Instructions for Oseltamivir
Dosage form Oseltamivir:
Hard gelatin two-tone capsules No. 1: body from white to light gray in color with a cap of light yellow color. The contents of the capsules is a powder from white to white with a yellowish tint.
Composition Oseltamivir:
1 capsule contains:
Active ingredient: oseltamivir phosphate in terms of 100% substance - 98.5 mg, which is equivalent to 75 mg;
Excipients: pregelatinized starch, povidone (type K30), croscarmellose sodium, talc, sodium stearyl fumarate.
Hard gelatin capsule [case: iron dye black oxide, titanium dioxide, gelatin; cap: iron dye oxide red, iron dye oxide yellow, titanium dioxide, gelatin].
Special conditions Oseltamivir:
Mental disorders
Patients (mainly children and adolescents) who took oseltamivir for the treatment of influenza were reported to have mental disorders, seizures, and delirium-like neuropsychiatric disorders. These cases were rarely accompanied by life-threatening actions. The role of oseltamivir in the development of these phenomena is unknown. Similar neuropsychiatric disorders have also been reported in patients with influenza who have not received.
The risk of developing neuropsychiatric disorders in patients receiving oseltamivir does not exceed that in patients with influenza who are not receiving antiviral drugs.
Careful monitoring of the condition and behavior of patients, especially children and adolescents, is recommended in order to identify signs of abnormal behavior and assess the risk of continuing to take the drug with the development of these phenomena.
There are no data on the effectiveness of oseltamivir in any diseases caused by pathogens other than influenza A and B viruses.
Oseltamivir-Akrikhin is not a substitute for vaccination.
Prophylactic administration of the drug Oseltamivir-Akrikhin is possible according to epidemiological indications.
Recommendations for dose adjustment in patients with kidney damage are presented in the subsection “Dosing in special cases” (also see “Pharmacokinetics in special patient groups”).
Oseltamivir in this dosage form should not be prescribed to children under 1 year of age.
Instructions for use, handling and disposal
The release of drugs to the environment should be minimized. Do not dispose of the product with wastewater or with household waste. If possible, use special systems for the disposal of drugs.
Influence on the ability to drive vehicles, mechanisms
Studies to study the effect of the drug the ability to drive vehicles and engage in other potentially dangerous types of detail that require increased concentration, attention and speed of psychomotor reactions have not been conducted. Based on the safety profile, the effects of oseltamivir on these activities are unlikely.
Drug interaction Oseltamivir
Clinically significant drug interactions are unlikely according to pharmacological and pharmacokinetic studies.
Oseltamivir extensively turns into an active metabolite under the influence of esterases, mainly located in the liver. Drug interactions due to competition for binding to the active centers of esterases are not widely represented in the literature. The low degree of binding of oseltamivir and the active metabolite to plasma proteins does not suggest that there are interactions associated with the displacement of drugs from protein binding.
In vitro studies show that neither oseltamivir nor its active metabolite is the preferred substrate for polyfunctional oxidases of the cytochrome P450 system or for glucuronyltransferases (see Pharmacokinetics subsection). There is no reason to interact with oral contraceptives.
Cimetidine, a non-specific inhibitor of isoenzymes of the cytochrome P450 system and competing in the process of tubular secretion with alkaline drugs and cations, does not affect the plasma concentrations of oseltamivir and its active metabolite.
Clinically significant inter-drug interactions associated with competition for tubular secretion are unlikely, taking into account the safety margin for most of these drugs, the excretion route of the active metabolite of (glomerular filtration and anionic tubular secretion), as well as the excretory capacity of each pathway.
Probenecid leads to an approximately 2-fold increase in the AUC of the active metabolite of oseltamivir (due to a decrease in active tubular secretion in the kidneys). However, dose adjustment with simultaneous use with probenecid is not required, given the safety margin of the active metabolite.
Simultaneous administration with amoxicillin does not affect the plasma concentrations of oseltamivir and its components, demonstrating little competition for excretion by anionic tubular secretion.
Concomitant use with paracetamol does not affect plasma concentrations of oseltamivir and its active metabolite or paracetamol.
