Algeron^® (Solution) Instructions for Use

Marketing Authorization Holder

Biocad, JSC (Russia)

ATC Code

L03AB14 (Cepeginterferon alfa-2b)

Active Substance

Cepeginterferon alfa-2b

Cepeginterferon alfa-2b (Rec.INN registered by WHO)

Dosage Form

Algeron®

Solution for subcutaneous administration 200 mcg/1 ml: syringes 1 ml 1 or 4 pcs.

Dosage Form, Packaging, and Composition

Solution for subcutaneous administration transparent, from colorless to light yellow.

Excipients: sodium acetate trihydrate – 0.115 mg, glacial acetic acid – to pH 5.0, mannitol – 54.47 mg, L-methionine – 0.2 mg, disodium edetate dihydrate – 0.005 mg, water for injection – to 1 ml.

1 ml – three-component syringes made of colorless glass (1) – contour cell packs (1) – cardboard boxes.
1 ml – three-component syringes made of colorless glass (1) – contour cell packs (4) – cardboard boxes.

Clinical-Pharmacological Group

Interferon. An immunomodulatory drug with antiviral action

Pharmacotherapeutic Group

Cytokine

Pharmacological Action

Cepeginterferon alfa-2b is formed by attaching a polymeric structure – polyethylene glycol (PEG) with a molecular weight of 20 kDa – to the interferon alfa-2b molecule. The biological effects of the drug Algeron^® are due to interferon alfa-2b. Interferon alfa-2b is produced by a biosynthetic method using recombinant DNA technology and is produced by a strain of the bacterium Escherichia coli, into which the gene for human interferon alfa-2b has been introduced by genetic engineering methods.

Interferons have antiviral, immunomodulatory and antiproliferative effects. The antiviral effect of interferon alfa-2b is due to its binding to specific cellular receptors, which in turn triggers a complex mechanism of sequential intracellular reactions, including the induction of certain enzymes (protein kinase R, 2′-5′-oligoadenylate synthetase and Mx proteins). As a result, the transcription of the viral genome is suppressed and the synthesis of viral proteins is inhibited. The immunomodulatory effect is manifested primarily by the enhancement of cell-mediated reactions of the immune system. Interferon increases the cytotoxicity of T-lymphocytes and natural killer cells, the phagocytic activity of macrophages, promotes the differentiation of T-helpers, and protects T-cells from apoptosis. The immunomodulatory effect of interferon is also due to its influence on the production of a number of cytokines (interleukins, interferon gamma). All these effects of interferon may mediate its therapeutic activity.

Pegylated interferon alfa drugs cause an increase in the concentration of effector proteins, such as serum neopterin and 2′-5′-oligoadenylate synthetase. When studying the pharmacodynamics of the drug Algeron^® after a single administration to volunteers, a dose-dependent increase in serum neopterin concentration was noted, the maximum increase of which was reached after 48 hours. When the drug Algeron^® was administered once a week at a dose of 1.5 mcg/kg, the serum neopterin concentration in patients with chronic hepatitis C was maintained at a constantly high level.

Just like unmodified interferon alfa-2b, Algeron^® exhibited antiviral activity in in vitro experiments.

Pharmacokinetics

Preclinical experiments have shown that pegylation of the interferon alfa-2b molecule leads to a significant slowdown in absorption from the injection site, an increase in V_d, and a decrease in clearance. The decrease in clearance leads to a more than 10-fold increase in the terminal T_1/2 compared to unmodified interferon alfa-2b (32 hours versus 2.2 hours). The elimination of the drug Algeron^® occurred over >153 hours (6.5 days).

When studying the pharmacokinetics of the drug Algeron^® after a single administration to volunteers at a therapeutic dose of 1.5 mcg/kg in combination with ribavirin, C_max in serum was reached on average after 31 (18-48) hours after administration and was 1401±233 (1250-1803) pg/ml. AUC_{(0-168 h)} was on average 144212±49839 (106845-226062) pg/ml/h. The drug clearance (Cl) averaged 9.9±3.2 (5.2-13) ml/(h×kg), T_1/2 – 57.8±8.4 (48-66.5) h. The value of the elimination constant (K_el) averaged 0.0124±0.002 h^-1.

When the drug Algeron^® was administered subcutaneously once a week as part of combination therapy for chronic hepatitis C, a dose-dependent gradual increase in drug concentration was observed up to week 8, after which no further accumulation was observed up to week 12 of therapy with Algeron^®.

Pharmacokinetics in special patient groups

Patients with impaired renal function. For patients with CC less than 50 ml/min, combination therapy with Algeron^® and ribavirin is contraindicated. Patients with moderate and severe renal failure require careful monitoring and, if adverse reactions occur, the dose of Algeron^® should be reduced.

Patients with impaired liver function. In patients with compensated liver cirrhosis, the pharmacokinetic characteristics are the same as in patients without cirrhosis. Since the use of Algeron^® is contraindicated in mono-infected patients with decompensated liver cirrhosis (Child-Pugh class B and C or bleeding from varicose veins) and in patients with HIV/chronic hepatitis C co-infection with liver cirrhosis with liver failure (Child-Pugh score ≥6), the pharmacokinetics of the drug in such patients has not been studied.

Elderly patients. Pharmacokinetics in patients over 70 years of age has not been studied.

