopoietic function;
• Convulsive disorders and/or other CNS function impairments;
• Chronic hepatitis with severe decompensation;
• Chronic hepatitis in patients receiving or having recently received immunosuppressants, except for short-term steroid treatment;
• Chronic myeloid leukemia, if the patient has an HLA-identical relative and is scheduled for or may undergo allogeneic bone marrow transplantation in the near future;
• Children under 3 years of age (contains benzyl alcohol as a preservative, which, according to reports, may lead to persistent neuropsychiatric disorders and multiorgan failure);
• Pregnancy when conducting combination therapy with ribavirin (see also the ribavirin prescribing information).

Use in Pregnancy and Lactation

The drug should be prescribed during pregnancy only if the benefit of treatment outweighs the potential risk to the fetus. Although animal experiments do not indicate teratogenicity of the drug, the possibility that its use during pregnancy could harm the fetus cannot be excluded. When rhesus monkeys were administered doses significantly exceeding those recommended for clinical use during early and mid-pregnancy, an increased number of miscarriages was noted. Men and women receiving Roferon^®-A should use reliable methods of contraception.

Benzyl alcohol, contained as an excipient, can cross the placenta. When prescribing the Roferon^®-A solution immediately before delivery or cesarean section, the toxic effect on premature infants should be considered.

Pregnant women should not use Roferon^®-A in combination with ribavirin. Women of childbearing potential and male partners of women of childbearing potential receiving Roferon^®-A in combination with ribavirin should use reliable methods of contraception (see also the ribavirin prescribing information).

It is not known whether Roferon^®-A is excreted in breast milk. The decision to discontinue breastfeeding or to discontinue the drug should be made based on the importance of treatment for the mother.

Use in Hepatic Impairment

Contraindication: severe hepatic impairment. In mild and moderate hepatic impairment, functional status must be carefully monitored.

Use in Renal Impairment

Contraindication: severe renal impairment. In mild and moderate renal impairment, their functional status must be carefully monitored.

Pediatric Use

Contraindication: children under 3 years of age.

Special Precautions

Roferon^®-A should be prescribed under the supervision of a physician experienced in treating the relevant indications.

Adequate therapy for the underlying disease and complications is possible only if adequate diagnostic and therapeutic capabilities are available.

In mild and moderate impairment of renal, hepatic, or bone marrow function, their functional status must be carefully monitored.

Changes in liver function. Caution should be exercised when treating chronic hepatitis patients with a history of autoimmune diseases with interferon alpha. Every patient who develops abnormal liver function tests during treatment with Roferon^®-A should be carefully monitored and the drug discontinued if necessary. During treatment with interferon alfa, severe liver dysfunction and liver failure have been rarely observed.

Neuropsychiatric changes. Severe psychiatric adverse reactions may manifest in patients receiving interferons, including Roferon^®-A. Depression, suicidal thoughts, and suicide can occur in patients both with and without a history of mental illness. Caution should be exercised when treating with Roferon^®-A in patients with a history of depression. Close monitoring of patients receiving Roferon^®-A for the emergence of depression is recommended. Before starting treatment, patients should be informed about the possibility of developing depression, and patients should immediately report any sign of depression to their doctor; if depression develops, psychiatric consultation and a decision on the advisability of discontinuing therapy are necessary.

Myelosuppression. Roferon^®-A should be used with extreme caution in patients with severe myelosuppression, as interferon alpha suppresses bone marrow, causing a drop in white blood cell count (especially granulocytes), platelet count, and, less commonly, hemoglobin level. This may lead to an increased risk of infection or bleeding. These changes must be carefully monitored, and patients should have complete blood counts performed before starting Roferon^®-A treatment and regularly during its course.

Infections. Fever may be associated with the flu-like syndrome often observed during interferon therapy. In case of persistent fever, especially in patients with neutropenia, infection should be ruled out. During therapy with interferon alfas, including Roferon^®-A, cases of severe infections (bacterial, viral, fungal) have been reported. If severe infectious complications occur, interferon should be discontinued and appropriate therapy instituted.

Ophthalmological changes. As during therapy with other interferons, cases of retinopathy (retinal hemorrhages, cotton wool exudates, optic disc edema, thrombosis of the central retinal artery and vein) and posterior ischemic neuropathy, which may lead to vision loss, have been reported during therapy with Roferon^®-A. If complaints of decreased visual acuity or vision loss occur, these patients should undergo an ophthalmological examination. Patients with diabetes mellitus, arterial hypertension should undergo an ophthalmological examination before initiating therapy to detect fundus pathology. Therapy with Roferon^®-A or Roferon^®-A/ribavirin should be discontinued if ophthalmological diseases worsen or occur.

Hypersensitivity reactions. Serious immediate-type hypersensitivity reactions (urticaria, angioedema, bronchospasm, and anaphylaxis) have been observed during therapy with interferons, including interferon alfa-2a. If such reactions develop during therapy with Roferon^®-A or Roferon^®-A/ribavirin, therapy should be discontinued and appropriate drug therapy immediately instituted. Transient rash does not require discontinuation of therapy.

Changes in endocrine organs. Rarely, hyperglycemia is observed during therapy with Roferon^®-A. If clinical symptoms of hyperglycemia are present, blood glucose monitoring and appropriate observation are necessary. Diabetic patients may require adjustment of the dose of hypoglycemic drugs.

Autoimmune disorders. Cases of formation of various autoantibodies have been reported during therapy with interferon alfas. Clinical manifestations of autoimmune diseases during interferon therapy occur more frequently in patients predisposed to developing such diseases.

Therapy with interferon alfa is rarely associated with the onset or exacerbation of psoriasis. In patients after transplantation (e.g., kidney or bone marrow), drug immunosuppression may be less effective, as interferons have a stimulating effect on the immune system. As with the use of other interferon alfas, cases of transplant rejection have been observed in patients receiving Roferon^®-A.

When conducting combination therapy with ribavirin – see also precautions for ribavirin.

Effect on ability to drive vehicles and operate machinery

Depending on the dosing regimen and individual patient sensitivity, Roferon^®-A may affect reaction speed, impacting the performance of certain operations, such as driving vehicles, working with machines and mechanisms.

Overdose

There are no reports of overdose, however, repeated administration of large doses of interferon may be accompanied by profound lethargy, fatigue, prostration, and coma. Such patients should be hospitalized for observation and appropriate supportive measures.

Drug Interactions

Interferon alfas may impair oxidative metabolic processes, reducing the activity of hepatic microsomal cytochrome P450 enzymes. This should be considered when co-administering drugs that are metabolized by this pathway. Reduced clearance of theophylline after simultaneous administration of interferon alfas has been described.

Interferons may enhance the neurotoxic, hematotoxic, or cardiotoxic effects of drugs administered previously or concurrently. Interactions may be observed after simultaneous administration of centrally acting drugs.

When conducting combination therapy with ribavirin – see also interactions for ribavirin.

Avastin (bevacizumab) does not significantly affect the pharmacokinetics of interferon alfa-2a.

Storage Conditions

The drug should be stored at a temperature of 2-8°C (17.6°F) in a place protected from light and out of reach of children; do not freeze.

Shelf Life

The shelf life is 2 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.