Roferon-A, 3000000 me 0.5 ml syringe-tube

Clinical efficacy

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

Roferon-A is effective in treating patients with Ph-positive chronic myeloleukemia (CML). Roferon-A leads to hematological remission in 60% of patients in the chronic stage of CML, regardless of previous therapy. Complete hematologic remission is still maintained 18 months after the start of treatment in two-thirds of the patients studied. In contrast to 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 in treating thrombocytosis in CML and other myeloproliferative diseases. Roferon-A reduces the number of platelets in a few days, reduces the incidence of concomitant thrombohemorrhagic complications and has no leukemicogenic potential.

In patients with low-grade non-Hodgkin’s lymphoma, when administered in addition to chemotherapy (with or without radiation therapy), Roferon-A prolongs recurrence-free survival and progression-free survival.

In patients with advanced renal cell carcinoma, the best therapeutic effect was seen with high doses of Roferon-A (36 million IU daily) as monotherapy or moderate doses of Roferon-A (18 million IU 3 times weekly) in combination with vinblastine, compared with monotherapy with moderate doses of Roferon-A 3 times weekly. In patients who received monotherapy with small doses of Roferon-A (2 million IU/m2 per day), there was no effect of treatment. The combination of Roferon-A with vinblastine leads to only a slight increase in the incidence of mild to moderate leukopenia and granulocytopenia compared to monotherapy.

The duration of response and survival with Roferon-A monotherapy and Roferon-A + vinblastine combination therapy are similar. Roferon-A in combination with vinblastine is more effective with respect to survival compared to chemotherapy alone.In patients with advanced malignant melanoma, treatment with Roferon-A resulted in objective regression of tumors of cutaneous and visceral localization. Also Roferon-A increases the time without recurrence of the disease in patients without lymph node involvement and distant metastases after resection of melanoma (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 to a combination of Roferon-A and placebo significantly increases progression-free survival (PFS) and objective response rates.

Lowering the dose of interferon alfa-2a from 9 million IU to 6 or 3 million IU 3 times weekly when used in combination with Avastin did not reduce the effectiveness of combination therapy according to measures of event-free survival (see also the Avastin Instructions for Use).

Roferon-A is effective for the treatment of patients with confirmed compensated (no signs of hepatic decompensation) hepatitis B and C.

Roferon-A is effective in the treatment of patients with acute condyloma.

Interferon alpha-2a is a highly purified protein containing 165 amino acids with a molecular weight of approximately 19000 daltons. It is produced using a medium-engineered DNA technology using a genetically engineered strain of E.coli, whose DNA encodes the synthesis of this human protein.

Roferon-A has an antiviral effect by inducing resistance to viral infections in cells and modulating the response of the immune system to neutralize viruses or destroy cells infected by them. Roferon-A has an antiproliferative effect on a number of human tumors in vitro and suppresses the growth of some human tumor xenografts in bestimus nude mutant mice.

Pharmacokinetics

Absorption

After p/k or i/m administration, bioavailability exceeds 80%. After subcutaneous administration of a 36 million IU dose, serum Cmax (1250 to 2320 pg/mL (mean, 1730 pg/mL)) was reached, on average, after 7.3 h. After an intravenous dose of 36 million IU, serum Cmax (1500-2580 pg/mL (mean, 2020 pg/mL)) was reached, on average, after 3.8 hr.

Distribution

In humans, the pharmacokinetics of Roferon-A at doses of 3 million to 198 million IU are linear. After an intravenous infusion of 36 million IU in healthy volunteers, Vd at equilibrium ranged from 0.22 to 0.75 L/kg (mean, 0.40 L/kg). Both healthy volunteers and patients with disseminated cancer showed large individual variations in serum interferon alfa-2a concentrations.

Metabolism and excretion

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

Hepatic metabolism and excretion with bile represent less significant routes of elimination. In healthy subjects, the T1/2 of interferon alfa-2a after an intravenous infusion of 36 million IU is 3.7-8.5 h (mean, 5.1 h) and total clearance is 2.14-3.62 ml/min/kg (mean, 2.79 ml/min/kg).

