Influtsein - instructions for use, doses, side effects, contraindications

Excipients: calcium hydrophosphate 25 mg, starch corn pregelatinized 46.3 mg, croscarmellose sodium 7.2 mg, sodium stearyl fumarate 1.5 mg, talc 1.5 mg;

Capsule hard gelatin №1: body: gelatin 45.2956 mg; titanium dioxide 0.9244 mg; lid: gelatin 29.1077 mg, titanium dioxide 0.3971 mg, dye quinoline yellow 0.2739 mg, dye sunset yellow 0.0013 mg.

Description:

Hard gelatin capsules number 1, the lid is yellow, the body is white. The contents of the capsules are a mixture of granules and powder of almost white color or a compacted mass of almost white color, crumbling when pressed lightly.

Pharmacotherapeutic group:Antiviral agent

ATX: & nbsp

J.05.A.H.02 Oseltamivir

Pharmacodynamics:

Mechanism of action

Antiviral drug. Oseltamivir phosphate is a prodrug, its active metabolite (oseltamivir carboxylate, OK) is an effective and selective neuraminidase inhibitor of influenza A and B viruses that catalyze the release of newly formed viral particles from infected cells, their penetration into respiratory epithelial cells and further spread virus in the body.

Stops the growth of the influenza virus in vitro and suppresses the replication of the virus and its pathogenicity in vivo, reduces the allocation of influenza A and B viruses from the body. Studies of clinical isolates of the influenza virus have shown that the concentration of OC needed to inhibit neuraminidase by 50% (IC₅₀), is 0.1-1.3 nM for influenza A and 2.6 nM for influenza B. According to published studies, the median values IC₅₀ for the influenza B virus is slightly higher and is 8.5 nM.

Clinical efficacy

In the conducted studies oseltamivir did not affect the formation of anti-influenza antibodies, including the production of antibodies in response to the introduction of an inactivated influenza vaccine.

Studies of natural influenza infection

In clinical studies conducted during seasonal influenza infection, patients began to receive oseltamivir no later than 40 hours after the appearance of the first symptoms of 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 (at 32 h).

In patients with confirmed influenza oseltamivir, the severity of the disease, expressed as the area under the curve for the total symptom index, was 38% less than in patients receiving placebo. Moreover, in young patients without concomitant diseases oseltamivir reduced by about 50% the incidence of complications of influenza requiring the use of antibiotics (bronchitis, pneumonia, sinusitis, otitis media). In these Phase III clinical trials, clear evidence of the effectiveness of the drug with respect to secondary efficacy criteria relating to antiviral activity was obtained: oseltamivir caused both a shortening of the time of virus isolation from the body, and a decrease in the area under the "viral titers-time" curve.

The data obtained in the study on oseltamivir therapy in elderly and elderly patients show that taking oseltamivir 75 mg twice daily for 5 days was accompanied by a clinically significant decrease in the median of the period of clinical manifestations of influenza infection similar to that in adult younger patients age, but the differences did not reach statistical significance.

In another study, patients with influenza older than 13 years who had concomitant chronic cardiovascular and / or respiratory diseases received oseltamivir in the same dosing regimen or placebo. Differences in the median of the period to a decrease in the clinical manifestations of influenza infection in groups oseltamivir and there was no placebo, but the period of temperature increase with oseltamivir was reduced by about 1 day. The proportion of patients who isolated the virus on days 2 and 4 became significantly less. The safety profile of oseltamivir in patients at risk did not differ from that in the general population of adult patients.

Treatment of influenza in children

Children aged 1-12 years (mean age 5.3 years),(> 37.8 ° C) and one of the symptoms on the part of the respiratory system (cough or rhinitis) during the circulation of the influenza virus among the population, a double-blind, placebo-controlled study was conducted. 67% of patients were infected with influenza A virus and 33% of patients with influenza B. Oseltamivir (at admission no later than 48 hours after the onset of 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 stopping coughing, nasal congestion, the disappearance of fever, a return to normal activity. In the group of children who received oseltamivir, the incidence of acute otitis media decreased by 40% compared with the placebo group. Recovery and return to normal activity occurred almost 2 days earlier in children who received oseltamivir, compared with the placebo group.

In another study, children aged 6-12 years with bronchial asthma participated; 53.6% of patients had influenza infection confirmed serologically and / or in culture. The median duration of the disease in the group of patients who received oseltamivir, did not decrease significantly. But by the last 6th day of therapy with oseltamivir, the volume of forced expiration in 1 sec (OFB₁) increased by 10.8% compared with 4.7% in patients receiving placebo (p = 0.0148).