No pharmacokinetic interactions between oseltamivir and its main metabolite were detected when taken with paracetamol, acetylsalicylic acid, cimetidine, antacids (magnesium and aluminum hydroxide, calcium carbonate), warfarin, rimantadine or amantadine.
When using oseltamivir with commonly used drugs, such as ACE inhibitors (enalapril, captopril), thiazide diuretics (bendroflumethiazide), antibiotics (penicillin, cephalosporins, azithromycin, erythromycin and doxycycline), H2-receptor blocking agents, 2-histamine receptors adrenergic blockers (propranolol), xanthines (theophylline), sympathomimetics (pseudoephedrine), opiates (codeine), glucocorticosteroids, inhaled bronchodilators and non-narcotic analgesics (acetylsalicylic acid, ibuprofen and paracetamol), no changes in the nature or frequency were observed.
Oseltamivir should be used with caution in combination with drugs that have a narrow breadth of therapeutic effect (for example, chlorpropamide, methotrexate, butadion).
Pharmacodynamics Oseltamivir:
Mechanism of action
Antiviral drug.
Oseltamivir is a prodrug, its active metabolite (oseltamivir carboxylate, OK) is an effective and selective inhibitor of neuraminidase of influenza viruses type A and B, an enzyme that catalyzes the release of newly formed virus particles from infected cells, their penetration into uninfected cells of the epithelium of the respiratory tract and further spread virus in the body. It inhibits the growth of the influenza virus in vitro and inhibits the replication of the virus and its pathogenicity in vivo, reduces the release of influenza A and B viruses from the body. The concentration of OK needed to inhibit neuraminidase by 50% (IC50) is 0.1-1.3 nM for influenza A virus and 2.6 nM for influenza B virus. The median IC50 for influenza B virus is slightly higher and is 8.5 nM.
Clinical efficacy
In the studies, oseltamivir did not affect the formation of influenza antibodies, including the production of antibodies in response to the administration of an inactivated influenza vaccine.
Studies of natural influenza infection
In clinical trials of oseltamivir during seasonal influenza infections, patients started receiving oseltamivir no later than 40 hours after the onset of the first symptoms of an influenza infection. 97% of patients were infected with influenza A virus and 3% of patients with influenza B. Oseltamivir significantly reduced the period of clinical manifestations of influenza infection (by 32 hours). In patients with a confirmed influenza diagnosis who were taking oseltamivir, the severity of the disease, expressed as the area under the curve for the total symptom index, was 38% less compared to patients receiving placebo. Moreover, in young patients without concomitant diseases, oseltamivir reduced the incidence of influenza complications requiring antibiotics (bronchitis, pneumonia, sinusitis, otitis media) by about 50%.
The data obtained in a study on oseltamivir therapy in elderly and senile patients show that taking oseltamivir in a dose of 75 mg 2 times a day for 5 days was accompanied by a clinically significant decrease in the median period of clinical manifestations of influenza infection, similar to that in adult patients of a younger age, however, the differences did not reach statistical significance. In another study, patients with influenza over 13 years old who had concomitant chronic diseases of the cardiovascular and / or respiratory systems received in the same dosing regimen or placebo. There were no differences in the median of the period until the clinical manifestations of influenza infection decreased in the oseltamivir and placebo groups, but the period of temperature increase with oseltamivir was reduced by about 1 day. Proportion of patients secreting the virus on the 2nd and 4th day, it became much less. The safety profile of oseltamivir in patients at risk did not differ from that in the general population of adult patients.
Influenza treatment in children
In children aged 1-12 years (average age 5.3 years) who had a fever (≥37.8 ° C) and one of the symptoms of the respiratory system (cough or rhinitis) during the period of influenza virus circulation in the population, a double-blind placebo was performed controlled study. 67% of patients were infected with influenza A virus and 33% of patients with influenza B. Oseltamivir (when taken no later than 48 hours after the first symptoms of influenza infection) significantly reduced the duration of the disease (by 35.8 hours) compared with placebo. The duration of the disease was defined as the time to stop coughing, nasal congestion, disappearance of fever, and return to normal activity. In the group of children receiving oseltamivir, the incidence of acute otitis media decreased by 40% compared with the placebo group.