Pharmacokinetics in special groups of patients

After a single intra-oral injection of interferon alfa-2a in patients with disseminated cancer and chronic hepatitis B, pharmacokinetic parameters are similar to those in healthy volunteers. There is a dose-dependent increase in serum concentrations of interferon alfa-2a after a single administration of doses up to 198 million IU. Distribution or excretion of interferon alfa-2a when administered 2 times per day (0.5-36 million IU), ! once per day (1-54 million IU) or 3 times per week (1-136 million IU) for up to 28 days does not change.

In some patients with disseminated cancer, administration of interferon alfa-2a once or several times daily for up to 28 days resulted in a 2-4-fold increase in serum Cmax compared to those after a single injection. However, multiple administration, according to any of the dosing regimens studied to date, did not alter the distribution or excretion parameters of the drug.

Indications

Hepatitis, HPV

Novoplasms of the lymphatic system and the hematopoietic system:

• Hairy cell leukemia;
• Myeloma disease;
• Skin T-cell lymphoma;
• Ph-positive chronic myeloleukemia;
• Thrombocytosis in myeloproliferative diseases;
• Nehodgkins lymphoma of low grade malignancy.

Solid tumors:

• Caposi sarcoma in AIDS patients without a history of opportunistic infections;
• chronic active hepatitis B, hepatitis C;
Metastasizing melanoma;
• Melanoma after surgical resection (tumor thickness greater than 1.
• Chronic active hepatitis B in adults with markers of viral replication (positive for HBV-DNA, DNA polymerase, HBeAg) and elevated ALT activity.
• Cerdominal condylomas

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Active ingredient

Interferon alpha-2a

Composition

1 syringe-tube with 0.5 ml (one dose) contains interferon alfa-2a,

free human serum albumin (Roferon-A RBA, or “solution without albumin”) – 3 million IU.

How to take, the dosage

Roferon-A should be given subcutaneously or intramuscularly. Subcutaneous administration is especially recommended for patients with thrombocytopenia (platelet count less than 50,000/μL) or those at risk of bleeding.

Hair cell leukemia.
Initial dose: 3 million IU daily for 16-24 weeks. In case of intolerance the daily dose is reduced to 1.5 million IU and/or the number of injections is reduced to three times a week.

The maintenance dose: 3 million IU 3 times a week. In case of intolerance it is 1.5 million IU 3 times a week.
Duration of treatment: for 6 months, after which if there is a positive effect it is continued, and if there is no effect it is abolished. Treatment was carried out up to 20 months in a row. The optimal duration of therapy with Roferon-A for hairy cell leukemia has not been established.

Myeloma disease.
By 3 million IU 3 times a week. Depending on individual tolerance, the dose may be increased weekly until the maximum tolerated dose (9-18 million IU) 3 times per week is reached.

The treatment on this regimen can be continued indefinitely unless the disease progresses or an intolerance to the drug develops.

Cutaneous T-cell lymphoma (CTCL).
Roferon-A may have an effect in patients with advanced cutaneous T-cell lymphoma, including those refractory to or unsuitable for conventional therapy.

The initial dose: in patients starting at 18 years of age, Roferon-A should be given by injection or intramuscularly for 12 weeks, gradually increasing daily dose to 18 million IU. It is recommended to increase the dose according to the following scheme: Day 1-3 – 3 million IU/day, Day 4-6 – 9 million IU/day, Day 7-84 – 18 million IU/day.

The maintenance dose: by injection or intramuscularly 3 times a week at the maximum dose tolerated by the patient, but not exceeding 18 million IU.

The duration of treatment: patients should take the drug for at least 8 weeks, preferably 12 weeks, after which if there is positive effect the therapy should be continued; if there is no effect the therapy should be discontinued. Treatment was carried out up to 40 months in a row. The optimal duration of treatment with Roferon-A for CTCL has not been established.