Indications

• Treatment of primary chronic active hepatitis C as part of combination therapy with ribavirin in adult patients with positive HCV RNA, including those with clinically stable human immunodeficiency virus (HIV)/chronic hepatitis C co-infection, in the absence of signs of liver disease decompensation.

ICD codes

Dosage Regimen

The drug Algeron^® is administered subcutaneously, into the area of the anterior abdominal wall or thigh. It is recommended to alternate injection sites.

Therapy should be initiated by a physician experienced in the treatment of patients with hepatitis C and subsequently conducted under his supervision.

For combination therapy with ribavirin, Algeron^® is used in patients with chronic hepatitis C, including those with clinically stable HIV co-infection, as a subcutaneous injection at a dose of 1.5 mcg/kg of body weight once a week. The dosing regimen of the drug Algeron^® is shown in Table 1.

Table 1. Dosing regimen of the drug Algeron^® in patients with chronic hepatitis C, including those with clinically stable HIV co-infection

Each syringe with the drug Algeron^® is intended for single use only. The solution contained in the syringe should not be mixed or administered concurrently with any other drug.

The drug Algeron^® must not be administered intravenously.

Instructions for use for patients

1. Choose a convenient time for the injection. It is advisable to do the injections in the evening before going to bed.
2. Before administering the drug, wash your hands thoroughly with soap and water.
3. Take one contour cell pack with a filled syringe from the cardboard box, which should be stored in the refrigerator, and keep it at room temperature for several minutes so that the temperature of the drug equalizes with the ambient air temperature. If condensation appears on the surface of the syringe, wait a few more minutes until the condensation evaporates.
4. Before use, inspect the solution in the syringe. If there are suspended particles or a change in the color of the solution, or if the syringe is damaged, the drug Algeron^® should not be used. If foam appears, which happens when the syringe is shaken or rocked strongly, wait for the foam to settle.
5. Choose the area of the body for the injection. Algeron^® is injected into the subcutaneous adipose tissue (the fat layer between the skin and muscle tissue), so choose areas with loose tissue away from areas of skin stretching, nerves, joints and blood vessels (Fig. 1 – one of four possible injection areas)

• Thigh (front surface of the thighs except the groin and knee);
• Abdomen (except for the midline and navel area).

Fig. 1. Diagram of injection site locations

Do not choose painful points, discolored, reddened areas of the skin or areas with indurations and nodules for injection.

Each time, choose a new site for the injection, this can reduce discomfort and pain on the area of the skin at the injection site. Within each injection area, there are many points for injection. It is necessary to constantly change the injection points within a specific area.

1. Preparation for injection. Take the prepared syringe in your dominant hand. Remove the protective cap from the needle.
2. The amount of Algeron^® solution that needs to be injected depends on the dose calculated by the doctor. The dose of the drug Algeron^® is expressed in mcg and is calculated taking into account body weight. Do not change the dose of the drug Algeron^® on your own. Do not store the drug remaining in the syringe for reuse.

Depending on the dose prescribed by the doctor, it may be necessary to remove the excess volume of the drug solution from the syringe. If necessary, slowly and carefully press the syringe plunger to remove the excess amount of solution. It is necessary to press the plunger until it reaches the required mark on the syringe surface.

1. After pre-disinfecting the area of skin where the drug Algeron^® will be injected, gently pinch the skin into a fold with your thumb and forefinger (Fig. 2).
2. Holding the syringe perpendicular to the injection site, insert the needle into the skin at a 90° angle (Fig. 3). The drug should be administered by pressing the syringe plunger down evenly until the end (until it is completely empty).

Fig. 2

Fig. 3

1. Remove the syringe with the needle with a vertical upward movement.
2. Used syringes should be discarded only in a specially designated place, inaccessible to children.
3. If the patient forgot to administer the drug Algeron^®, the injection should be made immediately as soon as he remembers it.

Do not administer a double dose of the drug.

Do not stop using the drug Algeron^® without consulting a doctor.

If necessary, it is permissible for patients to store an unopened syringe once in a place protected from light for no more than 30 days at a temperature not exceeding 25°C (77°F). The date of starting storage at room temperature should be marked on the package.

Ribavirin should be taken orally, with meals, daily. The daily dose of ribavirin is calculated depending on body weight (see Table 2).

Table 2. Dosing regimen of ribavirin for combination therapy with the drug Algeron^® in patients with chronic hepatitis C, including those with clinically stable HIV co-infection

Duration of treatment in patients with chronic hepatitis C

The duration of treatment depends on the virus genotype.

HCV genotype 1. The presence of an early virological response (disappearance of HCV RNA or a decrease in viral load by 2 log₁₀ (100 times) or more by week 12 of treatment) may predict the achievement of a sustained response. In the absence of an early virological response, achieving remission is unlikely. In clinical studies of the use of peginterferon alfa in chronic hepatitis C, a sustained response was achieved in only 2% of patients with a negative early response. If an early virological response is achieved, therapy is recommended to be continued for another 9 months (total duration of treatment 48 weeks). Consideration should be given to discontinuing therapy if an early virological response is not achieved after 12 weeks of treatment or if HCV RNA is detectable after 24 weeks of therapy.

HCV genotype 2 and 3. If an early virological response is achieved by week 12 of treatment (disappearance of HCV RNA or a decrease in viral load by 2 log₁₀ (100 times) or more), it is recommended to continue treatment for another 12 weeks (total duration of treatment 24 weeks). Longer therapy has no advantages.

