PegAltevir lyophilizate 120 µg 1 pc.

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

The biological activity of PegAltevir is due to interferon alpha-2b. Recombinant interferon alpha-2b is obtained from Escherichia coli clone, which contains genetically engineered plasmid hybrid encoding human leukocyte interferon alpha-2b. Interferon alpha-2b has antiviral, immunomodulatory and antiproliferative effects. Its antiviral action is conditioned by binding to specific receptors on the cell surface and by initiation of a sequence of intracellular reactions, including induction of specific enzymes (protein kinase R, 2′-5′ oligoadenylate synthetase, Mx proteins).

This leads to suppression of transcription of the viral genome and inhibition of viral protein synthesis. Immunomodulatory effect is associated with increase of cytotoxicity of T-lymphocytes and natural killer cells and phagocytic activity of macrophages. In addition, interferon alfa-2b promotes differentiation of T-helpers, protects T-cells from apoptosis and affects the production of a number of cytokines (interleukins, interferon gamma).

All these effects may mediate the therapeutic activity of interferon. Pharmacodynamics of PegAltevir was studied by concentration in blood of effector protein neopterin which is a marker of human cellular immunity activation. After a single subcutaneous injection of PegAltevir and PegIntron in healthy volunteers at the dose of 1.5 µg/kg of body weight we observed comparable dynamics of neopterin concentration in blood, C_max was reached after 48 hours.

In a preclinical comparative study of the biological activity on relevant animal groups of PegAltevir and PegIntron, comparable results were obtained.

Indications

Adults (triple therapy)

The 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 who have not previously received antiviral therapy or with a history of failure of antiviral therapy./p>

Adults (dual therapy and monotherapy).

The treatment of chronic hepatitis C with PegAltevir® in adult patients who are seropositive for hepatitis C virus RNA, including patients with compensated cirrhosis and/or in combination with clinically stable HIV infection.

The treatment of chronic hepatitis C with PegAltevir® in combination with ribavirin in adult patients who have not previously received antiviral therapy, including patients with concurrent clinically stable HIV infection, and in adult patients who have previously failed antiviral therapy with a combination of interferon alfa (pegylated or unpegylated) with ribavirin or interferon alfa monotherapy.

Monotherapy with pegAltevir® in chronic hepatitis C is indicated only if there is intolerance or contraindication to ribavirin.

Children (dual therapy).

The treatment of chronic hepatitis C with PegAltevir® in combination with ribavirin in children aged 3 years and older who have not previously received antiviral therapy, with compensated liver disease and who are seropositive for hepatitis C virus RNA.

If a decision is made not to delay treatment until adulthood, it should be kept in mind that combination therapy may cause growth retardation. The reversibility of growth retardation is not known. The decision to prescribe treatment must be made on an individual basis.

Active ingredient

Composition

How to take, the dosage

The therapy with PegAltevir should be started by a doctor with experience in treating patients with hepatitis C and should be monitored thereafter.

PegAltevir is given 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.

PegAltevir combination therapy (dual or triple)

Double therapy (PegAltevir with ribavirin): It is indicated for adult patients and children 3 years and older.

Triple therapy (PegAltevir with ribavirin and an NS3/4A protease inhibitor): indicated for adult patients who are infected with hepatitis C virus genotype 1.

Dosing regimen in adults

In combination therapy with ribavirin, PegAltevir is given as a subcutaneous injection at a dose of 1.5 mcg per 1 kg body weight once weekly. It is recommended that the injection sites be alternated. Ribavirin should be taken orally daily. Ribavirin should be taken together with a meal. The daily dose of ribavirin in combination therapy is calculated according to body weight. The combined dosing table for PegAltevir and ribavirin can be used in combination therapy:

a: 2 in the morning + 2 in the evening
b: 2 in the morning + 3 in the evening
c: 3 in the morning + 3 in the evening
d: 2 in the morning + 4 in the evening

When prescribing PegAltevir as part of triple therapy, please review the medical instructions for the NS3/4A protease inhibitor.

The duration of treatment in untreated adults

Trice therapy: Read the instructions for medical use of the NS3/4A protease inhibitor.

