Tamiflu - instructions for use, dose, side effects, contraindications

active substance: oseltamivir - 30 mg (in the form of oseltamivir phosphate - 39.4 mg); Excipients: pregelatinized starch - 18.56 mg, povidone K30- 2.68 mg, croscarmellose sodium - 1.36 mg, talc - 3.32 mg, sodium stearyl fumarate - 0.68 mg;

shell capsules - 38 mg (gelatin, iron oxide red (E172), iron oxide yellow (E172), titanium dioxide (E171));

ink for applying the inscription on the capsule: ethanol, shellac, butanol, titanium dioxide (E171), aluminum based on indigo carmine, ethanol denatured [methylated alcohol].

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One capsule of 45 mg contains:

active substance: oseltamivir - 45 mg (in the form of oseltamivir phosphate - 59.1 mg); Excipients: pregelatinized starch - 27.84 mg, povidone K30 - 4.02 mg, croscarmellose sodium - 2.04 mg, talc - 4.98 mg, sodium stearyl fumarate - 1.02

capsule shell - 38 mg (gelatin, ferric oxide black oxide (E172), titanium dioxide (E171));

ink for applying the inscription on the capsule: ethanol, shellac, butanol, titanium dioxide (E171), aluminum based on indigo carmine, ethanol denatured [methylated alcohol].

Description:

Capsules 30 mg

Hard gelatin capsules, size 4. Body and cap capsule - light yellow, opaque. The contents of the capsules are white to yellowish white powder. On the capsule there is an inscription "ROCHE"(on the case) and" 30 mg"(on the lid) is light blue.

Capsules 45 mg

Hard gelatin capsules, size 4. Body and cap capsule - gray, opaque. The contents of the capsules are white to yellowish white powder. On the capsule there is an inscription "ROCHE"(on the case) and" 45 mg"(on the lid) is light blue.

Note: after 5 years of storage the signs of "aging" of the capsules may be observed, which can lead to their increased brittleness or other physical disorders that do not affect the efficacy and safety of the drug.

Pharmacotherapeutic group:Antiviral agent

ATX: & nbsp

J.05.A.H.02 Oseltamivir

Pharmacodynamics:

Mechanism of action

Antiviral drug. Oseltamivir is its prodrug, its active metabolite (osltamivir 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 viral particles from infected cells, their penetration into uninfected respiratory epithelial cells, and further the spread of the 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. The OC concentration necessary for inhibiting neuraminidase by 50% (IC50) is 0.1-1.3 nM for the influenza A virus and 2.6 nM for the influenza B virus. Median values IC50 for influenza B virus is slightly higher and is 8.5 nM.

Clinical efficacy

In the studies conducted, Tamiflu * had no effect on 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 Tamiflu * no later than 40 hours after the onset of the first symptoms of influenza infection. 97% of patients were infected with influenza A virus and 3%

of patients with the influenza virus B. Tamiflu significantly reduced the period of clinical manifestations of influenza infection (at 32 hours). In patients with confirmed influenza diagnosis who took Tamiflu, the severity of the disease, expressed as the iodine area of the curve for the total symptom index, was 38% less than in patients receiving placebo. Moreover, in young patients without concomitant diseases, Tamiflu reduced approximately 50% of the incidence of complications of influenza requiring antibiotics (bronchitis, pneumonia, sinusitis, otitis media). Clear evidence was obtained of the effectiveness of the drug with regard to secondary efficacy criteria related to antiviral activity: Tamiflu caused both a shortening of the time of virus isolation from the body and a decrease in the iodine area of the "viral titers-time" curve.

The data obtained in the study on the therapy of Tamiflu® in elderly and senile patients,show that taking Tamiflu 75 mg twice daily for 5 days was accompanied by a clinically significant decrease in the median period of clinical manifestations of influenza infection, similar to that in older adults, but the differences did not reach statistical significance. In another study, patients with influenza older than 13 years who had concomitant chronic diseases of the cardiovascular and / or respiratory systems received Tamiflu in the same dosing regimen or placebo. There were no differences in the median of the period until the clinical manifestations of influenza infection in the Tamiflu and placebo groups were reduced, but the period of temperature increase with the use of Tamiflu was reduced by approximately 1 day. The proportion of patients who isolated the virus on days 2 and 4 became significantly less. The safety profile of Tamiflu® in patients at risk did not differ from that in the general population of adult patients.

