Agrippa 75 mg capsules No. 10

Instructions for Agrippa 75 mg capsules No. 10

Composition

active ingredient: oseltamivir;

1 hard capsule contains oseltamivir 75 mg (as oseltamivir phosphate);

excipients:

capsule contents: pregelatinized corn starch, povidone, talc, croscarmellose sodium, sodium stearyl fumarate;

capsule shell: titanium dioxide (E 171), iron oxide yellow (E 172), gelatin.

Dosage form

The capsules are hard.

Main physicochemical properties: white granular or slightly compressed powder in a size 2 capsule; white opaque body, deep yellow cap.

Inscriptions: OS in black (on the lid), 75 in black (on the body).

Pharmacotherapeutic group

Antivirals for systemic use. Direct-acting antivirals. Neuraminidase inhibitors. Oseltamivir. ATC code J05A H02.

Pharmacological properties

Pharmacodynamics.

Oseltamivir phosphate is a prodrug of the active metabolite (oseltamivir carboxylate). The active metabolite is a selective inhibitor of the influenza virus enzyme neuraminidase, which is a glycoprotein on the surface of the virion. The activity of the viral enzyme neuraminidase is important for the entry of the virus into uninfected cells, the release of newly formed viral particles from infected cells, and the subsequent spread of the virus in the body.

Oseltamivir carboxylate inhibits neuraminidase of influenza A and B viruses in vitro. Oseltamivir phosphate inhibits viral replication and pathogenicity in vitro. Oseltamivir administered orally inhibits replication of influenza A and B viruses and pathogenicity in animal models of influenza infection in vivo at antiviral exposures similar to those achieved in humans at a dose of 75 mg twice daily.

The antiviral activity of oseltamivir has been confirmed against influenza A and B viruses in experimental studies in healthy volunteers.

The IC50 values of oseltamivir for the neuraminidase enzyme of clinical isolates of influenza A viruses ranged from 0.1 nmol to 1.3 nmol, and for influenza B viruses it was 2.6 nmol. In published data, higher IC50 values were noted for influenza B viruses, with a median of 8.5 nmol.

Oseltamivir resistance

Clinical studies. The risk of emergence of influenza viruses with reduced susceptibility or high resistance to oseltamivir has been studied in clinical studies. The development of oseltamivir-resistant virus during treatment was more common in children than in adults, ranging from less than 1% in adults to 18% in infants <1 year of age. Children carrying oseltamivir-resistant virus generally shed virus for a longer period of time compared with those carrying non-resistant virus. However, treatment-emergent resistance to oseltamivir did not affect response to treatment or result in prolonged influenza symptoms.

Overall, a higher incidence of oseltamivir resistance was observed in immunocompromised adults and adolescents who received standard or double doses of oseltamivir for 10 days [14.5% (10/69) in the standard dose group and 2.7% (2/74) in the double dose group] compared with studies in adults and adolescents without other conditions who received oseltamivir. The majority of adult patients who developed resistance were transplant patients (8/10 patients in the standard dose group and 2/2 patients in the double dose group). The majority of patients with oseltamivir-resistant virus were infected with influenza A virus and shed virus for a longer period.

The incidence of oseltamivir resistance in immunocompromised children (≤12 years) treated with oseltamivir in two studies was 20.7% (6/29). Of the 6 immunocompromised children who developed resistance to oseltamivir during treatment, 3 patients received the standard dose and 3 patients received the high (double or triple) dose. The majority had acute lymphoblastic leukemia and were ≤5 years of age.

Incidence of resistance to oseltamivir in clinical trials

*Full genotyping was not performed in all studies.

Clinical and observational data. Influenza A and B viruses isolated from patients not exposed to oseltamivir have been shown to have naturally occurring mutations associated with reduced susceptibility to oseltamivir in vitro. Resistant strains selected during oseltamivir treatment have been isolated from both normal and immunocompromised patients. Immunocompromised patients and young children were at higher risk of developing oseltamivir resistance during treatment with the virus.

Oseltamivir-resistant viruses isolated from patients treated with oseltamivir and oseltamivir-resistant laboratory strains of influenza viruses have been found to contain mutations in the N1 and N2 neuraminidases. Resistance mutations tended to be specific to the viral subtype. Since 2007, naturally occurring resistance associated with the H275Y mutation has been sporadically identified in seasonal H1N1 strains. Oseltamivir susceptibility and prevalence of such viruses have been shown to vary seasonally and geographically. In 2008, H275Y was found in >99% of circulating H1N1 isolates in Europe. In 2009, the H1N1 influenza virus (“swine flu”) was almost uniformly susceptible to oseltamivir, with sporadic reports of resistance when the drug was used for treatment and prophylaxis.