Patients who respond positively to treatment should continue it for at least 12 months to maximize the likelihood of achieving complete remission and increase the likelihood of long-term remission.
Caution:In approximately 40% of patients with CTCL no objective anti-tumor effect can be achieved. Partial remission is usually seen within 3 months of treatment and complete remission within 6 months, but sometimes it takes 12 months of therapy to achieve the best effect.

Cronic myeloleukemia (CML).

Roferon-A is indicated to treat patients in the chronic stage of chronic myeloleukemia who are Philadelphia chromosome positive. Whether it cures the disease remains to be seen.

Roferon-A leads to hematologic remission in 60% of patients with chronic stage CML, regardless of prior therapy. In 2/3 of these patients, complete hematologic remission is still maintained 18 months after the start of treatment.

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

Dosing recommendations: In patients 18 years of age or older, Roferon-A should be administered p/k or i.m. for 8 to 12 weeks. The following scheme of gradual dose increase is recommended: 1-3 days – 3 million IU/day, 4-6 days – 6 million IU/day, 7-84 days – 9 million IU/day. Duration of treatment: Patients should receive the drug for at least 8 weeks, preferably – 12 weeks, after which, if there is a positive effect, therapy should be continued (until complete hematological remission is achieved, but not longer than 18 months).

All patients with complete hematological remission should continue treatment with 9 million IU daily (optimal dose) or 9 million IU 3 times per week (minimum dose), to achieve cytogenetic remission as soon as possible. The optimal duration of treatment for chronic myeloleukemia has not been established, but there are observations of cytogenetic remissions lasting 2 years after initiation of treatment.

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

Thrombocytosis associated with myeloproliferative diseases.
Thrombocytosis often accompanies chronic myeloleukemia and is a major sign of essential thrombocytopenia. Clinically, severe thrombocytosis is manifested by a high frequency of severe thrombotic diathesis.

Roferon-A reduces the number of platelets within a few days, reduces the incidence of associated thrombohemorrhagic complications and has no leukosogenic potential. Therefore it is recommended to use non-leukosogenic therapy with Roferon-A when treating patients with excessive thrombocytosis in chronic myeloleukemia and other myeloproliferative diseases.

In case of thrombocytosis in chronic myeloleukemia the following scheme of dose increase is recommended: 1-3 days – 3 million IU/day, 4-6 days – 6 million IU/day, 7-84 days – 9 million IU/day. The therapy duration is 8 weeks, preferably not less than 12 weeks. If there is a positive effect the therapy is continued, in case of absence of dynamics of hematologic indices the therapy is stopped.

In case of thrombocytosis in myeloproliferative diseases (except chronic myeloleukosis) the following scheme of the dose increase is recommended: 1-3 days – 3 million IU/day, 4-30 days – 6 million IU/day.

Treatment duration: For platelet count maintenance within normal limits a well tolerated dose of 1-3 million IU 2-3 times a week is usually sufficient. The maximum tolerated doses are chosen individually for each patient.

Non-Hodgkin’s lymphoma of low-grade malignancy.

When given in addition to chemotherapy (with or without radiation therapy), Roferon-A prolongs recurrence-free survival and progression-free survival.

Dosing recommendations: as maintenance therapy after standard chemotherapy (with or without radiation therapy) p/k in a dose of 3 million IU 3 times a week for 12 months. Treatment with Roferon-A should be started as soon as possible when the patient’s condition improves (usually 4-6 weeks after chemotherapy and radiation therapy).

Roferon-A may also be administered simultaneously with traditional chemotherapy regimens (for example, with a combination of cyclophosphamide, prednisolone, vincristine and doxorubicin), p/k or i/m, 6 million IU/m2 on days 22 to 26 of each 28-day cycle. In this case, treatment with Roferon-A is started simultaneously with chemotherapy.

Kaposi’s sarcoma with AIDS.

