PegAltevir (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Pharmapark, LLC (Russia)

Manufactured By

Pharmstandard-UfaVITA OJSC (Russia)

ATC Code

L03AB10 (Peginterferon alfa-2b)

Active Substance

Peginterferon alfa-2b

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

Dosage Forms

	PegAltevir	Lyophilisate for preparation of solution for subcutaneous administration 50 mcg: vial in a kit with solvent
		Lyophilisate for preparation of solution for subcutaneous administration 80 mcg: vial in a kit with solvent
		Lyophilisate for preparation of solution for subcutaneous administration 100 mcg: vial in a kit with solvent
		Lyophilisate for preparation of solution for subcutaneous administration 120 mcg: vial in a kit with solvent
		Lyophilisate for preparation of solution for subcutaneous administration 150 mcg: vial in a kit with solvent

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for s/c administration white or almost white in color; solvent – a transparent, colorless liquid without odor or taste.

Excipients: sodium hydrogen phosphate (calculated as anhydrous substance) – 0.75 mg, sodium dihydrogen phosphate dihydrate (calculated as anhydrous substance) – 0.75 mg, sucrose – 40 mg, polysorbate 80 – 0.05 mg, water for injections – up to 0.5 ml (per dose).

Solvent water for injections – 0.7 ml*.
* – the solvent is added in an excess amount to compensate for losses during dissolution of the lyophilisate and administration of the prepared solution.

100 mcg – glass vials (1) in a kit with solvent 0.7 ml amp. 1 pc. – contour cell packaging (1) – cardboard packs.

Lyophilisate for preparation of solution for s/c administration white or almost white in color; solvent – a transparent, colorless liquid without odor or taste.

Excipients: sodium hydrogen phosphate (calculated as anhydrous substance) – 0.75 mg, sodium dihydrogen phosphate dihydrate (calculated as anhydrous substance) – 0.75 mg, sucrose – 40 mg, polysorbate 80 – 0.05 mg, water for injections – up to 0.5 ml (per dose).

Solvent water for injections – 0.7 ml*.
* – the solvent is added in an excess amount to compensate for losses during dissolution of the lyophilisate and administration of the prepared solution.

120 mcg – glass vials (1) in a kit with solvent 0.7 ml amp. 1 pc. – contour cell packaging (1) – cardboard packs.

Lyophilisate for preparation of solution for s/c administration white or almost white in color; solvent – a transparent, colorless liquid without odor or taste.

Excipients: sodium hydrogen phosphate (calculated as anhydrous substance) – 0.75 mg, sodium dihydrogen phosphate dihydrate (calculated as anhydrous substance) – 0.75 mg, sucrose – 40 mg, polysorbate 80 – 0.05 mg, water for injections – up to 0.5 ml (per dose).

Solvent water for injections – 0.7 ml*.
* – the solvent is added in an excess amount to compensate for losses during dissolution of the lyophilisate and administration of the prepared solution.

150 mcg – glass vials (1) in a kit with solvent 0.7 ml amp. 1 pc. – contour cell packaging (1) – cardboard packs.

Lyophilisate for preparation of solution for s/c administration white or almost white in color; solvent – a transparent, colorless liquid without odor or taste.

Excipients: sodium hydrogen phosphate (calculated as anhydrous substance) – 0.75 mg, sodium dihydrogen phosphate dihydrate (calculated as anhydrous substance) – 0.75 mg, sucrose – 40 mg, polysorbate 80 – 0.05 mg, water for injections – up to 0.5 ml (per dose).

Solvent water for injections – 0.7 ml*.
* – the solvent is added in an excess amount to compensate for losses during dissolution of the lyophilisate and administration of the prepared solution.

50 mcg – glass vials (1) in a kit with solvent 0.7 ml amp. 1 pc. – contour cell packaging (1) – cardboard packs.

Lyophilisate for preparation of solution for s/c administration white or almost white in color; solvent – a transparent, colorless liquid without odor or taste.

Excipients: sodium hydrogen phosphate (calculated as anhydrous substance) – 0.75 mg, sodium dihydrogen phosphate dihydrate (calculated as anhydrous substance) – 0.75 mg, sucrose – 40 mg, polysorbate 80 – 0.05 mg, water for injections – up to 0.5 ml (per dose).

Solvent water for injections – 0.7 ml*.
* – the solvent is added in an excess amount to compensate for losses during dissolution of the lyophilisate and administration of the prepared solution.

80 mcg – glass vials (1) in a kit with solvent 0.7 ml amp. 1 pc. – contour cell packaging (1) – cardboard packs.

Clinical-Pharmacological Group

Interferon. An immunomodulatory drug with antiviral action

Pharmacotherapeutic Group

Immunostimulants; interferons

Pharmacological Action

PegAltevir is a preparation of pegylated interferon alfa-2b, which is obtained by covalent conjugation of recombinant interferon alfa-2b and monomethoxypolyethylene glycol.

