Oseltamivir-LF capsules 75mg in №10×1

Name Oseltamivir-LF, 75 mg capsules. International non-proprietary name Oseltamivir (Oseltamivir) COMPOSITION Active ingredient: oseltamivir 75.0 mg (as oseltamivir phosphate – 98.5 mg) A complete list of excipients is given in section 6.1. PHARMACEUTICAL FORMcapsules. Hard gelatin capsules, white, about 19 mm long, cylindrical in shape with hemispherical ends. Indications for useTreatment of influenza The drug Oseltamivir-LF is indicated for adults and children over 13 years of age (weighing more than 40 kg) with symptoms typical of influenza during the period of influenza virus circulation in the population. The effectiveness of the drug has been proven when treatment is started within 48 hours of the onset of the first flu symptoms. Influenza prophylaxis Post-exposure prophylaxis in adults and children over 13 years of age (weighing more than 40 kg) after exposure to clinically diagnosed influenza during the period of circulation of the virus in the population. The correct use of the medicinal product Oseltamivir-LF for the prevention of influenza must be determined in each case, depending on the circumstances and the need to protect the population. In some cases (for example, in the event of a mismatch between the circulating strain of the virus and the vaccine, including during a pandemic), seasonal prophylaxis may be considered in patients aged one year and older. Oseltamivir-LF is not a substitute for influenza vaccination. The use of antiviral drugs for the treatment and prevention of influenza should be based on official recommendations. Decisions regarding the use of oseltamivir for treatment and prophylaxis should be made taking into account what is known about the characteristics of circulating influenza viruses, available information on drug susceptibility patterns for each season, and the impact of the disease on different geographic regions and populations. Dosage regimen and route of administration Adults and adolescents over 13 years of age Treatment: The recommended oral dose of oseltamivir is 75 mg twice daily for 5 days for adolescents (13 to 17 years of age) and adults. Body weight Recommended dose for 5 days Recommended dose for 10 days Immunocompromised patients >40 kg 75 mg twice daily 75 mg twice daily Treatment should be initiated as soon as possible within 48 hours of the onset of influenza symptoms. Post-exposure prophylaxis: The recommended dose for influenza prophylaxis after close contact with an influenza patient is 75 mg oseltamivir once daily for 10 days in adolescents (13-17 years) and adults. Treatment must begin within 48 hours of contact with the patient. Body weight Recommended dose for 10 days Recommended dose for 10 days Immunocompromised patients >40 kg 75 mg once a day 75 mg twice a day Prevention during an influenza epidemic in the community For the prevention of influenza during an outbreak, oseltamivir 75 mg alone is recommended once a day for 6 weeks or up to 12 weeks in immunocompromised patients. Special groups: Patients with hepatic insufficiency Dose adjustment in the treatment and prevention of influenza in patients with hepatic insufficiency is not required. Studies of pediatric patients with hepatic insufficiency have not been conducted. Patients with renal insufficiency Treatment of influenza Patients with creatinine clearance greater than 60 ml / min dose adjustment is not required. With a creatinine clearance of less than 60 ml / min, this dosage form of the drug is not recommended for use. With creatinine clearance less than 10 ml / min, the use of oseltamivir is not recommended. Influenza prophylaxis For patients with creatinine clearance greater than 60 ml/min, the recommended oral dose of oseltamivir is 75 mg once daily. With a creatinine clearance of less than 60 ml / min, this dosage form of the drug is not recommended for use. With creatinine clearance less than 10 ml / min, the use of oseltamivir is not recommended. Elderly Patients Elderly patients do not require dose adjustment, except in cases of moderate or severe renal insufficiency. Immunocompromised patients Treatment: The recommended oral dose of oseltamivir is 75 mg twice daily for 10 days in adults. Treatment must begin within 48 hours of the onset of flu symptoms. Seasonal prophylaxis: For immunocompromised patients, the possibility of extending seasonal prophylaxis to 12 weeks is being considered. Method of application For oral administration. Contraindications Hypersensitivity to the active substance and other components of the drug. Special instructions and precautions for use Oseltamivir is effective only in diseases caused by influenza viruses. There are no data on the effectiveness of oseltamivir against diseases caused by agents other than influenza viruses. Oseltamivir is not a substitute