Prevention of influenza in adults and adolescents

The prophylactic efficacy of oseltamivir for natural influenza A and B infection has been demonstrated in 3 separate clinical trials III phase. Approximately 1% of patients were ill with influenza oseltamivir. Oseltamivir also significantly reduced the frequency of virus isolation and prevented transmission of the virus from one member of the family to another.

Adults and teens who have been in contact with a sick family member, began receiving oseltamivir for two days after the onset of flu symptoms in family members and kept it within 7 days, which significantly reduced the incidence of influenza in individuals exposed to 92%.

In unvaccinated and generally healthy adults aged 18-65 years receiving oseltamivir during a flu epidemic, significantly reduced the incidence of influenza (76%). Patients took the drug for 42 days.

In elderly and elderly people who were in nursing homes, 80% of whom were vaccinated before the season, when the study was conducted, oseltamivir significantly reduced the incidence of influenza by 92%. In the same study oseltamivir authentically (by 86%) reduced the frequency of complications of influenza: bronchitis, pneumonia, sinusitis. Patients took the drug for 42 days.

Prevention of influenza in children

The prophylactic efficacy of oseltamivir in cases of natural influenza infection was demonstrated in a study in children from 1 year to 12 years after contact with an affected family member or someone from a constant environment. The main efficacy parameter in this study was the frequency of a laboratory-confirmed influenza infection. In a study in children who received oseltamivir (Powder for oral suspension) at a dose of 30 to 75 mg 1 time per day for 10 days, and no virus was isolated initially, the frequency of laboratory-confirmed influenza decreased to 4% (2/47) compared to 21% ( 15/70) in the placebo group.

Prevention of influenza in immunocompromised individuals

In immunocompromised individuals, with seasonal influenza infection and in the absence of viral shedding initially, the prophylactic use of oseltamivir resulted in a decrease in the frequency of laboratory-confirmed influenza infection accompanied by clinical symptoms, and 0.4% (1/232) as compared to 3% (7 / 231) in the placebo group.Laboratory-confirmed influenza infection, accompanied by clinical symptoms, was diagnosed in the presence of oral temperature above 37.2 ° C, cough and / or acute rhinitis (all recorded on the same day while taking the drug / placebo), and a positive result reverse transcriptase polymerase chain reaction to influenza RNA.

Resistance

Clinical researches

All patients-carriers OK-resistant virus carrier was temporary, did not affect the elimination of the virus and did not cause a deterioration in the clinical state.

	Patients with mutations leading to resistance
Patient population	Phenotyping *	Geno - 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%)

* Complete genotyping has not been carried out in any of the studies.

When taking oseltamivir for postexposure prophylaxis (7 days), prevention of family contact (10 days) and seasonal prophylaxis (42 days) in cases with a normal function of the immune system, there are no cases of resistance to the drug.

In a 12-week study on seasonal prophylaxis in immunocompromised individualsthe occurrence of resistance was also not observed.

Data from selected clinical cases and observational studies

In patients who did not receive oseltamivir, the mutations of influenza A and B viruses, which appeared in the wild, had a reduced sensitivity to oseltamivir. In 2008, a mutation by replacement type H275Y, leading to resistance, was detected in more than 99% of strains of the 2008 H1 virusN1, circulating in Europe. Influenza virus 2009 H1N1 ("swine flu") in most cases was sensitive to oseltamivir. Resistant to oseltamivir strains were found in persons with normal immune system function and persons with weakened immunity who took oseltamivir. The degree of decrease in sensitivity to oseltamivir and the frequency of occurrence of such viruses may differ depending on the season and the region. Resistance to oseltamivir is found in patients with pandemic influenza H1N1, who received the drug, both for treatment and for prevention.

The incidence of resistance may be higher in younger patients and in immunocompromised patients.Oseltamivir-resistant laboratory strains of influenza viruses and influenza viruses from patients treated with oseltamivir carry neuraminidase mutations N1 and N2. Mutations that lead to resistance are often specific for the subtype of neuraminidase.

When deciding to use oseltamivir, the seasonal sensitivity of the influenza virus to the drug should be taken into account (the latest information can be found on the WHO website).

Preclinical data

Preclinical data obtained on the basis of standard studies on the study of pharmacological safety, genotoxicity and chronic toxicity, did not reveal a particular danger to humans.

Carcinogenicity: results of 3 studies on the detection of carcinogenic potential (two 2-year studies in rats and mice for oseltamivir and one 6-month study in transgenic mice Tg: AC for the active metabolite) were negative.

Mutagenicity: standard genotoxic tests for oseltamivir and the active metabolite were negative.