The biological activity of PegAltevir is due to interferon alfa-2b. Recombinant interferon alfa-2b is obtained from an Escherichia coli clone that contains a gene-engineered plasmid hybrid encoding human leukocyte interferon alfa-2b. Interferon alfa-2b has antiviral, immunomodulatory, and antiproliferative actions. The antiviral action is due to binding to specific receptors on the cell surface and initiating a sequence of intracellular reactions, including the induction of certain enzymes (protein kinase R, 2′-5′ oligoadenylate synthetase, Mx proteins). This leads to suppression of viral genome transcription and inhibition of viral protein synthesis. The immunomodulatory action is associated with increased cytotoxicity of T-lymphocytes and natural killer cells and the phagocytic activity of macrophages. Furthermore, interferon alfa-2b promotes the differentiation of T-helpers, protects T-cells from apoptosis, and influences the production of a number of cytokines (interleukins, interferon gamma). All these effects may mediate the therapeutic activity of interferon. The pharmacodynamics of PegAltevir were studied based on the blood concentration of the effector protein neopterin, which is a marker of human cellular immunity activation. After a single subcutaneous administration of PegAltevir and PegIntron to healthy volunteers at a dose of 1.5 mcg/kg body weight, a comparable dynamics of neopterin concentration in the blood was noted, with C_max reached after 48 hours.

In preclinical comparative studies of biological activity in relevant animal groups, comparable results were obtained for PegAltevir and PegIntron preparations.

Pharmacokinetics

Pegylation of the interferon alfa-2b molecule leads to an increase in the volume of distribution and a decrease in clearance. The decrease in clearance leads to a more than 10-fold increase in T_1/2 compared to unmodified interferon alfa-2b.

The pharmacokinetics of PegAltevir were studied in comparison with PegIntron. In preclinical studies, no statistically significant differences were identified. With a single subcutaneous administration at a dose of 1.5 mcg/kg to healthy volunteers, the main pharmacokinetic parameters were comparable. C_max of peginterferon alfa-2b after a single subcutaneous administration of PegAltevir was reached, on average, after 16.5 hours and was approximately 579 ng/ml. The volume of distribution (Vd) was, on average, 2.84 L/kg. T_1/2 was, on average, 26.9 hours; the elimination constant (K_el) – 0.03 hours^-1; clearance (Cl) (rate of blood clearance of peginterferon alfa-2b), on average, 90.43 ml/h/kg.

Pharmacokinetics in patients with impaired renal function

Renal clearance accounts for 30% of the total clearance of peginterferon alfa-2b. According to a study with a single administration (1.0 mcg/kg) in patients with renal failure, an increase in C_max, AUC, T_1/2 proportional to the degree of renal failure is noted. With multiple administrations (1.0 mcg/kg subcutaneously once a week for four weeks), the clearance of peginterferon alfa-2b decreases on average by 17% in moderate renal failure (creatinine clearance 30-49 ml/min) and on average by 44% – in severe renal failure (creatinine clearance 15-29 ml/min), compared to patients with unchanged renal function. In patients with severe renal failure, hemodialysis does not affect the clearance of peginterferon alfa-2b. In this regard, in patients with moderate and severe renal failure, the dose of PegAltevir, when prescribed as monotherapy, should be reduced.

With creatinine clearance < 50 ml/min, combination therapy with PegAltevir and ribavirin is contraindicated. Due to individual variability in interferon pharmacokinetics, patients with severe renal failure receiving PegAltevir should be under careful observation.

Pharmacokinetics in patients with impaired liver function

The pharmacokinetics of peginterferon alfa-2b in patients with severe liver impairment have not been studied.

Pharmacokinetics in elderly people

The pharmacokinetics of peginterferon alfa-2b do not depend on age, therefore a change in the dose of PegAltevir in elderly people is not required. Pharmacokinetics in patients older than 70 years have not been studied.

Pharmacokinetics in children

In children and adolescents receiving Peginterferon alfa-2b at a dose of 60 mcg/m²/week, the logarithmically transformed exposure ratio during the dosing interval is expected to be 58% (90% confidence interval: 141-177%) higher than in adults receiving Peginterferon alfa-2b at a dose of 1.5 mcg/kg/week.

Neutralizing antibodies to interferon

Neutralizing antibodies to interferon were analyzed in serum samples from patients who received PegAltevir in a clinical study. These antibodies neutralize the antiviral activity of interferon. The frequency of detection of neutralizing antibodies in patients receiving PegAltevir at a dose of 1.5 mcg/kg was 1.9%.

Indications

Adults (triple therapy)

• Treatment of chronic hepatitis C, genotype 1, with PegAltevir in combination with ribavirin and an NS3/4A protease inhibitor in adult patients with compensated liver disease, previously untreated or with unsuccessful prior antiviral therapy experience.

