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Instructions

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Instruction for use: Algeron

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Dosage form: Solution for subcutaneous administration

Active substance: Tsepeginterferon alfa-2b

ATX

L03AB Interferons

Pharmacological groups:

Cytokine [Antiviral (except HIV) agents]

Cytokine [Interferons]

The nosological classification (ICD-10)

B18.2 Chronic viral hepatitis C: Hepatitis C; Recurrence of chronic hepatitis C; Chronic active hepatitis C; Chronic viral hepatitis C; Chronic hepatitis C without cirrhosis; Chronic hepatitis C with compensated cirrhosis; Chronic hepatitis C

Composition

Solution for subcutaneous administration 1 ml

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

Auxiliary substances: sodium acetate trihydrate - 2,617 mg; Glacial acetic acid - up to pH 5; Sodium chloride - 8 mg; Polysorbate 80 - 0.05 mg; Disodium edetate dihydrate 0.056 mg; Water for injection - up to 1 ml

Description of dosage form

Transparent, from a colorless to light yellow solution.

Pharmachologic effect

Mode of action - antiviral, immunomodulating.

Pharmacodynamics

Zepeginferferon alfa-2b is formed by attachment to the interferon alpha-2b molecule of a polymeric structure - polyethylene glycol (PEG) with a molecular weight of 20 kDa. The biological effects of the Algeron® preparation are due to interferon alpha-2b. Interferon alfa-2b is produced by a biosynthetic method using recombinant DNA technology and is produced by a strain of the bacterium Escherichia coli into which the human interferon alpha-2b gene has been introduced into the human genome. 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. Immunomodulatory effect is manifested primarily by the intensification of cell-mediated reactions of the immune system. Interferon increases the cytotoxicity of T-lymphocytes and natural killers, 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 (IL, 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'-oligoadenylate synthetase. In the study of the pharmacodynamics of Algeron®, a single dose of volunteers showed a dose-dependent increase in serum neopterin concentration, Cmax of which was achieved 48 hours later. When Algerone® was administered once a week at a dose of 1.5 μg / kg, serum neopterin concentration in patients with chronic hepatitis C Was maintained at a constantly 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 interferon alpha-2b molecule results in a significant slowing of the intake from the injection site, an increase in Vd, and a decrease in clearance. A decrease in clearance leads to more than a 10-fold increase in the duration of terminal T1 / 2 compared to unmodified interferon alpha-2b (32 vs. 2.2 h). Excretion of Algeron ® occurred within> 153 h (6.5 days).

In the study of the pharmacokinetics of the Algeron® preparation, with single administration to volunteers at a therapeutic dose of 1.5 μg / kg in combination with ribavirin, serum Cmax was achieved on average 31 (18-48) h after administration and was 1401 ± 233 (1250-1803) pg / ml . AUC0-168 hours averaged 144212 ± 49839 (106845-226062) pg / ml / h. The clearance of the preparation averaged 9.9 ± 3.2 (5.2-13 ml / h · kg), T1 / 2 - 57.8 ± 8.4 (48-66.5) h. The value of the elimination constant Kel in The average was (0.0124 ± 0.002) h-1.

When AlGeRON® was administered once a week, a dose-dependent gradual increase in the concentration of the drug before the 8th week was observed in the combined therapy of chronic hepatitis C, after which no further cumulation before the 12th week 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 Cl creatinine in patients with impaired renal function (Cl creatinine 20 to 100 mL / min). When studying peginterferon alfa-2b, an increase in Cmax, AUC and T1 / 2 was found in proportion to the degree of renal failure.

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

Pharmacokinetics in patients with impaired liver function. Pharmacokinetic 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 hepatic impairment, the pharmacokinetics of peginterferon alfa preparations have not been studied, and 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.

Indication of the Algeron

Treatment of primary chronic active hepatitis C in combination therapy with ribavirin in adult patients with positive HCV RNA in the absence of signs of liver decompensation.