Pharmacokinetics.

Absorption

After oral administration, oseltamivir phosphate (prodrug) is readily absorbed from the gastrointestinal tract and is extensively converted to the active metabolite (oseltamivir carboxylate) by hepatic esterases. At least 75% of an oral dose enters the systemic circulation as the active metabolite, less than 5% as the parent drug. Plasma concentrations of both the prodrug and the active metabolite are dose-proportional and therefore independent of food intake.

Distribution

In humans, the mean volume of distribution of the active metabolite at steady state is approximately 23 L, a volume equivalent to the volume of extracellular body fluid. Because neuraminidase activity is extracellular, oseltamivir carboxylate reaches all major sites of influenza infection.

The binding of the active metabolite to human plasma proteins is low (approximately 3%).

Metabolism

Oseltamivir is extensively converted to oseltamivir carboxylate by esterases, which are predominantly found in the liver. Neither oseltamivir phosphate nor the active metabolite are substrates or inhibitors of the major cytochrome P450 isoenzymes in vitro. No phase 2 conjugates were detected for either compound in vivo.

Breeding

Absorbed oseltamivir is eliminated primarily (>90%) by conversion to oseltamivir carboxylate, which is not further transformed and is excreted in the urine. In most patients, the maximum plasma concentration of the active metabolite declines with a half-life of 6-10 hours. The active metabolite is eliminated entirely by the kidneys. Renal clearance (18.8 l/h) exceeds glomerular filtration rate (7.5 l/h), indicating that the drug is also eliminated by tubular secretion. Less than 20% of an orally administered radiolabeled drug is excreted in the feces.

Pharmacokinetics in special groups.

Children aged 1 year and older. The pharmacokinetics of oseltamivir have been studied in children aged 1 to 16 years in a single-dose pharmacokinetic study. Multiple-dose pharmacokinetics have been studied in a small number of children in a clinical efficacy study. In younger children, elimination of the prodrug and active metabolite occurred more rapidly than in adults, resulting in lower exposures expressed on a mg/kg basis. A dose of 2 mg/kg provides the same exposure to oseltamivir carboxylate as that achieved in adults after a single dose of 75 mg (equivalent to approximately 1 mg/kg). The pharmacokinetics of oseltamivir in children and adolescents aged 12 years and older are similar to those in adults.

Elderly patients. In elderly patients (65-78 years), the exposure of the active metabolite at steady state is 25-35% higher than in younger patients (<65 years) when using similar doses of oseltamivir. The half-life of the drug in elderly patients is similar to that in younger patients. Based on drug exposure and tolerability, no dose adjustment is necessary for elderly patients, except for patients with moderate or severe renal impairment (creatinine clearance <60 ml/min) (see section "Method of administration and dosage").

Patients with renal impairment: Administration of oseltamivir phosphate 100 mg twice daily for 5 days to patients with varying degrees of renal impairment demonstrated that oseltamivir carboxylate exposure is inversely proportional to the decrease in renal function. For dosage, see section 4.2.

Pregnant women. A pooled population pharmacokinetic analysis indicates that the oseltamivir dosing regimen described in the Dosage and Administration section results in lower exposure (on average 30% across all trimesters) to the active metabolite in pregnant women compared to non-pregnant women. However, the lower predicted exposure remains above the inhibitory concentrations (IC95 values) and therapeutic influenza strain ranges. In addition, observational data suggest a benefit of the current dosing regimen in this patient population. Therefore, no dose adjustment is recommended for pregnant women for the treatment or prevention of influenza (see Use during pregnancy and lactation).

Immunocompromised patients: Population pharmacokinetic analyses have demonstrated that administration of oseltamivir to immunocompromised adults and children (<18 years of age) (as described in section 4.2) results in an increase in predicted exposure (approximately 5-50%) to the active metabolite compared to immunocompetent patients with comparable creatinine clearance. Due to the wide safety profile of the active metabolite, no dose adjustment is necessary in immunocompromised patients. However, for immunocompromised patients with renal impairment, the dose should be adjusted according to the recommendations outlined in section 4.2. Analysis of pharmacokinetic and pharmacodynamic data from two studies in immunocompromised patients demonstrated no significant additional benefit from doses exceeding the standard dose.