Adults (dual therapy and monotherapy)

• Treatment of chronic hepatitis C with PegAltevir in adult patients, seropositive for hepatitis C virus RNA, including patients with compensated liver cirrhosis and/or in combination with clinically stable HIV infection.
• Treatment of chronic hepatitis C with PegAltevir in combination with ribavirin in adult patients, previously untreated, including patients with concomitant clinically stable HIV infection, and in adult patients who previously had unsuccessful antiviral therapy experience with a combination of interferon alfa (pegylated or non-pegylated) with ribavirin or interferon alfa monotherapy.
• Monotherapy with PegAltevir for chronic hepatitis C is indicated only in case of intolerance or presence of contraindications for the administration of ribavirin.

Children (dual therapy)

• Treatment of chronic hepatitis C with PegAltevir in combination with ribavirin in children aged 3 years and older, previously untreated, with compensated liver disease and seropositive for hepatitis C virus RNA.
• If a decision is made not to postpone treatment until adulthood, it is necessary to take into account that combination therapy may cause growth retardation. The reversibility of growth retardation is not known. The decision to prescribe treatment should be made individually.

ICD codes

Dosage Regimen

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

PegAltevir is prescribed as a subcutaneous injection once a week. The dose of the drug in adults depends on whether it is prescribed as part of combination therapy (dual or triple) or monotherapy.

Combination therapy with PegAltevir (dual or triple)

Dual therapy (PegAltevir with ribavirin) is prescribed to adult patients and children 3 years and older.

Triple therapy (PegAltevir with ribavirin and an NS3/4A protease inhibitor) is prescribed to adult patients infected with hepatitis C virus, genotype 1.

Dosage regimen in adults

In combination therapy with ribavirin, PegAltevir is prescribed as a subcutaneous injection at a dose of 1.5 mcg per 1 kg of body weight once a week. It is recommended to alternate injection sites. Ribavirin should be taken orally daily. Ribavirin intake should be combined with food intake. The daily dose of ribavirin in combination therapy is calculated depending on body weight. In combination therapy, one can be guided by the combined table for dosing PegAltevir and ribavirin:

* In patients with body weight > 120 kg, the dose of PegAltevir is calculated based on body weight.

Monotherapy with PegAltevir in patients with HCV/HIV co-infection has not been studied.

Duration of treatment

In patients who have a virological response at 12 weeks, treatment should be continued for another 3 months (total course duration – 6 months). Extension of therapy up to 1 year (48 weeks) may be based on prognostic factors (virus genotype, age > 40 years, male sex, presence of bridging fibrosis).

Dose adjustment in all patients (monotherapy and combination therapy)

If serious adverse events or deviations in laboratory parameters occur during monotherapy or combination therapy including PegAltevir, adjustment of the dose of PegAltevir and/or ribavirin is required until the adverse events cease. Dose reduction of the NS3/4A protease inhibitor is not recommended. The NS3/4A inhibitor should not be prescribed without PegAltevir and ribavirin. Since the doses of PegAltevir and ribavirin affect the treatment outcome, they should, as far as possible, remain close to the recommended standard doses.

Notes

¹In adults, the first reduction in the ribavirin dose is by 200 mg/day (in those receiving 1400 mg – by 400 mg/day). If necessary, the second reduction in the ribavirin dose is by another 200 mg/day. Patients whose ribavirin dose is reduced to 600 mg/day should receive one capsule/tablet of the drug (200 mg) in the morning and two capsules/tablets (200 mg) in the evening.

In children and adolescents, the first reduction in the ribavirin dose is to 12 mg/kg/day, the second reduction in the ribavirin dose is to 8 mg/kg/day.

In adults, the first dose reduction of PegAltevir is to 1.0 µg/kg/week. If necessary, the second dose reduction of PegAltevir is to 0.5 µg/kg/week.

In children and adolescents, the first dose reduction of PegAltevir is to 40 µg/m²/week, the second dose reduction of PegAltevir is to 20 µg/m²/week.

* – upper limit of normal.

** – Alanine aminotransferase / Aspartate aminotransferase.

Dose reduction of PegAltevir in adults can be achieved by decreasing the volume of the administered solution or by using a preparation with a lower dosage. In children and adolescents – by adjusting the recommended dose in two stages: from the starting dose of 60 µg/m²/week to 40 µg/m²/week, then, if necessary, to 20 µg/m²/week.

Recommendations for two-stage dose reduction of PegAltevir in combination therapy in adults

Recommendations for dose reduction of PegAltevir in monotherapy in adults

In adults receiving PegAltevir monotherapy at a dose of 0.5 µg/kg, dose reduction can be achieved by halving the volume of the administered drug solution.

* In patients with body weight > 120 kg, the dose of PegAltevir is calculated based on body weight. This may require a combination of different volumes and doses of the drug.

In adults receiving PegAltevir monotherapy at a dose of 1.0 µg/kg, dose reduction can be achieved by halving the volume of the administered drug solution or by reducing its concentration.

* In patients with body weight > 120 kg, the dose of PegAltevir is calculated based on body weight. This may require a combination of different volumes and doses of the drug.