Treatment of influenza in children

In children aged 1-12 years (mean age 5.3 years) who had fever (> 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 trial.67% of patients were infected with influenza A virus and 33% of patients with influenza B. The drug Tamiflu (when taken 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, disappearance of fever, return to normal activity. In the group of children receiving Tamiflu. 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 receiving Tamiflu, compared with the placebo group.

In another study, children aged 6-12 years with bronchial asthma participated; 53.6% of patients had an influenza infection confirmed serologically and / or in culture. The median duration of the disease in the group of patients receiving Tamiflu did not significantly decrease. But by the last 6th day of Tamiflu therapy, the volume of forced expiration in 1 sec (FEV1) 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 Tamiflu® with natural influenza A and B infection was demonstrated in 3 separate Phase III clinical trials. On the background of taking Tamiflu, influenza caused about 1% of patients. Tamiflu also significantly reduced the frequency of virus isolation and prevented transmission of the virus from one member of the family to another.

Adults and adolescents who were in contact with a sick family member began receiving Tamiflu within two days of the onset of flu symptoms among family members and continued it for 7 days, which reliably reduced the incidence of influenza in 92% of the contactees.

In unvaccinated and generally healthy adults aged 18-65 years, the use of Tamiflu during the flu 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 whom were vaccinated before the season when the study was conducted, Tamiflu significantly reduced the incidence of influenza by 92%. In the same study, Tamiflu reliably (by 86%) reduced the incidence of complications of influenza: bronchitis, pneumonia, sinusitis. Patients took the drug for 42 days.

Prevention of influenza in children

Prophylactic efficacy of Tamiflu in natural influenza infection has been demonstrated in children from 1 year to 12 years after exposure to a sick family member or someone from the permanent environment. The main parameter of effectiveness was the frequency of a laboratory-confirmed influenza infection. Children who received Tamiflu / powder for suspension for oral / in 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 with 21% (15/70) in the placebo group.

Prevention of influenza in immunocompromised individuals

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

Resistance Clinical researches

The risk of the emergence of influenza viruses with reduced sensitivity or resistance to the drug has been studied in clinical trials sponsored by Roche. 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.

Patient population	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 Tamiflu was administered for the purpose of post-exposure prophylaxis (7 days), prevention of family contact (10 days) and seasonal prophylaxis (42 days), there was no evidence of drug resistance in persons with normal immune system function. In a 12-week study on seasonal prophylaxis in immunocompromised individuals, cases ofresistance 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 individuals 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 for both treatment and 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 mutations of neuraminidase N1 and N2.Mutations that lead to resistance are often specific for the subtype of neuraminidase. When deciding on the use of Tamiflu, 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 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 of 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 dose-inactive dose in rats (500 mg / kg / day) for 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.

While very high oral single doses (657 mg / kg and above) of oseltamivir had no effect on adult rats, these doses had toxic effects on immature 7-day-old rats, including death of 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 is easily absorbed in the gastrointestinal tract and extensively converted to an active metabolite under the influence of hepatic and intestinal esterases. The concentrations of the active metabolite in plasma are determined within 30 minutes, the time to reach a maximum concentration of 2-3 hours, and more than 20 times the concentration of the prodrug. He less than 75% of the ingested dose enters 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

Volume of distribution (V_ss) active metabolite - 23 liters.

According to studies conducted in animals, after taking oseltamivir inward, 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 is extensively converted to an active metabolite under the action of esterases, which are predominantly in the liver. Neither oseltamivir, nor active metabolites 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 groups of patients BOlive with kidney damage

When applying Tamiflu (100 mg twice daily for 5 days) in patients with varying degrees of kidney damage, the area under the curve "concentration of active metabolite in plasma - time" (AUC oseltamivir carboxylate) 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 has not been studied. Patients with liver damage

Received in vitro and in animal studies, the absence of a significant increase in AUC oseltamivir or its active metabolite in the case of violations of mild to moderate liver function have been confirmed in clinical studies (see "Dosage in special cases"). The safety and pharmacokinetics of oseltamivir in patients with severe impairment of liver function has not been studied.