The optimal dosing regimen for Roferon-A has not been established.

HIV patients with Kaposi’s sarcoma with AIDS are more likely to respond favorably to therapy if they have no history of opportunistic infections, no history of group B symptoms (weight loss greater than 10%, fever > 38°C with no known site of infection, night sweats), and a baseline T4-lymphocyte count greater than 200 cells/μL.

The initial dose: Patients 18 years of age and older should be given by p/k or intramuscularly for 10-12 weeks, gradually increasing the daily dose to at least 18 million IU, and if possible, to 36 million IU. It is recommended to increase the dose according to the following scheme: Day 1-3 – 3 million IU/day, Day 4-6 – 9 million IU/day, Day 7-9 – 18 million IU/day; if tolerated, increase the dose on Day 10-84 to 36 million IU/day.

Maintenance dose: per/month or by injection in the maximum dose tolerated by the patient, but not more than 36 million IU 3 times a week.
Frequency of remission in patients with Kaposi sarcoma with AIDS who received Roferon-A in a daily dose of 3 million IU was less than with administration of the recommended doses.

Treatment duration: Tumor progression should be documented to determine response to treatment. Patients should receive the drug for at least 10 weeks, preferably 12 weeks, after which therapy is continued if there is a positive effect, and discontinued if there is no effect. Usually, the effect begins to show after 3 months of treatment. Treatment was carried out for up to 20 months in a row. The optimal duration of treatment with Roferon-A for Kaposi sarcoma against the background of AIDS has not been established. If there is a clinical effect, treatment should be continued until the tumor disappears.

Note: Kaposi’s sarcoma often relapses after stopping therapy with Roferon-A.

That is, advanced renal cell cancer.
In patients with tumor recurrence or metastases, the best therapeutic effect was seen with high-dose Roferon-A (36 million IU/day) as monotherapy or moderate-dose Roferon-A (18 million IU 3 times weekly) in combination with vinblastine, compared with monotherapy with moderate-dose Roferon-A 3 times weekly. In patients who received low-dose Roferon-A (2 million IU/m2/day), no treatment effect was observed.

The combination of Roferon-A with vinblastine leads to a slight increase in the incidence of mild to moderate leukopenia and granulocytopenia compared to monotherapy.

Monotherapy with Roferon-A.
Initial dose: p/k or intram for 8-2 weeks, gradually increasing the daily dose to 18 million IU, and if possible, to 36 million IU. A dose of 36 million IU is recommended by injection/m. Gradual dose increase is recommended according to the following scheme: (p/u or i/m) 1-3 days – 3 million IU/day, 4-6 days – 9 million IU/day, 7-9 days – 18 million IU/day, if tolerated the dose is increased on day 10-84 to 36 million IU/day.
Maintenance dose: maximum dose, but no more than 36 million IU 3 times a week.

Treatment duration: Patients should take the preparation for at least 8 weeks, preferably 12 weeks, after which in case of positive effect the therapy should be continued, in case of absence of positive effect the therapy should be discontinued. Treatment was carried out up to 16 months in a row. The optimal duration of treatment of neglected renal cell carcinoma has not been established.

The combination therapy with Roferon-A and vinblastine.
Combination therapy gives an overall remission rate of about 20%, slows disease progression and prolongs overall survival of patients with advanced kidney cancer.

Dosing: Roferon-A (w/v/m) – in 1 week – 3 million IU 3 times a week, in 2 weeks – 9 million IU 3 times a week, then – 18 million IU 3 times a week.

For this period, vinblastine should be administered by IV, according to the manufacturer’s instructions, at a dose of 0.1 mg/kg of body weight once every 3 weeks. If the patient cannot tolerate the 18 million IU dose, it can be reduced to 9 million IU 3 times a week.

The duration of treatment is 3-12 months or until disease progression begins. If complete remission occurs, treatment may be discontinued 3 months after onset.