Special patient populations

Dosage adjustment in renal impairment

Monotherapy

PegAltevir should be used with caution in patients with moderate and severe renal impairment. In patients with moderate renal impairment (creatinine clearance 30-50 ml/min), the initial dose of PegAltevir should be reduced by 25%. In patients with severe renal impairment (creatinine clearance 15-29 ml/min), including patients on hemodialysis, the initial dose of PegAltevir should be reduced by 50%. There are no data on the use of pegylated interferon alfa-2b in patients with creatinine clearance < 15 ml/min. Patients with moderate and severe renal impairment, including those on hemodialysis, should be closely monitored. If renal function deteriorates during treatment, therapy with PegAltevir should be discontinued.

Combination therapy

In patients with creatinine clearance < 50 ml/min, the use of PegAltevir in combination with ribavirin is contraindicated. When prescribing combination therapy to patients with renal impairment, careful monitoring for the development of anemia should be carried out.

Hepatic impairment

The safety and efficacy of treatment with PegAltevir in patients with severe hepatic impairment have not been studied, therefore PegAltevir should not be used in such patients.

Elderly patients (65 years and older)

No age-dependent pharmacokinetics of peginterferon alfa-2b have been identified. Data from pharmacokinetic studies in elderly individuals after a single subcutaneous administration of peginterferon alfa-2b indicate that no dose adjustment based on age is required. The pharmacokinetics of peginterferon alfa-2b have not been studied in patients over 70 years of age.

Children

PegAltevir in combination with ribavirin can be prescribed to children aged 3 years and older.

Instructions for preparation of the injection solution

The PegAltevir lyophilisate should be reconstituted only with the supplied solvent. PegAltevir should not be mixed with other medicinal products. Using a sterile syringe, 0.7 ml of water for injections is introduced into the vial with PegAltevir. The vial is gently swirled until the powder is completely dissolved. The dissolution time should not exceed 10 minutes; usually the powder dissolves faster. The required dose is drawn into a sterile syringe. Up to 0.5 ml of the solution is used for administration. Like any other parenteral preparations, the prepared solution should be inspected before administration. The solution should be clear, colorless, and free of visible particles. If the color changes or visible particles appear, the solution should not be used.

Adverse Reactions

Adults

Triple therapy

It is necessary to read the instructions for medical use of the NS3/4A protease inhibitor.

Dual therapy and monotherapy

General safety profile

The most frequent (based on clinical studies in more than half of the patients) adverse reactions of combination therapy with peginterferon alfa-2b and ribavirin were asthenia, headache, and injection site reaction. Nausea, chills, insomnia, anemia, pyrexia, myalgia, asthenia, pain, alopecia, anorexia, weight decreased, depression, rash, and irritability were observed in more than 25% of cases. As a rule, adverse reactions were mild or moderate in severity, were well controlled and did not require dose reduction or discontinuation of therapy. Asthenia, alopecia, pruritus, nausea, anorexia, weight decreased, irritability, and insomnia occurred less frequently with peginterferon alfa-2b monotherapy than with combination therapy.

Adverse reactions

The adverse reactions listed below, noted with the use of peginterferon alfa-2b, are listed according to system organ classes and frequency, in accordance with the following gradation: very common – ≥ 1/10, common – ≥ 1/100 and < 1/10, uncommon – ≥ 1/1000 and < 1/100, rare – ≥ 1/10000 and < 1/1000, very rare – < 1/10,000, frequency not known (cannot be estimated from the available data). Within each frequency group, adverse reactions are presented in order of decreasing clinical significance.

* Adverse reactions that were common (≥ 1/100 and < 1/10) with peginterferon alfa-2b monotherapy.

Description of selected adverse reactions in adults

In most cases, neutropenia and thrombocytopenia are moderate (Grade 1 or 2 (WHO)). Several cases of more severe neutropenia have been described in patients receiving recommended doses of peginterferon alfa-2b and ribavirin.

Approximately 1.2% of patients receiving Peginterferon alfa-2b or interferon alfa-2b in combination with ribavirin experienced life-threatening psychiatric disorders, such as suicidal ideation and suicide attempts.

Cardiovascular system adverse effects, in particular arrhythmia, are most likely associated with pre-existing cardiovascular disease and previous therapy with cardiotoxic agents. Rarely, cardiomyopathy has been observed in patients with no history of cardiovascular disease, which may be reversible after discontinuation of interferon alfa therapy.

Ophthalmological disorders, including retinopathy (including macular oedema), retinal haemorrhage, retinal artery or vein occlusion, retinal exudates, reduced visual acuity or visual field defects, optic neuritis, and papilloedema, have been rarely observed during treatment with peginterferon alfa-2b.

A large number of autoimmune and immune disorders have been reported during treatment with peginterferon alfa-2b, including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new onset or exacerbation), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies, including mononeuropathies and Vogt-Koyanagi-Harada syndrome.

According to a clinical study, the spectrum of adverse events recorded during therapy with PegAltevir and ribavirin did not differ from therapy with PegIntron and ribavirin, as well as from literature data.