HCV genotype 4. In general, patients with genotype 4 are difficult to treat. The lack of specific studies determines the possibility of using the same treatment tactics as for genotype 1.

Duration of treatment in patients with HIV/chronic hepatitis C co-infection

The recommended duration of treatment is 48 weeks, regardless of the hepatitis C virus genotype.

Dosage regimen adjustment

If adverse events or deviations in laboratory parameters of moderate severity occur, it is necessary to reduce the doses of the drug Algeron^® or ribavirin, or suspend treatment. After normalization of the condition or laboratory parameters, the issue of increasing the dose, up to the initial one, can be considered. If the tolerability of therapy does not improve after dose adjustment, treatment is recommended to be discontinued.

Hematological disorders. If the number of leukocytes in the peripheral blood decreases to less than 1.5×10⁹/L, neutrophils to less than 0.75×10⁹/L, and platelets to less than 50×10⁹/L, it is recommended to reduce the dose of the drug Algeron^® by an amount equal to 1/3 of the therapeutic dose (1/3 TD). If the number of neutrophils and platelets does not increase, it is recommended to reduce the dose of the drug Algeron^® by another 1/3 TD. It is recommended to increase the dose if the number of leukocytes exceeds 2.0×10⁹/L, neutrophils – 1×10⁹/L, and platelets – 90×10⁹/L for at least 4 weeks.

Ribavirin dose adjustment. If hemoglobin decreases to a level of less than 100 g/L, it is recommended to reduce the dose of ribavirin to 600 mg/day. Treatment at the previous dose can be resumed after the hemoglobin level exceeds 100 g/L for at least 4 weeks. If the hemoglobin level decreases to less than 85 g/L, Algeron^® and ribavirin must be discontinued. In patients with cardiovascular diseases (in the compensation phase) with a decrease in hemoglobin by ≥20 g/L during any 4 weeks of treatment, it is recommended to reduce the dose of the drug Algeron^® to half the therapeutic dose and ribavirin to 600 mg/day and constantly use the reduced dose. If the hemoglobin level in patients with cardiovascular diseases (in the compensation phase) is less than 120 g/L after 4 weeks of dose reduction – administration of the drug Algeron^® and ribavirin intake are discontinued.

After discontinuation of ribavirin, with normalization of hemoglobin levels, it is possible to resume treatment at a reduced dose – 600 mg/day, without further dose increase.

Use in special patient groups

Elderly patients

No dose adjustment is required in elderly patients.

Children

The efficacy and safety of the drug Algeron^® in combination with ribavirin in children and adolescents under 18 years of age have not been studied. The drug is contraindicated for use in children under 18 years of age.

Liver function impairment

In compensated liver cirrhosis, no dose adjustment of the drug Algeron^® is required. In decompensated liver cirrhosis (Child-Pugh class B and C or bleeding from varicose veins), the use of the drug is contraindicated. If the concentration of free bilirubin increases to 85.5 µmol/L, it is recommended to reduce the dose of ribavirin to 600 mg/day.

With a progressive increase in ALT or AST activity more than 2 times from the initial value or more than 10 times from the ULN, administration of the drug Algeron^® and ribavirin intake are discontinued. If the concentration of conjugated bilirubin increases more than 2.5 times from the ULN or free bilirubin >68.4 µmol/L for at least 4 weeks with signs of liver function decompensation, Algeron^® and ribavirin must be discontinued.

Renal failure

When prescribing combination therapy for mild renal failure (CC >50 ml/min), caution should be exercised regarding the development of anemia. For CC less than 50 ml/min, combination therapy with the drug Algeron^® and ribavirin is contraindicated. If during therapy the creatinine concentration increases >0.177 mmol/L, Algeron^® and ribavirin must be discontinued.

Patients with depression

For mild depression, no dose adjustment is required. If moderate depression develops, it is recommended to reduce the dose of the drug Algeron^® by 1/3 TD, if required – by another 1/3 TD. If the condition does not change, it is recommended to continue treatment at a reduced dose. If improvement occurs, which is noted for at least 4 weeks, the dose of the drug Algeron^® can be increased. If severe depression develops, as well as suicidal thoughts, it is necessary to discontinue Algeron^® and ribavirin and conduct specific treatment under the supervision of a psychiatrist.

Table 3. Algorithm for dose adjustment of Algeron^® and ribavirin in case of adverse reactions

* In patients with cardiovascular diseases (in the compensation phase) with a decrease in hemoglobin by ≥20 g/L during any 4 weeks of treatment, it is recommended to reduce the dose of Algeron^® to half of the therapeutic dose and ribavirin to 600 mg/day and to consistently use the reduced dose. If the hemoglobin level in patients with cardiovascular diseases (in the compensation phase) is less than 120 g/L after 4 weeks of dose reduction – administration of Algeron^® and ribavirin is discontinued.

** Ribavirin at a dose of 600 mg/day is taken as 1 capsule of 200 mg in the morning and 2 capsules of 200 mg in the evening, with meals.

*** First reduction of the Algeron^® dose by 1/3 of the therapeutic dose (to 1.0 µg/kg/week), second reduction (if necessary) of Algeron^® – further reduction by 1/3 of the therapeutic dose (to 0.5 µg/kg/week).