Another study involved children aged 6–12 years with bronchial asthma; 53.6% of patients had influenza infection confirmed serologically and / or in culture. The median disease duration in the group of patients receiving oseltamivir did not significantly decrease. But by the last 6th day of oseltamivir therapy, the forced expiratory volume in 1 sec (FEV1) increased by 10.8% compared with 4.7% in patients receiving placebo (p = 0.0148).
Influenza Prevention in Adults and Adolescents
The prophylactic efficacy of oseltamivir in natural influenza A and B infections has been proven in 3 separate clinical trials of phase III. About 1% of patients fell ill with . Oseltamivir also significantly reduced the frequency of virus isolation and prevented the transmission of the virus from one family member to another.
Adults and adolescents who were in contact with a sick family member started taking oseltamivir for two days after the onset of flu symptoms in family members and continued it for 7 days, which significantly reduced the incidence of influenza in contactees by 92%.
In unvaccinated and generally healthy adults aged 18-65, taking oseltamivir during an influenza epidemic significantly reduced the incidence of influenza (by 76%). Patients took the drug for 42 days.
In elderly and elderly people, who were in nursing homes, 80% of which were vaccinated before the season when the study was conducted, oseltamivir significantly reduced the incidence of influenza by 92%. In the same study, oseltamivir significantly (by 86%) reduced the incidence of influenza complications: bronchitis, pneumonia, sinusitis. Patients took the drug for 42 days.
Influenza Prevention in Children
Clinical researches
In all patients carrying OK-resistant virus, carriage was temporary, did not affect the elimination of the virus, and did not cause a worsening of the clinical condition.
Patient population
Patients with mutations leading to resistance
Phenotyping * Gene and phenotyping *
Adults and teenagers 4/1245 (0.32%) 5/1245 (0.4%)
Children (1-12 years old) 19/464 (4.1%) 25/464 (5.4%)
Full genotyping has not been conducted in any of the studies.
When taking for postexposure prophylaxis (7 days), family contact prophylaxis (10 days) and seasonal prophylaxis (42 days) in patients with normal immune system function, there were no cases of drug resistance.
In a 12-week study on seasonal prophylaxis in people with immunocompromised cases of resistance were also not observed.
Data from selected clinical cases and observational studies
The degree of decrease in sensitivity to oseltamivir and the frequency of occurrence of such viruses may vary depending on the season and region. Resistance to oseltamivir was found in patients with pandemic H1N1 flu who received the drug for both treatment and prevention.
The incidence of resistance may be higher in younger patients and immunocompromised patients. Oseltamivir-resistant laboratory strains of influenza viruses and influenza viruses from patients treated with oseltamivir therapy carry mutations of neuraminidase N1 and N2. Mutations leading to resistance are often specific for the neuraminidase subtype.
When deciding on the use of the seasonal sensitivity of the influenza virus to the drug should be considered (the latest information can be found on the WHO website).
Preclinical data
Preclinical data obtained on the basis of standard studies on the pharmacological safety, genotoxicity and chronic toxicity did not reveal any particular danger to humans.
Carcinogenicity: the results of 3 studies to identify carcinogenic potential (two 2-year studies on rats and mice for oseltamivir and one 6-month study on transgenic mice Tg: AC for the active metabolite) were negative.
Mutagenicity: standard genotoxic tests for oseltamivir and an active metabolite were negative.
Effect on fertility: oseltamivir at a dose of 1500 mg / kg / day did not affect the generative function of male and female rats.
Teratogenicity: in studies on the teratogenicity of oseltamivir at a dose of up to 1500 mg / kg / day (in rats) and up to 500 mg / kg / day (in rabbits), no effect on embryo-fetal development was found. In studies on the antenatal and postnatal developmental periods in rats with the introduction of oseltamivir at a dose of 1500 mg / kg / day, an increase in the period of labor was observed: the safety margin between exposure for humans and the maximum non-effective dose in rats (500 mg / kg / day) for oseltamivir is 480 times higher, and 44 times higher for its active metabolite. Exposure to the fetus was 15-20% of that of the mother.