Combination therapy of chronic hepatitis C with ribavirin in HIV-infected patients

General safety profile

Adverse reactions

In HIV-infected patients with chronic hepatitis C receiving Peginterferon alfa-2b in combination with ribavirin, the following adverse events with a frequency above 5%, which were absent in patients with mono-infection, were observed: oral candidiasis (14%), acquired lipodystrophy (13%), CD4 lymphocytes decreased (8%), decreased appetite (8%), gamma-glutamyltransferase increased (9%), back pain (5%), blood amylase increased (6%), blood lactic acid increased (5%), hepatitis with cytolysis (6%), lipase increased (6%), and pain in extremity (6%).

Description of Selected Adverse Reactions

Mitochondrial Toxicity

Cases of mitochondrial toxicity and lactic acidosis have been described in HIV-infected patients with chronic hepatitis C who received 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, blood abnormalities could be managed by dose reduction in most cases and therefore rarely led to premature treatment discontinuation. Blood abnormalities developed more frequently during treatment with peginterferon alfa-2b in combination with ribavirin than during treatment with interferon alfa-2b and ribavirin.

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, which was not associated with 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 effect on HIV RNA levels either during treatment or after its completion. Safety data for the treatment of HIV-infected patients with hepatitis C with a CD4+ cell count < 200/µl are limited.

When prescribing antiviral therapy for chronic hepatitis C in patients infected with HIV, it is necessary to read the instructions for medical use of the corresponding antiretroviral drugs.

Combination Therapy of Chronic Hepatitis C with Ribavirin in Children and Adolescents

General Safety Profile

During combination therapy with peginterferon alfa and ribavirin in children and adolescents, dose adjustment is required in 25% of cases. The main reasons are anemia, neutropenia, and weight loss. In general, the adverse reaction profile in children and adolescents is similar to that in adults, except for growth suppression specific to children.

The most common adverse reactions are pyrexia (80%), headache (62%), neutropenia (33%), asthenia (30%), anorexia (29%), and injection site erythema (29%). Adverse reactions are generally mild or moderate in severity.

Adverse Reactions

The adverse reactions listed below, noted during the use of the drug peginterferon alfa-2b, are listed according to system organ classes and frequency, according to the following gradation: very common – ≥ 1/10, common – ≥ 1/100 and < 1/10, uncommon – ≥ 1/1000 and < 1/100, rare – ≥ 1/10000 and < 1/1000, very rare – < 1/10,000, frequency not known (cannot be estimated from the available data). Within each frequency group, adverse reactions are listed in order of decreasing clinical significance.

Description of selected adverse reactions in children and adolescents

Laboratory parameter deviations are mostly mild or moderate in nature. Decreased hemoglobin, white blood cell, platelet, and neutrophil counts, and increased bilirubin levels may require dose reduction or therapy discontinuation (See “Dosage and Administration”). Changes in laboratory parameters detected in a clinical study in patients receiving ribavirin and Peginterferon alfa-2b returned to baseline within a few weeks after the end of therapy.

Contraindications

• Hypersensitivity to interferon or any component of the drug;
• History of severe cardiovascular disease, including disease with unstable or uncontrolled course within the last 6 months;
• Patients with severe debilitating diseases;
• Autoimmune hepatitis or other autoimmune disease in history;
• Severe hepatic impairment or decompensated liver cirrhosis;
• Thyroid dysfunction that cannot be maintained at a normal level by drug therapy;
• Epilepsy and/or central nervous system dysfunction;
• Liver cirrhosis with hepatic failure (Child-Pugh score ≥6) in patients with HCV/HIV co-infection;
• Concomitant use of the drug PegAltevir with telbivudine;
• Severe mental illness or severe mental disorders, including in history, in particular severe depression, suicidal thoughts or suicide attempts in pediatric patients;
• Breastfeeding period;
• Children under 18 years of age (triple therapy, monotherapy);
• Children under 3 years of age (dual therapy);
• Pregnancy, including pregnancy in the female partner of a male patient for whom treatment with PegAltevir is planned (monotherapy, dual or triple therapy);
• Rare hereditary diseases — fructose intolerance, glucose-galactose malabsorption, sucrase-isomaltase deficiency (due to the presence of sucrose in the drug composition);
• Renal impairment – creatinine clearance less than 50 ml/min (when used in combination with ribavirin).

When prescribing the drug PegAltevir in combination with ribavirin and an NS3/4A protease inhibitor, it is necessary to read the instructions for medical use of these drugs.