Impact on fertility: oseltamivir in 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 in a dose of up to 1500 mg / kg / day (in rats) and up to 500 mg / kg / day (rabbits), no effect on embryo-fetal development was detected. In studies on antenatal and postnatal developmental periods in rats, when oseltamivir was administered at a dose of 1500 mg / kg / day, there was an increase in the period of labor: the safety margin between exposure for humans and the maximum non-effecting dose in rats (500 mg / kg / day) for rats Oseltamivir is 480 times higher, and for its active metabolite 44 times. Exposure of the fetus was 15-20% of that of the mother.

Other: oseltamivir and active metabolite penetrate the milk of lactating rats. According to limited data oseltamivir and its active metabolite penetrate the human breast milk. Based on the results of extrapolation of data obtained in studies in animals, their amount in breast milk can be 0.01 mg / day and 0.3 mg / day, respectively.

Approximately 50% of the guinea pigs tested, when the maximum doses of the active substance of oseltamivir were administered, skin sensitization in the form of erythema was observed. Also, reversible eye irritation in rabbits has been identified.

At that time, as a very high oral single doses (657 mg / kg and above) oseltamivir phosphate had no effect on adult rats, dose data have toxic effects on immature 7-day-old rat pups, including, resulted in death of the animals. Undesirable effects were not observed with chronic administration at a dose of 500 mg / kg / day from day 7 to day 21 of the postnatal period.

Pharmacokinetics:

Suction

Oseltamivir phosphate is easily absorbed in the gastrointestinal tract and is highly converted into an active metabolite under the action of hepatic and intestinal esterases. The concentrations of the active metabolite in the plasma are determined within 30 minutes, the time to reach maximum concentration of 2-3 hours, and more than 20 times the concentration of the prodrug. At least 75% of the ingested dose falls into the systemic bloodstream as an active metabolite, less than 5% in the form of the starting drug. The plasma concentrations of both the prodrug and the active metabolite are proportional to the dose and do not depend on the intake of food.

Distribution

The volume of distribution (V_d) active metabolite - 23 liters.

According to studies conducted on animals,after ingestion of oseltamivir phosphate, its active metabolite was found in all major foci of infection (lungs, bronchial washings, nasal mucosa, middle ear and trachea) in concentrations providing antiviral effect.

The association of the active metabolite with plasma proteins is 3%. The relationship of prodrug with plasma proteins is 42%, which is not enough to cause significant drug interactions.

Metabolism

Oseltamivir phosphate is highly converted into an active metabolite by the action of esterases, which are predominantly in the liver. Neither oseltamivir phosphate nor active metabolite are substrates or inhibitors of cytochrome P450 isoenzymes.

Excretion

It is excreted (> 90%) in the form of active metabolite mainly by the kidneys. The active metabolite is not further transformed and is excreted by the kidneys (> 99%) by glomerular filtration and tubular secretion. The 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. Through the intestine, less than 20% of the drug taken is excreted.The half-life of the active metabolite is 6-10 hours.

Pharmacokinetics in special patient groups

Patients with renal involvement

When oseltamivir (100 mg twice daily for 5 days) was used in patients with various degrees of kidney damage, the area under the curve "concentration of active metabolite in plasma is time" (AUC) is inversely proportional to a decrease in renal function.

The pharmacokinetics of oseltamivir in patients with terminal renal failure (with creatinine clearance ≤10 ml / min) not on dialysis was not studied.

Patients with hepatic damage

Received in vitro and in animal studies, the absence of a significant increase in AUC oseltamivir phosphate in patients with mild to moderate liver function was confirmed in clinical trials (see Dosage in special cases). The safety and pharmacokinetics of oseltamivir phosphate in patients with severe liver dysfunction has not been studied.

Patients of elderly 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 administered.The half-life of the drug in elderly and senile patients did not differ significantly from that in younger patients. Taking into account the data on the exposure of the drug and its tolerability, patients of the elderly and senile age do not need dose adjustment for the treatment and prevention of influenza.

Children aged ≥1 year

The pharmacokinetics of oseltamivir was studied in children from 1 to 16 years of age in a pharmacokinetic study with a single dose of the drug and in a clinical study on multiple drug intake in a small number of children aged 3-12 years. The rate of excretion of the active metabolite, adjusted for body weight in young children is higher than in adults, which leads to a lower AUC in relation to a specific dose. Admission of the drug at a dose of 2 mg / kg and single doses of 30 mg or 45 mg in accordance with the recommendations for dosing for children, given in the section "Method of administration and dose", provides the same AUC oseltamivir carboxylate, which is achieved in adults after a single capsule administration with 75 mg of the drug (equivalent to about 1 mg / kg).