Other: oseltamivir and the active metabolite penetrate the milk of lactating rats.
According to limited data, oseltamivir and its active metabolite pass into human breast milk. According to the extrapolation of data obtained in animal studies, their amount in breast milk can be 0.01 mg / day and 0.3 mg / day, respectively.
Approximately 50% of the tested guinea pigs with the introduction of the maximum doses of the active substance showed skin sensitization in the form of erythema. Reversible eye irritation in rabbits has also been identified.
While very high oral single doses (657 mg / kg and above) of oseltamivir did not affect adult rats, these doses had a toxic effect on immature 7-day-old rat pups, including the death of animals. Adverse effects were not observed with chronic administration at a dose of 500 mg / kg / day from 7 to 21 days of the postnatal period.
Pharmacokinetics Oseltamivir:
Suction
Oseltamivir is easily absorbed in the gastrointestinal tract and extensively turns into an active metabolite under the influence of hepatic and intestinal esterases. The concentration of the active metabolite in plasma is determined within 30 minutes, the time to reach the maximum concentration of 2-3 hours, and more than 20 times the concentration of the prodrug. At least 75% of the ingested dose enters the systemic circulation as an active metabolite, less than 5% in the form of the starting drug. Plasma concentrations of both the prodrug and the active metabolite are proportional to the dose and are independent of food intake.
Distribution
The distribution volume (Vss) of the active metabolite is 23 liters.
According to animal studies, after ingestion of oseltamivir, its active metabolite was found in all major foci of infection (lungs, lavage water of the bronchi, nasal mucosa, middle ear and trachea) in concentrations that provide an antiviral effect.
The relationship of the active metabolite with plasma proteins is 3%. The relationship of the prodrug with plasma proteins is 42%, which is not enough to cause significant drug interactions.
Metabolism
Oseltamivir extensively turns into an active metabolite under the influence of esterases, located mainly in the liver. Neither oseltamivir nor the active metabolite are substrates or inhibitors of cytochrome P450 isoenzymes.
Breeding
It is excreted (> 90%) as an active metabolite mainly by the kidneys. The active metabolite does not undergo further transformation and is excreted by the kidneys (> 99%) by glomerular filtration and tubular secretion. Renal clearance (18.8 l / h) exceeds the glomerular filtration rate (7.5 l / h), which indicates that the drug is also excreted by tubular secretion. Less than 20% of the drug taken through the intestines is excreted. The half-life of the active metabolite is 6-10 hours.
Pharmacokinetics in special patient groups
Patients with kidney damage
When using oseltamivir (100 mg twice a day for 5 days) in patients with varying degrees of kidney damage, the area under the curve "plasma active metabolite concentration - time" (AUC of oseltamivir carboxylate) is inversely proportional to a decrease in renal function.
The pharmacokinetics of in patients with end-stage renal failure (with creatinine clearance ≤10 ml / min) who are not on dialysis have not been studied.
Patients with liver damage
The data obtained in vitro and in animal studies on the absence of a significant increase in the AUC of oseltamivir or its active metabolite for impaired liver function of mild to moderate severity were also confirmed in clinical studies (see “Dosage in special cases”). The safety and pharmacokinetics of oseltamivir in patients with severely impaired hepatic function have not been studied.
Patients of advanced and senile age
In elderly and senile patients (65-78 years), the exposure of the active metabolite in the equilibrium state is 25-35% higher than in younger patients when similar doses of oseltamivir are prescribed. The half-life of the drug in elderly and senile patients did not significantly differ from that in younger patients. Taking into account the data on the exposure of the drug and its tolerability by elderly and senile patients, dose adjustment in the treatment and prevention of influenza is not required.
Children aged 1 to 8 years and adolescents
The pharmacokinetics of Oseltamivir ere studied in children from 1 to 16 years old in a pharmacokinetic study with a single dose of the drug and in a clinical study to study multiple doses of the drug in a small number of children aged 3-12 years.
The rate of elimination of the active metabolite, adjusted for body weight in young children is higher than in adults, which leads to lower AUC in relation to a specific dose.