Indication

Flu treatment

Agrippa is indicated for adults and children aged 1 year and over who have symptoms of influenza during the period of influenza virus circulation. Efficacy has been demonstrated when treatment is initiated within 2 days of the first onset of symptoms.

Flu prevention

Prevention of influenza in adults and children aged 1 year and older after contact with a person with clinically diagnosed influenza during influenza virus circulation.

The appropriate use of Agrippa for the prevention of influenza should be determined on a case-by-case basis, taking into account the circumstances and the patient population requiring protection. In exceptional situations (e.g. in cases of discrepancies between the circulating influenza virus and the influenza virus against which vaccination was carried out and during a pandemic), seasonal prophylaxis may be administered to persons aged 1 year and over.

The use of Agrippa does not replace vaccination against influenza.

The use of antivirals for the treatment and prevention of influenza should be based on official recommendations. The decision to use oseltamivir for treatment and prevention should take into account the characteristics of circulating influenza viruses, available information on the susceptibility of influenza viruses to drugs in each season, the impact of the disease in different geographical regions and patient groups.

Contraindication

Hypersensitivity to oseltamivir phosphate or to any component of the drug.

Interaction with other medicinal products and other types of interactions

The pharmacokinetic properties of oseltamivir, such as low protein binding and metabolism independent of CYP450 and glucuronidase systems (see section 5.2), suggest that clinically significant interactions with other medicinal products via these mechanisms are unlikely.

Probenecid

No dose adjustment is required when oseltamivir and probenecid are co-administered in patients with normal renal function. Concomitant administration of probenecid, a potent inhibitor of the anion pathway of renal tubular secretion, approximately doubles the exposure to the active metabolite of oseltamivir.

Amoxicillin

Oseltamivir does not show a kinetic interaction with amoxicillin, which is eliminated by the same pathway as oseltamivir, indicating a weak interaction with oseltamivir via this pathway.

Renal excretion

Clinically significant interactions with other drugs involving competition for renal tubular secretion are unlikely due to the known safety margins of most of these drugs, the elimination characteristics of the active metabolites (glomerular filtration and anionic tubular secretion), and the volume of excretion by these routes. However, caution should be exercised when prescribing oseltamivir to patients taking drugs with a similar excretion pathway and a narrow therapeutic index (e.g., chlorpropamide, methotrexate, phenylbutazone).

Additional information

In phase III clinical trials of oseltamivir for the treatment and prevention of influenza, oseltamivir was administered with commonly used medicinal products such as angiotensin-converting enzyme (ACE) inhibitors (enalapril, captopril), thiazide diuretics (bendrofluazide), antibiotics (penicillin, cephalosporin, azithromycin, erythromycin, doxycycline), H2-receptor blockers (ranitidine, cimetidine), beta-blockers (propranolol), xanthines (theophylline), sympathomimetics (pseudoephedrine), opioids (codeine), corticosteroids, inhaled bronchodilators, analgesics (acetylsalicylic acid, ibuprofen, paracetamol). When oseltamivir was used together with the listed drugs, no changes in the safety profile and incidence of adverse reactions were recorded.

There is no mechanism of interaction with oral contraceptives.

Application features

Oseltamivir is effective only against diseases caused by influenza viruses. There are no data on the effectiveness of oseltamivir in any diseases caused by pathogens other than influenza viruses.

The use of oseltamivir is not a substitute for influenza vaccination. The use of oseltamivir should not influence the assessment of individuals for annual influenza vaccination. Protection against influenza is only maintained while taking oseltamivir. Oseltamivir should be used for the treatment and prevention of influenza only when there is reliable epidemiological evidence of virus circulation. The susceptibility of circulating influenza virus strains to oseltamivir has been shown to be highly variable, and the physician should consider the most recent information on the susceptibility of currently circulating viruses to oseltamivir before making a decision to use oseltamivir.

Severe skin reactions and hypersensitivity reactions

Anaphylaxis and severe skin reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme, have been reported during post-marketing use of oseltamivir. Oseltamivir should be discontinued and appropriate treatment instituted if such reactions are observed or suspected.

Severe comorbidities

There is no information on the safety and efficacy of oseltamivir in patients with severe or unstable illness at imminent risk of hospitalization.

Immunocompromised patients

The safety and efficacy of oseltamivir for the treatment and prevention of influenza in immunocompromised patients have not been established.

Heart/respiratory disease

The efficacy of oseltamivir in the treatment of individuals with chronic heart and/or respiratory disease has not been established. In such patients, no difference in the incidence of complications was observed between the treatment and placebo groups.