Melanoma.
In 10-25% of patients with advanced malignant melanoma treatment with Roferon-A resulted in objective regression of tumors of cutaneous and visceral localization. When doses of less than 18 million IU 3 times a week were used, the therapeutic effect was observed less frequently. Patients who responded to treatment had a longer survival time than those who did not respond.

The starting dose: 18 million IU by p/k or IU/m 3 times a week for 8-12 weeks.

The maintenance dose: 18 million IU (or maximum tolerated dose) p/k or i.m. 3 times a week.

The duration of treatment: patients should take the preparation for at least 8 weeks, preferably – at least 12 weeks, after which in case of positive effect the therapy should be continued; if there is no effect the therapy should be discontinued. Treatment was carried out for up to 17 months in a row. The optimal duration of treatment of advanced melanoma has not been established.

Melanoma after surgical operation.
Adjuvant therapy with low doses of Roferon-A increases the duration of time without relapse of the disease in patients without lymph node affection and distant metastases after resection of melanoma (tumor thickness >1,5 mm).
Dose: p/cm or i.m. 3 mln IU 3 times a week.
Duration of treatment – 18 months, and the treatment should be begun not later than 6 weeks after the operation.

Chronic viral hepatitis B.
The optimal dosing regimen has not yet been established. Usually it is prescribed (by injection or intramuscularly) by 4,5 mln IU 3 times per week during 6 months.
If the content of markers of viral replication or HBe-antigen after a month of treatment didn’t decrease, the dose can be increased. Further dose adjustment is carried out depending on the tolerability of the drug. If there is no improvement after 3-4 months the therapy should be discontinued. In children with chronic hepatitis B the administration of Roferon-A in dose up to 10 mln IU/m2 is safe, but efficacy of this therapy is not proved. Efficacy of Roferon-A in patients with chronic hepatitis B concurrently infected with human immunodeficiency virus (HIV) has not been proved.

Chronic viral hepatitis C.
Combined therapy with Roferon-A and ribavirin
Efficacy of interferon alfa-2a is increased if administered in combination with ribavirin.

Roferon-A and ribavirin combination therapy for relapse in adult patients in whom prior interferon-alpha monotherapy had a temporary effect.

The dosing regimen for Roferon-A: (p/u or i/m) 4.5 million IU 3 times a week for 6 months.

Ribavirin dosing regimen: 1000-1200 mg/day in 2 intakes (during breakfast and supper) – see ribavirin administration instructions.
Combined therapy of Roferon-A and ribavirin in previously untreated patients with chronic hepatitis C

Rosing regimen of Roferon-A: (p/u or i/m) 3-4.5 million IU 3 times weekly during 6 months (at least).

Ribavirin dosing regimen: See above. If there is no HCV RNA after 6 months of therapy and the patient was infected with genotype I virus and had a high viral load before treatment, treatment should be continued for another 6 months. Other negative prognostic factors (age over 40 years, male gender, bridging fibrosis) should also be considered when deciding whether to continue treatment for up to 12 months. If virological remission (HCV RNA below the detection limit) is not achieved after the first 6 months of therapy, then further stable virological remission (HCV RNA below the detection limit in 6 months after drug withdrawal) is unlikely.
Monotherapy with Roferon-A

Used if ribavirin is intolerant or there are contraindications for it.

The starting dose: (p/u or i/m) 6 million IU 3 times a week for 3 months.

The maintenance dose: to consolidate complete remission in patients with normalized serum ALT levels, 3 million IU 3 times a week for another 3-9 months. If after 3 months of treatment serum ALT level has not normalized, the treatment should be stopped.

Note. Most cases of disease relapse after adequate therapy occur no later than 4 months after the end of treatment.

Acute condylomas
P/k or i/m 1-3 million IU 3 times a week for 1-2 months.

Interaction

Interferon alpha can disrupt oxidative metabolic processes by reducing the activity of hepatic microsomal enzymes of cytochrome P450 systems. This should be considered when concomitant administration of drugs that are metabolized by this pathway.
Decreased clearance of theophylline after concomitant administration of alpha-interferons has been described.

