Algeron - instructions for use, dose, side effects, contraindications

Active substanceCepeginferferon alfa-2bCepeginferferon alfa-2b

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Algeron®

solution PC

BIOCAD, CJSC Russia

Dosage form: & nbsphypodermic solution

Composition:

1 ml of the solution contains:

active substance: pegylated interferon alfa-2b (chaineginterferon alfa-2b) - 200 μg;

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 1.0 ml.

Description:Transparent, from a colorless to light yellow solution.

Pharmacotherapeutic group:Cytokine

ATX: & nbsp

L.03.A.B Interferons

Pharmacodynamics:

Zepeginferferon alfa-2b is formed by attachment to a molecule of interferon alpha-2b polymer structure - polyethylene glycol (PEG) with a molecular weight of 20 kD (kilo Dalton). Biological effects of the Algeron® drug are caused by interferon alpha-2b. Interferon alfa-2b is produced by a biosynthetic method using recombinant DNA technology (deoxyribonucleic acid) and is produced by a strain of the bacterium Escherichia coli into which the gene for human interferon alpha-2b has been introduced by genetic engineering techniques. Interferons have an antiviral, immunomodulatory and antiproliferative effect. The antiviral effect of interferon alpha-2b is due to its binding to specific cellular receptors,which in turn triggers a complex mechanism of sequential intracellular reactions involving 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. Immunomodulating effect is manifested, first of all, by intensification of cell-mediated immune system reactions. Interferon increases the cytotoxicity of T-lymphocytes and natural killers, the phagocytic activity of macrophages, promotes the differentiation of T-helper cells, protects T cells from apoptosis. Immunomodulatory effect of interferon is also due to the effect on production of a number of cytokines (interleukins, interferon gamma). All these effects of interferon may mediate its therapeutic activity.

Preparations of pegylated interferon alfa cause an increase in the concentration of effector proteins, such as serum neopterin and 2'5'-oligoadenyl synthetase. In studying the pharmacodynamics of the Algeron® preparation, a single dose of volunteers showed a dose-dependent increase in serum neopterin concentration, the maximum increase in which was achieved after 48 hours.With the introduction of Algeron® once a week at a dose of 1.5 μg / kg, the serum neopterin concentration in patients with chronic hepatitis C was maintained at a consistently high level.

As well as unmodified interferon alpha-2b, Algeron® had antiviral activity in in vitro experiments.

Pharmacokinetics:

In preclinical experiments, it was shown that the pegylation of the molecule of interferon alfa-2b leads to a significant slowing of absorption from the injection site, an increase in the volume of distribution, a decrease in clearance. A decrease in clearance leads to more than a 10-fold increase in the duration of the terminal half-life (T_1/2) as compared to the unmodified interferon alpha-2b (32 hours versus 2.2 hours). Excretion of Algeron® occurred within> 153 h (6.5 days).

When studying the pharmacokinetics of the Algeron® preparation with a single dose of 1.5 μg / kg to the volunteers at a therapeutic dose in conjunction with ribavirin, the maximum serum concentration (C_ma_x) was achieved on average 31 (18-48) h after the administration and was 1 401 ± 233 (1250 - 1803) pg / ml. Area under the concentration-time curve from 0 to 168 h (AUQ_(0-168)) averaged 144 212 ± 49 839 (106 845 - 226 062) pg / ml / h. The clearance of the drug (C1) averaged 9.9 ± 3.2 (5.2 - 13) ml / (h * kg), the half-life (T_1/2) - 57.8 ± 8.4 (48-66.5) h. The value of the elimination constant (K_el) on the average was 0.0124 ± 0.002 h^-1.

When AlGeRON® was administered subcutaneously once a week, a dose-dependent gradual increase in the drug concentration before 8 weeks was observed in the combined therapy of chronic hepatitis C, after which no further cumulation of up to 12 weeks of therapy with Algeron® was observed.

Pharmacokinetics in patients with impaired renal function

In studies of peginterferon alfa-2a, there was no association between pharmacokinetic parameters and creatinine clearance (CC) in patients with impaired renal function (QC from 20 to 100 ml / min). In the study of peginterferon alfa-2b, an increase C_ma_x, AUC and T_1/2 in proportion to the degree of renal failure.

Patients with moderate to severe renal insufficiency should be closely monitored and, in case of adverse reactions, reduce the dose of Algeron®.

Pharmacokinetics in patients with impaired hepatic function

Pharmacokinistic parameters of peginterferon alfa preparations in healthy individuals and patients with hepatitis C are the same. In patients with compensated cirrhosis of the liver, pharmacokinetic characteristics are the same as in patients without cirrhosis. In patients with severe impairment of liver function, the pharmacokinetics of peginterferon alfa preparations have not been studied, therefore, Algeron® is not recommended for this group of patients.

Pharmacokinetics in the elderly

Parameters of pharmacokinetics of peginterferon alfa preparations do not depend on age, so dose changes in elderly people are not required. Pharmacokinetics in patients older than 70 years have not been studied.

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

Contraindications:

- Hypersensitivity to interferon, polyethylene glycol and any other components of the Algeron® preparation.

- Hypersensitivity to ribavirin or any other component of the drug.

- Decompensated hepatic cirrhosis (grade B and C on the Child-Pugh scale or bleeding from varicose veins).

- Cirrhosis of the liver with hepatic insufficiency in patients with co-infection with HIV / chronic hepatitis C (Child-Pugh index ≥6).

- Autoimmune hepatitis or other autoimmune diseases in the anamnesis.

- Dysfunction of the thyroid gland, which can not be maintained at a normal level by drug therapy.

- Epilepsy and / or dysfunction of the central nervous system.

- Severe diseases of the cardiovascular system, unstable or uncontrolled for at least 6 months preceding treatment.

- Severe diseases (including kidney failure, CC <50 ml / min, the need for hemodialysis).

- Malignant neoplasms.

- Rare hereditary diseases, such as lactose intolerance, lactase deficiency or glucose-galactose malabsorption (with ribavirin lactose in the formulation).

- Hemoglobinopathies (for example, thalassemia, sickle cell anemia).

- Pregnancy and lactation.

- Conducting therapy in men whose partners are pregnant.