The dual therapy: in patients infected with hepatitis C genotype 1 who do not achieve an undetectable viral RNA level or adequate virologic response after 4 or 12 weeks of antiviral therapy, there is very little chance of achieving a sustained virologic response and they should be evaluated for the appropriateness of continuing treatment.

Genotype 1:

Genotype 2 or 3:

Genotype 4:

Treatment duration in adults with HCV/HIV co-infection

Dual therapy: The recommended treatment duration is 48 weeks, regardless of the virus genotype. Early virologic response – reduction in viral RNA ≥2 logs from baseline or undetectable RNA levels after 12 weeks of treatment – is a predictor of achieving sustained virologic response.

Duration of treatment in adults who have not responded to treatment (repeat course)

Triple therapy: refer to the instructions for medical use of the NS3/4A protease inhibitor. Dual therapy: In all patients, regardless of genotype, who have achieved an undetectable level of viral RNA after 12 weeks of therapy, treatment should continue for 48 weeks. If there is no virologic response after 12 weeks of therapy, the probability of achieving a sustained virologic response after 48 weeks of therapy is low. Duration of repeated therapy with peginterferon alfa-2b and ribavirin for more than 48 weeks in patients with hepatitis C virus genotype 1, whose response was not achieved, was not studied.

The dosing regimen in children (dual therapy only)

The dosing regimen in children 3 years and older and adolescents is determined by body surface area for PegAltevir and body weight for ribavirin. The recommended dose of PegAltevir is 60 mcg/m2/week subcutaneously in combination with ribavirin at a dose of 15 mg/kg/day orally, divided into two doses, along with meals (morning and evening).

Treatment duration in children (dual therapy only)

Genotype 1:

Genotypes 2 or 3:

Genotype 4:

Monotherapy with PegAltevir (adults)

Dosing regimen

PegAltevir is given subcutaneously at a dose of 0.5 or 1.0 µg/kg once weekly:

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

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

The duration of treatment

In patients who have a virologic response after 12 weeks, treatment should be continued for an additional 3 months (total course length is 6 months). Extension of therapy to 1 year (48 weeks) may be based on prognostic factors (virus genotype, age > 40 years, male gender, presence of bridging fibrosis).

Dose adjustment in all patients (monotherapy and combination therapy)

If serious adverse events or abnormal laboratory values occur with monotherapy or combination therapy including PegAltevir, dose adjustment of PegAltevir and/or ribavirin is required until adverse events cease. Reducing the dose of NS3/4A protease inhibitor is not recommended. NS3/4A inhibitor should not be prescribed without PegAltevir and ribavirin. Because doses of PegAtevir and ribavirin affect treatment outcomes, they should remain as close as possible to the recommended standard doses.

Notes:

1 In adults, the first dose reduction of ribavirin is 200 mg/day (in those who received 1400 mg, 400 mg/day). If necessary, a second reduction in the dose of ribavirin is made by another 200 mg/day. Patients who have had their ribavirin dose reduced to 600 mg/day should receive one capsule/tablet (200 mg) in the morning and two capsules/tablets (200 mg) in the evening.

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

2 In adults, the first dose reduction of PegAltevir is performed to 1.0 mcg/kg/day. If necessary, the second dose reduction of PegAltevir is carried out to 0.5 µg/kg/week.

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

* is the upper limit of normal.

** – Alanianaminotransferase/Aspartataminotransferase.

Lower doses of PegAltevir in adults may be achieved by reducing the volume of the solution administered or by using a lower dosage of the drug. In children and adolescents, by adjusting the recommended dose in two steps: from a starting dose of 60 mcg/m2/week to 40 mcg/m2/week, then to 20 mcg/m2/week if necessary.

Recommendations for reducing the dose of PegAltevir in two steps during combination therapy in adults

Recommendations for reducing the dose of PegAltevir for monotherapy in adults

In adults receiving PegAltevir monotherapy at a dose of 0.5 mcg/kg, a dose reduction can be achieved by reducing the volume of the administered drug solution by half:

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

In adults receiving PegAltevir monotherapy at a dose of 1.0 mcg/kg, dose reduction may be achieved by reducing the volume of drug solution administered by half or by reducing the drug concentration:

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

Special patient populations

Dose adjustment in renal failure

Monotherapy:

PegAltevir should be used with caution in patients with moderate to severe renal impairment. In patients with moderate renal insufficiency (creatinine clearance 30-50 ml/min), the initial dose of PegAltevir should be reduced by 25%. In patients with severe renal insufficiency (creatinine clearance 15-29 ml/min), including patients undergoing 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 to severe renal insufficiency, including those on hemodialysis, should be under close supervision. If renal function decreases during treatment, therapy with PegAltevir should be discontinued.