Patients of elderly and senile age

In patients of the elderly and senile age (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 tampflu 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. Fly at the age of 1 to 8 years and teenagers

The pharmacokinetics of Tamiflu were 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 or a component of the drug. Terminal stage of renal failure (creatinine clearance <10 ml / min). Children up to 1 year.

Severe hepatic insufficiency.

Carefully:

Pregnancy, the period of breastfeeding.

Pregnancy and lactation:

Controlled studies in pregnant women were not conducted. However, the results of postmarketing and observational studies have demonstrated the benefits of the proposed standard dosing 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 but compared with non-pregnant women. Nevertheless, the value of the calculated exposure remains above the inhibitory concentrations (value IC95) 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 the section "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 appointing Tamiflu, pregnant women should take into account 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 be considered

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.

Adults, adolescents, or children who can not swallow the capsule may also receive treatment with Tamiflu in their dosage form "powder for oral suspension."

In cases where Tamiflu in the dosage form is "not available for oral suspension", or if there are signs of "aging" of the capsules (eg, increased brittleness or other physical disability), it is necessary to open the capsule and pour its contents into a small amount maximum 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 "Extemporaneous preparation of the Tamiflu suspension >> 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

For 75 mg (one capsule 30 mg + one capsule 45 mg) 2 times a day inside 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 can swallow capsules can also receive treatment by taking one capsule of 30 mg + one capsule of 45 mg twice a day for 5 days.

Children aged 1 to 8 years

The recommended dosage regimen for Tamiflu capsules is 30 and 45 mg or an extemporaneously prepared suspension:

Body mass	The recommended dose for 5 days
<15 kg	30 mg twice daily
> 15-23 kg	45 mg twice daily
> 23-40 kg	60 mg twice daily
> 40 kg	75 mg twice daily

Prevention

The drug should be taken no later than 2 days after contact with patients. Adults and adolescents aged> 12 years

For 75 mg (one capsule 30 mg + one capsule 45 mg) 1 time per 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 capsule 30 mg + one capsule 45 mg once a day for 10 days.

Children aged 1 to 8 years

The recommended dosage regimen for Tamiflu capsules is 30 and 45 mg or an extemporaneously prepared suspension:

Body mass	The recommended dose for 10 days
<15 kg	30 mg once a day
> 15-23 kg	45 mg once a day
> 23-40 kg	60 mg once a day
> 40 kg	75 mg once a day

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 Tamiflu 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 Tamiflu should be reduced to 30 mg once daily for 5 days. Patients who are on permanent hemodialysis, Tamiflu in the initial dose of 30 mg can be taken before the onset of dialysis,

if the flu symptoms appeared within 48 h between dialysis sessions. To maintain plasma concentrations at the therapeutic level, Tamiflu should be taken but 30 mg after each dialysis session.For patients on peritoneal dialysis, Tamiflu should be taken at the initial dose of 30 mg before 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 to reduce the dose of Tamiflu to 30 mg every other day. Patients who are on permanent hemodialysis, Tamiflu 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, Tamiflu should be taken at 30 mg after each subsequent odd dialysis session. For patients on peritoneal dialysis, Tamiflu should be taken at an initial dose of 30 mg before the start of dialysis, then 30 mg every 7 days.also "Dosing 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. Safety and pharmacokinetics Tamiflu 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 weakened immunity at the age of> 1 year - within 12 weeks, dose adjustment is not required (see section "Method of administration and dose").

Tamiflu in this dosage form should not be administered to children under 1 year of age. Extemporaneous preparation of a suspension of Tamiflu®

B cases where in adults, adolescents and children there is a problem with the ingestion of capsules,and Tamiflu in the dosage form "powder for oral suspension" is absent or if there are signs of "aging" of the 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) for 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.