Contraindications

Algeron® preparation;

Hypersensitivity to ribavirin or any other component of the drug;

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

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

Autoimmune hepatitis or other autoimmune diseases in the anamnesis;

Dysfunction of the thyroid gland, which cannot be maintained at a normal level by drug therapy;

Epilepsy and / or dysfunction of the CNS;

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

Severe CAS diseases, including unstable and uncontrolled forms that existed for at least 6 months prior to treatment;

Severe diseases (including renal failure, Cl creatinine <50 ml / min, the need for hemodialysis);

Malignant neoplasms;

Rare hereditary diseases, such as lactose intolerance, lactase deficiency or glucose-galactose malabsorption;

Hemoglobinopathies (for example, thalassemia, sickle cell anemia);

Treatment in men whose partners are pregnant;

Marked suppression of bone marrow hematopoiesis (neutrophils <0.5 · 109 / l, platelets <25 · 109 / l, hemoglobin <85 g / l);

pregnancy;

Lactation period;

Children's age till 18 years.

With caution: severe lung disease (eg, chronic obstructive pulmonary disease); Diabetes mellitus with a tendency to develop a ketoacidotic coma; Disorders associated with the coagulating system of blood (for example, with thrombophlebitis, pulmonary embolism, transferred); Neutrophils <1.5 · 109 / l, platelets <90 · 109 / l, hemoglobin <100 g / l; In combination with myelotoxic drugs; In patients with HIV / chronic hepatitis C coinfection, the CD4 + lymphocyte count is less than 200 cells / μl or less than 100 cells / μl with a HIV RNA level of more than 5000 copies / ml.

Application in pregnancy and breastfeeding

Preparations of peginterferon-alpha should not be administered during pregnancy. The teratogenic effects of peginterferon-alpha 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, in the treatment of 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, in order to avoid undesirable effects on the child, either breastfeeding or therapy should be canceled, 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 exerted pronounced teratogenic effects and caused fetal death. Ribavirin is contraindicated in pregnant women and men whose partners are pregnant. Ribavirin therapy should not be given until a negative pregnancy test is performed immediately before the start of therapy. Women capable of childbearing, 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 ways) during treatment and for 7 months after the end of therapy.

Side effects

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

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

Side effects observed with combination therapy with Algeron® at a dose of 1.5 μg / kg / week and ribavirin

The most frequent adverse reactions (≥1 / 10)

From the central and peripheral nervous system: headache, irritability, depression, emotional lability.

From the digestive tract: nausea, diarrhea.

On the part of the respiratory system: dry cough.

From the musculoskeletal system: pain in the joints, muscle pain.

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

Reactions together with administration: inflammation at the site of administration.

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

On the part of the blood and lymphatic system: leukopenia, neutropenia, anemia, thrombocytopenia. Reduction of hematological parameters, as a rule, was noted in the first 4 weeks of treatment; They improved after correction of the dose within 4-8 weeks. Thrombocytopenia less than 75 · 109 / l was observed in approximately 6% of patients. In most cases, changes in blood levels could be eliminated by reducing the dose, so they did not lead to early termination of treatment. Modification of the dose of ribavirin for anemia was required in 2% of patients.

Laboratory indicators: hypoglycemia, hypertriglyceridemia.

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

From the central and peripheral nervous system: dizziness.

From the gastrointestinal tract: decreased appetite, abdominal pain, dry mouth, heartburn.

From the CVS: tachycardia, arterial hypotension.

From the skin and subcutaneous fat: alopecia.

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

Reactions at the site of administration: pain, infiltration, itching at the injection site.

Laboratory indicators: hyperglycemia, changes in levels of thyroid hormones (increased concentration of TSH).

Using Algeron® at a dose of 2 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: pain in the region of the heart (6%), menorrhagia (2%), in places of administration (2%) - cyanosis, spot hemorrhage, furuncle.