With caution

• Women of reproductive potential;
• Male partners of women of reproductive potential;
• Children over 3 years of age and adolescents (dual therapy);
• Patients with moderate and severe renal failure (in case of monotherapy);
• HIV-infected patients;
• Patients receiving drugs metabolized by cytochrome P450 isoenzymes CYP2D6 and CYP2C8/9, especially drugs with a narrow therapeutic window;
• Patients receiving methadone;
• Adult patients with mental disorders;
• Patients abusing alcohol, marijuana or other substances;
• Patients with compensated cardiovascular diseases;
• Patients predisposed to autoimmune disorders;
• Patients with eye diseases;
• Patients with compensated thyroid diseases;
• Patients with metabolic disorders;
• Patients who have undergone organ transplantation;
• Patients with psoriasis;
• Patients with sarcoidosis;
• Patients driving a car or operating machinery.

Use in Pregnancy and Lactation

Women of reproductive potential/Contraception in men and women

The drug PegAltevir may be prescribed to women of reproductive potential only if effective contraception is used during treatment.

Combination therapy with ribavirin

In female patients or female partners of male patients receiving the drug PegAltevir in combination with ribavirin, special precautions must be taken to prevent pregnancy. Women of reproductive potential should use effective methods of contraception throughout the treatment period and for 4 months after its completion. Male patients or their female partners should use effective methods of contraception throughout the treatment period and for 7 months after its completion.

Pregnancy

Data on the use of interferon alfa-2b in pregnant women are insufficient. Its reproductive toxicity has been demonstrated in animals. An abortifacient effect was shown in primates. Most likely, the drug PegAltevir has the same effect. The potential risk to humans is unknown. The use of the drug PegAltevir during pregnancy is contraindicated.

Combination therapy with ribavirin

Ribavirin causes serious birth defects when administered during pregnancy. Thus, the prescription of ribavirin is contraindicated in pregnant women.

Breastfeeding

It is not known whether the components of peginterferon alfa-2b are excreted in breast milk. Due to the potential risk of adverse reactions in breastfed infants, breastfeeding should be discontinued before starting therapy.

Fertility

There is no information on the effect of peginterferon alfa-2b on fertility in men and women.

Use in Hepatic Impairment

Use with caution in patients with moderate and severe renal failure (in case of monotherapy);

Use in Renal Impairment

The use of the drug is contraindicated in patients with severe hepatic impairment or decompensated liver cirrhosis, liver cirrhosis with hepatic failure (Child-Pugh score ≥6) in patients with HCV/HIV co-infection.

Pediatric Use

The drug is contraindicated in children under 18 years of age (triple therapy, monotherapy).
The drug is contraindicated in children under 3 years of age (dual therapy).

Special Precautions

Mental sphere and central nervous system (CNS).

Some patients may experience severe CNS disorders during therapy with the drug peginterferon alfa-2b and for up to 6 months after its discontinuation, in particular depression, suicidal thoughts and suicide attempts. Other CNS disorders may also occur, including aggressive behavior (sometimes homicidal thoughts), bipolar disorder, mania, confusion, and altered consciousness. Patients should be carefully monitored for symptoms of mental disorders. If these adverse reactions develop, due to their potential severity, the need for therapeutic correction should be assessed. If mental symptoms persist or worsen, or suicidal intentions appear, treatment with PegAltevir should be discontinued and a timely psychiatric consultation should be provided.

Patients with severe mental disorders, including in history.

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

Children and adolescents with current or history of severe mental disorders should not be prescribed ribavirin in combination with peginterferon alfa-2b. During combination therapy with interferon alfa-2b in children and adolescents, a higher frequency of suicidal thoughts and suicide attempts was observed than in adults, both during treatment and in the subsequent 6 months. Also, as in adults, children and adolescents may experience other psychiatric adverse reactions (such as depression, emotional lability, somnolence).

Patients abusing various substances

Patients infected with hepatitis C virus who abuse substances (alcohol, marijuana or other substances) have an increased risk of developing and/or exacerbating mental disorders during interferon alfa therapy. If interferon therapy is necessary for such patients, a thorough examination for the presence of mental disorders and abuse of other substances is indicated before starting treatment, as well as careful monitoring during treatment and after its completion. In case of primary or recurrent development of mental disorders and substance abuse, early intervention is recommended to prevent the recurrence or development of mental disorders and drug use.

Growth and development (children and adolescents)

Combination therapy causes growth delay, the reversibility of which is unclear. The benefit-risk assessment should be carried out in each case individually, taking into account data on disease progression (especially the degree of fibrosis), the presence of concomitant diseases (for example, HIV co-infection), as well as predictors of virological response (virus genotype and viral load). Whenever possible, children should receive treatment after the pubertal growth spurt. There are no data on the long-term effect on puberty.

More frequent cases of confusion and coma, including cases of encephalopathy, may be noted in some patients, usually elderly, taking high doses of interferon alfa for oncological indications. While these effects are mostly reversible, it may take up to 3 weeks for full recovery. Very rarely, seizures may occur against the background of high doses of interferon alfa.

Immediate-type hypersensitivity

In rare cases, therapy with interferon alfa-2b has been complicated by immediate-type hypersensitivity reactions (urticaria, angioedema, bronchospasm, anaphylaxis). If such reactions occur, the drug PegAltevir should be discontinued and adequate symptomatic therapy should be immediately prescribed. Transient rash does not require treatment discontinuation.