For proper dosing, the following instructions should be followed:

1. Determine the amount of Tamiflu® capsules required for the

mixture:

Body mass*	The number of Tamiflu capsules to provide the recommended dose for treatment within 5 days	The number of Tamiflu capsules to provide the recommended dose for prevention
<15 kg	1 capsule 30 mg twice daily	1 capsule 30 mg once a day
> 15-23 kg	1 capsule 45 mg twice daily	1 capsule 45 mg once a day
> 23-40 kg	2 capsules 30 mg twice daily	2 capsules 30 mg once a day

* Children with a body weight> 40 kg and adults can receive Tamiflu using a mixture

one capsule 45 mg + one capsule 30 mg twice a day for treatment or once a day for prevention.

2. Be sure to use the correct dose of the drug (in accordance with the above table). While holding one or several Tamiflu capsules over a small container, gently uncover one or several capsules and pour the powder into a container.

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

4. 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:

In studies on the treatment of influenza 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.The HPs described in most cases did not require the drug to be discontinued.

Treatment and prevention of influenza the adults and teenagers

Table 1 presents HP, which occurred most often (> 1%) when taking the recommended dose of Tamiflu in studies on the 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 Tamiflu (75 mg once a day to 6 weeks) did not differ from that in studies but treatment of influenza, despite the longer duration of the drug.

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

Systemorganic class Undesirable reaction	Treatment		Prevention		Frequency Category ^a
Systemorganic class Undesirable reaction	Oseltamivir (75 mg 2 times per day) N=2647	Platz bo N = 1977	Oseltamivir (75 mg 1 time / svt) N=1945 *	Platz bo N = 1588
Disturbances from the gastrointestinal tract
Nausea	10%	6%	8%	4%	Often
Vomiting	8%	3%	2%	1%	often
Disturbances from the nervous system
Headache	2%	1%	17%	16%	Often

Table 1. Percentage of adults / adolescents with HP, occurring with a frequency> 1% in the group

General disorders
Pain	<1%	<1%	4%	3%	often

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

The following are undesirable phenomena that occurred with a frequency> 1% in adults and adolescents who received oseltamivir as a therapy and prevention 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 (Tamiflu versus placebo): treatment - diarrhea (6% vs. 7%), abdominal pain (including pain in the upper abdomen, 2% versus 3%);

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

Infections and infestations (Tamiflu 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 (Tamiflu 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 (Tamiflu versus placebo): treatment - insomnia (1% vs. 1%); prevention - insomnia (1% vs. 1%).

Disturbances from the respiratory, thoracic and mediastinal (Tamiflu vs. placebo):

treatment - cough (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 (Tamiflu versus placebo):

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

Violations of the genitals and mammary gland (Tamiflu versus placebo): prevention - dysmenorrhea (3% vs. 3%).

Treatment and prevention of influenza infection in elderly and senile patients The safety profile of 942 elderly and senile patients receiving Tamiflu 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 a Tamiflu® patient (n = 238), the safety profile was similar to that described earlier in studies on influenza prevention .

Treatment and prevention of influenza infection the children without concomitant diseases in age 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 was used (n = 858), noted with a frequency> 1% and at least 1% more often than in the placebo (n = 622), there was vomiting.

In children who received the recommended dose of Tamiflu once a day as post-exposure prophylaxis at home, vomiting was most common (8% in the oseltamivir group versus 2% in the untreated group). Tamiflu® was well tolerated, and the reported adverse events were consistent with those described earlier in the treatment of influenza in children.

The following are undesirable phenomena observed in children with a frequency> 1% in studies on influenza (n = 858) or> 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%.

Disorders from the gastrointestinal tract (Tamiflu 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 (Tamiflu 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 (Tamiflu versus placebo):

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

prophylaxis - cough (12% vs. 26%), nasal congestion (11% against 20%). Impaired skin and subcutaneous tissue (Tamiflu versus placebo): treatment - dermatitis (including allergic and atopic dermatitis, 1% vs. 2%). Hearing disorders and labyrinthine disorders (Tamiflu versus placebo):

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

Impaired vision (Tamiflu® versus placebo):

conjunctivitis treatment (including reddening of the eyes, discharge from the eye and pain in the eyes,

1% against <1%).

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

Violations from the blood and lymphatic system (Tamiflu versus placebo): treatment - lymphadenopathy (<1% vs. 1%).