Interferons may increase the neurotoxic, hematotoxic or cardiotoxic effects of drugs previously or concomitantly prescribed.

Interferons may interact after administration of centrally acting drugs.

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Special Instructions

Roferon-A should be prescribed under the supervision of a physician experienced in the treatment of appropriate indications.

The proper therapy of the underlying disease and complications is only possible if adequate diagnostic and therapeutic options are available.

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

Changes in liver function. A change in transaminase activity in hepatitis B usually indicates an improvement in the clinical condition of the patient. Caution should be used when treating patients with chronic hepatitis with autoimmune diseases in anamnesis with interferon-alpha. Any patient who under treatment with Roferon-A shows abnormal changes of liver function tests should be closely monitored and if necessary the drug should be discontinued.

Psychoneurological changes. In patients receiving interferons, including Roferon-A, severe psychiatric adverse reactions may manifest. Depression, suicidal thoughts and suicide can occur in patients with or without a history of mental illness. Caution should be exercised during therapy with Roferon-A in patients with a history of depression. Close monitoring of patients receiving Roferon-A is recommended in order to detect depression. Patients should be informed about the possibility of depression before treatment begins, and patients should immediately inform their physician about any sign of depression; if depression develops, a consultation with a psychiatrist is necessary to decide whether therapy should be discontinued.

Myelosuppression. It is necessary to use Roferon-A with extreme caution in patients with severe myelosuppression, because the drug suppresses the bone marrow, causing a decrease of the number of leukocytes (especially granulocytes), platelet count and, rarely, hemoglobin level. This can lead to an increased risk of infection or bleeding. These changes should be monitored closely and patients should undergo detailed blood tests before and regularly during treatment with Roferon-A.

Infections. Fever may be associated with a flu-like syndrome, which is often seen with interferon therapy. In persistent fever, especially in patients with neutropenia, infection (bacterial, viral, fungal) should be excluded. If severe infectious complications occur, interferon should be withdrawn and appropriate therapy should be prescribed.

Ophthalmologic changes. As during therapy with other interferons, during therapy with Roferon-A cases of retinopathy (retinal hemorrhages, cotton exudates, optic disc edema, central retinal artery and vein thrombosis) and posterior ischemic neuropathy have been reported, which may lead to loss of vision. These patients should have an ophthalmologic examination if they complain of worsening visual acuity or vision loss. Patients with diabetes mellitus, arterial hypertension should undergo ophthalmologic examination to detect ocular fundus pathology before the therapy is prescribed. Therapy with Roferon-A or Roferon-A/ribavirin should be discontinued if ophthalmologic conditions worsen or arise.

Hypersensitivity reactions. During therapy with interferons, including interferon alfa-2a, serious reactions of immediate hypersensitivity (urticaria, angioneurotic edema, bronchospasm and anaphylaxis) are observed. In case of such reactions during therapy with Roferon-A or Roferon-A/ribavirin, the therapy should be cancelled and an appropriate drug therapy should be prescribed immediately. Transient rash does not require withdrawal of therapy.

Endocrine changes. Rarely during therapy with Roferon-A hyperglycemia is observed. In the presence of clinical symptomatology of hyperglycemia, blood glucose level control and appropriate monitoring are necessary. Patients with diabetes mellitus may require adjustment of the dose of antidiabetic drugs.

Autoimmune disorders. During therapy with interferon alpha, cases of formation of various autoantibodies have been registered. Clinical manifestations of autoimmune diseases during interferon therapy more often occur in patients predisposed to the development of these diseases.

Interferon alpha therapy is rarely associated with the occurrence or exacerbation of psoriasis. In patients after transplantation (e.g., kidney or bone marrow), medication-assisted immunosuppression may be less effective because interferons have a stimulating effect on the immune system.