Cardiovascular system

During treatment with the drug PegAltevir, 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 the drug PegAltevir. Data on children and adolescents with cardiovascular diseases are absent.

Liver function

If signs of decompensated liver disease appear, treatment with the drug PegAltevir should be discontinued.

Pyrexia

Although pyrexia may be a manifestation of the flu-like syndrome, which is often recorded during interferon treatment, it is nevertheless necessary to exclude other causes of persistent pyrexia.

Hydration

Adequate hydration should be ensured in patients receiving therapy with the drug PegAltevir, as some patients receiving peginterferon alfa experienced hypotension associated with a decrease in fluid volume. In such cases, fluid replacement may be required.

Lung changes

In rare cases, patients receiving interferon alfa developed infiltrates of unclear etiology, pneumonitis or pneumonia in the lungs, sometimes with a fatal outcome. 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, such patients should be monitored more closely and, if necessary, interferon alfa should be discontinued. Immediate discontinuation of interferon alfa and treatment with glucocorticosteroids lead to the disappearance of adverse pulmonary events.

Autoimmune Diseases

The appearance of autoantibodies and the occurrence of autoimmune diseases have been observed during treatment with interferon alfa preparations. Clinical manifestations of autoimmune diseases appear to occur more frequently during interferon treatment in patients predisposed to the development of autoimmune disorders. In patients with symptoms suggestive of an autoimmune disease, a thorough examination and a benefit/risk assessment of continuing interferon therapy should be performed. Cases of Vogt-Koyanagi-Harada syndrome have been reported in patients with chronic hepatitis C receiving interferon therapy. The syndrome is based on granulomatous inflammation of the eyes, hearing organ, meninges, and skin. If Vogt-Koyanagi-Harada syndrome is suspected, antiviral treatment should be discontinued and the question of prescribing glucocorticosteroids should be considered.

Changes in the Organ of Vision

Ophthalmological disorders, including retinal hemorrhages, retinal exudates, and occlusion of the retinal artery or vein, are rare during treatment with interferon alfa. All patients should undergo an ophthalmological examination before starting therapy. If any symptoms are detected, including decreased visual acuity or changes in visual fields, a complete ophthalmological examination is necessary. During therapy with PegAltevir, periodic ophthalmological examinations are recommended, especially in patients with conditions associated with the development of retinopathy, such as diabetes mellitus or arterial hypertension. If new ophthalmological disorders develop or existing ones worsen, PegAltevir should be discontinued.

Changes in the Thyroid Gland

Sometimes in patients with chronic hepatitis C receiving interferon alfa, hypothyroidism or hyperthyroidism develops. Before starting therapy with PegAltevir, the concentration of thyroid-stimulating hormone (TSH) should be determined; if any abnormalities in thyroid function are detected, appropriate treatment should be prescribed. If symptoms of possible thyroid dysfunction appear during therapy, the TSH concentration should be determined. In case of thyroid dysfunction, combination therapy with PegAltevir can be continued if it is possible to medically maintain the TSH concentration within normal limits. In children and adolescents, thyroid function (e.g., by determining TSH concentration) should be examined every 3 months.

Metabolic Disorders

Hypertriglyceridemia and its progression may be observed. Monitoring of the lipid profile is recommended.

Chronic Hepatitis C in HIV-Infected Patients

Mitochondrial Toxicity and Lactic Acidosis

HIV-infected patients receiving highly active antiretroviral therapy (HAART) are at increased risk of developing lactic acidosis. Caution should be exercised when adding PegAltevir and ribavirin to HAART (see the ribavirin prescribing information).

Decompensation of Liver Disease in Patients with HCV/HIV Co-infection

HIV-infected patients with advanced cirrhosis caused by the hepatitis C virus receiving HAART are at increased risk of liver disease decompensation and fatal outcome. The use of interferon alfa as monotherapy or in combination with ribavirin may increase the aforementioned risk in this patient group. Other risk factors for liver disease decompensation in HIV-infected patients include treatment with didanosine and elevated serum bilirubin levels. Patients with co-infection receiving antiretroviral therapy and treatment for hepatitis C should be continuously monitored, and the Child-Pugh score should be periodically assessed. In case of liver disease decompensation, hepatitis C treatment should be stopped immediately and antiretroviral therapy should be reviewed.

Blood Changes in HIV-Infected Patients with Hepatitis C

In HIV-infected patients with chronic hepatitis C receiving combination treatment with peginterferon alfa-2b and ribavirin simultaneously with HAART, the risk of developing neutropenia, thrombocytopenia, and anemia is higher than in patients infected with HCV alone. These changes can be resolved in most cases by dose reduction; however, blood counts should be carefully monitored in this category of patients. Patients receiving combination therapy with PegAltevir and ribavirin together with zidovudine have an increased risk of developing anemia; therefore, concomitant administration of this combination with zidovudine is not recommended.