Side effects observed with the use of similar peginterferon alfa-2b preparations in combination with ribavirin

The most frequent adverse reactions (≥1 / 10)

From the central and peripheral nervous system: headache, insomnia, dizziness, impaired concentration, depression, irritability, anxiety.

From the gastrointestinal tract: nausea, diarrhea, abdominal pain, decreased appetite.

From the respiratory system: shortness of breath, cough, pharyngitis.

From the musculoskeletal system: joint pain, musculoskeletal pain.

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

Reactions at the site of administration: pain and inflammation at the site of administration.

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

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

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

From the central and peripheral nervous system: a violation of taste, ataxia, paresthesia, hypesthesia, emotional lability, aggressive behavior, decreased libido, drowsiness, hyperesthesia, confusion, excitability, apathy, tremor, fainting.

From the digestive tract: dyspepsia, unstable stools, constipation, vomiting, bloating, dry mouth, bleeding gums, stomatitis, ulcerative stomatitis, glossitis.

From the hepatobiliary system: hepatomegaly, jaundice.

From the CVS: palpitations, tachycardia, arterial hypertension, arterial hypotension, hot flushes.

On the part of the respiratory organs: rhinitis, bronchitis, sinusitis, nasal congestion, respiratory disorders, rhinorrhea, unproductive cough.

From the musculoskeletal system: arthritis.

From the skin and subcutaneous fat: psoriasis, deterioration of the already existing psoriasis, eczema, photosensitivity reactions, maculopapular rash, erythematous rash, dermatitis, acne, furunculosis, skin disorders, bruising, sweating, hair structure disorder, Hand nails.

Common symptoms: malaise, pain in the chest, thirst, pain in the right hypochondrium.

On the part of the blood system and lymphatic system: neutropenia, thrombocytopenia, lymphadenopathy. Reduction of CD4 + lymphocytes. Treatment with drugs peginterferon alfa HIV-infected patients was accompanied by a decrease in the absolute number of CD4 + lymphocytes without changing their percentage. These changes were completely reversible. The administration of peginterferon alfa preparations did not adversely affect the level of viral load of HIV in patients with HIV / chronic hepatitis C coinfection during and after treatment.

On the part of the endocrine system: hypothyroidism, hyperthyroidism.

On the part of the organs of vision: conjunctivitis, blurring of vision, pain in the eye, lesion of the lacrimal gland.

On the part of the hearing organs: violation / loss of hearing, tinnitus, otitis media.

From the kidneys and urinary system: frequent urination, polyuria.

On the part of the reproductive system: women - amenorrhea, hypermenorrhea, dysmenorrhea, pain in the mammary glands, dysfunction of the ovaries, violations of the vagina; Men - impotence, prostatitis, violations of sexual function (without specifying an exact diagnosis).

Other: viral infections, fungal infections.

Laboratory indicators: increased ALT activity, hyperbilirubinemia, changes in thyroid hormone levels (hypo- and hyperthyroidism), hypo- and hyperglycemia, hyperuricemia, hypocalcemia.

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

From the central and peripheral nervous system: suicidal thoughts and attempts, aggressive behavior, sometimes directed at others, psychosis, including hallucinations, peripheral neuropathy, convulsive seizures.

From the gastrointestinal tract: pancreatitis.

From the CVS: arrhythmia, cardiomyopathy.

From the musculoskeletal system: rhabdomyolysis, myositis.

From the kidney and urinary system: impaired renal function, kidney failure.

On the part of the organs of vision: retinopathy, bleeding in the retina of the eye, blockage of veins or arteries of the retina, focal changes in the retina, reduced visual acuity or limitation of the visual fields, optic neuritis, edema of the optic nerve.

Very rare adverse reactions (<1/10000)

From the central and peripheral nervous system: cerebral hemorrhage, cerebrovascular ischemia, encephalopathy, polyneuropathy.

From the gastrointestinal tract: ischemic colitis, ulcerative colitis.

On the part of the respiratory organs: pulmonary infiltrates, pneumonitis, interstitial pneumonitis.

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: pancytopenia, aplastic anemia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura.