Adverse Reactions

During combination therapy with Algeron^® at a dose of 1.5 µg/kg/week and ribavirin, adverse reactions were mainly mild or moderate and did not require treatment discontinuation.

Information on undesirable reactions is provided below in accordance with MedDRA terminology.

The following categories were used to describe the frequency of adverse reactions: very common (≥1/10), common (≥1/100; <1/10), uncommon (≥1/1000; <1/100), rare (≥1/10000; <1/1000), very rare (<1/10000).

Table 4. Undesirable reactions observed during the use of Algeron^®

* Decrease in hematological parameters was generally noted in the first 4 weeks of treatment; they improved after dose adjustment within 4-8 weeks. Thrombocytopenia less than 75×10⁹/L was observed in approximately 6% of patients. In most cases, changes in blood parameters could be managed with granulocyte colony-stimulating factor preparations or by dose reduction, so the identified deviations did not lead to premature treatment discontinuation. Ribavirin dose modification due to anemia was required in approximately 7% of patients.

When using Algeron^® at a dose of 2.0 µg/kg/week in combination with ribavirin, in addition to undesirable events observed with Algeron^® at a dose of 1.5 µg/kg/week, the following adverse reactions were also noted

Reproductive system and breast disorders common – menorrhagia.

General disorders and administration site conditions common – injection site cyanosis, injection site petechiae, injection site furuncle.

Adverse effects observed during the use of Algeron^® for the treatment of chronic hepatitis C in HIV-infected patients

Below are the undesirable reactions observed in patients with HIV/chronic hepatitis C co-infection receiving therapy with Algeron^® in combination with ribavirin, which were absent in patients with mono-infection when using Algeron^®.

Table 5. Undesirable reactions observed in patients with HIV/chronic hepatitis C co-infection receiving therapy with Algeron^® in combination with ribavirin, and absent in patients with mono-infection when using Algeron^®

Undesirable reactions from clinical trials and the post-marketing period in adult patients receiving both monotherapy and combination therapy with ribavirin with peginterferon alfa-2b

The most common treatment-related adverse reactions observed in clinical trials with peginterferon alfa-2b in combination with ribavirin in more than half of all patients were fatigue, headache, and injection site reactions. In more than 25%, nausea, chills, insomnia, anemia, pyrexia, myalgia, asthenia, pain, alopecia, anorexia, weight loss, depression, rash, and irritability were observed. Adverse reactions of mild or moderate severity were most frequently reported, which did not require dose reduction or therapy discontinuation. Fatigue, alopecia, pruritus, nausea, anorexia, weight loss, irritability, and insomnia in patients receiving peginterferon alfa-2b monotherapy were observed significantly less frequently compared to patients receiving combination therapy.

The following treatment-related adverse reactions have been reported in clinical trials or in the post-marketing period in adult patients receiving either monotherapy or combination therapy with ribavirin with peginterferon alfa-2b. These reactions are listed in Table 6 by system organ class and frequency: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10000 and <1/1000), very rare (<1/10000), unknown (cannot be estimated from the available data). Within each row, adverse reactions are presented in decreasing order of severity.

Table 6. Adverse reactions reported in clinical trials and the post-marketing period in adult patients receiving both monotherapy and combination therapy with ribavirin with peginterferon alfa-2b

* These adverse reactions were common in patients receiving monotherapy with peginterferon alfa-2b during clinical studies.

Most cases of neutropenia and thrombocytopenia were mild (WHO grade 1 or 2). Several cases of more severe neutropenia were observed in patients receiving recommended doses of peginterferon alfa-2b in combination with ribavirin (WHO grade 3 – 21% (39 out of 186 patients), grade 4 – 7% (13 out of 186)).

In clinical studies, life-threatening psychiatric conditions were reported during treatment in approximately 1.2% of patients receiving interferon alfa-2b or peginterferon alfa-2b in combination with ribavirin. These conditions included suicidal thoughts and suicide attempts.

Adverse reactions from the cardiovascular system, in particular arrhythmia, are most likely associated with pre-existing cardiovascular disease or prior therapy with agents having cardiotoxic effects. Rarely, cardiomyopathy, which could be reversible after discontinuation of interferon alfa therapy, was noted in patients with no history of cardiovascular disease.

Ophthalmological disorders, rarely reported during therapy with interferon alfa, included retinopathies (including optic disc edema), retinal hemorrhage, occlusion of retinal veins or arteries, focal retinal changes, decreased visual acuity or visual field defects, optic neuritis, papilledema.

A wide spectrum of autoimmune and immune-mediated disorders has been reported with the use of alpha interferons, including thyroid disorders, systemic lupus erythematosus, development or worsening of rheumatoid arthritis, idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic purpura, vasculitis, neuropathies (including mononeuropathies and Vogt-Koyanagi-Harada syndrome.

The adverse reactions listed in this section may also be observed with the use of the drug Algeron^®.

Chronic Hepatitis C with HIV Co-infection

In HIV-infected patients with chronic hepatitis C receiving peginterferon alfa-2b in combination with ribavirin in large studies, the following adverse effects were observed with a frequency above 5%, which were absent in patients with mono-infection: oral candidiasis (14%), acquired lipodystrophy (13%), decrease in CD4 cell count (8%), decreased appetite (8%), increased GGT activity (9%), back pain (5%), increased blood amylase activity (6%), increased blood lactic acid concentration (5%), hepatitis with cytolysis (6%), increased lipase activity (6%), and limb pain (6%).