Patients with Low CD4 Cell Count

Information on the efficacy and safety of treatment in HIV-infected patients with hepatitis C with a CD4 cell count
< 200/µl is limited, so caution should be exercised in such cases. For information on the toxic effects of antiretroviral drugs planned to be used in combination with PegAltevir and ribavirin, and possible cross-toxic reactions, see the prescribing information for the respective drugs.

Changes in Teeth and Periodontium

Pathological changes in teeth and periodontal tissues, which can lead to tooth loss, have been observed in patients receiving combination therapy with peginterferon alfa-2b and ribavirin. Dry mouth during long-term combination therapy with ribavirin and peginterferon alfa-2b may contribute to damage to teeth and the oral mucosa. Patients should brush their teeth twice a day and have regular dental check-ups. Patients who experience vomiting should rinse their mouth thoroughly afterwards.

Organ Recipients

The efficacy and safety of PegAltevir in organ transplant recipients have not been studied. Preliminary data suggest that interferon alfa therapy may increase the incidence of kidney and liver transplant rejection.

Psoriasis and Sarcoidosis

Since cases of exacerbation of psoriasis and sarcoidosis during interferon alfa therapy have been described, the prescription of PegAltevir to such patients is indicated only if the potential benefit outweighs the potential risk.

Laboratory Tests

All patients are recommended to have a complete blood count, biochemical blood tests, and thyroid function tests before starting treatment with PegAltevir.

The following baseline blood count values are acceptable

• Platelets ≥100×10⁹/L

• Neutrophils ≥1.5×10⁹/L

• Thyroid-stimulating hormone within normal limits

Subsequent laboratory tests are recommended at weeks 2 and 4 of treatment and then regularly, as needed. Hepatitis C virus RNA levels should be determined periodically during treatment.

Long-Term Maintenance Therapy

Due to the lack of relevant clinical trial data for peginterferon alfa-2b, PegAltevir should not be used for long-term maintenance monotherapy.

Rare Hereditary Diseases

PegAltevir is contraindicated in patients with fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Effect on Ability to Drive and Operate Machinery

If fatigue, drowsiness, or confusion occurs during therapy with PegAltevir, it is not recommended to drive a car or operate machinery.

Overdose

No cases of overdose with PegAltevir have been reported. A case of exceeding the recommended dose of peginterferon alfa-2b by more than 10.5 times has been described. The maximum daily dose reported was 1200 mcg. In general, the side effects in cases of overdose are consistent with the known safety profile of pegylated interferon alfa-2b, but their severity may be higher. Standard methods to accelerate drug elimination are not used. There is no specific antidote. In case of overdose, symptomatic treatment and a complete patient examination are recommended.

Drug Interactions

Since the metabolism of peginterferon alfa-2b is accompanied by an increase in the activity of cytochrome P450 isoenzymes CYP2D6 and CYP2C8/9, caution should be exercised when co-administering PegAltevir and drugs metabolized by these isoenzymes. This is especially important when prescribing drugs with a narrow therapeutic window, such as warfarin, phenytoin (CYP2C9), and flecainide (CYP2D6).

This may be partly due to improved metabolic function resulting from the resolution of the inflammatory process during therapy with peginterferon alfa-2b. Thus, caution is required when prescribing peginterferon alfa-2b to patients receiving drugs with a narrow therapeutic window, the metabolism of which may change with moderate liver impairment.

No signs of pharmacokinetic interaction between PegAltevir and ribavirin were identified during repeated co-administration.

Methadone

In patients with chronic hepatitis C receiving maintenance therapy with methadone, who were first prescribed Peginterferon alfa-2b at a dose of 1.5 µg/kg/week, an increase in the AUC of methadone by approximately 15% was observed after 4 weeks. The clinical significance of this effect is unclear. However, when prescribing PegAltevir to such patients, monitoring for sedative effects, respiratory depression, and QT interval prolongation is required.

Chronic Hepatitis C in HIV-Infected Patients

The use of nucleoside analogues alone or in combination with other nucleosides has led to the development of lactic acidosis. In vitro, ribavirin caused an increase in the levels of phosphorylated metabolites of purine nucleosides. This effect may contribute to an increased risk of lactic acidosis caused 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 with fatal outcomes (see the ribavirin prescribing information).

Cases of worsening of ribavirin-induced anemia upon administration of zidovudine are known, although the exact mechanism of this effect is unclear. Thus, due to the increased risk of anemia, the combination of ribavirin with zidovudine is not recommended. In patients receiving combined antiretroviral therapy, especially those with a history of zidovudine-induced anemia, the possibility of replacing zidovudine should be considered.

Telbivudine

Co-administration of telbivudine with peginterferon alfa-2b is associated with an increased risk of peripheral neuropathy. The mechanism of this effect is unclear. The combination of PegAltevir with telbivudine is contraindicated.

Storage Conditions

At a temperature of 2 to 8°C (46.4°F). Do not freeze. Keep out of reach of children.

Shelf Life

The shelf life is 3 years.

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.