- Children under 18 years.

- Severe oppression of bone marrow hematopoiesis (neutrophils <0.5x10⁹/ l, platelets <25x10⁹/ l, hemoglobin <85 g / l).

- Heavy debilitating conditions.

- Simultaneous reception with telbivudine.

Carefully:

- Severe lung diseases (eg, chronic obstructive pulmonary disease).

- Severe mental illness, in particular, depression, suicidal thoughts or attempts (including in the anamnesis).

- Diabetes mellitus with a tendency to develop a ketoacidotic coma.

- Violations associated with the blood coagulation system (eg, thrombophlebitis, pulmonary embolism).

- Neutrophils <1.5x 10⁹/ l, platelets <90x 10⁹/ l, hemoglobin <100 g / l.

- In combination with myelotoxic drugs.

- In patients with co-infection with HIV / chronic hepatitis C, the number of CD4 + lymphocytes is less than 200 cells / μl or less than 100 cells / μl with an HIV RNA level of more than 5000 copies / ml.

Pregnancy and lactation:Preparations of peginterferon alfa should not be administered during pregnancy. The teratogenic effects of peginterferon alfa preparations have not been studied. The use of interferon alpha-2a in high doses led to a significant increase in the number of spontaneous abortions in animals.In the offspring born on time, there were no teratogenic effects. However, when treating interferon alfa drugs, women of childbearing age should use effective methods of contraception. There is no data on the penetration of peginterferon alfa into breast milk, therefore, to avoid undesirable effects on the child, either breastfeeding or therapy should be abolished, taking into account the potential benefits for the mother. The combination of peginterferon alfa and ribavirin is contraindicated for use during pregnancy. In animal studies ribavirin had pronounced teratogenic effects and caused death of the fetus. Ribavirin contraindicated pregnant women and men whose partners are pregnant. Ribavirin therapy should not be prescribed until a negative pregnancy test is performed immediately before the start of therapy. Women who are capable of giving birth or men whose partners are capable of giving birth should be informed of the teratogenic effects of ribavirin and the need for effective contraception (at least 2 methods) during treatment and within 7 months after completiontherapy.

Dosing and Administration:

The preparation Algeron® is injected subcutaneously, into the area of the anterior abdominal wall or thigh. It is recommended to alternate the injection site.

Therapy should be initiated by a physician with experience in the treatment of patients with hepatitis C, and further iodine is monitored.

In combination therapy with ribavirin, Algeron® is used in patients with chronic hepatitis C, including clinically stable co-infection with HIV, in the form of a subcutaneous injection at a dose of 1.5 μg per kg of body weight once a week. The dosage regimen of Algeron® is indicated in Table 1.

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

Body mass	Dosage for administration once a week	The amount of Algeron® solution	Minimum syringe volume
40 kg	60 μg	0.3 ml	A syringe of 0.4 ml
41-46 kg	70 μg	0.35 ml
47-53 kg	80 μg	0.4 ml
54-60 kg	90 μg	0.45 ml	Syringe but 0.5 ml
61-66 kg	100 μg	0.5 ml	Syringe but 0.5 ml
67-73 kg	110 μg	0.55 ml	0.6 ml syringe
74-80 kg	120 μg	0.6 ml	0.6 ml syringe
81-86 kg	130 μg	0.65 ml	0.8 ml syringe
87-93 kg	140 μg	0.7 ml
94-100 kg	150 μg	0.75 ml
101-106 kg	160 μg	0.8 ml
107-113 kg	170 μg	0.85 ml	1 ml syringe
114-120 kg	180 μg	0.9 ml
121-126 kg	190 μg	0.95 ml
127-133 kg	200 μg	1 ml

Each syringe / vial with Algeron® is for single use only. Do not mix the solution contained in the syringe / vial or inject it in parallel with any other drug. Preparation Algeron "® can not be administered intravenously.

Recommendations for use in patients:

1. Choose the time of your injection convenient for you. Injections should be done in the evening before bedtime.

2. Wash hands thoroughly with soap and water before you start the treatment.

3. Take one out-of-the-box package with a filled syringe / vial of cardboard pack that should be stored in the refrigerator and let it sit at room temperature for a few minutes so that the temperature of the drug is equal to the ambient temperature. In case of condensation on the surface of the syringe / vial, wait a few more minutes until the condensation evaporates.

4. Before use, inspect the solution in a syringe / vial. In the presence of suspended particles or a discoloration of the solution or damage to the syringe / vial, Algeron® should not be used.If there is foam, which happens, when the syringe / bottle shakes or shakes a lot, wait until the foam settles.

5. Select the area of the body for injection. Algeron® is injected into the subcutaneous adipose tissue (the fat layer between the skin and the muscle tissue), so use places with loose fiber away from the stretch of the skin, nerves, joints and vessels (see Figure 1 -one of the four possible areas for injection):

- Hip (anterior thighs other than groin and knee);

- Abdomen (except the midline and umbilical region).

Fig.1 Location of injection sites.

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

Each time, choose a new site for the injection, so you can reduce discomfort and pain on the skin area at the injection site. Within each injection area, there are many points for the injection. Constantly change injection points within a specific area.

6. Preparation for injection.

If the patient uses Algeron® in syringes

Take the prepared syringe in the hand that you are writing. Remove the protective cap from the needle.

If the patient uses Algeron® in vials

Take the vial of Algeron® and gently place the vial on a flat surface (table). Tweezers (or other convenient device), remove the lid of the vial. Disinfect the top of the vial. Take a sterile syringe into the hand that you are writing, remove the protective cap from the needle and, without violating sterility, carefully insert the needle through the rubber cap of the bottle so that the tip of the needle (3-4 mm) is visible through the glass of the vial. Turn the bottle over so that its neck is pointing down.

7. The amount of Algeron solution®, which must be entered at the time of injection, depends on the dose calculated by your doctor. The dose of Algeron® is expressed in micrograms (μg) and is calculated taking into account the body weight. Do not change the dosage of Algeron® alone if your doctor has not told you to do so. Do not store residues of the drug left in the syringe / vial for reuse.