Severe renal failure

Dose adjustment of oseltamivir for treatment and prophylaxis is recommended for adults and adolescents (13-17 years) with severe renal impairment. There are insufficient clinical data in children aged 1 year and older with renal impairment to make dosage recommendations (see sections 5.2 and 5.2).

Neuropsychiatric disorders

Neuropsychiatric disorders have been reported in influenza patients (predominantly children and adolescents) receiving oseltamivir. Such disorders have also been reported in influenza patients not receiving oseltamivir. Patients should be closely monitored for behavioral changes, and the benefits and risks of continued treatment should be carefully weighed for each patient (see section 4.8).

Disposal of unused and expired medicinal products. Release of medicinal products into the environment should be minimised. The medicinal product should not be disposed of in wastewater or household waste. For disposal, a so-called waste collection system should be used, if available.

Excipients

Sodium: This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, i.e. essentially ‘sodium-free’.

Use during pregnancy or breastfeeding

Pregnancy

However, in one observational study, in the absence of an increased overall risk of congenital malformations, the results for major congenital heart defects diagnosed within 12 months of birth were inconclusive. In this study, the incidence of major congenital heart defects after first-trimester oseltamivir exposure was 1.76% (7 infants from 397 pregnancies) compared with 1.01% for pregnancies not exposed to oseltamivir in the general population (hazard ratio 1.75, 95% confidence interval 0.51 to 5.98). The clinical significance of these findings is unclear because the study had a limited sample size. The study was also underpowered to reliably assess specific types of major congenital malformations; in addition, it was not possible to fully compare women with and without oseltamivir exposure and, in particular, to determine whether they had influenza.

Animal studies do not indicate reproductive toxicity.

If necessary, the use of oseltamivir during pregnancy may be considered based on available safety and benefit information, as well as the pathogenicity of the circulating influenza virus strain.

Breast-feeding

In lactating rats, oseltamivir and its active metabolite are excreted in human milk. There is very limited information on infants whose mothers took oseltamivir during lactation and on the excretion of oseltamivir in human milk. Limited data demonstrate that oseltamivir and its active metabolite have been detected in human milk, but their levels were low, which may result in subtherapeutic doses to the infant. Given these data, as well as the pathogenicity of the circulating influenza virus strain and the condition of the nursing woman, the use of oseltamivir may be considered if the potential benefit to the nursing woman is clear.

Fertility

Based on preclinical data, there is no evidence of an effect of oseltamivir on male or female fertility.

Ability to influence reaction speed when driving vehicles or other mechanisms

The drug does not affect the reaction speed when driving vehicles or other mechanisms.

Method of administration and doses

Method of application

For oral use. Patients who are unable to swallow a capsule may receive appropriate doses as oseltamivir suspension.

Dosage

Adults and adolescents aged 13 and over

Treatment. The recommended dosage regimen of Agrippa is 1 capsule of 75 mg 2 times a day orally for 5 days for adults and adolescents (13-17 years) with a body weight of more than 40 kg.

For immunocompromised patients (adults and adolescents (13-17 years) with a body weight of more than 40 kg), the recommended dosage regimen of Agrippa is 1 capsule of 75 mg 2 times a day orally for 10 days (see the subsection “Dosage in special cases. Immunocompromised patients”).

Treatment should be started as early as possible, within the first two days of flu symptoms.

Post-exposure prophylaxis The recommended dose of Agrippa for the prevention of influenza after close contact with an infected person is 75 mg orally once daily for 10 days in adults and adolescents (13-17 years) weighing more than 40 kg, including immunocompromised patients (adults and adolescents (13-17 years) weighing more than 40 kg). Treatment should be started as soon as possible within two days of contact with an infected person.

Prophylaxis during seasonal influenza epidemics. The recommended dose for prophylaxis during an outbreak of seasonal influenza epidemics is 75 mg once daily for 6 weeks (or up to 12 weeks for immunocompromised patients, see sections “Special warnings and precautions for use” and “Adverse reactions”).

Children aged 1 to 12 years

Treatment. The recommended dosage regimen for Agrippa is 1 capsule of 75 mg twice daily orally for 5 days for children over 1 year of age with a body weight of more than 40 kg who are able to swallow the capsule.

For immunocompromised children aged 1 year and over with a body weight of more than 40 kg who are able to swallow a capsule, the recommended dosage regimen for Agrippa is 1 capsule of 75 mg 2 times a day orally for 10 days (see section “Dosage in special cases. Immunocompromised patients”).