for the flu vaccine. The use of oseltamivir should not affect the determination of individuals for annual influenza vaccination. Protection against influenza continues only while taking oseltamivir. Oseltamivir should be used for the treatment and prevention of influenza only with accurate epidemiological data that confirm the fact that influenza is circulating in the population. The sensitivity of circulating influenza strains to oseltamivir is highly variable. It follows that healthcare professionals prescribing prescription drugs should take into account the most up-to-date information on the nature of susceptibility of currently circulating viruses to oseltamivir when deciding whether to prescribe oseltamivir. Concomitant serious conditions There is no information on the safety and efficacy of oseltamivir in patients with any sufficiently severe or unstable medical conditions, in which the risk of hospitalization is inevitable. Immunocompromised patients There is no definitive information on the safety and efficacy of oseltamivir in the treatment and prevention of influenza in immunocompromised patients. However, the duration of treatment for influenza in immunocompromised adults should be 10 days, as there are no studies in this group of patients regarding a shorter course of oseltamivir. Cardiac/Respiratory Disease The efficacy of oseltamivir in the treatment of patients with chronic heart and/or respiratory disease has not been established. In these patients, there were no differences in the incidence of complications between the groups that received the drug or placebo. Severe renal insufficiency Dose adjustments are recommended in the treatment and prophylaxis of adults and adolescents (13-17 years) with severe renal insufficiency. Neuropsychiatric events Neuropsychiatric events have been reported during the administration of oseltamivir in patients with influenza, especially in children and adolescents. But the same events were also observed in patients who had influenza and did not take oseltamivir. Patients should be monitored for behavioral changes and the benefit/risk balance of continued treatment should be carefully assessed for each patient. The drug contains less than 1 mmol sodium (23 mg) per capsule, i.e. practically does not contain sodium. Interactions with other medicinal products and other forms of interaction The pharmacokinetic properties of oseltamivir, such as low plasma protein binding and metabolism that is independent of CYP450 and the system, suggest that clinically significant interactions through these mechanisms are unlikely. Probenecid In patients with normal renal function, the co-administration of oseltamivir and probenecid does not require dose adjustment. Co-administration of probenecid, a strong inhibitor of renal tubular anionic secretion, resulted in an almost two-fold increase in the concentration of the active metabolite of oseltamivir. Amoxicillin There is no pharmacokinetic interaction between oseltamivir and amoxicillin. Amoxicillin is eliminated in the same way, therefore weak competition of oseltamivir for this route of administration is expected. Renal Elimination Clinically significant drug interactions involving competition for renal tubular secretion are unlikely due to the known safety profile of most of these substances, the elimination characteristics of the active metabolite (glomerular filtration and tubular anionic secretion), and due to their excretion mechanisms. Caution should be exercised when prescribing oseltamivir to patients who are taking drugs with a narrow therapeutic interval that are eliminated by the same route (eg, chlorpropamide, methotrexate, phenylbutazone). Additional information No pharmacokinetic interactions between oseltamivir or its main metabolites. Fertility, pregnancy and lactation Fertility Based on clinical data, there is no evidence of an effect of oseltamivir on male and female fertility. Pregnancy Influenza is associated with adverse pregnancy and fetal outcomes, with the risk of severe congenital malformations, including congenital heart disease. The large body of data on exposure to oseltamivir in pregnant women from post-marketing reports and observational studies (more than 1000 outcomes with exposure during the first trimester) does not indicate either malformative or feto/neonatal toxicity of oseltamivir. However, in one observational study where the risk of a general malformation was not increased, outcomes for severe congenital heart disease diagnosed within 12 months of birth were inconclusive. In this study, the incidence of severe congenital heart disease after exposure to oseltamivir during the first trimester was 1.76% (7 infants out of 397 pregnancies) compared to 1.01% in pregnancies without exposure from the general population (odds ratio 1.75, 95% CI 