Taking the drug at a dose of 2 mg / kg and single doses of 30 mg or 45 mg in accordance with the dosage recommendations for children given in the section “Dosage and administration” provides the same AUC carboxylate, which is achieved in adults after a single dose capsules with 75 mg of the drug (equivalent to about 1 mg / kg). The pharmacokinetics of oseltamivir in children over 12 years of age is the same as in adults.
Indications Oseltamivir
Flu treatment in adults and children over the age of 1 year.
Influenza prophylaxis in adults and adolescents over the age of 12 who are at high risk of infection with the virus (in military units and large production teams, in debilitated patients).
Influenza prophylaxis in children over 1 year old.
Contraindications Oseltamivir
Hypersensitivity to oseltamivir or any component of the drug.
End-stage renal failure (creatinine clearance ≤ 10 ml / min).
Children's age up to 1 year.
Severe liver failure.
Carefully
Pregnancy, the period of breastfeeding.
Use during pregnancy and during breastfeeding
No controlled studies in pregnant women have been conducted. However, the results of post-marketing and observational studies have demonstrated the benefits of the proposed standard dosage regimen for this patient population. The results of pharmacokinetic analysis showed a lower exposure of the active metabolite (approximately 30% during all trimesters of pregnancy) in pregnant women compared with non-pregnant women. However, the calculated exposure value remains above the inhibitory concentrations (IC95 value) and therapeutic values for many strains of the influenza virus. Changing the dosage regimen in pregnant women during therapy or prophylaxis is not recommended (see section "Pharmacokinetics in special patient groups"). No direct or indirect adverse effects of the drug on pregnancy, embryo-fetal or postnatal development were found (see "Preclinical data"). When prescribing oseltamivir to pregnant women, both safety data and the course of pregnancy and the pathogenicity of the circulating strain of the influenza virus should be taken into account.
During preclinical studies, oseltamivir and the active metabolite penetrated into the milk of lactating rats. Data on the excretion of oseltamivir in human milk and the use of oseltamivir in nursing women are limited. Oseltamivir and its active metabolite in small quantities penetrate into breast milk (see "Preclinical data"), creating subtherapeutic concentrations in the blood of an infant. When prescribing oseltamivir to nursing women, the concomitant disease and pathogenicity of the circulating strain of the influenza virus should also be considered. During pregnancy and during breastfeeding, oseltamivir is used only if the intended benefits to the mother outweigh the potential risk to the fetus and the baby.
Overdose Oseltamivir
In most cases, an overdose during clinical trials and with the post-marketing use of oseltamivir was not accompanied by any adverse events. In other cases, the symptoms of an overdose corresponded to the adverse events presented in the section “Side effects”.
Oseltamivir Side Effects:
In adult / adolescent patient flu studies, the most common adverse reactions (HP) were nausea, vomiting, and headache. Most HP occurred on the first or second day of treatment and passed on their own within 1-2 days. In influenza prevention studies in adults and adolescents, the most common HPs were nausea, vomiting, headache, and pain. In children, vomiting was most common. The described HP in most cases did not require discontinuation of the drug.
Treatment and prevention of influenza in adults and adolescents
Table 1 presents the HP that occurred most frequently (≥1%) when taking the recommended dose of oseltamivir in studies on the prevention and treatment of influenza in adults and adolescents (75 mg 2 times a day for 5 days for treatment and 75 mg 1 time per day up to 6 weeks for prevention), and the frequency of which is at least 1% higher compared with placebo. Studies on treatment of influenza included adults / adolescents without concomitant pathology and patients at risk, i.e. patients with a high risk of developing complications of influenza (elderly patients, patients with chronic heart or respiratory diseases). In general, the safety profile in patients at risk was consistent with that in adults / adolescent patients without comorbidity.
In influenza prevention studies, the safety profile in patients receiving the recommended dose of oseltamivir (75 mg once daily for up to 6 weeks) did not differ from that in studies for influenza treatment, despite the longer use of the drug.
Table 1. The percentage of adults / adolescents with HP that occurred with a frequency of ≥1% in the oseltamivir group in studies on the treatment and prevention of influenza infection (difference from placebo ≥1%).
Organ system class
Adverse reaction Treatment Prevention Frequency category