Treatment should be started as soon as possible, within the first two days of flu symptoms.

Post-exposure prophylaxis. The recommended dosage regimen for Agrippa is 1 capsule 75 mg once daily orally for 10 days for children aged 1 year and older with a body weight of more than 40 kg (including immunocompromised children) who are able to swallow the capsule, for prophylaxis after contact with a person with influenza.

Prophylaxis during seasonal influenza epidemics. Prophylaxis during seasonal influenza epidemics in children under 12 years of age has not been studied.

Dosage in special cases

Patients with liver dysfunction

No dose adjustment is necessary for treatment or prophylaxis in patients with hepatic impairment. The safety and pharmacokinetics of oseltamivir have not been studied in children with hepatic impairment.

Treatment of influenza. Agrippa, 75 mg capsules should not be used in adults and adolescents (13-17 years) with severe or moderate (creatinine clearance ≤60 ml/min) renal insufficiency, as a dose reduction is required (in such cases, oseltamivir preparations in other dosage forms, such as 30 mg capsules or powder for oral suspension, are used). With creatinine clearance >60 ml/min, the recommended dose for the treatment of influenza is 75 mg 2 times a day.

Prevention of influenza. Adults and adolescents (13-17 years) with severe or moderate (creatinine clearance ≤60 ml/min) renal insufficiency should not use Agrippa, capsules 75 mg, as a dose reduction is required (in such cases, oseltamivir preparations in other dosage forms, such as 30 mg capsules or powder for oral suspension, are used). With creatinine clearance >60 ml/min, the recommended dose for prevention of influenza is 75 mg once daily.

There are insufficient clinical data to provide dosage recommendations for children under 12 years of age with renal impairment.

Elderly patients

There is no need to adjust the dose, except in the presence of moderate or severe renal impairment.

Immunocompromised patients

Treatment. The recommended duration of treatment for influenza in immunocompromised patients is 10 days (see sections "Special instructions" and "Adverse reactions"). No dose adjustment is required. Treatment should be started as soon as possible within the first two days of flu symptoms.

Seasonal prophylaxis: Longer durations (up to 12 weeks) of seasonal prophylaxis have been studied in immunocompromised patients (see sections 4.4 and 4.8).

Children.

Available safety information on the use of oseltamivir for the treatment of influenza in children aged 1 year and older, obtained from prospective and retrospective studies and observations, as well as data from an epidemiological database and post-marketing use, indicate that the safety profile in children aged 1 year and older is comparable to the established safety profile in adults.

Used in children over 1 year of age with a body weight of more than 40 kg who are able to swallow the capsule.

Overdose

Reports of overdose with oseltamivir have been received during clinical trials and during post-marketing use of the drug. In most cases of overdose, no adverse reactions were reported.

Adverse reactions reported in overdose were similar in nature and distribution to those observed with therapeutic doses of oseltamivir (see section "Adverse reactions").

Specific antidote is unknown.

Children: Overdose has been reported more frequently in children than in adults and adolescents. Caution should be exercised when administering oseltamivir to children.

Side effects

The overall safety profile of oseltamivir is based on data from the treatment of influenza in 6049 adults/adolescents and 1473 children treated with oseltamivir or placebo, and from data from the prevention of influenza in 3990 adults/adolescents and 253 children treated with oseltamivir or placebo in clinical trials. In addition, 245 immunocompromised patients (including 7 adolescents and 39 children) received oseltamivir for the treatment of influenza and 475 immunocompromised patients (including 18 children, 10 in the oseltamivir group, 8 in the placebo group) received oseltamivir or placebo for the prevention of influenza.

In adults/adolescents taking oseltamivir in studies of use for the treatment of influenza, the most common adverse reactions were nausea and vomiting, and in studies of use for the prevention of influenza - nausea. Most of these adverse reactions were reported in isolated cases, were transient in nature and usually occurred on the first or second day of treatment and resolved spontaneously after 1-2 days. In children, the most common adverse reaction was vomiting. In most cases, these adverse reactions did not lead to the withdrawal of oseltamivir.

The following serious adverse reactions have been reported rarely during post-marketing use of oseltamivir: anaphylactic and anaphylactoid reactions, liver disorders (fulminant hepatitis, liver function abnormalities and jaundice), angioedema, Stevens-Johnson syndrome and toxic epidermal necrolysis, gastrointestinal bleeding and neuropsychiatric disorders (for neuropsychiatric disorders, see section 4.4).