0.51 to 5.98 ). The clinical significance of this result is not clear, as the study is of limited power. In addition, the study was not large enough to reliably assess individual types of severe malformations; moreover, oseltamivir-exposed women and unexposed women are not fully comparable, in particular with respect to whether or not they had influenza. Animal studies do not indicate reproductive toxicity. Use of oseltamivir during pregnancy may be considered, if appropriate, based on available data on the safety and benefit and pathogenicity of the circulating strain of influenza virus. Lactation In lactating rats, oseltamivir and its active metabolite were excreted in breast milk. Limited data on infants whose mothers took oseltamivir and on the excretion of oseltamivir in breast milk demonstrated that oseltamivir and its active metabolite were found in breast milk in very small amounts, which are below the therapeutic dose for an infant. Given this information, the pathogenicity of the circulating influenza virus strain, and the condition of the mother, oseltamivir may be considered if there is potential benefit to the nursing mother. Influence on the ability to drive vehicles and work with mechanisms Oseltamivir does not affect the ability to drive vehicles and control mechanisms. Adverse reactions Summary safety profile of oseltamivir The overall safety profile of oseltamivir is based on data from clinical studies of 6049 adults/adolescents and 1473 pediatric patients treated with oseltamivir or placebo for the treatment of influenza, and 3990 adults/adolescents and 253 children treated with oseltamivir or placebo (or no treatment) for the prevention of influenza. In addition, 245 immunocompromised patients (including 7 adolescents and 39 children) received oseltamivir for the treatment of influenza and 475 immunocompromised patients (including 18 children, of whom 10 received oseltamivir and 8 placebo) received oseltamivir or placebo for influenza prevention. In adults/adolescents, side effects such as nausea and vomiting were more often described in influenza treatment studies, and nausea was more often described in prevention studies. Most of these side effects were reported once on the first or second day of treatment and spontaneously resolved within 1-2 days. In children, the most commonly reported side effect is vomiting. Most of these side effects did not lead to discontinuation of treatment. The following serious adverse reactions to oseltamivir have been rarely reported since the start of marketing: anaphylactic shock and anaphylactoid reactions, liver disease (fulminant hepatitis, abnormal liver function and jaundice), angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, neuropsychiatric disorders and gastrointestinal bleeding. List of adverse reactions The adverse reactions listed in the table below fall into the following categories: very common (≥1/10), frequent (≥1/100 and <1/10), infrequent (≥1/1000 and <1/100), rare (≥1/10000 and <1/1000), very rare (<1/10000). Adverse effects are added to the appropriate category of the table based on the combined analysis of clinical studies. Treatment and Prophylaxis in Adults and Adolescents In treatment and prevention studies in adults and adolescents, the most commonly reported adverse reactions at recommended doses (75 mg twice daily for 5 days and 75 mg once daily for up to 6 weeks for prophylaxis ) were quantitatively similar to those in the treatment studies despite longer dosing durations in the prevention studies. Table 1. Adverse reactions in studies of oseltamivir for the treatment and prevention of influenza in adults and adolescents or during post-marketing surveillance Organ system class Very common Common Infrequent Rare Adverse reactions according to frequency Infections and infestations Bronchitis, herpes simplex, nasopharyngitis, upper respiratory tract infections , sinusitis Blood disorders Thrombocytopenia and lymphatic system disorders Immune system disorders Reactions Anaphylactic hypersensitivity reactions, anaphylactoid reactions Mental disorders Agitation, unusual behavior, anxiety, confusion, mania, delirium, hallucinations, nightmares, self-mutilation Nervous system disorders Headache Insomnia Blurred consciousness, convulsions Visual disturbances Visual disturbances Cardiac disturbances Heart rhythm disturbances Respiratory, thoracic and mediastinal disorders Cough, pain sore throat, rhinorrhea Gastrointestinal disorders Nausea Vomiting, abdominal pain Gastrointestinal (including pain in the upper bleeding, abdominal region), hemorrhagic colitis dyspepsia Liver disorders and Increased activity Fulminate hepatitis, biliary tract liver enzymes, renal failure, hepatitis Skin disorders and eczema, dermatitis, Angioedema subcutaneous tissue rash, urticaria