Mitochondrial Toxicity

Cases of mitochondrial toxicity and lactic acidosis have been described in HIV-infected patients with chronic hepatitis C receiving nucleoside reverse transcriptase inhibitors in combination with ribavirin.

Laboratory Parameters

Although neutropenia, thrombocytopenia, and anemia occurred more frequently in HIV-infected patients with chronic hepatitis C, in most cases, hematological changes could be managed by dose reduction, so they rarely led to premature treatment discontinuation. Changes in hematological parameters developed more frequently during treatment with peginterferon alfa-2b in combination with ribavirin than with interferon alfa-2b and ribavirin. In a clinical study, a decrease in absolute neutrophil count <500/mm³ was observed in 4% (8/194) of patients receiving peginterferon alfa-2b and ribavirin, a decrease in platelet count <50,000/mm³ in 4% (8/194), and anemia (hemoglobin <9.4 g/dL) in 12% (23/194).

Decrease in CD4 Lymphocyte Count

Treatment with peginterferon alfa-2b in combination with ribavirin was accompanied by a reversible decrease in the absolute CD4+ cell count during the first 4 weeks without a decrease in the percentage of these cells. The CD4+ cell count increased after dose reduction or therapy discontinuation. Combination therapy with peginterferon alfa-2b and ribavirin did not have a clear negative impact on HIV viremia either during treatment or after its completion. Safety data for treatment in HIV-infected patients with hepatitis C with a CD4+ cell count <200/µl are limited (N=25).

The adverse reactions listed in this section may also be observed with the use of the drug Algeron^® in patients with chronic hepatitis C and HIV co-infection.

Contraindications

• Hypersensitivity to interferon, polyethylene glycol or any other component of the drug;
• Hypersensitivity to ribavirin or any other component of the drug;
• Decompensated liver cirrhosis (Child-Pugh class B and C or bleeding from varicose veins);
• Liver cirrhosis with liver failure in patients with HIV/chronic hepatitis C co-infection (Child-Pugh score ≥6);
• Autoimmune hepatitis or other autoimmune diseases in history;
• Thyroid dysfunction that cannot be maintained at a normal level by drug therapy;
• Epilepsy and/or impaired CNS function;
• Severe cardiovascular diseases, unstable or uncontrolled for at least 6 months prior to treatment;
• Severe kidney diseases (including renal failure, CrCl <50 ml/min, need for hemodialysis);
• Malignant neoplasms;
• Rare hereditary diseases such as lactose intolerance, lactase deficiency or glucose-galactose malabsorption;
• Hemoglobinopathies (e.g., thalassemia, sickle cell anemia);
• Pregnancy;
• Breastfeeding period;
• Therapy in men whose partners are pregnant;
• Childhood and adolescence under 18 years;
• Severe bone marrow suppression (neutrophils <0.5×10⁹/L, platelets <25×10⁹/L, hemoglobin <85 g/L);
• Severe debilitating conditions;
• Concomitant use with telbivudine.

With caution

• Severe lung diseases (e.g., chronic obstructive pulmonary disease);
• Severe mental illnesses, in particular, depression, suicidal thoughts or attempts (including in history);
• Diabetes mellitus with a tendency to develop ketoacidotic coma;
• Disorders associated with the blood coagulation system (e.g., in thrombophlebitis, history of pulmonary embolism);
• Bone marrow suppression (neutrophils <1.5×10⁹/L, platelets <90×10⁹/L, hemoglobin <100 g/L);
• In combination with myelotoxic drugs;
• In patients with HIV/chronic hepatitis C co-infection – CD4+ lymphocyte count less than 200 cells/µl or less than 100 cells/µl with HIV RNA level more than 5000 copies/ml.

Use in Pregnancy and Lactation

Women of reproductive age/contraception in men and women

Special precautions must be taken to prevent pregnancy in women receiving combination therapy with Algeron^® and ribavirin, or in partners of men receiving this therapy. Women of childbearing potential should use a reliable method of contraception during therapy and for 4 months after completion of therapy. Male patients or their partners should use a reliable method of contraception during therapy and for 7 months after its completion.

Pregnancy

The use of the drug Algeron^® during pregnancy is contraindicated.

Teratogenic effects of the drug Algeron^® have not been studied. When treating with Algeron^®, women of childbearing age should use effective contraceptive methods.

The use of interferon alfa-2a in high doses led to a significant increase in the number of spontaneous abortions in animals. No teratogenic effects were noted in offspring born at term.

The combination of Algeron^® with ribavirin is contraindicated for use during pregnancy. In animal studies, ribavirin had pronounced teratogenic effects and caused fetal death. Ribavirin is contraindicated in pregnant women and in men whose partners are pregnant. Ribavirin therapy should not be initiated until a negative pregnancy test result is obtained immediately before starting therapy. Women of childbearing potential or men whose partners are of childbearing potential should be informed about the teratogenic effects of ribavirin and the need for effective contraception (at least 2 methods) during treatment and for 7 months after the end of therapy.

Breastfeeding period

The use of the drug Algeron^® during breastfeeding is contraindicated.