Combination therapy:

Patients with creatinine clearance < 50 ml/min are contraindicated in combination with ribavirin. If combined therapy is administered to patients with renal insufficiency, close monitoring should be carried out with respect to the development of anemia.

Hepatic impairment

The safety and effectiveness of PegAltevir treatment in patients with severe hepatic impairment have not been studied, so PegAltevir should not be used in these patients.

Elderly patients (65 years and older)

There is no relationship of peginterferon alfa-2b pharmacokinetics with age. The data on results of study of pharmacokinetics in elderly patients after single subcutaneous injection of peginterferon alfa-2b testifies that there is no need to adjust the drug dose taking into account the age. In patients older than 70 years old the pharmacokinetics of peginterferon alfa-2b has not been studied.

In children

PegAltevir in combination with ribavirin can be used in children 3 years of age and older.

Instructions for preparation of the solution for injection

The lyophilizate of PegAtevir should only be diluted with the included solvent. PegAltevir must not be mixed with other medicinal products. Using a sterile syringe, 0.7 ml of water for injection is injected into the vial with PegAtevir. The vial is gently shaken 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 injection. As with any other preparations for parenteral use, the prepared solution should be inspected before administering. The solution should be clear, colorless and contain no visible particles. If the color changes or visible particles appear, the solution should not be used.

Interaction

Due to the fact that metabolism of peginterferon alfa-2b is accompanied by increased activity of cytochrome Р450 CYP2D6 and CYP2C8/9 isoenzymes, caution should be exercised when coadministering PegAltevir and drugs metabolized with participation of these isoenzymes. Especially when prescribing drugs with a narrow therapeutic window, such as warfarin, phenytoin (CYP2C9) and flecainide (CYP2D6).

This may be due in part to an improvement in metabolic function resulting from the resolution of inflammation with peginterferon alfa-2b therapy. Thus, caution is required when prescribing peginterferon alfa-2b to patients receiving drugs with a narrow therapeutic window whose metabolism may be altered by moderate liver damage.

In repeated co-administration of PegAltevir and ribavirin, no evidence of pharmacokinetic interaction between the two has been identified.

Methadone

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

Chronic hepatitis C in HIV-infected patients

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

There have been known cases of worsening of ribavirin-induced anemia with zidovudine administration, although the exact mechanism of this effect is unclear. Therefore, due to the increased risk of anemia, the combination of ribavirin with zidovudine is not recommended. In patients receiving combination antiretroviral therapy, especially those with a history of zidovudine-induced anemia, zidovudine replacement should be considered.

Telbivudine

The co-administration of telbivudine with peginterferon alfa-2b is associated with an increased risk of peripheral neuropathy. The mechanism of this effect is not clear. The combination of PegAltevir with telbivudine is contraindicated.

Special Instructions

The mental sphere and the central nervous system (CNS).

In some patients during therapy with peginterferon alfa-2b and for 6 months after discontinuation, severe CNS abnormalities may occur, such as depression, suicidal ideation, and suicide attempts. Other CNS abnormalities may also occur, including aggressive behavior (sometimes homicidal thoughts), bipolar disorders, mania, confusion, and altered consciousness. Symptoms of psychiatric disorders should be monitored closely in patients. If these adverse events develop, due to their potential severity, the need for therapeutic correction should be evaluated. If psychiatric symptoms persist or increase, or suicidal ideation occurs, treatment with PegAltevir should be discontinued and timely consultation with a psychiatrist ensured.

Patients with a history or history of severe mental illness.

If it is necessary to prescribe PegAltevir to patients with severe mental disorders (including patients with a history of such disorders), treatment may only be initiated after a thorough evaluation and appropriate therapy of the mental disorder.