The pharmacokinetics of oseltamivir in children older than 12 years is the same as in adults.

Indications:

- Treatment of influenza in adults and children over the age of 1 year.

- Prevention of influenza in adults and adolescents over 12 years of age who are at high risk of infection with the virus (in military units and large production teams, in weakened patients).

- Prevention of influenza in children older than 1 year.

Contraindications:

- Hypersensitivity to oseltamivir phosphate or any component of the drug;

- tThe terminal stage of renal failure (creatinine clearance ≤ 10 ml / min);

- dEthnic age up to 1 year;

- tsevere hepatic impairment.

Carefully:

Pregnancy, the period of breastfeeding.

Pregnancy and lactation:

Controlled studies in pregnant women were not conducted. However, the results of post-marketing and observational studies have demonstrated the benefits of the proposed standard dosing regimen for this patient population. 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 ones. Nevertheless, the value of the calculated exposure remains above the inhibitory concentrations (IC value₉₅) and therapeutic values for many strains of the influenza virus. Changing the dosage regimen in pregnant women during therapy or prevention is not recommended (see "Pharmacokinetics in special patient groups"). There was no direct or indirect adverse effect of the drug on pregnancy, embryo-fetal or postnatal development (see "Pre-clinical data"). When prescribing oseltamivir, pregnant women should consider both the safety data and the course of pregnancy, and the pathogenicity of the circulating strain of the influenza virus.

During preclinical research oseltamivir and the active metabolite penetrated into the milk of lactating rats. Data on the excretion of oseltamivir with human breast milk in humans and the use of oseltamivir in lactating women are limited. Oseltamivir and its active metabolite penetrate into breast milk in small amounts (see "Pre-clinical data"), creating sub-therapeutic concentrations in the blood of the infant. When oseltamivir is prescribed, lactating women should also take into account the concomitant disease and pathogenicity of the circulating strain of influenza virus.During pregnancy and during breastfeeding oseltamivir apply only if the intended benefit to the mother exceeds the potential risk to the fetus and the baby.

Dosing and Administration:

Inside, with meals or regardless of food intake. The tolerability of the drug can be improved if taken with food.

If there are signs of "aging" of the capsules (for example, increased brittleness or other physical disorders), it is necessary to open the capsule and pour its contents into a small amount (as much as 1 teaspoon) of a suitable sweetened food product (chocolate syrup with normal sugar content or sugar-free , honey, light brown sugar or table sugar, dissolved in water, sweet dessert, condensed milk with sugar, apple puree or yogurt) in order to hide the bitter taste. The mixture must be thoroughly mixed and given to the patient as a whole. It is necessary to swallow the mixture immediately after preparation. Detailed recommendations are given in subsection "Extemporal suspension preparation".

Standard dosing regimen

Treatment

The drug should be taken no later than 2 days after the onset of symptoms of the disease.

Adults and adolescents aged ≥ 12 years

75 mg twice daily for 5 days. An increase in the dose of more than 150 mg / day does not lead to an enhanced effect.

Children with a body weight> 40 kg or between the ages of 8 and 12 years

Children who know how to swallow capsules can also receive treatment, taking one 75 mg capsule twice a day for 5 days.

Children aged 1 to 8 years

It is possible to use a suspension prepared extemporally (see subsection "Extemporaneous suspension preparation").

Prevention

The drug should be taken no later than 2 days after contact with patients.

Adults and adolescents aged ≥ 12 years

75 mg once a day inside for at least 10 days after contact with the patient. During the seasonal flu epidemic - 75 mg once a day for 6 weeks. Prophylactic action lasts as long as the drug takes.

Children with a body weight> 40 kg or between the ages of 8 and 12 years

Children who can swallow capsules can also receive preventive therapy, taking one 75 mg capsule once a day for 10 days.

Children aged 1 to 8 years

It is possible to use a suspension prepared externally (see FIG.subsection "Extemporaneous preparation of a suspension").

Dosing in special cases

Patients with renal involvement

Treatment

Patients with a creatinine clearance greater than 60 ml / min are not required to adjust the dose. In patients with creatinine clearance from 30 to 60 ml / min, the dose of oseltamivir should be reduced to 30 mg twice daily for 5 days. In patients with a creatinine clearance of 10 to 30 ml / min, the dose of oseltamivir should be reduced to 30 mg once daily for 5 days. Patients on permanent hemodialysis, oseltamivir in the initial dose of 30 mg can be taken before the beginning of dialysis, if the flu symptoms appeared within 48 hours between dialysis sessions. To maintain plasma concentrations at the therapeutic level oseltamivir should be taken at 30 mg after each dialysis session. Patients on peritoneal dialysis, oseltamivir should be taken at the initial dose of 30 mg before the start of dialysis, then 30 mg every 5 days (see also "Dosage in special cases" and "Special instructions"). The pharmacokinetics of oseltamivir in patients with terminal renal failure (with creatinine clearance <10 mL / min) not on dialysis has not been studied. In this regard, there are no recommendations for dosing in this group of patients.