There are no data on the penetration of the drug Algeron^® into breast milk, therefore, to avoid undesirable effects on the child, either breastfeeding or therapy should be discontinued, taking into account the potential benefits for the mother.

Use in Hepatic Impairment

The use of the drug is contraindicated in decompensated liver cirrhosis (Child-Pugh class B and C or bleeding from varicose veins), liver cirrhosis with liver failure in patients with HIV/chronic hepatitis C co-infection (Child-Pugh score ≥6), autoimmune hepatitis.

Use in Renal Impairment

The use of the drug is contraindicated in severe kidney diseases (including renal failure, CrCl <50 ml/min, need for hemodialysis).

Pediatric Use

The use of the drug is contraindicated in patients under 18 years of age.

Geriatric Use

Dose adjustment in elderly people is not required.

Special Precautions

The efficacy and safety of Algeron^® in monotherapy or combination with ribavirin in persons under 18 years of age, as well as in patients after liver or other organ transplantation, have not been established.

Algeron^® should be used with caution in diseases such as COPD or diabetes mellitus with a tendency to develop ketoacidosis. Caution is also necessary in patients with coagulation disorders (e.g., thrombophlebitis, pulmonary embolism) or severe myelosuppression.

Mental sphere and CNS

Serious CNS disorders, especially depression, suicidal thoughts and suicide attempts, were observed in some patients during therapy with interferon alfa drugs, as well as after therapy discontinuation (mainly within 6 months). Other CNS disorders, including aggressive behavior (in some cases directed at other people, e.g., homicidal thoughts), bipolar disorders, mania, confusion and altered mental status, were observed in patients receiving interferon alfa therapy. Patients should be closely monitored for any signs or symptoms of mental disorders. If such symptoms appear, the potential risk should be assessed and the need for drug therapy for these conditions should be considered. If mental disorders persist or worsen, or if suicidal thoughts appear, it is recommended to discontinue therapy with Algeron^® and continue monitoring the patient, providing psychiatric consultation if necessary.

In some patients, usually elderly, receiving high doses of interferon alfa for cancer therapy, impaired consciousness, coma, including cases of encephalopathy, were observed. Although these disorders were generally reversible, in some patients it took up to 3 weeks for complete resolution. Very rarely, epileptic seizures developed in patients receiving high doses of interferon alfa.

Patients with severe mental disorders, including in history

If it is necessary to prescribe Algeron^® to patients with severe mental disorders (including patients with a history of such disorders), treatment can be started only after a thorough individual examination and appropriate therapy for the mental disorder.

Patients using narcotic substances

In patients infected with hepatitis C virus who use alcohol and narcotic substances (marijuana and others), the risk of developing mental disorders (or worsening current ones) increases during interferon alfa therapy. If interferon alfa therapy is necessary in such patients, the presence of concomitant mental illnesses and the risk of substance use should be carefully assessed before starting therapy, and adequate therapy should be provided. If necessary, observation by a psychiatrist or narcologist is indicated for examination, therapy and management of such patients. Close monitoring of such patients during and after completion of interferon therapy is necessary. Timely measures should be taken to prevent relapse or worsening of mental disorders, as well as resumption of drug use.

Cardiovascular system

Patients with heart failure, myocardial infarction and/or arrhythmias (including in history) should be under constant supervision. In patients with heart disease, ECG is recommended before starting and during treatment. Arrhythmias (mainly supraventricular) are generally amenable to conventional therapy but may require discontinuation of Algeron^®. Anemia caused by ribavirin intake may worsen the course of cardiovascular diseases. In case of worsening of cardiovascular diseases, therapy should be interrupted or discontinued.

Hypersensitivity

In rare cases, therapy with peginterferon alfa drugs has been complicated by immediate-type hypersensitivity reactions. If anaphylactic reactions, urticaria, angioedema, bronchospasm occur, the drug should be discontinued and appropriate therapy should be immediately prescribed. Transient rash does not require discontinuation of therapy.

Renal function

It is recommended to examine renal function in all patients before starting therapy with Algeron^®. With CrCl less than 50 ml/min, combination therapy with Algeron^® and ribavirin is contraindicated. If serum creatinine concentration increases >0.177 mmol/L during therapy, administration of Algeron^® and ribavirin intake must be discontinued.

In patients with reduced renal function, as well as those over 50 years of age, when using Algeron^® in combination with ribavirin, their condition should be carefully monitored for the possible development of anemia.

Liver function

If liver failure develops, treatment with Algeron^® and ribavirin is discontinued. Combination therapy with Algeron^® and ribavirin is contraindicated in patients with decompensated liver cirrhosis (Child-Pugh class B and C or bleeding from varicose veins).

Fever

Fever may be observed as part of the flu-like syndrome, which is often reported during treatment with interferons; nevertheless, other causes of persistent fever must be excluded.

Hydration

Adequate hydration of patients is recommended, since arterial hypotension associated with a decrease in fluid volume in the body was observed in some patients during treatment with peginterferon alfa-2b.

Lung diseases

In rare cases, infiltrates of unclear etiology, pneumonitis or pneumonia, including fatal cases, developed in the lungs of patients receiving interferon alfa. If fever, cough, shortness of breath and other respiratory symptoms appear, all patients should undergo chest X-ray. If infiltrates are present on the lung X-ray or signs of impaired lung function, more careful monitoring of patients should be established and, if necessary, Algeron^® should be discontinued. Immediate discontinuation of interferon and administration of corticosteroids lead to the disappearance of pulmonary adverse events.