From the kidneys and urinary system: nephrotic syndrome.

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

Laboratory indicators: hypertriglyceridemia, hyperlactatacidemia, lactatacidosis.

Frequency not set

From the central and peripheral nervous system: paralysis of the facial nerve, neuropathy (including mononeuropathy).

From the gastrointestinal tract: violations from the periodontal, dental disorders.

On the part of the immune system: Fogl-Koyanagi-Harada syndrome, systemic lupus erythematosus, rheumatoid arthritis (first arising or worsening of the condition), vasculitis, acute hypersensitivity reactions, including hives, angioedema, bronchospasm, anaphylaxis.

Interaction

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

Therapy with peginterferon alfa-2a at a dose of 180 mcg / week for 4 weeks did not affect the pharmacokinetic profile of tolbutamide (CYP 2C9), mephenitone (CYP2S19), debrisoquine (CYP2D6) and dapsone (CYP3A4) in healthy male volunteers. Therapy with peginterferon alfa-2b (1.5 mg / kg / 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.

Given the property of peginterferon alfa to inhibit the activity of the 1A2 cytochrome P450 isoenzyme and increase the theophylline AUC (by about 25%) with the simultaneous administration of Algeron® and theophylline, it is necessary to monitor the concentration of theophylline in the serum and adjust its dose accordingly.

Therapy with peginterferon alfa-2a at a dose of 180 μg / 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 to carefully monitor the symptoms of methadoxine intoxication during treatment with Algeron®. In patients with HIV receiving highly active antiretroviral therapy (HAART), the risk of developing lactic acidosis is increased. Therefore, when adding the combination of Algeron® and ribavirin to HAART, care should be taken.

There was no interaction between ribavirin and nucleoside reverse transcriptase inhibitors (lamivudine, zidovudine, stavudine).

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 hepatic insufficiency, peripheral neuropathy, pancreatitis, symptomatic lactic acidosis.

Dosing and Administration

SC, in the area of the anterior abdominal wall or thigh. It is recommended to alternate the injection site.

Therapy should be started by a doctor with experience in the treatment of patients with hepatitis C, and further under his supervision.

In combination therapy with ribavirin, Algeron® is used as a subcutaneous injection at a dose of 1.5 mkg / kg once a week. The dosage regimen of the Algeron® preparation is indicated in Table 1.

Table 1

Algeron® dosing regimen in patients with chronic hepatitis C

Body weight, kg Dose for administration once a week, mkg Amount of solution Algeron®, ml Minimum volume of syringe, ml
40 60 0,3 0,4
41–46 70 0,35
47–53 80 0,4
54–60 90 0,45 0,5
61–66 100 0,5
67–73 110 0,55 0,6
74–80 120 0,6
81–86 130 0,65 0,8
87–93 140 0,7
94–100 150 0,75
101–106 160 0,8
107–113 170 0,85 1
114–120 180 0,9
121–126 190 0,95
127–133 200 1
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. The drug Algeron® cannot be administered iv.Recommendations for use in patients

1. Choose the time convenient for the patient to carry out the injection. Injections should be done in the evening before bedtime.

2. Wash hands thoroughly with soap and water before applying the product.

3. Take one contoured package with a filled syringe / vial from the cardboard bundle that should be stored in the refrigerator and allow it to stand 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 change in the color of the solution or damage to the syringe / vial, Algeron® should not be used. If there is foam, which happens, when the syringe / vial is shaking or strongly shaking, 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 it is necessary to use places with loose fiber far from the stretch of the skin, nerves, joints and vessels (see Figure 1 - possible areas for injection):

- the thigh (the anterior surface of the thighs except the groin and knee);

- stomach (except the midline and umbilical region).

Picture 1. Schematic location of injection sites.

Do not use painful points, discolored, reddened areas of 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 in the area of the skin 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 the patient is writing. Remove the protective cap from the needle.