Prevention

In patients with a creatinine clearance of 10 to 30 ml / min, it is recommended that the dose of oseltamivir be reduced to 30 mg every other day. Patients on permanent hemodialysis, oseltamivir in the initial dose of 30 mg can be taken before the start of dialysis ("1st session"). To maintain plasma concentrations at the therapeutic level oseltamivir should be taken at 30 mg after each subsequent odd dialysis session. Patients on peritoneal dialysis, oseltamivir should be taken at the initial dose of 30 mg before the start of dialysis, then 30 mg every 7 days (see also "Dosage in special cases" and "Special instructions").

The pharmacokinetics of oseltamivir in patients with terminal renal failure (with creatinine clearance ≤ 10 mL / min) not on dialysis has not been studied. In this regard, there are no recommendations for dosing in this group of patients.

Patients with liver damage

Dose adjustments in the treatment and prevention of influenza in patients with impaired liver function of mild to moderate severity are not required. The safety and pharmacokinetics of oseltamivir in patients with severe impairment of liver function has not been studied.

Patients of elderly and senile age

Dose adjustments for the prevention or treatment of influenza are not required.

Patients with weakened immunity (after transplantation)

For seasonal prophylaxis of influenza in patients with immunocompromised patients aged ≥1 years - within 12 weeks, dose adjustment is not required (see section "Method of administration and dose").

Children

Oseltamivir in this dosage form should not be administered to children under 1 year of age.

Extemporal suspension preparation Influucine®

In cases where there is a problem with swallowing capsules in adults, teenagers and children, or if there are signs of "aging" of capsules, it is necessary to open the capsule and pour its contents into a small amount (as much as 1 teaspoon) of a suitable sweetened food product (see above) in order to hide the bitter taste. The mixture must be thoroughly mixed and given to the patient as a whole.It is necessary to swallow the mixture immediately after preparation.

If patients need a dose of 75 mg, then the following instructions should be followed:

1. Holding one capsule of 75 mg of Influtsein® over a small container, gently uncover the capsule and pour the powder into the container.

2. Add a small amount (not more than 1 teaspoon) of a suitable sweetened food product (to hide a bitter taste) and mix well.

3. Stir the mixture thoroughly and drink it immediately after preparation. If a small amount of the mixture remains in the container, rinse the container with a small amount of water and drink the remaining mixture.

If patients require doses of 30-60 mg, then for proper dosing, the following instructions should be followed:

1. Holding one capsule of 75 mg of Influtsein® over a small container, gently uncover the capsule and pour the powder into the container.

2. Add 5 ml of water to the powder with a syringe with labels indicating the amount of liquid collected. Stir well for 2 minutes.

3. Inject the necessary amount of the mixture from the container into the syringe according to the table below:

Body mass	The recommended dose	Amount of mixture for one reception
≤ 15 kg	30 mg	2 ml
> 15-23 kg	45 mg	3 ml
> 23-40 kg	60 mg	4 ml

There is no need to take an undissolved white powder, because it is an inactive filler. Pressing the plunger of the syringe, enter all its contents into the second container. The remaining unused mixture must be discarded.

4. In the second container add a small amount (not more than 1 teaspoon) of a suitable sweetened food product to hide the bitter taste, and mix well.

5. Stir the mixture thoroughly and drink it immediately after preparation. If a small amount of the mixture remains in the container, rinse the container with a small amount of water and drink the remaining mixture.

Repeat this procedure before each drug intake.

Side effects:

Clinical researches

In studies on influenza treatment in adults / adolescent patients, the most frequent adverse reactions (HP) had nausea, vomiting and a headache. Most HP occurred on the first or second day of treatment and passed independently for 1-2 days. In studies on the prevention of influenza in adults and adolescents, the most frequent HP there was nausea, vomiting, headache and pain.Vomiting was most common in children. Described HP in most cases, did not require the withdrawal of the drug.