If the patient uses Algeron® in syringes

Depending on the dose that the doctor prescribed for you, you may need to remove the excess volume of the drug solution from the syringe.If necessary, slowly and gently press the plunger of the syringe to remove excess solution. Press the piston until the piston reaches the required mark on the surface of the syringe.

If the patient uses Algeron® in vials

Slowly pull the piston back and draw into the syringe from the vial the required volume of the solution, corresponding to the dose of Algeron®, which you were prescribed by the doctor. Then, without violating sterility, remove the bottle from the needle, holding the needle at the base (make sure that the needle does not come off the syringe). Turn the syringe upside down with a needle, and, moving the piston, remove air bubbles by gently tapping on the syringe and pressing on the piston.

8. Pre-disinfecting the area of skin where the Algeron® preparation will be injected, slightly gather the skin into the fold with the thumb and forefinger (Fig. 2).

9. With the syringe perpendicular to the injection site, insert the needle into the skin at an angle of 90 ° (Figure 3). Introduce the drug, evenly pressing the plunger of the syringe down to the end (until it is completely emptied).

10. Remove the syringe with the needle vertically upwards.

11. Dispose of used syringes / vials only in a specially designated place, which is not suitable for children.

12. If you forget to inject Algeron®, inject immediately, as soon as you remember it.

Do not administer a double dose of the drug.

Do not stop using Algeron® without consulting your doctor.

Ribavirin should be taken orally, during meals, daily. The daily dose of ribavirin is calculated according to body weight (see Table 2).

Table 2. Ribavirin dosage regimen for combination therapy with Algeron® in patients with chronic hepatitis C, including clinically stable co-infection with HIV.

Body weight, kg	The daily dose of ribavirin, mg	Dosing regimen (in capsules or tablets of 200 mg)
≤65	800	400 mg in the morning, 400 mg in the evening
65-85	1000	400 mg in the morning, 600 mg in the evening
86-105	1200	600 mg in the morning, 600 mg in the evening
>105	1400	600 mg in the morning, 800 mg in the evening

duration of treatment in patients with chronic hepatitis C

the duration of treatment depends on the genotype of the virus.

genotype hcv 1. presence of an early virologic response (disappearance iicv RNA or decrease in viral load by 2 log₁₀ (100 times) and more to 12 weeks of treatment) can predict the achievement of a sustainable response.in the absence of an early virologic response, remission is unlikely to be achieved. in clinical studies of the use of peginterferopal alfa in chronic hepatitis with a sustained response was achieved in only 2% of patients with a negative early response. when an early virologic response is reached, therapy is recommended to continue for another 9 months (the total duration of treatment is 48 weeks). it is necessary to consider the termination of therapy if no early virologic response is achieved after 12 weeks of treatment or after 24 weeks of RNA therapy hcv will lend itself to detection.

genotype ncv 2 and 3. if to 12th week of treatment, an early virologic response will be achieved (disappearance iicv RNA or decrease in viral load by 2 log₁₀ (100 times) and more), it is recommended to continue treatment for another 12 weeks (the total duration of treatment is 24 weeks). longer therapy has no advantages.

genotype ncv 4. at in general, patients with a genotype 4 difficult to treat. the absence of special studies determines the possibility of applying the same treatment tactics as in genotype 1.

duration of treatment in patients with co-infectious HIV / chronic hepatitis with

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

dosage adjustment

if there are undesirable phenomena or deviations of laboratory indicators of moderate severity, it is necessary to reduce the doses of the preparation Algeron® or ribavirin, or to suspend treatment. with the normalization of the condition or laboratory indicators, you can consider increasing the dose, up to the initial dose. if after correction of the dose tolerability of therapy does not improve, treatment is recommended to be discontinued.

hematologic disorders. with a decrease in the peripheral blood number of leukocytes less than 1.5 × 10⁹/ л, neutrophils less than 0,75х10⁹/ l, the number of platelets less than 50x10⁹/ l, it is recommended to reduce the dose of algeron® preparation by an amount equal to 1/3 of the therapeutic dose (1/3 td). if the number of neutrophils and platelets does not increase, a dose of the Algerone® drug should be reduced by another 1/3 td. Increase the dose is recommended if the number of leukocytes exceeds 2.0x10⁹/ l, neutrophils - 1x10⁹/ l, and thrombocytes - 90x10⁹/ l for at least 4 weeks.

correction of ribavirin dose. with a decrease in hemoglobin to less than 100 g / L, a dose of ribavirin should be reduced to 600 mg / day. treatment in the previous dose can be resumed after the hemoglobin level exceeds 100 g / l for at least 4 weeks. with a decrease in hemoglobin level of less than 85 g / l of Algeron® and ribavirin necessary cancel. in patients with diseases of the cardiovascular system (in the phase of compensation) with a decrease in hemoglobin on ≥20 g / L for any 4 weeks of treatment, it is recommended to reduce the dose of Algerone® to half the therapeutic and ribaviria to 600 mg per day and constantly use a reduced dose. if the hemoglobin level in patients with diseases of the cardiovascular system (in the compensation phase) is less than 120 g / l 4 weeks after the dose reduction - the introduction of the preparation algeron® and ribavirin intake is canceled.

after discontinuation of ribavirin while normalizing the hemoglobin level, it is possible to resume treatment at a reduced dosage of 600 mg per day, without further dose increase.

violations of the liver. with compensated cirrhosis of the liver, correction of the dose of Algeron® is not required. when decompensating the hepatic function, the use of the drug is not recommended.

if the concentration of free bilirubin rises to 85.5 μmol / l, a dose of ribavirin should be reduced to 600 mg / day.

with a progressive increase in the activity of alanine aminotransferase (alt) or aspartate aminotransferase (act) more than 2 times of the initial value or more than 10 times the upper limit of the norm (BH), the administration of the AlGeRON® preparation and the ribavirin intake are canceled. if the concentration of bound bilirubin increases by more than 2.5 times from BH or free bilirubin> 68.4 μmol / L for at least 4 weeks, with signs of liver function decompensation, Algeron® and ribavirin necessary cancel.

patients with depression. with depression, an easy degree of dose adjustment is not required. with the development of moderate depression, the dose of the Algeron® preparation should be reduced by 1/3 td, if necessary - by another 1/3 td. If the condition does not change, it is recommended to continue treatment in a reduced dosage. if an improvement occurs that lasts for at least 4 weeks, the dose of Algeron® can be increased. with the development of severe depression, as well as suicidal thoughts, it is necessary to abolish Algeron® and ribavirin and conduct specific treatment under the supervision of a psychiatrist.

renal insufficiency. when prescribing combined therapy for mild renal failure (kk> 50 ml / min), care should be taken with respect to the development of anemia. at less than 50 ml / min, combined therapy with Algerone ® and ribavirin should not be prescribed. if during therapy the creatinine concentration increases> 0.177 mmol / l, Algeron® and ribavirin necessary cancel.