Autoimmune disorders

During treatment with interferon alfa, the appearance of autoantibodies was noted in individual cases. Clinical manifestations of autoimmune diseases occur more often when treating patients predisposed to the development of autoimmune disorders. If symptoms similar to manifestations of autoimmune diseases appear, a thorough examination of the patient should be conducted and the possibility of continuing interferon therapy should be assessed. Cases of Vogt-Koyanagi-Harada syndrome development have been reported in patients with chronic hepatitis C receiving interferon therapy. This syndrome is a granulomatous inflammatory disease affecting the eyes, hearing organs, meninges and skin. If Vogt-Koyanagi-Harada syndrome is suspected, antiviral therapy should be discontinued and the need for corticosteroid use should be considered.

Psoriasis and sarcoidosis

Due to reports of exacerbation of psoriasis or sarcoidosis in patients receiving interferon alfa therapy, the use of Algeron^® in patients with these diseases is recommended only in cases where the expected benefit of treatment justifies the potential risk. If psoriasis or sarcoidosis exacerbates in patients receiving therapy with Algeron^®, the issue of drug discontinuation should be considered.

Changes in the organ of vision

Disorders of the organ of vision (including retinal hemorrhage, retinal exudates, obstruction of retinal veins or arteries) have been reported in rare cases after interferon alfa therapy. All patients must undergo an ophthalmological examination before starting therapy. Every patient receiving therapy with Algeron^® should undergo an ophthalmological examination in case of complaints of decreased visual acuity or visual field defects. Patients with diseases that can cause retinal changes, such as diabetes mellitus or arterial hypertension, are recommended to undergo regular ophthalmological examination during therapy with Algeron^®. If visual disorders appear or worsen, discontinuation of therapy with Algeron^® should be considered.

Changes in teeth and periodontium

Pathological changes in teeth and periodontal tissues have been noted in patients receiving combination therapy with peginterferon alfa-2b and ribavirin. Dry mouth during long-term therapy may contribute to damage to teeth and oral mucosa. Patients are advised to maintain oral hygiene and have regular dental check-ups.

Thyroid gland condition

The mechanism of the effect of interferon alfa on thyroid function is unknown. In patients with chronic hepatitis C receiving interferon alfa-2b, hypothyroidism or hyperthyroidism developed in 2.8% of cases. These disorders were controlled with standard therapy. Before starting treatment with Algeron^®, serum TSH concentrations should be determined in patients, and if thyroid dysfunction is detected, standard therapy should be prescribed. TSH concentration should also be determined if symptoms of thyroid dysfunction appear during interferon alfa treatment. Treatment with Algeron^® should not be carried out if TSH activity cannot be maintained at a normal level.

Laboratory Tests

Before starting treatment with Algeron^®, standard clinical and biochemical blood tests must be performed. It is also recommended to perform them during therapy every 2 weeks (clinical blood test) and every 4 weeks (biochemical blood test).

Algeron^® can be used with the following laboratory parameters: hemoglobin ≥100 g/L, platelet count >90×10⁹/L, absolute neutrophil count >1.5×10⁹/L, TSH and thyroxine concentrations within normal limits or thyroid function is medically controlled.

Algeron^® should be used with caution with the following laboratory parameter values: absolute neutrophil count <1.5×10⁹/L, platelet count <90×10⁹/L, hemoglobin <100 g/L.

The use of Algeron^® is contraindicated with the following laboratory parameter values: absolute neutrophil count <0.5×10⁹/L, platelet count <25×10⁹/L, hemoglobin <85 g/L.

In cases of severe hypertriglyceridemia, before adjusting the dose of Algeron^®, diet or drug therapy should be prescribed taking into account the fasting serum triglyceride concentration. Hypertriglyceridemia resolves rapidly after drug discontinuation.

Alpha interferon therapy may be accompanied by the development of ulcerative and hemorrhagic and/or ischemic colitis within 12 weeks of starting therapy. Abdominal pain, blood in the stool, and fever are typical symptoms of colitis manifestation. If corresponding complaints appear, Algeron^® must be immediately discontinued. Recovery usually occurs within 1-3 weeks after drug discontinuation.

Cases of pancreatitis, sometimes fatal, have been observed during treatment with peginterferon alfa-2a in combination with ribavirin. If symptoms of pancreatitis develop, therapy with Algeron^® and ribavirin should be discontinued.

Serious infectious complications (bacterial, viral, fungal), sometimes fatal, have been described with the use of alpha interferon drugs. Some of them were accompanied by the development of neutropenia. If severe infectious complications occur, therapy should be discontinued and appropriate treatment initiated.

HIV/Chronic Hepatitis C Co-infection

Before starting treatment, one should carefully familiarize themselves with the possible side effects of the antiretroviral drugs the patient will be taking concomitantly with the drugs for chronic hepatitis C therapy. In patients simultaneously receiving stavudine and interferon with or without ribavirin, the incidence of pancreatitis and/or lactic acidosis was 3%.

Patients with HIV/chronic hepatitis C co-infection on HAART may be at risk for developing lactic acidosis. Therefore, caution should be exercised when adding Algeron^® and ribavirin to HAART (see the ribavirin prescribing information).