Treatment and prevention of influenza the adults and teenagers

Table 1 presents HP(≥ 1%) when taking the recommended dose of oseltamivir in studies on prevention and treatment of influenza in adults and adolescents (75 mg twice daily for 5 days for treatment and 75 mg once a day for up to 6 weeks for prophylaxis ), and whose frequency is at least 1% higher compared with placebo. The study on influenza treatment included adults / adolescents without concomitant pathology and patients at risk, i.e. patients with a high risk of developing complications of influenza (elderly and senile patients, patients with chronic heart or respiratory diseases). In general, the safety profile in patients at risk was consistent with that in adult / adolescent patients without concomitant pathology.

In studies on influenza prevention, the safety profile of patients receiving the recommended dose of oseltamivir (75 mg once a day to 6 weeks) did not differ from that in studies on the treatment of influenza, despite the longer administration of the drug.

Table 1. Percentage of adults / adolescents with HP, occurring with a frequency of ≥1% in the oseltamivir group in studies on the treatment and prevention of influenza infection (difference from placebo ≥ 1%)

System-Organ Class	Treatment		Prevention		Frequency Category ^a
Unwanted reaction	Oseltamivir (75 mg 2 times / day) N = 2647	Placebo N = 1977	Oseltamivir (75 mg once a day) N = 1945	Placebo N = 1588
Disorders from the gastrointestinal tract:
Nausea	10%	6%	8%	4%	Often
Vomiting	8%	3%	2%	1%	often
Impaired nervous system:
Headache	2%	1%	17%	16%	Often
General disorders:
Pain	<1%	<1%	4%	3%	often

^a The frequency category is only for the oseltamivir group. To estimate the frequency of HP, the following frequency categories are used: very often (≥1 / 10); often (≥1 / 100, <1/10).

The following are undesirable phenomena that occurred at a frequency of ≥1% in adults and adolescents who received oseltamivir in research on treatment (n= 2647) and prevention (n= 1945) of influenza infection. These adverse events were either more frequently observed in patients receiving placebo, or the difference in frequency between oseltamivir and placebo groups was less than 1%:

Disorders from the gastrointestinal tract (oseltamivir versus placebo):

treatment - diarrhea (6% vs. 7%), abdominal pain (including pain in the upper abdomen, 2% vs. 3%);

prevention - diarrhea (3% vs. 4%), pain in the upper abdomen (2% vs. 2%), dyspepsia (1% vs 1%).

Infections and infestations (oseltamivir versus placebo):

treatment - bronchitis (3% vs. 4%), sinusitis (1% vs. 1%), herpes simplex (1% vs 1%).

prevention - nasopharyngitis (4% vs. 4%), upper respiratory tract infection (3% vs. 3%), influenza infection (2% vs. 3%).

General disorders (oseltamivir versus placebo):

treatment - dizziness (including vertigo, 2% vs. 3%);

prevention - fatigue (7% versus 7%), pyrexia (2% vs. 2%), flu-like disease (1% vs. 2%), dizziness (1% vs. 1%), pain in the extremities (1% vs 1%).

Disturbances from the nervous system (oseltamivir versus placebo):

treatment - Insomnia (1% vs. 1%);

prevention - Insomnia (1% vs. 1%).

Disturbances from the respiratory, thoracic and mediastinal (oseltamivir versus placebo):

treatment - coughing (2% vs. 2%), nasal congestion (1% vs. 1%);

prevention - Nasal congestion (7% vs. 7%), angina (5% vs. 5%), cough (5% vs. 6%), rhinorrhea (1% vs 1%).

Disturbances from musculoskeletal and connective tissue (oseltamivir versus placebo):

prevention - Back pain (2% vs. 3%), arthralgia (1% vs. 2%), myalgia (1% vs. 1%).

Violations of the genitals and breast (oseltamivir vs. placebo):

preventiona - dysmenorrhea (3% vs. 3%).

Treatment and prevention of influenza infection or elderly and senile age

The safety profile of 942 elderly and senile patients receiving oseltamivir or placebo did not clinically differ from that in younger patients (up to 65 years of age).

Prevention of influenza infection the patients with weakened immunity

In a 12-week study on influenza prevention involving 475 immunocompromised patients (including 18 children aged 1 to 12 years), in patients taking oseltamivir (n= 238), the safety profile was consistent with that described earlier in studies on influenza prevention.

Treatment and prevention of influenza infection the children without concomitant diseases at the age of 1-12 years and patients with bronchial asthma

In studies on the treatment of natural influenza infection in children aged 1 to 12 years HP when oseltamivir is used (n= 858), marked with a frequency of ≥1% and at least 1% more frequently than placebo (n= 622), was vomiting.