Table 3. algorithm for correcting doses of the preparation of algerone® and ribavirin in the event of adverse reactions.

laboratory indicators	a reduction in the dose of ribavirin to 600 mg per day **	decrease in the dose of Algeron®	discontinuation of Algeron® and ribavirin
hemoglobin content *	<100 g / l	-	<85 g / l
number of leukocytes	-	<1.5x10⁹/ l ***	<1.0х10⁹/ l
number of neutrophils	-	<0.75x10⁹/ l ***	<0.5x10⁹/ l
platelet count	-	<50x10⁹/ l ***	<25x10⁹/ l
bound bilirubin content	-	-	> 2.5 hrs
free bilirubin content	> 85.5 μmol / l	-	> 68.4 μmol / l (> 4 weeks)
creatinine content	-	-	> 0.177 mmol / l
activity alt, act			2х (from the initial value) or> 10 volts

* in patients with diseases of the cardiovascular system (in the compensation phase) with a decrease in hemoglobin on ≥20 g / l for any 4 treatment regimens it is recommended to reduce the dose of Algerone® to half the therapeutic and ribavirin to 600 mg per day and constantly use a reduced dose.

if the hemoglobin level in patients with diseases of the cardiovascular system (in the compensation phase) is less than 120 g / l 4 weeks after the dose reduction - the introduction of the preparation algeron® and ribavirin intake is canceled.

** Ribavirin in a dose of 600 mg per day is taken by 1 capsule 200 mg in the morning and 2 200 mg capsules in the evening, while eating.

*** the first reduction in the dose of Algeron® to 1/3 td (up to 1.0 mcg / kg / week), the second reduction (if necessary) of the Algeron® preparation, another 1/3 td decrease (up to 0.5 μg / kg / week).

use in specific patient groups

elderly patients. dose adjustment in the elderly is not required.

children. in children and adolescents under the age of 18, the efficacy and safety of the drug

Algerone® in combination with ribavirin has not been studied.

patients after liver transplantation and other organs. efficacy and safety of peginterferon alfa preparations is not established.

Side effects:

When combined therapy with Algeron ® in a dose1.5 μg / kg / week and ribavirin, adverse reactions were mostly mild or moderate and did not require discontinuation of treatment.

To describe the incidence of adverse reactions, the following categories were used: very often (≥ 1/10), often (≥ 1/100; <1/10), infrequently (≥ 1/1000; <1/100), rarely (≥ 1/10000; <1/1000), very rarely (<1/10000).

Very frequent adverse reactions ( ≥ 1/10) were:

From the central and peripheral nervous system: headache, dizziness.

From the side of the psyche: irritability, emotional lability, depression.

From the gastrointestinal tract: diarrhea, nausea.

From the respiratory system, chest and mediastinum: dry cough.

From the side of the musculoskeletal and connective tissue: pain in the joints, muscle pain.

From the skin and subcutaneous fat: alopecia, dryness and flaky skin, itching, rash.

Reactions together: inflammation and itching at the injection site.

Common symptoms: fever, flu-like syndrome, asthenia, fatigue, weight loss.

On the part of the blood system and lymphatic system: leukopenia, anemia, neutropenia, thrombocytopenia, increased ESR (erythrocyte sedimentation rate), lymphocytosis, monocytosis.Reduction of hematological parameters, as a rule, was noted in the first four weeks of treatment; they improved after a dose adjustment within 4-8 weeks. Thrombocytopenia less than 75x10⁹/ l was observed in about 6% of patients. In most cases, changes in blood levels could be eliminated with the help of colony-stimulating granulocyte factor preparations or by lowering the dose, so the detected abnormalities did not lead to an early cessation of treatment. Modification of the dose of ribavirin for anemia was required in approximately 7% of patients.

Laboratory indicators: Hyperbilirubinemia, hypertriglyceridemia, gipshrholestsrinemia, hypoglycemia, hyperglycemia, increased thyroid-stimulating hormone (TSH) concentration.

Frequent adverse reactions (≥1/100; <1/10):

From the central and peripheral nervous system: paresthesia.

From the side of the psyche: sleep disorders, memory and attention disorders, anxiety,

anxiety.

From the gastrointestinal tract: loss of appetite, abdominal pain, dry mouth, vomiting, heartburn, change in taste.

From the respiratory system, chest and mediastinum: rhinitis, nasal congestion, perspiration, sore throat, epistaxis, shortness of breath, pneumonia.

From the side of the hearing organ and labyrinthine disorders: noise in ears.

From the side of the musculoskeletal and connective tissue: ossalgia.

From the cardiovascular system: pain in the heart, tachycardia, hypotension, arterial hypertension.

From the skin and subcutaneous fat: increased sweating, furunculosis.

From the mucous membranes: blepharitis, conjunctivitis, stomatitis, gingivitis, angular stomatitis.

Reactions together: pain, infiltration. Common symptoms: thirst, faint.

Infectious and parasitic diseases: acute respiratory viral infections, infection caused by the herpes simplex virus.

On the part of the blood system and lymphatic system: lymphopenia, lymphadenopathy, eosinophilia, monocytopenia.

From the endocrine system: hypothyroidism.

From the immune system: Pollinosis.

From the nochek and urinary tract: violation of urine.

From the genitals and the breast: dysmenorrhea.

Laboratory indicators: decrease in the concentration of TSH, hypocholesterolemia.