Concomitant use of ribavirin and zidovudine is not recommended due to an increased risk of anemia. Careful monitoring for signs and symptoms of hepatic decompensation (including ascites, encephalopathy, variceal bleeding, impaired liver synthetic function; a score of ≥7 on the Child-Pugh scale) is necessary in patients with co-infection. The Child-Pugh score does not always reliably reflect the presence of hepatic decompensation and may be influenced by factors such as elevated blood indirect (free) bilirubin concentration, hypoalbuminemia due to drug therapy. If hepatic decompensation develops, therapy with Algeron^® should be immediately discontinued.

Caution should be exercised when prescribing Algeron^® to patients with a low CD4+ lymphocyte count. There is insufficient data on the efficacy and safety of pegylated interferon alpha drugs in patients with HIV/chronic hepatitis C co-infection with a CD4+ lymphocyte count of less than 200 cells/μL.

Organ Transplantation

The efficacy and safety of Algeron^® (in combination with ribavirin or as monotherapy) for the treatment of hepatitis C in organ transplant recipients have not been studied. Preliminary data suggest that alpha interferon therapy may increase the risk of kidney transplant rejection. Liver transplant rejection has also been reported.

Effect on Ability to Drive and Use Machines

During treatment, weakness, dizziness, drowsiness, and confusion may occur. If these phenomena occur, one should refrain from driving a car or operating machinery.

Overdose

In clinical studies of Algeron^®, when using a dose of 2 mcg/kg compared to the recommended 1.5 mcg/kg, dose adjustments were more frequently required due to dose-dependent adverse events.

Treatment There is no specific antidote. In case of overdose, symptomatic treatment and careful monitoring of the patient’s condition are recommended.

Drug Interactions

Drug interactions have been studied only in adult patients.

Telbivudine

A clinical study investigating the combined use of telbivudine (600 mg daily) with peginterferon alfa-2a (180 mcg subcutaneously, once weekly) showed that the use of this combination is associated with an increased risk of peripheral neuropathy. The mechanism of this phenomenon is unknown. Furthermore, the safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B have not been confirmed. Concomitant use of Algeron^® and telbivudine is contraindicated.

Methadone

In patients with chronic hepatitis C receiving stable maintenance methadone therapy and not treated with peginterferon alfa-2b, therapy with pegylated interferon alfa-2b subcutaneously at a dose of 1.5 mcg/kg per week for 4 weeks increased the AUC of R-methadone by approximately 15% (95% CI AUC: 103-128%). The clinical significance of this change is unknown; however, these patients should be monitored for signs and symptoms of increased sedation and respiratory depression. In patients receiving high-dose methadone, the risk of QT interval prolongation should be carefully assessed.

Effect of Peginterferon Alfa-2b on Co-administered Drugs

The potential interaction of peginterferon alfa-2b with substrates of metabolic enzymes was studied in multiple-dose administration in three clinical pharmacology studies. These studies examined the effect of peginterferon alfa-2b upon its multiple administration in patients with hepatitis C at a dose of 1.5 mcg/kg per week or in healthy patients at a dose of 1 mcg/kg per week or 3 mcg/kg per week (see Table 7).

No clinically significant pharmacokinetic interaction was identified between peginterferon alfa-2b and tolbutamide, midazolam, and dapsone; thus, dose adjustment is not required when peginterferon alfa-2b is co-administered with drugs metabolized via CYP2C9 or CYP3A4 isoenzymes and N-acetyltransferase.

Co-administration of peginterferon alfa-2b with caffeine and desipramine slightly increases the exposure to caffeine and desipramine.

It is unlikely that the decrease in cytochrome P450 activity is clinically significant when peginterferon alfa-2b drugs are co-administered with drugs metabolized via CYP1A2 and CYP2D6 isoenzymes, except for drugs with a narrow therapeutic window (see Table 8).

Table 7. Effect of Peginterferon Alfa-2b on Co-administered Drugs

N – number of patients;

* Calculated based on urine assay data obtained at 48-hour intervals.

** Calculated based on urine assay data obtained at 24-hour intervals.

Table 8. Precautions for Co-administration ( Algeron^® should be used with caution when co-administered with the drugs listed below)

Chronic Hepatitis C in HIV-Infected Patients

Nucleoside Analogues

The use of nucleoside analogues alone or in combination with other nucleosides has led to the development of lactic acidosis. In vitro, ribavirin caused increased levels of phosphorylated metabolites of purine nucleosides. This effect may contribute to an increased risk of lactic acidosis induced by purine nucleoside analogues (e.g., didanosine or abacavir). Concomitant use of ribavirin and didanosine is not recommended. Mitochondrial toxicity, particularly lactic acidosis and pancreatitis, has been reported, in some cases fatal (see the ribavirin prescribing information).

Worsening of anemia associated with ribavirin intake was observed during HIV therapy with zidovudine, although the exact mechanism of this effect has not been studied. Concomitant use of ribavirin and zidovudine is not recommended, as it leads to an increased risk of anemia. Consideration should be given to replacing zidovudine in the combined antiretroviral therapy if it is already being used. This is especially important in patients with a history of zidovudine-associated anemia.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature between 2°C (35.6°F) and 8°C (46.4°F). Do not freeze.

Shelf Life

Shelf life – 2 years. Do not use after the expiration date stated 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.