If the patient uses Algeron® in vials

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

7. The amount of Algeron® solution that must be administered during the injection depends on the dose calculated by the doctor. The dose of Algeron® is expressed in μg and is calculated taking into account the body weight. Do not independently change the dosage of Algeron® if the doctor does not say 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 prescribed to the patient by the doctor, the patient 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 on the piston until the piston reaches the necessary mark on the surface of the syringe.

If the patient uses Algeron® in vials

Slowly pull the piston back and dial into the syringe from the vial the required volume of solution, corresponding to the dose of Algeron®, which the patient prescribed 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 the needle and move the piston, remove the air bubbles by gently tapping on the syringe and pressing on the piston.

Picture 2.

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

Picture 3.

9. With a syringe perpendicular to the injection site, insert the needle into the skin at an angle of 90 ° (Picture 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 moving vertically upwards.

11. Dispose of used syringes / vials only in a specially designated place inaccessible to children.

12. If the patient forgot to enter Algeron®, inject immediately, as soon as he remembered 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

Dosing regimen of ribavirin in combination therapy with Algeron® in patients with chronic hepatitis C

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

Genotype HCV 2 and 3. If the early virologic response is reached by the 12th week of treatment (disappearance of HCV RNA or a decrease in viral load by 2 log10 (100 times) and more), it is recommended to treat for another 12 weeks (total treatment time - 24 weeks). Longer-term therapy has no advantages.

Genotype of HCV 4. In general, patients with genotype 4 are difficult to treat. The absence of special studies determines the possibility of applying the same treatment tactics as in genotype 1.

Correction of the dosing regimen

In the event of undesirable events or deviations of laboratory indicators of moderate severity, it is necessary to reduce the dose of Algeron® or ribavirin or to suspend treatment. With the normalization of the condition or laboratory indicators, you can consider increasing the dose right up to the initial dose. If, after dose adjustment, tolerability of therapy does not improve, treatment is recommended to be discontinued.

Hematologic disorders. When the number of leukocytes is less than 1.5 · 109 / L in peripheral blood, neutrophils less than 0.75 · 109 / L, the number of platelets is less than 50 · 109 / L, it is recommended to reduce the dose of Algeron ® by an amount equal to 1/3 of the therapeutic dose (1/3 TD). If the number of neutrophils and platelets does not increase, the dose of Algeron® should be reduced by another 1/3 TD. It is recommended to increase the dose if the number of leukocytes exceeds 2 · 109 / l, neutrophils - 1 · 109 / l, and platelets - 90 · 109 / 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. When the hemoglobin level is lower than 85 g / l Algeron® ≥20 g / l for any 4 weeks of treatment, it is recommended to reduce the dose of Algeron® to half the therapeutic and ribavirin to 600 mg / day and constantly use a reduced dose. If the level of hemoglobin in patients with SSS (in the compensation phase) is less than 120 g / l after 4 weeks after the dose reduction - the introduction of Algeron® and taking ribavirin is canceled. After discontinuation of taking ribavirin with the normalization of hemoglobin levels, it is possible to resume treatment at a reduced dosage of 600 mg / day, without further dose increase.

Violation of the liver. With compensated cirrhosis, dose adjustment 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 ALT or ACT activity more than 2-fold from the baseline value or more than 10-fold from the VLN, administration of the Algeron® preparation and ribavirin administration is canceled. If the concentration of bound bilirubin increases by more than 2.5 times from IHH or free bilirubin> 68.4 μmol / L for at least 4 weeks, with signs of liver function decompensation, Algeron® and ribavirin should be discontinued.

Patients with depression. With mild depression, dose adjustment is not required. With the development of moderate depression, the dose of Algeron® 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, you can increase the dose of Algeron®. With the development of severe depression, as well as suicidal thoughts, it is necessary to cancel Algeron® and ribavirin and to conduct specific treatment under the supervision of a psychiatrist.