edema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis General disorders and reactions Pain, dizziness at the injection site (including vestibular), fatigue, hyperthermia, pain in extremities Further information on selected adverse reactions Psychiatric and nervous system disorders Influenza may be associated with a variety of neurological and behavioral symptoms such as hallucinations, delirium and unusual behavior, which in some cases has been fatal. These disorders may present in the presence of encephalitis and encephalopathy, and may also occur without concomitant severe disease. Seizures and delirium (including symptoms such as clouding of consciousness, confusion, unusual behavior, mania, hallucinations, agitation, anxiety, nightmares) have been reported in patients with influenza treated with oseltamivir in the post-marketing period, which in very rare cases cases have resulted in injury or death. These events have been reported mainly in children and adolescents, and often began suddenly and quickly resolved. The role of oseltamivir in causing these disorders is unknown. Such neuropsychiatric disorders were also manifested in patients with influenza who did not receive oseltamivir. Liver and biliary tract disorders Liver and biliary tract disorders, including hepatitis and elevated liver enzymes, in patients with influenza-like illness. They cover cases of fulminant hepatitis/liver failure with a fatal outcome. Special Populations Elderly patients and patients with chronic heart or respiratory disease The population included in influenza treatment trials consists of healthy adults/adolescents and “at risk” patients (patients at high risk of developing influenza-related complications, such as older patients and patients with chronic heart or respiratory diseases). In general, the safety profile in patients at risk was similar to that in healthy adults/adolescents. Immunocompromised patients The treatment of influenza in immunocompromised patients was evaluated in two studies using standard doses or high doses (two or three doses) of oseltamivir. The safety profile of oseltamivir observed in these studies was consistent with that observed in previous clinical trials where oseltamivir was used to treat influenza in immunocompetent patients in all age groups (otherwise healthy or “at risk” patients, i.e. . with concomitant diseases of the respiratory system and / or heart). In immunocompromised children, vomiting was most frequently reported (28%). In a 12-week prophylaxis study in 475 immunocompromised patients, the safety profile in 238 patients treated with oseltamivir was similar to that observed in clinical prophylaxis studies with oseltamivir. Children with a history of asthma In general, the adverse reaction profile in children with a history of bronchial asthma was qualitatively similar to that of otherwise healthy children. Reporting Suspected Adverse Reactions It is important to report suspected adverse reactions after registration of a medicinal product in order to ensure continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national system for reporting adverse reactions (UE Center for Expertise and Testing in Healthcare, http://www.rceth.by). OverdoseOseltamivir overdose has been reported in clinical trials and post-marketing monitoring. In most cases of overdose reports, no adverse reactions have been reported. Adverse events reported in connection with overdose were similar in nature and frequency to those observed with oseltamivir at therapeutic dosages and are described in section 4.8 "Adverse reactions". There is no specific antidote. Pharmacodynamic properties Pharmacotherapeutic group Antiviral drug for systemic use, neuraminidase inhibitors. ATX code: J05AH02 Oseltamivir phosphate is a prodrug of the active metabolite (oseltamivir carboxylate). The active metabolite is a selective inhibitor of virus neuraminidase enzymes, glycoprotein enzymes located on the surface of the virion. The activity of the viral enzyme neuraminidase is important for the release of the formed viral particles from infected cells and further spread of the virus in the body. Oseltamivir carboxylate in vitro inhibits the neuraminidase of influenza A and B viruses. Oseltamivir phosphate inhibits the growth of the influenza virus and suppresses its replication in vitro. Oral oseltamivir inhibits influenza A and B virus replication and pathogenicity in vivo in animal models of influenza at doses similar to human administration of 75 mg twice daily. The antiviral activity of oseltamivir against influenza A and B has been confirmed by experimental studies with provocative tests in healthy volunteers. The value of the median inhibitory concentration (IC50) of oseltamivir in relation to the neuraminidase enzyme for clinically isolated influenza A ranged from 0.1 nM to 