When Algeron® was used at a dose of 2.0 μg / kg / week in combination with ribavirin, in addition to the adverse events that were observed with Algeron® at a dose of 1.5 μg / kg / week, the following adverse reactions were also noted: menorrhagia (2% ), in places of administration (2%) - cyanosis, spot hemorrhage, furuncle.

Infrequent adverse reactions (≥1/1000; <1/100):

From the central and peripheral nervous system: muscle weakness, impaired coordination of movements, confusion of speech.

From the gastrointestinal tract: erosive gastritis, cholecystitis, pancreatitis, cheilitis, glossitis.

From the respiratory system, chest and mediastinum: bronchoobstructive syndrome, tonsillitis.

From the side of the musculoskeletal and connective tissue: periostitis.

From the cardiovascular system: arrhythmia.

From the skin and subcutaneous fat: erythema, rosacea.

On the part of the blood system and lymphatic system: poikilocytosis.

From the endocrine system: thyrotoxicosis, thyroiditis.

Side effects observed with Algeron® for the treatment of chronic hepatitis C in HIV-infected patients:

In patients with co-infection with HIV / chronic hepatitis C. treated with Algeron ® in combination with ribavirin, the following adverse events were observed that were not present in patients with a monoinfection: toothache (2.86%), inhibition (1.43%) , apathy (1.43%), hallucinations (1.43%), hypomania (1.43%), back pain (5.71%), icterus of the skin (1.43%), ear pain (1, 43%); among laboratory abnormalities - increased activity ACT (40%), ALT (35.71%), gamma glutamyltranspeptidase (30%), alkaline phosphatase (10%); hyperalbuminemia (22.86%); increase (15.71%) or decrease (2.86%) of the creatinine concentration; neutrophilia (2.86%), leukocytosis (1.43%), thrombocytosis (1.43%). In HIV-infected patients, there was a decrease in the number Cd4-I- lymphocytes (11.43%) and more often than in patients with monoinfection, lymphopenia was registered (61.43%).

Side effects observed with the use of similar peginterferon alfa-2b preparations in adult patients in combination with or without ribavirin:

Very frequent adverse reactions (≥1/10):

From the central and peripheral nervous system: headache, dizziness.

From the side of the psyche: depression, anxiety, emotional lability, violation of concentration, insomnia.

From the gastrointestinal tract: vomiting, nausea, abdominal pain, diarrhea, dry mouth.

From the respiratory system, chest and mediastinum: shortness of breath, cough.

From the side of the musculoskeletal and connective tissue: myalgia, arthralgia, musculoskeletal pain.

From the skin and subcutaneous fat: alopecia, itching, dry skin, rash.

Reactions at the site of administration: reaction at the injection site, inflammation at the site of administration.

Common symptoms: fatigue, asthenia, sensitivity, chills, fever, flu-like syndrome, pain.

Infectious and parasitic diseases: viral infections, pharyngitis.

On the part of the blood and lymphatic system: anemia, neutropenia.

From the side of metabolism and nutrition: anorexia.

Laboratory and instrumental data, decrease in body weight.

Frequent adverse reactions (≥1/100; <1/10):

From the central and peripheral nervous system: amnesia, memory disorders, syncope, migraine, ataxia, confusion, neuralgia, paresthesia, hypesthesia, hyperstasy, hypertonic muscle, drowsiness, attention disturbance, tremor, dysgeusia.

From the side of the psyche: aggression, agitation, anger, mood changes, behavior change, nervousness, sleep disorders, decreased libido, apathy, unusual dreams, tearfulness.

From the gastrointestinal tract: dyspepsia, gastroesophageal reflux disease, stomatitis, ulcerative stomatitis, glossodynia, gum bleeding, constipation, flatulence, hemorrhoids, cheilitis, bloating, gingivitis, glossitis, dental abnormalities.

From the liver and bile ducts: hyperbilirubinemia, hepatosglia.

From the cardiovascular system: palpitation, tachycardia, arterial hypertension, arterial hypotension, hot flashes.

From the respiratory system, chest and mediastinum: dysphonia, bleeding from the nasal cavity, disorders of the respiratory system (respiration), obstruction of the airways, swelling of the mucous membrane of the paranasal sinuses, nasal congestion, rhinorrhea, increased secretion of the mucosa of the upper respiratory tract, pain in the pharynx and larynx.

From the side of the hearing organ and labyrinthine disorders: disorder / loss of hearing, tinnitus, vertigo.

From the side of the musculoskeletal and connective tissue: arthritis, back pain, muscle spasms, pain in the limbs.

From the skin and subcutaneous fat: psoriasis, photosensitivity reactions, maculopapular rash, dermatitis, erythematous rash, eczema, night sweats, hyperhidrosis, acne, furuncle, erythema, urticaria, dysfunction of the hair, nail abnormalities.

Reactions together: pain at the injection site.

Common symptoms: chest pain, chest discomfort, malaise, face swelling, peripheral edema, discomfort, thirst.

Infectious and parasitic diseases: bacterial infections (including sepsis), fungal infections, influenza, upper respiratory tract infections, bronchitis, an infection caused by the herpes simplex virus, sinusitis, otitis media, rhinitis.

On the part of the blood system and lymphatic system: Hemolytic anemia, leukopenia, thrombocytopenia, lymphadenopathy.

From the endocrine system: hypothyroidism, hyperthyroidism.

From the side of the organ of vision: impaired vision, blurred vision, photophobia, conjunctivitis, eye irritation, tearing disorders, eye pain, dry eyes.

From the side of metabolism and nutrition: hypocalcemia, hyperuricemia, dehydration, increased appetite.

From the side of the kidneys and the urinary system: frequent urination, polyuria, a violation of urine.

From the genitals and the breast: amenorrhea, pain in the mammary gland, menorrhagia, menstrual disorders, ovarian disorders, vaginal discharge, sexual dysfunction, prostatitis, erectile dysfunction.

Infrequent adverse reactions (≥1/1000; <1/100):

From the side of the central and peripheral overtax system: neuropathy, peripheral neuropathy.

From the side of the psyche: suicide, attempted suicide, suicidal thoughts, psychosis, hallucinations, panic attacks.

From the gastrointestinal tract: pancreatitis, pain in the oral cavity.