Children and adolescents with current or history of severe psychiatric disorders should not receive ribavirin in combination with peginterferon alfa-2b. With combination therapy with interferon alfa-2b, children and adolescents had a higher rate of suicidal ideation and suicide attempts than adults, both during treatment and in the following 6 months. As in adults, other mental side effects (such as depression, emotional lability, and somnolence) may occur in children and adolescents.

Patients who abuse different substances

Patients infected with hepatitis C virus who abuse substances (alcohol, marijuana or other substances) have an increased risk of development and/or exacerbation of mental disorders during therapy with interferon alfa. If interferon therapy is necessary, such patients should be carefully evaluated for psychiatric disorders and other substance abuse before treatment is prescribed, and closely monitored during and after treatment. If there is a primary or recurrent development of mental disorder and substance abuse, earlier intervention is recommended to prevent the recurrence or development of mental disorder and substance abuse.

Growth and development (children and adolescents)

Combination therapy causes growth retardation, the reversibility of which is not clear. The benefit-risk assessment should be done on a case-by-case basis, taking into account data on disease progression (especially the degree of fibrosis), the presence of comorbidities (e.g., HIV co-infection), and predictors of virologic response (virus genotype and viral load). Whenever possible, children should receive treatment after the pubertal growth spurt. There are no data on long-term effects on puberty.

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

Hypersensitivity of immediate type

In rare cases interferon alfa-2b therapy has been complicated by immediate hypersensitivity reactions (urticaria, angioedema, bronchospasm, anaphylaxis). If such reactions occur, discontinue PegAltevir and immediately prescribe adequate symptomatic therapy. Transient rash does not require discontinuation of treatment.

The cardiovascular system

Patients with heart failure, myocardial infarction and/or arrhythmias, including those with a history of heart disease, should be kept under constant observation during treatment with PegAltevir. In patients with heart disease, an ECG is recommended before and during treatment. Arrhythmias (mainly supraventricular) are usually amenable to conventional therapy, but may require withdrawal of PegAltevir. There are no data on children and adolescents with cardiovascular disease.

Liver function

In case of signs of decompensation of liver disease, treatment with PegAltevir should be discontinued.

While fever may be a manifestation of the flu-like syndrome often seen with interferon therapy, other causes for persistent fever should be excluded.

Hydration

In patients treated with PegAltevir, adequate hydration should be provided, since some patients who received peginterferon alfa have been hypotensive due to decreased fluid volume in the body. Fluid replacement may be necessary in these cases.

Consecutive laboratory tests are recommended at weeks 2 and 4 of treatment and then regularly as needed. Periodically during treatment the RNA level of hepatitis C virus should be determined.

Long-term maintenance therapy

In the absence of relevant data from clinical studies of peginterferon alfa-2b, PegAltevir should not be used for long-term maintenance monotherapy.

Patients with fructose intolerance, glucose-galactose malabsorption or sugar-isomaltase deficiency are contraindicated with PegAltevir.

Influence on driving and operating machinery

If fatigability, drowsiness or confusion occur during therapy with PegAltevir, it is not recommended to drive or operate machinery.

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

Contraindications

Side effects

Adults

Triple therapy

The instructions for medical use of the NS3/4A protease inhibitor must be read.

Double therapy and monotherapy

General information about the safety profile:

The most common side effects (based on clinical studies in more than half of patients) of combination therapy with peginterferon alfa-2b and ribavirin were weakness, headache, and injection site reactions. In more than 25% of cases, nausea, chills, insomnia, anemia, fever, myalgia, asthenia, pain, alopecia, anorexia, weight loss, depression, rash, and irritability were observed. As a rule, the side effects were mild to moderate in severity, were well controlled, and did not require dosage reduction or therapy withdrawal. Weakness, alopecia, pruritus, nausea, anorexia, weight loss, irritability, and insomnia were less common with peginterferon alfa-2b monotherapy than with combination therapy.

Side effects:

The adverse effects noted with peginterferon alfa-2b listed below are listed according to systemic organ class and frequency, according to the following gradation: very common ≥ 1/10, common ≥ 1/100 and < 1/10, infrequent ≥ 1/1000 and < 1/100, rare ≥ 1/10000 and < 1/1000, very rare < 1/10,000, unspecified frequency (cannot be counted from available data). Within each frequency group, side effects are arranged in descending order of clinical significance.

Overdose