1.3 nM, for influenza B it was 2.6 nM. Published studies have reported higher IC50 values for influenza B, up to 8.5 nM. Clinical Studies Treatment of Influenza Virus Infection This indication is based on clinical studies of natural influenza cases in which influenza A was predominant. Oseltamivir is effective only in influenza virus infections. Therefore, analysis statistics are presented for influenza-infected patients only. In a pooled population study of positive and negative influenza virus (ITT) patients, primary efficacy declined in proportion to the number of influenza negative patients. In the entire treatment population, influenza infection is confirmed in 67% (range 46% to 74%) of recruited patients. Of all elderly patients, 64% were positive for influenza virus, and of all elderly patients with chronic heart failure and/or respiratory disease, 62% were positive for influenza virus. In all Phase III clinical trials, patients were only recruited during an influenza epidemic in the area. Adults and adolescents aged 13 years and older Patients were selected who reported onset of symptoms within 36 hours, who had a fever >37.8°C with at least one respiratory symptom (cough, nasal symptoms, sore throat) and at least one systemic symptom (muscle pain, chills/sweats, malaise, fatigue, or headache). In a pooled analysis of all influenza positive adults and adolescents (n=2413) enrolled in the treatment study, oseltamivir 75 mg twice daily for 5 days reduced the mean duration of influenza by one day compared with placebo, with 5.2 days (95% CI 4.9-5.5 days) to 4.2 days (95% CI 4.0-4.4 days; p<0.0001). The proportion of patients who developed lower respiratory tract complications requiring antibiotic treatment (mainly bronchitis) decreased from 12.7% (135/1063) in the placebo group to 8.6% (116/1350) in patients treated with oseltamivir (p =0.0012). Influenza treatment in high-risk populations The mean duration of influenza was not significantly reduced in elderly subjects (>65 years) and in patients with chronic heart and/or respiratory disease treated with oseltamivir 75 mg twice daily for 5 days. In the oseltamivir treatment group, the duration of the fever period decreased by one day. In influenza positive elderly patients, oseltamivir significantly reduced the incidence of lower respiratory complications requiring antibiotic treatment (mainly bronchitis) from 19% (52/268) in the placebo group to 12% (29/ 250) in patients treated with oseltamivir (p=0.0156). In influenza virus-positive patients with chronic heart and/or respiratory disease, the combined incidence of lower respiratory tract infections requiring antibiotic treatment (mainly bronchitis) in the placebo group was 17% (22/133) and in the group treated with oseltamivir – 14% (16/118) (p=0.5976). Treatment of Influenza in Pregnancy There are no controlled clinical studies on the use of oseltamivir during pregnancy, but there is evidence of benefit of this dosing regimen in this patient population based on post-marketing and retrospective observational studies in terms of lower morbidity/mortality. The results of the pharmacokinetic analysis indicate a lower concentration of the active metabolite, however, dosage adjustment during pregnancy for the purpose of treating or preventing influenza is not recommended (see sections 5.2 “Pharmacokinetics” “Special populations”). Treatment of Influenza in Children In a study of otherwise healthy children (65% positive for influenza infection) aged 1–12 years (mean age 5.3 years) who had a fever (>37.8°C) along with a cough or runny nose, 67 % of influenza-infected patients were infected with influenza A and 33% with influenza B. Treatment with oseltamivir, started within 48 hours after the onset of symptoms of the disease, significantly reduced the time required to treat the disease (as defined as the simultaneous restoration of normal health, activity, decrease in temperature , cough and runny nose) for 1.5 days (95% confidence interval 0.6-2.2 days; p<0.000l) compared with placebo. Oseltamivir reduced the incidence of acute otitis media from 26.5% (53/200) in the placebo group to 16% (29/183) in the oseltamivir group (p = 0.013). Another study included 334 asthmatic children aged 6-12 years, of which 53.6% were positive for the influenza virus. In the oseltamivir-treated group, the mean duration of illness did not decrease significantly. On day 6 (the last day of treatment) in this population, forced expiratory volume in 1 second increased by 10.8% in the oseltamivir group, compared with 4.7% in the placebo group (p = 0.0148). The European Medicines Agency (EMA) has deferred the need to report results from trials of oseltamivir in one or more subsets of the pediatric influenza population. See section 4.2 for information on use in the pediatric population. The