Renal insufficiency. When prescribing combination therapy for mild renal failure (Cl creatinine> 50 mL / min), care should be taken with regard to the development of anemia. When Cl creatinine is less than 50 ml / min, combination therapy with Algeron® and ribavirin should not be prescribed. If, during therapy, the creatinine concentration rises> 0.177 mmol / L, Algerone® and ribavirin should be discontinued.

Table 3

Algorithm for correcting doses of Algeron® and ribavirin in case of adverse reactions

Laboratory indicators Reduction of ribavirin dose to 600 mg / day ** Reducing the dose of the drug Algeron ® Termination of Algeron® and ribavirin
The content of hemoglobin, g / l * 100 <85
Number of leukocytes <1,5·109/l*** <1 • 109 / L
Number of neutrophils <0,75·109/;*** <0.5 • 109 / L
Platelet count <50·109/l*** <25 • 109 / L
Content of bound bilirubin > 2.5 VGN
Free bilirubin content >85,5 Μmol / l > 68.4 μmol / l (> 4 weeks)
Creatinine content > 0.177 mmol / l
Activity of ALT, AST 2 × (from the original value) or> 10 VGN

* In patients with CVS diseases (in the compensation phase), if hemoglobin level is reduced by ≥20 g / l for any 4 weeks of treatment, it is recommended to reduce the dose of Algeron® to half the TD and ribavirin to 600 mg / day and constantly use a reduced dose.

If the level of hemoglobin in patients with SSS (in the compensation phase) is less than 120 g / l after 4 weeks after the dose reduction - the introduction of Algeron® and taking ribavirin is canceled.

** Ribavirin in a dose of 600 mg / day take 1 caps. 200 mg in the morning and 2 caps. On 200 mg in the evening, during meal.

*** The first reduction in the dose of Algeron® at 1/3 TD (up to 1 μg / kg / week), the second reduction (if necessary) of the Algeron® dose is a decrease of another 1/3 TD (up to 0.5 μg / kg / Week).

Use in special patient groups

Elderly patients. Correction of dose in the elderly is not required.

Children. In children and adolescents under the age of 18, the efficacy and safety of the Algeron® drug in combination with ribavirin has not been studied.

Patients after liver transplantation and other organs. The efficacy and safety of peginterferon alfa preparations has not been established.

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. At a random dose of peginterferon alfa-2b, which exceeded the recommended dose by no more than 2 times, serious symptoms of an overdose were not observed. Undesirable phenomena pass independently and do not require withdrawal of the drug. 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 / 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.

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, have not been 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 impaired coagulation (eg, thrombophlebitis, pulmonary embolism) or severe myelosuppression.

Mental and CNS. If Algeron® is to be prescribed for patients with severe mental disorders (including patients with a history of such abnormalities), treatment can be initiated only after a thorough individual examination and appropriate therapy for a mental disorder. Patients receiving interferons can develop severe side reactions from the psyche, in particular depression, suicidal tendencies and suicidal attempts. In some patients, especially the elderly, who took higher doses of interferon alpha-2b, there was a marked decrease in pain sensitivity, coma, and encephalopathy. Although these phenomena are mostly reversible, some patients may need up to 3 weeks for complete recovery. Patients with a history of depression should be monitored for signs of depression during treatment and for 6 months after it ends. Patients should immediately inform the doctor of any sign of depression. If symptoms persist or worsen, especially depression, suicidal intentions or aggressive behavior, treatment should be discontinued and the psychiatrist promptly intervened.

CVS. Patients with heart failure, myocardial infarction and / or arrhythmias (including in the anamnesis) should be under constant supervision. In patients with heart disease, an ECG is recommended before and during treatment. Arrhythmias (mostly supraventricular) are usually 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. Transient rashes do not require the abolition of therapy.

Function of the kidneys. It is recommended that the kidney function be studied in all patients before Algeron® therapy begins. When Cl creatinine is 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 therapy, the administration of Algeron® and ribavirin should be discontinued.

In patients with impaired renal function, and also over the age of 50, when using Algeron® in combination with ribavirin, their condition should be carefully monitored for possible anemia.

