Pegasys solution for subcutaneous injection 180 μg syringes 0.5 ml
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Active ingredients
Peginterferon Alfa-2a (40 kDa)
Release form
Solution
Composition
1 syringe tube contains: peginterferon alpha-2a (40 kDa) 180 mcg. Adjuvants: sodium chloride - 4 mg, benzyl alcohol - 5 mg, sodium acetate trihydrate - 1.3085 mg, glacial acetic acid - 0.0231 mg, polysorbate 80 - 0.025 mg, sodium acetate solution 10% - to pH 6.0, acetic acid 10% - to pH 6.0, water d / and - to 0.5 ml.
Pharmacological effect
The structure of PEG (bis-monomethoxy polyethylene glycol) directly affects the clinical and pharmacological characteristics of Pegasis; In particular, the size and degree of branching of a PEG with a molecular mass of 40 kDa determines the rates of absorption, distribution and excretion of peginterferon alfa-2a. The activity of Pegasis; should not be compared with other pegylated or non-negylated proteins of the same therapeutic class. As well as interferon alpha-2a, Pegasys; possesses antiviral and antiproliferative activity in vitro. In patients with chronic hepatitis C (CHC) a decrease in the level of RNA of the hepatitis C virus (HCV) in response to therapy with Pegasys; at a dose of 180 mcg occurs in 2 phases. The first phase is noted in 24-36 hours after the first injection of the drug, the second phase occurs within the next 4-16 weeks in patients with a sustained virological response. Ribavirin does not have a significant effect on the kinetics of the virus during the first 4-6 weeks in those patients who receive combination therapy with ribavirin and peginterferon alfa-2a or interferon alpha.
Pharmacokinetics
Absorption After a single sc injection of 180 μg of peginterferon alfa-2a to healthy individuals, the drug is determined in the blood serum after 3-6 hours. After 24 hours, the concentration in the blood serum reaches 80% of the maximum. Peginterferon alpha-2a absorption is prolonged, Cmax in serum is noted 72-96 h after drug administration. The absolute bioavailability of peginterferon alfa-2a is 84% and is similar to that of interferon alfa-2a. Distribution Peginterferon alfa-2a is found predominantly in the blood and extracellular fluid. The volume of distribution in the equilibrium state (Vss) after the on / in the introduction is 6-14 liters. According to mass spectrometry, tissue distribution and autoradioluminography obtained in studies in rats, peginterferon alfa-2a is found in high concentrations in the blood and also in the liver, kidney, and bone marrow. Metabolism Pegiferferon alpha 2a metabolism features are not fully understood.Experimental studies have shown that in rats, the radiolabeled drug is excreted primarily by the kidneys. Introduction The systemic clearance of peginterferon alpha-2a in humans is 100 times lower than that of interferon alpha-2a. After in / in the administration, the terminal T1 / 2 in healthy volunteers is 60 -80 h, compared with 3-4 h for normal interferon. After s / c administration, the terminal T1 / 2 is about 160 hours (from 84 to 353 hours). Terminal T1 / 2 after s / c administration may not show excretion, but rather the duration of absorption of peginteronone alpha-2a. When peginterferon alpha-2a is administered 1 time a week, a dose-dependent increase in systemic exposure is observed in healthy volunteers and in patients with chronic hepatitis B or C. In patients with chronic hepatitis B or C after 6-8 weeks of treatment with peginterferon alpha-2a, Css is achieved once a week, which is 2-3 times higher than after a single injection. After the 8th week of treatment with the introduction of the drug 1 time per week no further cumulation occurs. After 48 weeks of therapy, the ratio of Cmax and Cmin is 1.5-2. The concentration of peginterferon alpha-2a in serum is maintained