In a study on post-exposure prophylaxis in the home (n= 99) and in a separate 6-week study on prevention (n= 49) in children who received the recommended dose of oseltamivir 1 time per day, the most common was vomiting (8% in the oseltamivir group versus 2% in the group who did not receive preventive treatment). Oseltamivir well tolerated in these studies, the reported adverse events were consistent with those described earlier in studies on the treatment of influenza in children.

The following are undesirable events noted in children with a frequency of ≥1% in studies on influenza (n= 858) or with a frequency of ≥5% in studies on the prevention of influenza (n= 148). These adverse events were more frequently observed in the placebo group / absence of prophylaxis, differences between oseltamivir and placebo / absence of prophylaxis were less than 1%.

Disturbances from the gastrointestinal tract (oseltamivir versus placebo):

treatment - diarrhea (9% vs 9%), nausea (4% vs. 4%), abdominal pain (including pain in the upper abdomen, 3% vs. 3%).

Infections and infestations (oseltamivir versus placebo):

treatment - otitis media (5% vs. 8%), bronchitis (2% vs. 3%), pneumonia (1% vs. 3%), sinusitis (1% vs. 2%).

Disturbances from the respiratory, thoracic and mediastinal (oseltamivir versus placebo):

treatment - Asthma (including exacerbation, 3% vs. 4%), epistaxis (2% vs. 2%);

prevention - cough (12% vs. 26%), nasal congestion (11% vs. 20%).

Disturbances from the skin and subcutaneous tissues (oseltamivir versus placebo):

treatment - dermatitis (including allergic and atopic dermatitis, 1% vs. 2%).

Hearing disorders and labyrinthine disturbances (oseltamivir versus placebo):

treatment - Pain in the ear (1% vs. 1%).

Disturbances from the side of the eye (oseltamivir versus placebo):

treatment - conjunctivitis (including reddening of the eyes, discharge from the eye and pain in the eyes, 1% vs. <1%).

Additional adverse events noted in studies on the treatment of influenza in children did not meet the criteria described above.

Violations of the blood and lymphatic system (oseltamivir versus placebo):

treatment - lymphadenopathy (<1% vs. 1%).

Hearing disorders and labyrinthine disturbances (oseltamivir versus placebo):

treatment - Damage to the tympanic membrane (<1% vs. 1%).

Postmarketing surveillance

The following are undesirable phenomena in the use of oseltamivir, which were observed during post-marketing surveillance. The incidence of these adverse events and / or a causal relationship with the use of oseltamivir can not be established, since the true size of the population is not known due to the voluntary nature of the messages.

Disturbances from the skin and subcutaneous tissues: hypersensitivity reactions - dermatitis, skin rash, eczema, urticaria, multiforme exudative erythema, Stevens-Johnson syndrome and toxic epidermal necrolysis, allergy, anaphylactic and anaphylactoid reactions, Quincke's edema.

Disturbances from the liver and bile ducts: hepatitis, an increase in the activity of "hepatic" enzymes in patients with influenza-like symptoms who received oseltamivir, fulminant hepatitis (including fatal outcome), liver failure, jaundice.

Disorders from the side of the neuropsychic sphere:

Influenza infection can be associated with various neurological symptoms and behavioral changes, including symptoms such as hallucinations, delusions, and abnormal behavior.In some cases, they can lead to death. Such phenomena can occur both against the background of the development of encephalopathy or encephalitis, and without the manifestation of these diseases. In patients (mainly children and adolescents) who took oseltamivir with the aim of treating the flu, convulsions and delirions were recorded (including such symptoms as impairment of consciousness, disorientation in time and space, abnormal behavior, delirium, hallucinations, agitation, anxiety, nightmares). These cases were rarely accompanied by life-threatening acts. The role of oseltamivir in the development of these phenomena is unknown. Similar psychoneurological disorders were also noted in patients with influenza who did not receive oseltamivir.

Disorders from the gastrointestinal tract: gastro-intestinal bleeding after taking oseltamivir (in particular, the connection between hemorrhagic colitis and the intake of oseltamivir can not be ruled out, since these events disappeared both after the patient recovered from the flu and after the drug was discontinued).

Disturbances on the part of the organ of sight: impaired vision.

Heart Disease: cardiac arrhythmia.

Overdose:

Cases of overdose during clinical trials and in the post-marketing application of oseltamivir have been described. In most cases, an overdose was not accompanied by any undesirable phenomena.

In all other cases, the symptoms of an overdose corresponded to the undesirable phenomena presented in the "Side effect" section.

Interaction:

Clinically significant drug interactions are unlikely according to pharmacological and pharmacokinetic data.