From the cardiovascular system: myocardial infarction. From the side of the hearing organ and labyrinthine disorders: earache.

From the side of the musculoskeletal and connective tissue: pain in the bones, muscle weakness.

Infectious and parasitic diseases: infection at the injection site, infection of the lower respiratory tract.

From the immune system: hypersensitivity reactions to the drug.

From the side of metabolism and nutrition: diabetes mellitus, hypertriglyceridemia.

From the side of the organ of vision: exudate in the retina.

Rare adverse reactions (≥1/10000; <1/1000):

From the central and peripheral nervous system: convulsions.

From the side of the psyche: bipolar disorders.

From the gastrointestinal tract: ischemic colitis.

From the cardiovascular system: congestive heart failure, cardiomyopathy, arrhythmia, pericarditis, vasculitis.

From the side of the musculoskeletal and connective tissue: rhabdomyolysis, myositis, rheumatoid arthritis.

From the skin and subcutaneous fat: cutaneous form of sarcoidosis (cutaneous sarcoidosis).

Reactions together: necrosis at the site of administration.

From the immune system: sarcoidosis.

From the side of metabolism and nutrition: diabetic ketoacidosis.

From the side of the organ of vision: loss of visual acuity or limitation of visual fields, retinal hemorrhage, retinopathy, blockage of retinal arteries, retinal vein occlusion, optic neuritis, optic disc edema, edema of the macula.

From the side of the kidneys and the urinary system: renal insufficiency.

Highly rare adverse reactions (<1/10000):

From the central and peripheral nervous system: cerebrovascular bleeding, cerebrovascular ischemia, encephalopathy.

From the gastrointestinal tract: ulcerative colitis.

From the cardiovascular system: ischemia of the heart.

From the respiratory system, chest and mediastinum: interstitial pulmonary disease.

From the skin and subcutaneous fat: Stevens-Johnson syndrome, toxic epidermal necrolysis, multiforme exudative erythema.

On the part of the blood system and lymphatic system: aplastic anemia.

From the immune system: sarcoidosis (or exacerbation of sarcoidosis).

Frequency not set:

From the central and peripheral nervous system: paralysis of the facial nerve, mononeuropathy.

From the side of the psyche: thoughts of murder, mania.

From the cardiovascular system: pericardial effusion.

On the part of the blood and lymphatic system: true erythrocyte aplasia.

From the immune system: immediate-type hypersensitivity reactions, including angioedema, anaphylaxis and anaphylactic reactions, including anaphylactic shock, idiopathic thrombocytopenic purpura, systemic lupus erythematosus.

From the side of the organ of vision: serous retinal detachment.

Side effects observed with the use of similar preparations of peginterferon alfa-2b for the treatment of chronic hepatitis C in HIV-infected patients

In HIV-infected patients with chronic hepatitis C who received a similar preparation of peginterferon alfa-2b in combination with ribavirin in large studies, the following adverse events were observed with a frequency above 5% that were absent in patients with a monoinfection: oral cavity (14%), acquired lipodystrophy (13%), a decrease in the number Cd4+ lymphocytes (8%), decreased appetite (8%), increased activity of gamma-glutamyltrans-neptidase (9%), back pain (5%), increased blood amylase activity (6%), acid in the blood (5%), hepatitis with cytolysis (6%), increased lipase activity (6%) and pain in the extremities (6%).

Overdose:

In case of an overdose of peginterferon alfa-2b preparations, no serious adverse events were noted. It is possible to increase dose-dependent side effects. In case of a random dose of peginterferon alfa-2b, which exceeded the recommended dose by no more than 2 times, no serious overdose symptoms were observed. Undesirable phenomena pass independently and do not require withdrawal of the drug. There were reported cases of the use of peginterferon alfa-2b in doses exceeding the recommended 10.5 times. The maximum daily dose was 1200 μg. The undesirable events observed during overdose are consistent with the available data on the safety profile of methylated interferons alpha.

Cases of overdose of peginterferon alfa-2a with the introduction of the drug for two consecutive days (without observing the weekly interval) and with daily administration for one week (total dose of 1260 μg per week) are described. No unusual, serious and treatment-related adverse events were noted. There is no specific antidote. Hemodialysis and peritoneal dialysis are ineffective. If necessary, symptomatic therapy is performed.

Interaction:

There was no pharmacokinetic interaction between the preparations of peginterferon alfa and ribavirin.

Therapy with peginterferon alfa-2a at a dose of 180 μg per week for 4 weeks did not affect the pharmacokinetic profile of tolbutamide (CYP 2C9), mephenitone (CYP 2S19), debrisoquine (CYP 2D6), and dansone (CYP-ZA4) in healthy male volunteers. Therapy with peginterferon alfa-2b (but 1.5 mg / kg per week for 4 weeks) did not affect the activity of the isoenzymes CYP1A2, CYP3A4 or N-acetyltransferase, but an increase in the activity of the isoenzymes CYP2C8 / C9 and CYP2D6 was noted.

Therefore, care should be taken when prescribing Algeron® together with drugs in the metabolism of which the isozymes CYP2C8 / C9 or CYP2D6 are involved.

Taking into account the property of peginterferopal alpha to inhibit the activity of the 1A2 cytochrome P450 isoenzyme and to increase the AUC of tsofillin (by about 25%) with simultaneous administration of Algeron® and theophylline, it is necessary to monitor the concentration of theophylline in the serum and correct its dose accordingly. Therapy with peginterferon alfa-2a at a dose of 180 μg per week was associated with an increase in the average levels of methadone metabolites by 10-15%.Although the clinical significance of this interaction is not determined, it is recommended that the symptoms of methadoxine intoxication be closely monitored during treatment with Algeron®. In patients with HIV receiving highly active antiretroviral therapy (HAART), the risk of developing lactic acidosis is increased. Therefore, with the addition of the Algeron® +ribavirin HAART should be used with caution.

There was no interaction between ribavirin and nucleoside reverse transcriptase inhibitors (lamivudine, zidovudine, stavudium). The worsening of the course of anemia caused by ribavirin was observed against the background of HIV therapy with zidovudine. Joint use of ribavirin and zidovudine is not recommended, since it leads to an increased risk of anemia. A combination of didanosine and ribavirin is not recommended. Ribavirin increases the exposure of didanosine and its active metabolite (dideoxyadenosine 5-triphosphate), which can lead to the development of fatal liver failure, peripheral neuropathy, pancreatitis, symptomatic lactic acidosis.