throughout the week (168 h) after administration. Pharmacokinetics in special populations of patients Patients with impaired renal function. Renal impairment is associated with a slight decrease in clearance (CL / F) and an increase in T1 / 2. In patients with CC 20–40 ml / min, clearance of peginterferon alfa-2a decreases by 25% compared with patients without impaired renal function. In patients with end-stage chronic renal failure receiving hemodialysis, there is a decrease in clearance of peginterferon alfa-2a by 25-45%. Pharmacokinetics of the drug was similar when prescribing the drug Pegasys; at a dose of 135 mcg in patients with end-stage chronic renal failure and in the appointment of 180 mcg to patients without impaired renal function. After a single sc injection of the pharmacokinetic parameters of the drug Pegasys; in women and men are comparable. Older age. In patients older than 62 years after a single sc injection of Pegasys; at a dose of 180 mcg, the absorption of peginterferon alfa-2a was slow, but steady compared with young healthy volunteers (Tmax 115 hours compared to Tmax 82 hours). AUC is slightly increased in patients older than 62 years (1663 ng × h / ml compared to 1295 ng × h / ml), but Cmax values in patients younger and older than 62 years are the same (9.1 ng / ml and 10.3 ng / ml, respectively).Based on the data of exposure, pharmacodynamic response and tolerability, no reduction in the initial dose of the drug in these patients is required. Patients with cirrhosis and without cirrhosis. Pharmacokinetics of the drug Pegasys; in healthy individuals and patients with hepatitis B or C is the same. In patients with compensated cirrhosis, the pharmacokinetic characteristics are the same as in patients without cirrhosis (class A on the Child-Pugh scale). Place injections. P / to the introduction of the drug Pegasys; should be limited to the area of the anterior abdominal wall and thighs, since the degree of absorption, based on AUC, was 20-30% higher when injected into these areas. The concentration of the drug was lower in studies in which Pegasys; Injected s / c in the shoulder area.
Indications
Chronic hepatitis C: - chronic hepatitis C in adult patients with positive HCV RNA, without cirrhosis or with compensated cirrhosis, incl. and with clinically stable HIV co-infection (monotherapy or combination with ribavirin). The combination with ribavirin is indicated in patients with chronic hepatitis C who have not previously received therapy, or with the failure of previous interferon alpha monotherapy (pegylated or nonpegylated) or combination therapy with ribavirin. Monotherapy shown in case of intolerance or the presence of contraindications to ribavirin. Chronic hepatitis B: - chronic hepatitis B HBeAg-positive and HBeAg-negative in adult patients with compensators nnym liver and signs of viral replication, increased ALT activity and histologically confirmed liver inflammation and / or fibrosis.
Contraindications
- autoimmune hepatitis; - severe liver failure; - decompensated liver cirrhosis; - cirrhosis with a score of ≥6 on the Child-Pugh scale in patients with co-infection with HIV-CHC, provided that the increase in this indicator is not associated with indirect hyperbilirubinemia due to drug administration , such as atazanavir and indinavir; - severe cardiovascular diseases in the stage of decompensation, including with unstable poorly controlled flow in the previous 6 months; - children's age up to 3 years (because the drug contains the excipient benzyl alcohol); - pregnancy; - breastfeeding period; - hypersensitivity to interferon alpha, genetic engineering preparations obtained with E .coli, polyethylene glycol or any other component of the drug. In combination with Pegasis; with ribavirin, contraindications for ribavirin should be considered.