Hearing disorders and labyrinthine disorders (Tamiflu versus placebo):

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

Postmarketing surveillance

The following are undesirable phenomena with the use of Tamiflu®, which were observed during post-marketing surveillance.The incidence of these adverse events and / or a causal relationship with the use of Tamiflu 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.

Disorders from the liver and bile ducts: hepatitis, an increase in the activity of "hepatic" enzymes in patients with influenza-like symptoms who received Ga-

myth; fulminant hepatitis (including fatal outcome), hepatic insufficiency, 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.Cramps and delirium (including symptoms such as impaired 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 Tamiflu in the development of these phenomena is unknown. Similar psychoneurological disorders were also noted in patients with influenza who did not receive Tamiflu.

Disorders from the gastrointestinal tract: gastrointestinal bleeding after taking Tamiflu (in particular, we can not exclude the connection between the phenomena of hemorrhagic colitis and the administration of Tamiflu®, since these phenomena disappeared both after the patient recovered from the flu and after the drug was discontinued).

Disorders from the side of the organ of vision: impaired vision.

Heart Disease: arrhythmia.

Overdose:

In most cases, overdose during clinical trials and in the postmarketing application of Tamiflu 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 is extensively converted to an active metabolite under 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. A low degree of binding of oseltamivir and an active metabolite

with plasma proteins do not give grounds to assume the presence of interactions associated with the displacement of drugs from the connection with proteins.

Research in vitro show that neither oseltamivir, 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 AUC The active metabolite of oseltamivir is approximately 2-fold (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 concurrent administration with paracetamol, acetylsalicylic acid, cimetidine, antacid agents (magnesium and aluminum hydroxide, calcium carbonate), warfarin, rimantadine, or amantadine.

When using Tamiflu® with commonly used drugs, such as ACE inhibitors (enalapril, captopril), thiazide diuretics (bendroflumethiazide), antibiotics (penicillin, cephalosporins, azithromycin, erythromycin and doxycycline), blockers of H2-histamine receptors (ranitidine, cimetidine), beta-adrenoblockers (propranolol), xanthines (theophylline), sympathomimetics (pseudoephedrine), opiates (codeine), glucocorticosteroids, inhaled bronchodilators and non-narcotic analgesics

(acetylsalicylic acid, ibuprofen and paracetamol), no change in the nature or incidence of adverse events was 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

Patients (mainly children and adolescents) who took Tamiflu for the purpose of treating the flu, were registered violations of the psyche, seizures and delirium-like neuropsychiatric disorders. These cases were seldom accompanied by life-threatening activities. The role of Tamiflu in the development of these phenomena is unknown. Similar psychoneurological disorders were also noted in patients with influenza who did not receive Tamiflu.

The risk of developing neuropsychiatric disorders in patients receiving Tamiflu 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 Tamiflu in any disease caused by other pathogens, except for influenza A and B viruses, there.

Tamiflu® is not a substitute for vaccination.

Preventive drug Tamiflu 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").

Tamiflu in this dosage form should not be administered to children under 1 year of age. Instructions for use, handling and destruction

The presence of drugs in the environment should be minimized. Do not dispose of the product with sewage or with household waste. If possible, it is necessary to use special systems for the disposal of medicinal products.

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 impact of Tamiflu on these activities is unlikely.

Form release / dosage:

Capsules 30 mg and 45 mg.

Packaging:Po 10 capsules in a contour mesh package (blister) made of a triplex (PVC / PE / PVDC) and aluminum foil.1 blister together with instructions for use are placed in a cardboard box.

Storage conditions:

7 years. Do not use after the expiration date printed on the package.

Shelf life:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Terms of leave from pharmacies:On prescription

Registration number:LSR-008794/10

Date of registration:26.08.2010

Date of cancellation:2018-02-27

The owner of the registration certificate:Hoffmann-La Roche IncHoffmann-La Roche Inc USA

Manufacturer: & nbsp

F.Hoffmann-La Roche, Ltd. Switzerland

Information update date: & nbsp27.02.2018

Illustrated instructions

Instructions

Tamiflu® (Tamiflu®)