Results of a clinical trial,in which studied the use of telbivudine (600mg daily) in combination with peginterferon alfa-2a (180 mg 1 time per week s.c.), demonstrated an increased risk of peripheral neuropathy when using this combination. The mechanism of this phenomenon is unknown. In addition, the safety and efficacy of telbivudine in combination with alpha interferons for the treatment of chronic hepatitis B have not been confirmed. The combined use of Algeron® and telbivudine is contraindicated.

Special instructions:

The efficacy and safety of Algeron® in monotherapy or combination with ribavirin in individuals younger than 18 years, as well as in patients after liver or other organ transplantation, are not established.

Algeron® should be used with caution in diseases such as chronic obstructive pulmonary disease or diabetes mellitus with a tendency to develop ketoacidosis. Care should also be taken in patients with bleeding disorders (eg, thrombophlebitis, pulmonary embolism) or severe myelosuppression.

The psychic sphere and the central nervous system (CSP). Serious CNS abnormalities, especially depression, suicidal ideation and suicide attempts, were observed in some patients with interferon alfa therapy, and after discontinuation of therapy (mainly for 6 months). Other CNS disorders, including aggressive behavior (in some cases directed at other people, for example, thoughts of murder), bipolar disorders, mania, confusion and changes in mental status were observed in patients receiving interferon alfa therapy. Care should be taken to monitor patients for any signs or symptoms of mental disorders. If such symptoms appear, you should evaluate the potential hazard and consider the need for drug therapy for these conditions. If mental disorders are worsened or worsened or suicidal thoughts appear, it is recommended that Algeron® therapy be stopped and patient follow-up, if necessary, provided with a psychiatrist consultation. In some patients, usually in the elderly who received interferon alfa in high doses for the therapy of cancer, there was a violation of consciousness, coma, including cases of encephalopathy. Although these disorders were generally reversible, some patients required up to 3 weeks to fully reverse their development. Very rarely, when interferon alfa was used in high doses, epileptic seizures developed.

Patients with severe psychiatric disorders, including in the anamnesis. If Algeron® is to be prescribed for patients with severe mental disorders (including patients with a history of such a history), treatment can be initiated only after a thorough individual examination and appropriate therapy for the mental disorder.

Ppatients who use narcotic substances. In patients infected with the hepatitis C virus, who use narcotic substances (alcohol, marijuana, etc.), the risk of developing mental disorders (or worsening of the current) increases with interferon alpha therapy. If such patients with interferon alpha therapy are necessary,then before the start of therapy should carefully assess the presence of concomitant mental illness and the risk of using drugs, to conduct adequate therapy. If necessary, the observation of a psychiatrist or an expert in narcology for the examination, therapy and management of such patients is shown. Careful monitoring of such patients during and after completion of interferon therapy is necessary. It is recommended that timely measures be taken to prevent the recurrence or aggravation of mental disorders, as well as the resumption of drug use.

The cardiovascular system. Patients with heart failure, myocardial infarction and / or arrhythmias (including in anamnesis) should be under constant supervision. In patients with heart disease, ECG (electrocardiography) is recommended before and during treatment. Arrhythmias (mostly supraventricular) tend to be amenable to conventional therapy, but may require the withdrawal of Algeron®. Anemia caused by taking ribavirin can aggravate the course of cardiovascular disease. In case of worsening of the course of cardiovascular diseases, therapy should be interrupted or canceled.

Hypersensitivity. In rare cases, therapy with peginterferon alfa drugs was complicated by immediate-type hypersensitivity reactions. With the development of anaphylactic reactions, urticaria, angioedema, bronchospasm, the drug is canceled and immediately prescribed appropriate therapy. A transient rash does not require the withdrawal of therapy.

Function of the kidneys. It is recommended that the kidney function be studied in all patients prior to the initiation of therapy with Algeron®. With QC less than 50 ml / min, combination therapy with Algeron ® and ribavirin should not be used. If the creatinine concentration is increased> 0.177 mmol / l during the treatment, the administration of Algeron® and ribavirin should be discontinued. In patients with impaired renal function and also over the age of 50, when AlGeron® is used in combination with ribavirin, their condition should be carefully monitored for possible anemia.

Function of the liver. With the development of hepatic insufficiency treatment with Algeron® and ribavirin is canceled.

Fever. Fever can be observed within the influenza-like syndrome,which is often recorded in the treatment of interferons, nevertheless, it is necessary to exclude other causes of persistent fever.

Hydration. It is recommended to provide adequate hydration of patients, since in some patients in the treatment of peginterferon alfa-2b, an arterial hypotension associated with a decrease in the volume of fluid in the body was observed.

Diseases of the lungs. In rare cases in patients who received interferon alfa, in the lungs, infiltrates of unclear etiology, pneumonitis or pneumonia developed, incl. with a lethal outcome. When fever, cough, dyspnea and other respiratory symptoms occur, all patients should be given a chest x-ray. In the presence of infiltrates on the chest radiograph or signs of pulmonary dysfunction, more careful monitoring of patients should be established and, if necessary, abolished Algeron®. Immediate withdrawal of interferon and administration of glucocorticosteroids lead to the disappearance of unwanted phenomena from the lungs.

Autoimmune disorders. In the treatment of interferon alfa in some cases, the occurrence of autoantibodies was noted.Clinical manifestations of autoimmune diseases occur more often in the treatment of patients predisposed to the development of autoimmune disorders. When symptoms similar to manifestations of autoimmune diseases occur, a thorough examination of the patient should be made and the possibility of continuing therapy with interferon should be assessed. In patients with chronic hepatitis C who received interferon therapy, cases of Vogt-Koyanagi-Harada syndrome were reported. This syndrome is a granulomatous inflammatory disease affecting the organ of vision, the organ of hearing, the soft meninges and the skin. In case of suspected Vogt-Koyanagi-Harada syndrome, antiviral therapy should be stopped and the need for glucocorticosteroids should be considered.