Dosage and administration
For patients over 18 years old. Treatment with Pegasys; should be carried out under the supervision of a qualified physician with experience in the treatment of chronic hepatitis B and C. In combination therapy with Pegasys; Ribavirin should be used in accordance with ribavirin's medical instructions. Standard dosage regimen The drug is injected s / c into the anterior abdominal wall or thigh once a week. Before administration, the drug should be examined for the absence of impurities and discoloration. Patients should be carefully instruct on the importance of proper storage and disposal of used materials and warn against the reuse of any needles and syringes. Chronic hepatitis B in HBeAg-positive and HB eAg-negative chronic hepatitis B drug is prescribed in a single dose of 180 mcg once a week for 48 weeks. Chronic hepatitis Patients who have not previously received treatment Recommended dose of Pegasys; is 180 mcg 1 time / week as monotherapy or in combination with ribavirin (orally). Ribavirin should be taken with food. In combination with ribavirin, the duration of therapy and the dose of ribavirin depend on the virus genotype. The duration of therapy in patients with genotype 1, in which the HCV RNA is determined at the 4th week of treatment, regardless of the initial viral load. Duration therapy for 24 weeks can be considered in patients: - with genotype 1 and initially low viral load (≤800 000 IU / ml); - with genotype 4, in which at 4 weeks the result of the determination of HCV RNA is negative and is negative at 24 weeks. However, the total duration of therapy for 24 weeks may be associated with a greater risk of relapse than therapy for 48 weeks. When deciding on the duration of therapy in such patients, consideration should be given to the tolerance of combination therapy and additional prognostic factors, such as the degree of fibrosis. With even greater caution should be approached the issue of reducing the duration of therapy in patients with genotype 1 and initially high viral load (greater than 800,000 IU / ml), in which at 4 weeks the result of HCV RNA determination is negative and remains negative at 24 weeks, since the limited available the data suggests that a reduction in the duration of therapy may negatively affect the sustained virologic response.In patients with genotype 2 or 3 and determined HCV RNA at 4 weeks of treatment, regardless of the initial viral load, the duration of therapy should be 24 weeks. Reduction of therapy to 16 weeks is possible in certain groups of patients with genotype 2 or 3, low viral load (initially ≤ 800 000 IU / ml), non-detected HCV RNA by week 4 and remaining negative up to week 16. With a 16-week duration of treatment, the risk of recurrence may increase as compared with 24-week therapy. When deciding on the duration of therapy in such patients, consideration should be given to tolerability of the combination therapy and additional clinical and prognostic factors, such as the degree of fibrosis. Care should be taken to reduce the duration of therapy in patients with genotype 2 or 3 and initially high viral load (greater than 800,000 IU / ml), which have negative results by week 4, since limited data suggest that the reduction in the duration of therapy may adversely affect the sustainability of the virologic response. Clinical data in patients with genotypes 5 and 6 are limited; combination therapy with Pegasys is recommended; and ribavirin (1000/1200 mg) for 48 weeks. The recommended duration of monotherapy with Pegasys; makes 48 weeks. The patients who earlier received treatment the Recommended dose drug Pegasys; in combination with ribavirin, it is 180 mcg 1 time / week. The dose of ribavirin is 1000 mg / day (body weight less than 75 kg) and 1200 mg (body weight ≥75 kg). If a virus is found at the 12th week of treatment, therapy should be stopped. The recommended total duration of therapy is 48 weeks. When deciding on the treatment of patients with genotype 1 who did not respond to previous treatment with pegylated interferon and ribavirin, the recommended total duration of therapy should be 72 weeks. Co-infection is HIV-HGSPEGASIS; 180 μg is administered once a week as monotherapy or in combination with ribavirin (800 mg), for 48 weeks, regardless of the genotype. The safety and efficacy of combination therapy with ribavirin at a dose of more than 800 mg and with a duration of less than 48 weeks has not been sufficiently studied. Predicting the effectiveness of treatment Patientspreviously not treated The definition of an early virologic response (reduction of viral load below the detection threshold or at least 2log10) at the 12th week of therapy can predict the achievement of a sustained virologic response (SVR), as shown in Tables 2 and 3. The prognostic value of the absence of SVR in Pegasis monotherapy; is 98%. A similar prognostic value of the absence of SVR was found in patients with co-infection with HIV-CHC who received Pegasys monotherapy; or Pegasys combination therapy; and ribavirin (100% and 98%), respectively. In case of co-infection with HIV-CHC, the predictive value of SVR is 45% and 70%, respectively, in patients with genotypes 1 and 2/3 who received combination therapy. Patients previously treated In patients who had not previously responded to treatment, with repeated treatment for 48 or 72 weeks, it was shown that suppression of the virus at week 12 (HCV