Oseltamivir phosphate is highly converted to an active metabolite by the action of esterases, mainly located in the liver.

Drug interactions caused by competition for binding to active centers of esterases are not widely reported in the literature. The low degree of binding of oseltamivir and the active metabolite to plasma proteins does not give grounds for assuming the presence of interactions associated with the displacement of drugs from binding to proteins.

Research in vitro show that neither oseltamivir phosphate nor its active metabolite is the preferred substrate for polyfunctional oxidases of the cytochrome P450 system or for glucuronyl transferases (see subsection "Pharmacokinetics").There are no grounds for interaction with oral contraceptives.

Cimetidine, a nonspecific inhibitor of cytochrome P450 isoenzymes and competing in tubular secretion with alkaline preparations 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 such drugs, the ways of excretion of the active metabolite of oseltamivir (glomerular filtration and anionic tubular secretion), and the yielding capacity of each pathway.

Probenecid leads to an increase in the AUC of the active metabolite of oseltamivir by about 2 times (due to a decrease in active tubular secretion in the kidneys). However, dose adjustment when used simultaneously with probenecid is not required, given the safety reserve of the active metabolite.

Simultaneous reception with amoxicillin does not affect the plasma concentrations of oseltamivir and its components, demonstrating weak competition for excretion by anionic tubular secretion.

Simultaneous reception with paracetamol does not affect the plasma concentrations of oseltamivir and its active metabolite or paracetamol.

Pharmacokinetic interactions between oseltamivir, its main metabolite was not detected with simultaneous administration with paracetamol, acetylsalicylic acid, cimetidine, antacid agents (magnesium and aluminum hydroxide, calcium carbonate), warfarin, rimantadine, or amantadine.

In Phase III clinical trials oseltamivir with commonly used drugs, such as ACE inhibitors (enalapril, captopril), thiazide diuretics (bendroflumethiazide), antibiotics (penicillin, cephalosporins, azithromycin, erythromycin and doxycycline), blockers H₂-gistaminovyh receptors (ranitidine, cimetidine), beta-blockers (propranolol), xanthines (theophylline), sympathomimetics (pseudoephedrine), opiates (codeine), corticosteroids, inhaled bronchodilators and non-narcotic analgesics (acetylsalicylic acid, ibuprofen and paracetamol). Changes in the nature or frequency of adverse events were not observed.

Use oseltamivir in combination with drugs that have a narrow breadth of therapeutic effect (for example, chlorpropamide, methotrexate, butadione), it is necessary with caution.

Special instructions:

Disorders of the psyche

In patients (mainly children and adolescents) who took oseltamivir with the purpose of treatment of influenza, convulsions and delirium-like psychoneurological disorders were recorded. These cases were rarely accompanied by life-threatening acts. The role of oseltamivir in the development of these phenomena is unknown. Similar psychoneurological disorders were also noted in patients with influenza who did not receive oseltamivir.

The risk of developing psychoneurological disorders in patients receiving oseltamivir, does not exceed that of patients with influenza who do not receive antiviral drugs. It is recommended to closely monitor the condition and behavior of patients, especially children and adolescents, in order to identify signs of abnormal behavior and assess the risk of continued use of the drug in the development of these phenomena.

Data on the effectiveness of oseltamivir for any diseases caused by other pathogens other than influenza A and B viruses, no.

Influtsein® is not a substitute for vaccination. Prophylactic intake of the drug Influcein ® is possible by 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 administered to children under 1 year of age.

Effect on the ability to drive transp. cf. and fur:

Studies to study the effect of the drug on the ability to drive vehicles and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions have not been carried out. Based on the safety profile, the effect of oseltamivir on these activities is unlikely.

Form release / dosage:

Capsules, 75 mg.

Packaging:

10 capsules per contour squeeze box of PVC film or PVC / PVC film, or PVC / PCTFE film and aluminum foil printed lacquer.

On 1 contour acheikova packing together with the instruction on application place in a pack from a cardboard.

Storage conditions:

At a temperature of no higher than 25 ° C, in the manufacturer's packaging.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003837

Date of registration:14.09.2016 / 28.02.2017

Expiration Date:14.09.2021

The owner of the registration certificate:CANONFARMA PRODUCTION, CJSC CANONFARMA PRODUCTION, CJSC Russia

Manufacturer: & nbsp

CANONFARMA PRODUCTION, CJSC Russia

Representation: & nbspCANONFARMA PRODUCTION CJSC CANONFARMA PRODUCTION CJSC Russia

Information update date: & nbsp14.06.2017

Illustrated instructions

Instructions

Influucine® (Influucine®)