There is no evidence of a direct cardiotoxic effect of the drug, but it is possible that the acute, self-limited toxic effects (e.g., fever, chills) that often accompany treatment with Roferon-A may exacerbate existing cardiac disease.

Preferon-A should not be used in newborns, especially premature infants and children younger than 3 years of age because it contains benzyl alcohol as a preservative, which has been reported to cause permanent neuropsychiatric disorders and multiple organ failure.

When combining therapy with ribavirin – see also “Precautions” for ribavirin.

Preclinical study. Rhesus macaques administered doses of the drug significantly higher than those recommended for the clinic observed transient menstrual irregularities, including prolongation of the menstrual period.

Manual Instructions for Use

The 18 million IU multi-dose cartridges in 0.6 ml are for single patient use only. They are only used in the Roferon-Pen syringe pen. Only Penfine needles must be used with the syringe pen and cartridge. A new sterile needle must be used for each injection. Roferon-A cartridges must be used within 30 days of the first injection. After each injection, the syringe pen with the inserted cartridge should be stored in a refrigerator, protected from light, but if necessary, the syringe pen with the cartridge can be stored at room temperature (up to 25 °C) for up to 28 days.

The date of the first cartridge use should be noted on the sticker supplied with the cartridge and placed on the syringe pen box. Detailed instructions for use of Roferon-Pen are included in the package.

Impact on the ability to drive vehicles and operate machines. Depending on the dosing regimen and individual sensitivity of the patient, Roferon-A may have an effect on reaction rate, affecting the performance of certain operations, such as driving vehicles, working with machines and mechanisms.

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Contraindications

• Severe heart disease (including history);
• Severe renal dysfunction;
• Severe liver dysfunction;
• Serious myeloid hematopoiesis disorders;
• Convulsive disorders and/or CNS dysfunction;
• Chronic hepatitis in patients receiving or recently receiving immunosuppressant therapy, except for short-term steroid treatment;
• Cronic hepatitis in patients receiving or recently receiving immunosuppressant therapyPatients with chronic myeloleukemia if the patient has an HLA-identical relative and has or may have an allogeneic bone marrow transplant in the near future;
• High sensitivity to recombinant interferon alfa-2a or any other component of the drug;
• Children under 3 years of age (because the drug contains benzyl alcohol as a preservative);
• If combined therapy with ribavirin is necessary, contraindications for ribavirin should be considered.

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Side effects

The data below are based on the experience of patients with a wide variety of malignant diseases, often refractory to previous treatment and in advanced stages, as well as patients with chronic hepatitis B and C.

The majority of cancer patients received doses significantly higher than currently recommended. This may explain the higher frequency and severity of adverse reactions in this group of patients compared to hepatitis B patients in whom adverse reactions were usually transient, so that patients returned to baseline condition 1-2 weeks after starting treatment. Increased hair loss may continue for several weeks.

General symptoms: often a flu-like syndrome (lethargy, fever, chills, loss of appetite, muscle and headaches, joint pain, sweating). These phenomena usually decrease or are eliminated by simultaneous administration of paracetamol, and their severity tends to decrease during treatment or by changing the dose of Roferon-A, though somnolence, weakness and lethargy may occur if therapy is continued.

Gastrointestinal organs: often in 2/3 of cancer patients – anorexia, in half – nausea. Quite often – vomiting, change in taste sensation, dry mouth, weight loss, diarrhea, mild to moderate abdominal pain. Rarely – constipation, flatulence, increased peristalsis and heartburn, aggravation of peptic ulcer disease, gastrointestinal bleeding, not life-threatening.

Changes in liver function: sometimes – increased levels of ALT, alkaline phosphatase, LDH, bilirubin (usually do not require dose adjustment). Rarely – changes of transaminase activity in hepatitis B (this indicates improvement of the clinical condition of the patient).
Very rarely – severe liver function impairment, liver failure.