RNA below 50 IU / ml) is a prognostic criterion for SVR. The probability of absence of SVR after 48 or 72 weeks of treatment in the event that suppression of the virus was not observed at week 12 was 96% and 96%, respectively. The likelihood of achieving SVR after 48 or 72 weeks of treatment if virus suppression was noted at week 12 was 35% and 57%, respectively. Dose adjustment guidelines due to adverse effects General If dose adjustment is required due to clinical or laboratory average reactions and severe severity is usually enough to reduce the dose to 135 μg. However, in some cases it is required to reduce the dose to 90 μg or 45 μg. After resolving adverse reactions, it is possible to consider increasing the dose of the drug, up to the initial one. In patients with an absolute neutrophil count (AChN) of less than 500 cells / mcl, treatment should be interrupted until this figure exceeds 1000 cells / mcl. Use of the drug Pegasys; should be resumed at a dose of 90 mcg under periodic monitoring of the number of neutrophils (the frequency of control is determined by the doctor in each case individually). Reducing the dose to 90 mcg is recommended while reducing the number of platelets less than 50,000 cells / mcl.In patients with a platelet count of less than 25,000 cells / mcl, the drug should be discontinued. Recommendations for the treatment of anemia that occurred during therapy: 1) The dose of ribavirin should be reduced to 600 mg / day (200 mg in the morning and 400 mg in the evening) in one of the following situations: - hemoglobin is reduced less than 10 g / dL, but more than 8.5 g remains / dl in patients without a concomitant cardiovascular pathology - hemoglobin decreases by 2 g / dl or more during any 4 weeks of therapy in patients with stable cardiovascular disease. It is not recommended to increase the ribavirin dose to the initial 2) Reception of ribavirin should be stopped in one of the following x situations: - hemoglobin decreases less than 8.5 g / dl in patients without concomitant cardiovascular pathology; - hemoglobin remains less than 12 g / dl after 4 weeks, despite dose reduction, in patients with stable cardiovascular disease. After discontinuation of ribavirin and allowing side effects, it is possible to resume its admission at a dose of 600 mg / day, followed by an increase to 800 mg / day at the discretion of the physician. It is not recommended to increase the dose of ribavirin to the initial one (1000 mg or 1200 mg). In cases of intolerance to ribavirin, monotherapy with Pegasys should be continued. In patients with chronic hepatitis C, fluctuations in liver function abnormalities are characteristic. As with the treatment of other interferon alfa drugs, with Pegasys therapy; there is an increase in ALT activity higher than before treatment, incl. and in patients with a virologic response. In clinical studies, 8 of 451 patients with chronic hepatitis C who received a combination therapy had an isolated increase in ALT activity (exceeding VGH by ≥10 times; or exceeding the baseline by ≥2 times for patients with baseline ALT activity is 10 times higher VGN), which disappeared without changing the dose. With a progressive increase in the activity of ALT in comparison with the figures before treatment, the dose of the drug Pegasys; you need to first reduce to 135 micrograms. If the activity of ALT, despite a dose reduction, continues to increase or is accompanied by an increase in the concentration of bilirubin, or signs of decompensation of the liver process, the drug should be discontinued. Patients with chronic hepatitis B may have a transient increase in ALT activity, sometimes exceeding VGN 10 times, which may indicate immune clearance. Treatment usually should not begin if the activity of ALT exceeds VGN more than 10 times.Continuing therapy requires more frequent control of ALT activity. With a dose reduction or temporary withdrawal of the drug Pegasys; therapy can be restored after normalization of ALT activity. Special groups of patients: Renal failure In the terminal stage of renal failure, a reduction in the dose of the drug Pegasys is recommended; up to 135 mcg. Regardless of the initial dose and the severity of renal failure in such patients, it is necessary to carefully monitor and reduce the dose in the event of adverse reactions. Hepatic insufficiency In patients with compensated liver cirrhosis (class A on the Child-Pugh scale) Pegasys; effective and safe. In patients with decompensated cirrhosis (class B / C on the Child-Pugh scale or bleeding from esophageal varices), Pegasys; not studied. Older age In elderly patients, the recommended dose adjustment (180 mcg 1 time / week) is not required. ChildrenSafety and efficacy of the drug in persons younger than 18 years old have not been established. Pegasys drug solution; It is contraindicated in newborns and children up to 3 years old, because it contains benzyl alcohol, which can cause neurological and other complications, sometimes fatal, in this age group of patients. Patients after transplantationPegasis is safe and effective in monotherapy; or its combination with ribavirin in patients after transplantation of the liver and other organs and tissues have not been established. As with the appointment of other interferon alpha, when using the drug Pegasys; as monotherapy or in combination with ribavirin, cases of rejection of hepatic and renal grafts have been identified.