Psoriasis and sarcoidosis. In connection with reports of exacerbation of psoriasis or sarcoidosis in patients treated with interferon alfa, the use of Algeron® in patients with these diseases is recommended only in cases where the perceived benefit of the treatment justifies the potential risk. With exacerbation of psoriasis or sarcoidosis in patients receiving therapy with Algeron®,the question of drug cancellation should be considered.

Changes on the part of the organ of sight. Disturbances from the visual organ (including retinal hemorrhage, exudates in the retina, vein or retinal artery obstruction) have been reported rarely after interferon alfa therapy. All patients need to have an ophthalmological examination before starting therapy. Each patient receiving therapy with Algeron® should undergo an ophthalmological examination in case of complaints about visual acuity reduction or restriction of visual fields. Patients with diseases in which retinal changes can occur, such as diabetes mellitus or hypertension, are recommended to undergo an ophthalmic examination during Algeron® therapy. When there is or worsening of vision disorders, consideration should be given to discontinuing therapy with Algeron®.

Changes in the teeth and non-dyroid. In patients who received combination therapy with peginterferon alfa-2b and ribavirin, there were pathological changes in the teeth and peri-toothed tissues. Dry mouth with prolonged therapy can contribute to damage to the teeth and mucous membrane of the oral cavity. Patients are advised to comply with oral hygiene and regularly undergo examination at the dentist.

Thyroid status. The mechanism of the influence of interferon alpha on thyroid function is unknown. In patients with chronic hepatitis C who received interferon alfa-2b, hypothyroidism or hyperthyroidism developed in 2.8% of cases. These disorders were controlled by standard therapy. Before starting treatment with Algeron ® in patients, serum TSH concentrations should be determined and standard therapy should be prescribed for thyroid dysfunction. The concentration of TSH should also be determined when symptoms of thyroid dysfunction occur when interferon alpha is treated. Treatment with Algeron® should not be carried out if the TSH activity is not maintained at a normal level.

Laboratory research. Before starting treatment with Algeron®, standard clinical and biochemical blood tests should be performed. They are also recommended during the therapy every 2 weeks (clinical blood test) and every 4 weeks (biochemical blood test).Algeron® can be used with the following laboratory indicators: hemoglobin ≥120 g / l (women) and ≥130 g / l (male), platelet count> 90x10⁹/ l, the absolute number of neutrophils -> 1.5x10⁹/ l, the concentration of TTG and thyroxine within the norm or thyroid function is medically controlled.

With severe hypertriglyceridemia, before adjusting the dose of Algeron®, it is necessary to prescribe a diet or medication with regard to the concentration of triglycerides in the fasting serum. After discontinuing the drug, hypertriglyceridemia quickly disappears.

Interferon alfa therapy may be accompanied by the development of ulcerative and hemorrhagic and / or ischemic colitis within 12 weeks of the initiation of therapy. Abdominal pain, the presence of blood in the feces, fever are typical symptoms of the manifestation of colitis. When appropriate complaints are made, Algeron® should be immediately canceled. Recovery usually begins 1-3 weeks after drug withdrawal.

In the treatment of peginterferon alfa-2a in combination with ribavirin, there have been cases of development of pancreatitis, sometimes fatal. When developing symptoms of pancreatitis, Algeron® and ribavirin therapy should be discontinued.

When taking interferon alfa preparations, serious infectious complications (bacterial, viral, fungal), sometimes fatal, are described. Some of them were accompanied by the development of neutropenia. If serious infectious complications occur, therapy should be discontinued and appropriate treatment should be prescribed.

HIV co-infection / chronic hepatitis C. Before starting treatment, you should carefully review the possible side effects of antiretroviral drugs that the patient will take together with drugs for chronic hepatitis C. In patients who simultaneously received stavudine and interferon with or without ribavirin, the incidence of pancreatitis and / or lactic acidosis was 3%. Patients with co-infection with HIV / chronic hepatitis C, HAART, may be at risk for developing lactic acidosis. Therefore, care should be taken when adding Algeron® and ribavirin to HAART (see the medical instructions for ribavirin).

The simultaneous use of ribavirin and zidovudine is not recommended because of the increased risk of anemia.Close monitoring is needed to detect signs and symptoms of hepatic decompensation (including ascites, encephalopathy, bleeding from varicose veins, impaired hepatic function, ≥7 on the Child-Pugh scale) in patients with co-infection. The Child-Pugh score does not always accurately reflect the presence of hepatic decompensation and can change iodine due to factors such as increased concentration of indirect (free) bilirubin in the blood, hypoalbuminemia due to drug therapy. With the development of hepatic decompensation, Algeron® should be immediately withdrawn.

Caution should be exercised in appointing Algeron® to patients with a low level Cd4+ lymphocytes. Insufficient data on the efficacy and safety of pegylated interferon alpha preparations in patients with HIV co-infection / chronic hepatitis C with Cd4+ lymphocytes less than 200 cells / μl.

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

Effect on the ability to drive transp. cf. and fur:During the treatment, there may be weakness, dizziness, snotty, confusion. When these phenomena occur, you should abandon driving the car or working with machines and mechanisms.

Form release / dosage:

Solution for subcutaneous administration, 200 μg / ml.

Packaging:

By 0.4, 0.5, 0.6, 0.8 or 1.0 ml in a three-component sterile syringe from a colorless neutral glass. For each syringe stick a label.

1 syringe in a contour cell box from a polymer film.

For 1 or 4 contour squares, together with the instructions for use, are placed in a pack of cardboard.

Storage conditions:

At a temperature of 2 to 8 ° C in a dark place. Do not freeze. Keep out of the reach of children.

If necessary, one-time storage by patients of an unopened vial / syringe in a place protected from light for not more than 30 days at a temperature of no higher than 25 ° C is permissible.The date of storage at room temperature should be marked on the package.

Shelf life:

2 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002017

Date of registration:28.02.2013 / 24.03.2017

Expiration Date:28.02.2018

The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia

Manufacturer: & nbsp

BIOCAD, CJSC Russia

Information update date: & nbsp16.07.2017

Illustrated instructions

Instructions

Algeron® (Algeron®)