Function of the kidneys. It is recommended that the kidney function be studied in all patients before Algeron® therapy begins. When Cl creatinine is 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 therapy, the administration of Algeron® and ribavirin should be discontinued.

In patients with impaired renal function, and also over the age of 50, when using Algeron® 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 interferon treatment, however, other causes of persistent fever need to be excluded.

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

Diseases of the lungs. In rare cases, in patients who received interferon alfa, infiltrates of unclear etiology, pneumonitis or pneumonia developed in the lungs, 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 function disorder, more careful monitoring of the patients should be established and, if necessary, the Algeron® should be canceled. Immediate withdrawal of interferon and the appointment of GCS lead to the disappearance of unwanted phenomena from the lungs.

Autoimmune disorders. In the treatment of interferon alpha 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. An exacerbation or occurrence of psoriasis, sarcoidosis and other autoimmune diseases is described. In patients with psoriasis and sarcoidosis, Algeron® should be used with caution, and with an exacerbation of the disease, consider abolishing the drug.

Changes on the part of the organ of vision. When there are complaints of reduced visual acuity or restriction of visual fields, an ophthalmologic examination should be performed. Such violations often occur in the presence of concomitant diseases, so patients with diabetes mellitus or hypertension are recommended to conduct a pre-treatment examination. Patients with diseases of the organ of vision are advised to have regular examinations during treatment.

Changes in the teeth and periodontal. Patients receiving combination therapy with peginterferon alfa-2b and ribavirin showed pathological changes in the teeth and peri-toothed tissues. Dry mouth with prolonged therapy can damage the teeth and mucous membranes of the mouth. Patients are advised to observe 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®, serum concentrations of TSH should be determined in patients and standard therapy should be prescribed when thyroid dysfunction is detected. The concentration of TSH should also be determined when there are symptoms of thyroid dysfunction in the background of treatment with interferon alpha. Treatment with Algeron® should not be carried out if the TSH activity is not maintained at a normal level.

ochemical blood tests should be performed. Also, they are recommended to be performed during therapy every 2 weeks (clinical blood test) and every 4 weeks (biochemical blood test).

Algeron® can be used in the following laboratory parameters: hemoglobin ≥120 g / l (female) and ≥ 130 g / l (male), platelet count> 90 · 109 / l (in patients with cirrhosis or cirrhosis> 75 · 109 / L), the absolute number of neutrophils -> 1.5 · 109 / l, the concentration of TSH and thyroxine within the norm or the function of the thyroid gland is medically controlled. With severe hypertriglyceridemia, before adjusting the dose of Algeron®, it is necessary to prescribe a diet or drug therapy taking into account 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 from the start of therapy. Abdominal pain, the presence of blood in the stool, fever are typical symptoms of the manifestation of colitis. When appropriate complaints are made, Algeron® must 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.

Influence on ability to drive vehicles, mechanisms. During the treatment, weakness, dizziness, drowsiness, confusion may occur. If these phenomena occur, you should abandon driving the car or working with machines and mechanisms.

Release form

Solution for subcutaneous administration, 200 μg / ml. According to 0.4, 0.5, 0.6, 0.8 or 1 ml in three-component sterile syringes from colorless neutral glass. 1 syringe in a contour cell box from a polymer film.

For 1 or 4 contour mesh packages are placed in a pack of cardboard.

1 ml in bottles of colorless neutral glass, sealed with Teflon-coated stoppers, crimped aluminum caps. For 1 or 4 fl. In the contour cell packaging from the polymer film placed in a pack of cardboard.

Manufacturer

CJSC BIOCAD. 198515, Russia, St. Petersburg

Produced: CJSC Biocad. 143422, Russia, Moscow Regio

Conditions of supply of pharmacies

On prescription.

Storage conditions of the drug Algeron

In the dark place at a temperature of 2-8 ° C. Do not freeze.

Keep out of the reach of children.

Shelf life of the drug Algeron

2 years.

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

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