indication for use in children under 1 year of age is based on extrapolation of efficacy data in older children; the recommended dosing regimen is based on pharmacokinetic modeling data (see section 5.2). Treatment of Influenza B Infection Overall, 15% of the influenza positive population were infected with influenza B; according to various studies, this proportion varied from 1 to 33%. The mean duration of illness in patients with influenza B did not differ significantly between treatment groups in the various studies. Data from all 504 influenza B patients included in all studies were pooled for analysis. Oseltamivir reduced the time required to resolve all symptoms by 0.7 days (95% confidence interval 0.1–1.6 days; p=0.022) and the duration of fever (>37.8°C), cough and runny nose by one day (95% confidence interval 0.4– 1.7 days; p<0.001), compared with placebo. Treatment of Influenza in Immunocompromised Patients A randomized, double-blind study evaluating the safety and characterizing the effects of oseltamivir on the development of resistant influenza virus (primary analysis) in influenza-infected immunocompromised patients included 151 adults, 7 adolescents, and 9 children to evaluate the efficacy of oseltamivir (secondary analysis, not enhanced). The study included SOT solid organ transplant patients, HSCT hematopoietic stem cell transplant patients, HIV-positive patients with CD4+ cell counts <500 cells/mm3, patients receiving systemic immunosuppressive therapy, and patients with hematologic malignancies. These patients were randomized to treatment within 96 hours of symptom onset for 10 days. Therapy was administered as a standard dose (75 mg or adjusted for body weight in children) twice daily (73 patients, 4 adolescents and 4 children) or a double dose (150 mg or adjusted for body weight in children) twice daily ( 78 patients, 3 adolescents and 5 children) oseltamivir. The median time to resolution of symptoms (TTRS) in adults and adolescents was similar between the standard dose group (103.4 hours 95% CI 75.4-122.7) and the double dose group (107.2 hours 95% CI 63.9-140.0). TTRS in children varied and interpretation is very limited due to the small sample size. The number of patients with secondary infections in the standard dose and double dose groups was comparable (8.2% vs. 5.1%). In the adolescent and pediatric group, only one patient (adolescent) in the standard dose group experienced a secondary infection (bacterial sinusitis). A pharmacokinetic and pharmacodynamic study was conducted in severely immunosuppressed children (<12 years, n=30) who received the standard (75 mg or weight-adjusted twice daily) or triple (225 mg or weight-adjusted twice daily) regimen. day) a dose of oseltamivir during an adaptive period of administration lasting from 5 to 20 days, depending on the duration of the period of virus shedding (average duration of treatment: 9 days). Secondary bacterial infections were not reported in the standard dose group, while secondary bacterial infections were reported in two patients in the triple dose group (bronchitis and sinusitis). Influenza prophylaxis Efficacy of oseltamivir for in vivo prophylaxis of influenza has been demonstrated in a post-exposure prophylaxis study in families and two seasonal prophylaxis studies. In all of these studies, the first measure of effectiveness was the incidence of laboratory-diagnosed influenza. Influenza virus virulence is unpredictable and varies within a region and from season to season, so the number needed to treat (NNT) also varies. Post-exposure prophylaxis In one study, in contacts of influenza patients (12.6% were vaccinated against influenza), oseltamivir 75 mg once daily was initiated within two days of the patient's symptoms onset and continued for 7 days. Influenza patients were confirmed in 163 of 377 cases. Oseltamivir significantly reduced the incidence of symptomatic influenza in contacts of confirmed influenza cases from 24/200 (12%) in the placebo group to 2/205 (1%) in the placebo group. oseltamivir (92% reduction, 95% confidence interval (CI) 6-16, p<0.0001). In contacts of confirmed influenza cases, the NNT-number needed to treat was 10 (95% CI 9-12) and 16 in all study participants (ITT) (95% CI 15-19) regardless of the influenza virus infection status of the source of infection. The efficacy of oseltamivir in vivo prevention of influenza has been demonstrated in a post-exposure prophylaxis study in families with adults, adolescents, and children aged 1 to 12 years, both as sources of infection and as contacts. The primary performance measure of this study was the incidence of laboratory and clinically diagnosed influenza in families. Prophylaxis with oseltamivir lasted 10 days. In the entire population, the incidence of laboratory and clinically diagnosable