The frequency of adverse reactions is as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); frequency unknown (cannot be estimated from the available data). Adverse reactions are assigned to a specific category based on the analysis of pooled clinical trial data.

Treatment and prevention of influenza in adults and adolescents

The safety profile observed in patients receiving oseltamivir at the recommended dose for prophylaxis (75 mg once daily for up to 6 weeks) was similar to that observed in treatment studies, despite the longer duration of the prophylaxis studies.

Infections and infestations: common – bronchitis, herpes simplex, upper respiratory tract infections, nasopharyngitis, sinusitis.

From the blood and lymphatic system: rarely - thrombocytopenia.

On the part of the immune system: infrequently - hypersensitivity reactions; rarely - anaphylactic and anaphylactoid reactions.

On the part of the psyche: rarely - agitation, pathological behavior, anxiety, confusion, delusions, delirium, hallucinations, nightmares, self-harm.

From the nervous system: very often - headache; often - insomnia; infrequently - impaired consciousness, convulsions.

On the part of the organs of vision: rarely - visual impairment.

Cardiac disorders: uncommon – cardiac arrhythmias.

From the respiratory system, thoracic organs and mediastinum: often - cough, rhinorrhea, sore throat.

From the gastrointestinal tract: very often - nausea; often - vomiting, abdominal pain (including upper), dyspepsia; rarely - gastrointestinal bleeding, hemorrhagic colitis.

Hepatobiliary system: infrequently - increased liver enzymes; rarely - fulminant hepatitis, hepatic failure, hepatitis.

Skin and subcutaneous tissue disorders: infrequently - dermatitis, rash, eczema, urticaria; rarely - angioedema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis; frequency unknown - allergy, facial edema.

General disorders and administration site conditions: common: dizziness (including vertigo), weakness, pain, hyperthermia, pain in extremities.

Treatment and prevention of influenza in children

A total of 1473 children (including healthy children aged 1-12 years and children with asthma aged 6-12 years) participated in clinical trials of oseltamivir for the treatment of influenza. Of these, 851 children were treated with oseltamivir suspension. A total of 158 children received the recommended dose of oseltamivir once daily in the home-based prophylaxis studies (n=99), the 6-week seasonal prophylaxis studies (n=49), and the 12-week seasonal prophylaxis studies in immunocompromised children (n=10).

The most common adverse reactions that have been reported in studies of oseltamivir for the treatment and prevention of influenza in children (when using age-based dosages of 30 mg to 75 mg once daily) are listed below.

Infections and infestations: common: otitis media; frequency unknown: bronchitis, pneumonia, sinusitis.

From the nervous system: often - headache.

From the blood and lymphatic system: frequency unknown - lymphadenopathy.

On the part of the organs of vision: often - conjunctivitis (including eye redness, discharge from the eyes and pain).

From the side of the organs of hearing and vestibular apparatus: often - earache; infrequently - disorders of the eardrum.

Respiratory, thoracic and mediastinal disorders: very common - cough, nasal congestion; common - rhinorrhea; frequency unknown - asthma (including exacerbation), epistaxis.

Gastrointestinal: very often - vomiting; often - nausea, abdominal pain (including upper), dyspepsia; frequency unknown - diarrhea.

Skin and subcutaneous tissue disorders: uncommon – dermatitis (including allergic and atopic dermatitis).

Description of selected adverse reactions

Mental and neurological disorders

Influenza can be associated with a variety of neurological and behavioral symptoms, including hallucinations, delirium, and inappropriate behavior, in some cases with fatal outcomes. These symptoms may be seen as a manifestation of encephalitis or encephalopathy, but may occur without obvious severe illness.

In patients with influenza, cases of seizures and delirium (including symptoms such as altered level of consciousness, confusion, inappropriate behavior, delusions, hallucinations, agitation, anxiety, nightmares), which in isolated cases led to accidental self-harm or death, have also been reported in post-marketing experience with oseltamivir. These events have occurred primarily in children and adolescents and often had a sudden onset and rapid resolution. It is not known whether neuropsychiatric disorders are associated with the use of oseltamivir, as neuropsychiatric disorders have also been reported in patients with influenza who did not use this drug.

Hepatobiliary disorders

Hepatobiliary disorders, including cases of hepatitis and elevated liver enzymes, have been observed in patients with influenza-like illness. These cases included fatal fulminant hepatitis/hepatic failure.

Additional