CNS disorders: sometimes – systemic and non-systemic dizziness, visual disturbances, mental deterioration, forgetfulness, depression, drowsiness, confusion, behavior disorders (anxiety, nervousness) and sleep disorders. Rarely, severe somnolence, seizures, coma, impaired cerebral circulation, temporary impotence and ischemic retinopathy, and suicide attempts (in the latter case, the drug should be stopped).

Peripheral nervous system disorders: sometimes – paresthesias, numbness of extremities, neuropathy, itching and tremor.

Cardiovascular and respiratory system disorders: quite often – about 1/5 of cancer patients – transient arterial hypo- and hypertension, edema, cyanosis, arrhythmias, palpitations, chest pain. Rarely – cough, pulmonary edema, pneumonia, minor dyspnea, congestive heart failure, cardiac arrest, respiratory arrest, myocardial infarction. In patients with hepatitis B, cardiovascular abnormalities are rare.

Urogenital system disorders: rarely – deterioration of renal function, acute renal failure (especially in cancer patients with a history of renal disease or with concomitant treatment with nephrotoxic drugs), electrolyte disorders (especially with anorexia or dehydration), proteinuria, increased content of cellular elements in urine sediment, increased levels of urea nitrogen in blood, and creatinine and uric acid in serum.

Hematopoietic system: quite often – transient leukopenia (rarely requiring dose reduction), in patients in myelosuppressed state – thrombocytopenia, decreased hemoglobin levels. Sometimes – thrombocytopenia in patients without myelosuppression. Rarely – decrease in hemoglobin and hematocrit levels. The return of severe hematological disorders to the initial level was usually observed in 7-10 days after discontinuation of treatment with Roferon-A.

Skin disorders: quite often (in 1/5 of patients) – mild to moderate hair loss, reversible after discontinuation of treatment. Rarely – exacerbation of herpetic rashes on the lips, rash, itching, dry skin and mucous membranes, nasal discharge and nasal bleeding, exacerbation or manifestation of psoriasis.

Other: rarely – hyperglycemia, reaction at the injection site, autoimmune pathology (vasculitis, arthritis, hemolytic anemia, thyroid disorders, lupus-like syndrome). Very rarely – asymptomatic hypocalcemia.

In rhesus macaques administered doses significantly higher than those recommended for the clinic, transient menstrual disorders, including prolongation of the menstrual period, were observed. The significance of these findings in humans has not been established.

Antibodies to interferon: In some patients, neutralizing antibodies to the active protein may form after administration of drugs containing the homologous protein. Therefore, it is likely that antibodies to all interferons – both natural and recombinant – may be found in a certain proportion of patients.

In some diseases (cancer, systemic lupus erythematosus, shingles) antibodies to human leukocyte interferon may occur spontaneously in patients who have never received interferon before.

In an experiment in mice, the relative immunogenicity of lyophilized Roferon-A increased over time if the drug was stored at 25 °C. In clinical studies in which lyophilized Roferon-A stored at 25 °C was used, neutralizing antibodies to Roferon-A were detected in about 1/5 of patients. There is no indication that in any of the clinical indications the presence of such antibodies would adversely affect the patient’s response to the drug.

There is no increase in immunogenicity when lyophilized Roferon-A is stored at 4°C (recommended storage conditions).

In combination therapy with ribavirin, see also ribavirin side effects.

Overdose

There are no reports of overdose, but repeated administration of large doses of interferon may be accompanied by profound lethargy, lethargy, prostration and coma.

These patients should be hospitalized for observation and appropriate supportive measures.

Pregnancy use

Men and women receiving Roferon-A should use reliable contraceptive methods.

Pregnancy is possible if the expected effect of therapy exceeds the potential risk to the fetus. The question of stopping breastfeeding or cancelling the drug should be decided according to the importance of the treatment for the mother.

Benzyl alcohol may also pass through the placenta. If Roferon-A is prescribed just before labor or cesarean section, it should be remembered about its toxic effect on premature infants.

In case of combination therapy with ribavirin – see also precautions for ribavirin.